Single-dose volume regulation algorithm for a gas-compensated intrathecal infusion pump.

PubMed

Nam, Kyoung Won; Kim, Kwang Gi; Sung, Mun Hyun; Choi, Seong Wook; Kim, Dae Hyun; Jo, Yung Ho

2011-01-01

The internal pressures of medication reservoirs of gas-compensated intrathecal medication infusion pumps decrease when medication is discharged, and these discharge-induced pressure drops can decrease the volume of medication discharged. To prevent these reductions, the volumes discharged must be adjusted to maintain the required dosage levels. In this study, the authors developed an automatic control algorithm for an intrathecal infusion pump developed by the Korean National Cancer Center that regulates single-dose volumes. The proposed algorithm estimates the amount of medication remaining and adjusts control parameters automatically to maintain single-dose volumes at predetermined levels. Experimental results demonstrated that the proposed algorithm can regulate mean single-dose volumes with a variation of <3% and estimate the remaining medication volume with an accuracy of >98%. © 2010, Copyright the Authors. Artificial Organs © 2010, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Initial Dosing and Taper Complexity of Methadone and Morphine for Treatment of Neonatal Abstinence Syndrome

PubMed Central

Ibach, Bethany W.; Johnson, Peter N.; Ernst, Kimberly D.; Harrison, Donald; Miller, Jamie L.

2016-01-01

Background: Methadone and morphine are commonly used to treat neonatal abstinence syndrome (NAS). Limited data exist to describe the most appropriate initial doses and taper regimens of these agents. Objectives: Describe the median initial dose and frequency of methadone and morphine for NAS. Compare dose adjustments, time to symptom relief, and taper complexity between groups. Methods: Retrospective study of neonates receiving enteral methadone or morphine for NAS over a 4-year period. Data collection included medication regimen, abstinence scores based on the Modified Finnegan Neonatal Abstinence Scoring Tool, and adverse events. Planned home taper complexity was assessed using the Medication Taper Complexity Score–Revised (MTCS-R). The primary outcome was initial opioid dose. Secondary outcomes included number of dose adjustments, time to symptom relief, and MTCS-R score. Results: Fifty neonates were initially treated for NAS with methadone (n = 36) or morphine (n = 14). The median initial dose was 0.09 mg/kg (range = 0.03-0.2) for methadone and 0.04 mg/kg (range = 0.03-0.4) for morphine. The most common initial dosing interval was q8h for methadone versus q3h for morphine. Number of dose adjustments and time to symptom relief were similar between groups. Median MTCS-R scores were similar between groups. There was no difference in adverse events between groups. Limitations included small sample size, preference toward methadone use, and variability of initial opioid dosing and titration. Conclusions: There was significant variability in initial doses of both agents. Neonates receiving methadone required less frequent dosing than morphine, which may result in easier administration and may allow for safer outpatient administration.

Comparison of a Frail-Friendly Nomogram with Physician-Adjusted Warfarin Dosage for Prophylaxis after Orthopaedic Surgery on a Geriatric Rehabilitation Unit

ERIC Educational Resources Information Center

Freter, Susan; Bowles, Susan K.

2005-01-01

Warfarin dosing for thromboprophylaxis in post-operative patients is time-consuming. Warfarin-dosing nomograms can be used in post-operative arthroplasty patients, but warfarin requirements are lower in frail older people. We modified an existing post-arthroplasty nomogram to a frail-friendly version and evaluated its performance in a frail…

A strategy for reaching therapeutic salicylate levels in patients with rheumatoid arthritis using standardized dosing regimens.

PubMed

Furst, D E; Blocka, K; Cassell, S; Dromgoole, S; Harris, E R; Hirschberg, J M; Josephson, N; Rupp, P A; Paulus, H E; Trimble, R B

1987-04-01

After one to 2 weeks of 45 mg/kg/day choline magnesium trisalicylate (CMT) in 2 divided doses, 51 of 71 patients with rheumatoid arthritis (72%) had observed steady state serum salicylate concentrations between 150 and 300 mg/l (mean salicylate: 213 +/- 10 mg/l), although 17 later required dose adjustment. CMT dosing was changed in 37 cases by using the formula: dosing rate = total clearance X concentration. The expected and observed concentrations were not different (p = 0.31); thus, this formula can help calculate salicylate dosing changes to bring the serum salicylate level to within the therapeutic range.

The Safety, Effectiveness and Concentrations of Adjusted Lopinavir/Ritonavir in HIV-Infected Adults on Rifampicin-Based Antitubercular Therapy

PubMed Central

Decloedt, Eric H.; Maartens, Gary; Smith, Peter; Merry, Concepta; Bango, Funeka; McIlleron, Helen

2012-01-01

Objective Rifampicin co-administration dramatically reduces plasma lopinavir concentrations. Studies in healthy volunteers and HIV-infected patients showed that doubling the dose of lopinavir/ritonavir (LPV/r) or adding additional ritonavir offsets this interaction. However, high rates of hepatotoxicity were observed in healthy volunteers. We evaluated the safety, effectiveness and pre-dose concentrations of adjusted doses of LPV/r in HIV infected adults treated with rifampicin-based tuberculosis treatment. Methods Adult patients on a LPV/r-based antiretroviral regimen and rifampicin-based tuberculosis therapy were enrolled. Doubled doses of LPV/r or an additional 300 mg of ritonavir were used to overcome the inducing effect of rifampicin. Steady-state lopinavir pre-dose concentrations were evaluated every second month. Results 18 patients were enrolled with a total of 79 patient months of observation. 11/18 patients were followed up until tuberculosis treatment completion. During tuberculosis treatment, the median (IQR) pre-dose lopinavir concentration was 6.8 (1.1–9.2) mg/L and 36/47 (77%) were above the recommended trough concentration of 1 mg/L. Treatment was generally well tolerated with no grade 3 or 4 toxicity: 8 patients developed grade 1 or 2 transaminase elevation, 1 patient defaulted additional ritonavir due to nausea and 1 patient developed diarrhea requiring dose reduction. Viral loads after tuberculosis treatment were available for 11 patients and 10 were undetectable. Conclusion Once established on treatment, adjusted doses of LPV/r co-administered with rifampicin-based tuberculosis treatment were tolerated and LPV pre-dose concentrations were adequate. PMID:22412856

Principles of self-adjustment of insulin dose in people with diabetes type 2 and flexible insulin therapy.

PubMed

Kramer, G; Kuniss, N; Kloos, C; Lehmann, T; Müller, N; Sanow, B; Lorkowski, S; Wolf, G; Müller, U A

2016-06-01

Structured treatment and education programmes for people with type 2 diabetes mellitus (T2DM) and flexible insulin therapy provide rules for self-adjustment of insulin dose, that are extensively trained. The aim of this cohort study was to register current principles and the frequency of self-adjustment of insulin dose and their association with metabolic control in people with T2DM. Details of insulin dose adjustment were assessed by a structured interview in 149 people with T2DM on flexible insulin therapy (mean HbA1c 7.1%/53.8mmol/mol, age 65y, diabetes duration 19.0y, BMI 33.8kg/m(2)) in a tertiary care centre. The frequency of insulin dose adjustments was obtained from the last 28days of the patients' diaries. Insulin dose adjustment by adjustment rules was used by 33 people (22.1%) and by personal experience/feeling in 111 participants (74.5%). People adjusting by rules were younger (60.9±9.8 vs. 65.7±9.2, p=0.011) and did more insulin dose adjustments per 28days (50.0±31.0 vs. 33.4±23.5, p=0.016). HbA1c and incidence of hypoglycaemia were comparable. There were no differences in satisfaction of treatment, quality of life as well as current well-being between the groups. Only a fifth of the participants used the rule trained within the education programme to adjust their insulin dose. The majority adjusted their insulin dose by personal experience/feeling. However, people in both groups were able to adjust their insulin dose. Although people using adjustment rules adjust their insulin dose more frequently, HbA1c and the incidence of hypoglycaemia was similar compared to those using personal experience/feeling. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Treatment of Parkinson's disease could be regulated by movement sensors: subcutaneous infusion of varying apomorphine doses according to the intensity of motor activity.

PubMed

Rodríguez-Molinero, Alejandro; Pérez-Martínez, David A; Català, Andreu; Cabestany, Joan; Yuste, Antonio

2009-04-01

Most recent therapeutic solutions to treat Parkinson's disease seek continuous administration of dopaminergic agonists, as for example rigotine patches or apomorphine infusion pumps. Such drug-delivery devices are aimed at preventing fluctuations in drug plasma levels, which could cause certain symptoms such as wearing-off periods or dyskinesia. However, we postulate that drug plasma levels should not keep constant, but rather adjust to the varying intensity of the different user's activities. The rationale behind this is that the drug amount appropriate to treat a patient at rest is lower than that required to treat the same patient when engaged in physical activity. We propose dynamic real-time dose adjustment, so that the doses increase as the patient starts performing physical activity, thus preventing off periods such as "freeze" phenomenon, and the doses reduce during the resting periods, thus preventing adverse effects. Small portable movement sensors are currently available, which detect the amount and type of activity in a continuous way. Combining such technology with infusion pumps to produce modified pumps capable of adjusting the infusion rate to the user's activity, seems to be feasible in the short-term.

Effect of metronidazole use on tacrolimus concentrations in transplant patients treated for Clostridium difficile.

PubMed

Early, C R; Park, J M; Dorsch, M P; Pogue, K T; Hanigan, S M

2016-10-01

Two case reports suggest that metronidazole treatment for Clostridium difficile infections (CDI) increases tacrolimus (TAC) trough levels. The primary objective of this study was to determine the clinical significance of this potential interaction in transplant patients receiving CDI treatment. Currently, no robust literature exists to estimate a magnitude of pharmacokinetic interaction between metronidazole and TAC. In this retrospective study, the effects of CDI and metronidazole treatment on TAC levels in 52 adult solid organ transplant patients were investigated. The primary outcome was to determine the difference in dose-normalized TAC levels between baseline and symptom resolution in patients treated with metronidazole or vancomycin. The secondary outcome was to determine the difference in dose-normalized TAC levels at baseline and CDI diagnosis. The average change in log-transformed dose-normalized TAC levels from baseline to symptom resolution was 0.99 for metronidazole (n = 35) and 1.04 for vancomycin (n = 17) treatment. The mean difference between the groups was 0.96 (95% confidence interval: 0.74-1.24). No significant difference was found between dose-normalized TAC levels at CDI diagnosis and baseline (P = 0.37). CDI treatment with metronidazole was not associated with a >30% increase in TAC levels compared with vancomycin. Both treatment groups required TAC dose adjustments to maintain goal TAC levels and those treated with metronidazole did not require a significantly greater dose adjustment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Clinical interpretation of opioid tolerance versus opioid-induced hyperalgesia.

PubMed

Chen, Lucy; Sein, Michael; Vo, Trang; Amhmed, Shihab; Zhang, Yi; Hilaire, Kristin St; Houghton, Mary; Mao, Jianren

2014-01-01

Opioid analgesics are commonly used to manage moderate to severe pain. However, the long-term use of opioids could lead to opioid tolerance (OT) and opioid-induced hyperalgesia (OIH). Distinguishing OIH from OT would impact the practice of opioid therapy because opioid dose adjustment may differentially influence OT and OIH. Currently, there are no standard criteria of OT versus OIH causing considerable ambiguity in clinical interpretation and management of these conditions. The authors designed a practitioner-based survey consisting of 20 targeted questions. Answering these questions would require responders' actual clinical experiences with opioid therapy. The survey was conducted between 2011 and 2012 through direct mails or e-mails to 1,408 physicians who are currently practicing in the United States. The authors find that certain clinical characteristics (eg, increased pain despite opioid dose escalation) are often used by practitioners to make differential diagnosis of OT and OIH despite some overlap in their clinical presentation. A key difference in clinical outcome is that OT and OIH could be improved and exacerbated by opioid dose escalation, respectively. Our survey results revealed a significant knowledge gap in some responders regarding differential diagnosis and management of OT and OIH. The results also identified several issues, such as opioid dose adjustment and clinical comorbidities related to OT and OIH, which require future patient-based studies.

Proton-Pump Inhibitors Reduce Gastrointestinal Events Regardless of Aspirin Dose in Patients Requiring Dual Antiplatelet Therapy.

PubMed

Vaduganathan, Muthiah; Bhatt, Deepak L; Cryer, Byron L; Liu, Yuyin; Hsieh, Wen-Hua; Doros, Gheorghe; Cohen, Marc; Lanas, Angel; Schnitzer, Thomas J; Shook, Thomas L; Lapuerta, Pablo; Goldsmith, Mark A; Laine, Loren; Cannon, Christopher P

2016-04-12

The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into "low-dose" (≤ 100 mg) and "high-dose" (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Practical guidance and considerations for transitioning patients from oxcarbazepine or carbamazepine to eslicarbazepine acetate--Expert opinion.

PubMed

Peltola, Jukka; Holtkamp, Martin; Rocamora, Rodrigo; Ryvlin, Philippe; Sieradzan, Kasia; Villanueva, Vicente

2015-09-01

There is currently a lack of guidance on methodology and special considerations for transitioning patients from oxcarbazepine (OXC) or carbamazepine (CBZ) to eslicarbazepine acetate (ESL), if deemed clinically necessary. An advisory panel of epilepsy experts was convened to share their experience on the use of adjunctive ESL in clinical practice and to provide practical recommendations to help address this gap. When changing over from OXC to ESL, an OXC:ESL dose ratio of 1:1 should be employed to calculate the ESL target dose, and the changeover can take place overnight. No changes to comedication are required. Since CBZ has a different mechanism of action to ESL and is a stronger inducer of cytochrome P450 (CYP) enzymes, the transitioning of patients from CBZ to ESL requires careful consideration on a patient-by-patient basis. In general, a CBZ:ESL dose ratio of 1:1.3 should be employed to calculate the ESL target dose, and patients should be transitioned over a minimum period of 1-2weeks. Special considerations include adjustment of titration schedule and target dose in elderly patients and those with hepatic or renal impairment and potential adjustment of comedications metabolized by CYP enzymes. In summary, due to structural distinctions between ESL, OXC, and CBZ, which affect mechanism of action and tolerability, there are clinical situations in which it may be appropriate to consider transitioning patients from OXC or CBZ to ESL. Changing patients over from OXC to ESL is generally more straightforward than transitioning patients from CBZ to ESL, which requires careful consideration. Copyright © 2015 Elsevier Inc. All rights reserved.

Pattern and Predictors of Medication Dosing Errors in Chronic Kidney Disease Patients in Pakistan: A Single Center Retrospective Analysis

PubMed Central

Saleem, Ahsan; Masood, Imran

2016-01-01

Background Chronic kidney disease (CKD) alters the pharmacokinetic and pharmacodynamic response of various drugs and increases the risk of toxicity. The data regarding the pattern and predictors of medication dosing errors is scare from the developing countries. Therefore, the present study was conducted to assess the pattern and predictors of medication dosing errors in CKD patients in a tertiary care setting in Pakistan. Methods A retrospective study design was employed and medical charts of all those CKD patients who had an eGFR ≤60ml/min/1.73m2, hospitalization ≥24 hours, and admitted in the nephrology unit during January 2013 to December 2014 were assessed. Descriptive statistics and the logistic regression analysis were done using IBM SPSS version 20. Results In total, 205 medical charts were assessed. The mean age of patients was 38.64 (±16.82) years. Overall, 1534 drugs were prescribed to CKD patients, of which, nearly 34.0% drugs required dose adjustment. Among those drugs, only 41.8% were properly adjusted, and the remaining 58.2% were unadjusted. The logistic regression analysis revealed that the medication dosing errors were significantly associated with the CKD stages, i.e. stage 4 (OR 0.054; 95% CI [0.017–0.177]; p <0.001) and stage 5 (OR 0.098; 95% CI [0.040–0.241]; p <0.001), the number of prescribed medicines ≥ 5 (OR 0.306; 95% CI [0.133–0.704]; p 0.005), and the presence of a comorbidity (OR 0.455; 95% CI [0.226–0.916]; p 0.027) such as the hypertension (OR 0.453; 95% CI [0.231–0.887]; p 0.021). Conclusions It is concluded that more than half drugs prescribed to CKD patients requiring dose adjustment were unadjusted. The predictors of medication dosing errors were the severe-to-end stages of chronic kidney disease, the presence of a comorbidity such as hypertension, and a higher number of prescribed medicines. Therefore, attention should be paid to these risk factors. PMID:27367594

Development and clinical application of a length-adjustable water phantom for total body irradiation.

PubMed

Chen, Zhi-Wei; Yao, Sheng-Yu; Zhang, Tie-Ning; Zhu, Zhen-Hua; Hu, Zhe-Kai; Lu, Xun

2012-08-01

A new type of water phantom which would be specialised for the absorbed dose measurement in total body irradiation (TBI) treatment is developed. Ten millimetres of thick Plexiglas plates were arranged to form a square cube with 300 mm of edge length. An appropriate sleeve-type piston was installed on the side wall, and a tabular Plexiglas piston was positioned inside the sleeve. By pushing and pulling the piston, the length of the self-made water phantom could be varied to meet the required patients' physical sizes. To compare the international standard water phantom with the length-adjustable and the Plexiglas phantoms, absorbed dose for 6-MV X ray was measured by an ionisation chamber at different depths in three kinds of phantoms. In 70 cases with TBI, midplane doses were metered using the length-adjustable and the Plexiglas phantoms for simulating human dimensions, and dose validation was synchronously carried out. There were no significant statistical differences, p > 0.05, through statistical processing of data from the international standard water phantom and the self-designed one. There were significant statistical differences, p < 0.05, between the two sets of data from the standard and the Plexiglas one. In addition, the absolute difference had a positive correlation with the varied depth of the detector in the Plexiglas phantom. Comparing the data of clinical treatment, the differences were all <1 % among the prescription doses and the validation data collected from the self-design water phantom. However, the differences collected from the Plexiglas phantom were increasing gradually from +0.77 to +2.30 % along with increasing body width. Obviously, the difference had a positive correlation with the body width. The results proved that the new length-adjustable water phantom is more accurate for simulating human dimensions than Plexiglas phantom.

Frequency, predictors, and economic impact of upward dose adjustment of infliximab in managed care patients with rheumatoid arthritis.

PubMed

Ollendorf, Daniel A; Massarotti, Elena; Birbara, Charles; Burgess, Somali Misra

2005-06-01

To examine dosing patterns and costs among rheumatoid arthritis (RA) patients newly treated with infliximab in a large national health care claims database. Using data from a proprietary database of pharmacy and medical claims for 75 U.S. health plans, RA patients newly treated with infliximab between June 2000 and June 2002 were selected and assigned an .index date. based on the first infusion. A pretreatment period of 6 months was created; patients were also followed for a minimum of 6 months after the initial infusion. Follow-up was allowed to vary beyond this minimum 6 months in order to preserve all available patient data. A maintenance number of infliximab vials was determined as of the second infusion; patients with 1 subsequent increase in vials used or 2 intervals between infusions of <49 days were considered to have had an upward dose adjustment. Differences (i.e., between those with upward dose adjustment and those with no upward dose) in patient characteristics were examined using descriptive statistics. In addition, time to upward dose adjustment and factors influencing its likelihood were analyzed using Kaplan-Meier and Cox proportional hazards techniques. Finally, differences in RA-related and unrelated costs (medication, outpatient, inpatient, and total, expressed in 2003 dollars) were examined using Wilcoxon rank-sum tests and were also stratified by a number of patient characteristics found to differ between the 2 groups. A total of 1,236 patients met all study entry criteria and were included in these analyses. One or more upward dose adjustments were experienced by 61.7% (N=762) of patients during an average of 15 months of follow-up (median =13 months, range=6 to 31 months). The majority (63.3%) of upward dose adjustments were due to increases in the number of billed vials. Median time to upward dose adjustment was 254 days and declined steadily based on year of initiation (from 330 days in 2000 to 224 days in 2002). Factors significantly influencing upward dose adjustment included pretreatment use of leflunomide, comorbid Crohn.s disease, and pretreatment liver function testing. During followup, patients in the upward dose adjustment group used a mean (SD) of 30.28 (20.90) vials of infliximab, compared with 15.90 (14.28) among those not adjusting dose (P<0.001). Annualized (i.e., standardized to a 365-day rate) RA-related costs were higher by more than 50% among patients with upward dose adjustment (SD $22,283 [$20,517] versus $14,425 [$10,828] for those without upward dose adjustment; P<0.001); differences were driven almost entirely by the costs of infliximab itself ($16,336 [$9,490] versus $9,573 [$6,790], P<0.001). In a cohort of managed care members with RA, upward dose adjustment with infliximab was frequent and appeared to occur earlier in the drug therapy in 2002 compared with 2000. Upward dose adjustment was associated with significant increases in drug treatment costs; therefore, payers and providers should consider the impact of current dosing trends when monitoring the use of biologics for autoimmune diseases.

Dose optimization of total or partial skin electron irradiation by thermoluminescent dosimetry.

PubMed

Schüttrumpf, Lars; Neumaier, Klement; Maihoefer, Cornelius; Niyazi, Maximilian; Ganswindt, Ute; Li, Minglun; Lang, Peter; Reiner, Michael; Belka, Claus; Corradini, Stefanie

2018-05-01

Due to the complex surface of the human body, total or partial skin irradiation using large electron fields is challenging. The aim of the present study was to quantify the magnitude of dose optimization required after the application of standard fields. Total skin electron irradiation (TSEI) was applied using the Stanford technique with six dual-fields. Patients presenting with localized lesions were treated with partial skin electron irradiation (PSEI) using large electron fields, which were individually adapted. In order to verify and validate the dose distribution, in vivo dosimetry with thermoluminescent dosimeters (TLD) was performed during the first treatment fraction to detect potential dose heterogeneity and to allow for an individual dose optimization with adjustment of the monitor units (MU). Between 1984 and 2017, a total of 58 patients were treated: 31 patients received TSEI using 12 treatment fields, while 27 patients underwent PSEI and were treated with 4-8 treatment fields. After evaluation of the dosimetric results, an individual dose optimization was necessary in 21 patients. Of these, 7 patients received TSEI (7/31). Monitor units (MU) needed to be corrected by a mean value of 117 MU (±105, range 18-290) uniformly for all 12 treatment fields, corresponding to a mean relative change of 12% of the prescribed MU. In comparison, the other 14 patients received PSEI (14/27) and the mean adjustment of monitor units was 282 MU (±144, range 59-500) to single or multiple fields, corresponding to a mean relative change of 22% of the prescribed MU. A second dose optimization to obtain a satisfying dose at the prescription point was need in 5 patients. Thermoluminescent dosimetry allows an individual dose optimization in TSEI and PSEI to enable a reliable adjustment of the MUs to obtain the prescription dose. Especially in PSEI in vivo dosimetry is of fundamental importance.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism.

PubMed

Hameed, Shihab; Mendoza-Cruz, Abel C; Neville, Kristen A; Woodhead, Helen J; Walker, Jan L; Verge, Charles F

2012-06-09

Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120-156 on the old regimen. She was discharged home. This practical regimen improved sodium control, parental independence, and allowed discharge home.

Home blood sodium monitoring, sliding-scale fluid prescription and subcutaneous DDAVP for infantile diabetes insipidus with impaired thirst mechanism

PubMed Central

2012-01-01

Background/Aims Infants with diabetes insipidus (DI), especially those with impaired thirst mechanism or hypothalamic hyperphagia, are prone to severe sodium fluctuations, often requiring hospitalization. We aimed to avoid dangerous fluctuations in serum sodium and improve parental independence. Methods A 16-month old girl with central DI, absent thirst mechanism and hyperphagia following surgery for hypothalamic astrocytoma had erratic absorption of oral DDAVP during chemotherapy cycles. She required prolonged hospitalizations for hypernatremia and hyponatremic seizure. Intensive monitoring of fluid balance, weight and clinical assessment of hydration were not helpful in predicting serum sodium. Discharge home was deemed unsafe. Oral DDAVP was switched to subcutaneous (twice-daily injections, starting with 0.01mcg/dose, increasing to 0.024mcg/dose). The parents adjusted daily fluid allocation by sliding-scale, according to the blood sodium level (measured by handheld i-STAT analyser, Abbott). We adjusted the DDAVP dose if fluid allocation differed from maintenance requirements for 3 consecutive days. Results After 2.5 months, sodium was better controlled, with 84% of levels within reference range (135-145 mmol/L) vs. only 51% on the old regimen (p = 0.0001). The sodium ranged from 132-154 mmol/L, compared to 120–156 on the old regimen. She was discharged home. Conclusion This practical regimen improved sodium control, parental independence, and allowed discharge home. PMID:22682315

Evaluation of Timing and Dosing of Caffeine Citrate in Preterm Neonates for the Prevention of Bronchopulmonary Dysplasia.

PubMed

Shenk, Eleni E; Bondi, Deborah S; Pellerite, Matthew M; Sriram, Sudhir

2018-01-01

The aim of this study was to evaluate the timing and dosing of caffeine therapy in relation to the development of bronchopulmonary dysplasia (BPD). This was a single-center, retrospective cohort study comparing early (days of life 0-2) to late (day of life 3 or greater) caffeine initiation in extremely low birth weight neonates, with a secondary analysis of large (10 mg/kg/day) to small dose (5 mg/kg/day) caffeine. There were 138 patients in the primary timing analysis. The early caffeine group had a lower incidence and reduced odds of the composite outcome of BPD or all-cause mortality, compared with the late caffeine group (64% vs. 88%, respectively; adjusted p < 0.05; adjusted OR 0.36 [95% CI 0.13-0.98]). No statistically significant difference was found between dosing groups (p = 0.29) in the primary outcome; however, there was a lower rate of patent ductus arteriosus requiring treatment (p = 0.05) and decreased likelihood of discharging home on oxygen (p = 0.02) in the large-dose group compared with the small-dose group. Early caffeine initiation significantly decreased the incidence of BPD or all-cause mortality in extremely low birth weight neonates. Patients receiving large-dose caffeine had improved secondary outcomes, although no difference in BPD was noted. Further studies are needed to determine the optimal dosing of caffeine.

The Impact of Dose and Simultaneous Use of Acid-Reducing Agents on the Effectiveness of Vemurafenib in Metastatic BRAF V600 Mutated Melanoma: a Retrospective Cohort Study.

PubMed

Knapen, Lotte M; Koornstra, Rutger H T; Driessen, Johanna H M; van Vlijmen, Bas; Croes, Sander; Schalkwijk, Stein; Colbers, Angela; Gerritsen, Winald R; Burger, David M; de Vries, Frank; van Erp, Nielka P

2018-04-11

The impact of dose and simultaneous use of acid-reducing agents (ARAs) on the effectiveness of vemurafenib is unknown. To determine the association between progression of metastatic BRAF V600 mutated melanoma and (1) dose reductions of vemurafenib and (2) simultaneous use of vemurafenib and ARAs. A retrospective cohort study of 112 first-line vemurafenib users for melanoma was conducted (March 2012-March 2016), using electronic patient records and pharmacy dispensing records of a Dutch academic hospital. Cox regression analysis was used to estimate the risk of progression with full-dose (n = 64) versus reduced-dose vemurafenib (n = 48) and with simultaneous use of vemurafenib and ARAs (n = 35) versus vemurafenib alone (n = 77). Analyses were adjusted for age and sex. In total, disease progression occurred in 55% of treated patients on vemurafenib, with a median progression-free survival of 6.0 (95% confidence interval [CI] 5.0-6.9) months. Compared to patients on vemurafenib alone, there was no increased risk of progression among patients requiring vemurafenib at a reduced dose or among patients receiving simultaneous therapy with vemurafenib and ARAs. In addition, there was no increased risk of progression among patients who used reduced-dose vemurafenib and ARAs versus those receiving full-dose vemurafenib as sole therapy. However, a tendency for progression was observed among patients who used full-dose vemurafenib and ARAs versus full-dose vemurafenib alone (adjusted hazard ratio [HRa] 2.37; 95% CI 0.97-5.76), which became statistically significant in a sensitivity analysis (HRa 4.56; 95% CI 1.51-13.75). There was no association between the use of vemurafenib in a reduced dose or the simultaneous use of vemurafenib and ARAs and the risk of progression. In addition, there was no association between the simultaneous use of vemurafenib in a reduced dose and ARAs and the risk of progression. However, patients tolerating  full-dose vemurafenib simultaneously with ARAs might have an increased risk of progression. This finding requires prospective validation.

Real-time dose adjustment using point-of-care platelet reactivity testing in a double-blind study of prasugrel in children with sickle cell anaemia.

PubMed

Jakubowski, Joseph A; Hoppe, Carolyn C; Zhou, Chunmei; Smith, Brendan E; Brown, Patricia B; Heath, Lori E; Inusa, Baba; Rees, David C; Small, David S; Gupta, Neehar; Yao, Suqin; Heeney, Matthew; Kanter, Julie

2017-02-28

Patients with sickle cell anaemia (SCA) have vaso-occlusive crises resulting from occlusive hypoxic-ischaemic injury. Prasugrel inhibits platelet activation and aggregation involved in SCA pathophysiology. Determining Effects of Platelet Inhibition on Vaso-Occlusive Events (DOVE) was a phase 3, double-blind, randomised, placebo-controlled trial assessing prasugrel efficacy. DOVE sought to bring patients' P2Y12 reaction unit (PRU) value within a targeted range via prasugrel dose adjustments using encrypted VerifyNow P2Y12 ® (VN-P2Y12) point-of-care testing and an interactive voice-response system (IVRS). After PRU determination, randomised patients received 0.08 mg/kg/day prasugrel or placebo. Encrypted PRUs and IVRS provided double-blind dose adjustments to achieve a defined PRU target range of 136-231; placebo patients had mock titrations. Of 341 randomised patients, 166 placebo and 160 prasugrel patients reached the fully titrated dose (FTD). Most prasugrel patients (n=104, 65 %) remained on the initial 0.08 mg/kg dose; doses escalations occurred in 23 % of patients (n=36). Mean PRUs for the pharmacodynamic population at baseline were similar in the prasugrel (273 ± 44.9) and placebo groups (273 ± 51.7), with significant reductions in PRU (p<0.001) for prasugrel patients at the FTD and at 9 months. Concomitant use of hydroxyurea did not affect platelet reactivity at any time. The majority of prasugrel patients (n=135, 84.4 %) at the FTD were within the target range of 136-231 PRUs. Mean VN-P2Y12 percentage inhibition at baseline was similar in the prasugrel (2.8  ± 5.4 %) and placebo groups (2.0 ± 4.7 %); prasugrel patients had significant increases in inhibition (p<0.001) at FTD and at 9 months. Patients with higher PRU values at baseline required higher prasugrel doses to bring PRU within the prespecified range. DOVE is the first study to successfully employ double-blind, real-time, encrypted, point-of-care platelet testing and IVRS to dose-adjust antiplatelet therapy to a targeted range of platelet inhibition.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic-Americans and African-Americans.

PubMed

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2012-12-01

The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. The following were assessed in a cohort of 260 African-Americans and 53 Hispanic-Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs 0.18; p < 0.05) allele frequencies were higher in Hispanic-Americans compared with African-Americans. Multiple regression analysis in the Hispanic-American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African-Americans after adjusting for known genetic and clinical predictors. In our cohort of inner-city Hispanic-Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic-Americans.

Effect of NQO1 and CYP4F2 genotypes on warfarin dose requirements in Hispanic–Americans and African–Americans

PubMed Central

Bress, Adam; Patel, Shitalben R; Perera, Minoli A; Campbell, Richard T; Kittles, Rick A; Cavallari, Larisa H

2013-01-01

Aim The objective of this study was to determine the additional contribution of NQO1 and CYP4F2 genotypes to warfarin dose requirements across two racial groups after accounting for known clinical and genetic predictors. Patients & methods The following were assessed in a cohort of 260 African–Americans and 53 Hispanic–Americans: clinical data; NQO1 p.P187S (*1/*2); CYP2C9*2, *3, *5, *6, *8 and *11; CYP4F2 p.V433M; and VKORC1 c.-1639G>A genotypes. Results Both the CYP4F2 433M (0.23 vs 0.06; p < 0.05) and NQO1*2 (0.27 vs. 0.18; p < 0.05) allele frequencies were higher in Hispanic–Americans compared with African–Americans. Multiple regression analysis in the Hispanic–American cohort revealed that each CYP4F2 433M allele was associated with a 22% increase in warfarin maintenance dose (p = 0.019). Possession of the NQO1*2 allele was associated with a 34% increase in warfarin maintenance dose (p = 0.004), while adjusting for associated genetic (CYP2C9, CYP4F2 and VKORC1) and clinical factors. In this population, the inclusion of CYP4F2 and NQO1*2 genotypes improved the dose variability explained by the model from 0.58 to 0.68 (p = 0.001), a 17% relative improvement. By contrast, there was no association between CYP4F2 or NQO1*2 genotype and therapeutic warfarin dose in African–Americans after adjusting for known genetic and clinical predictors. Conclusion In our cohort of inner-city Hispanic–Americans, the CYP4F2 and NQO1*2 genotypes significantly contributed to warfarin dose requirements. If our findings are confirmed, they would suggest that inclusion of the CYP4F2 and NQO1*2 genotypes in warfarin dose prediction algorithms may improve the predictive ability of such algorithms in Hispanic–Americans. PMID:23215885

Body size-adjusted dose analysis of pirfenidone in patients with interstitial pneumonia.

PubMed

Uehara, Masahiro; Enomoto, Noriyuki; Oyama, Yoshiyuki; Suzuki, Yuzo; Kono, Masato; Furuhashi, Kazuki; Fujisawa, Tomoyuki; Inui, Naoki; Nakamura, Yutaro; Suda, Takafumi

2018-03-01

Pirfenidone is an effective anti-fibrotic agent for idiopathic pulmonary fibrosis (IPF). Although adverse events (AE) sometimes prevent patients from continuing treatment, current dose adjustment guidance does not consider patient body size or weight (BW). The aim of this study was to evaluate the importance of pirfenidone dose adjustment by body surface area (BSA) or BW for preventing AE and permitting continuous treatment in patients with interstitial pneumonia (IP). Sixty-seven Japanese patients with IP including 46 patients with IPF treated with pirfenidone between 2009 and 2015 were retrospectively evaluated. Pirfenidone doses were adjusted by BSA or BW and were compared with clinical parameters. Forty-two of 67 patients (62.7%) with IP showed AE, most commonly gastrointestinal symptoms (77.5%). Patients having AE received significantly higher adjusted doses of pirfenidone by both BSA and BW (P = 0.024 and P = 0.010, respectively), while unadjusted doses did not differ. BSA-adjusted dose discriminated patients with AE from those without (area under the curve = 0.666 at 1085 mg/m 2 ). Six of seven patients (85.7%) who discontinued pirfenidone due to AE took ≥1085 mg/m 2 of pirfenidone. In a subgroup with IPF, patients taking a medium dose (median: 876 median-1085 mg/m 2 ) showed a lower annual decline in % forced vital capacity than patients taking a lower dose (P = 0.025). BSA-adjusted pirfenidone dosing may be useful to prevent AE whilst achieving a long-term treatment effect in patients with IP. © 2017 Asian Pacific Society of Respirology.

Dosimetric properties of a proton beamline dedicated to the treatment of ocular disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Mamalui, M.; Yeung, D.

2014-01-15

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Slopsema, R. L., E-mail: rslopsema@floridaproton.org; Mamalui, M.; Yeung, D.

Purpose: A commercial proton eyeline has been developed to treat ocular disease. Radiotherapy of intraocular lesions (e.g., uveal melanoma, age-related macular degeneration) requires sharp dose gradients to avoid critical structures like the macula and optic disc. A high dose rate is needed to limit patient gazing times during delivery of large fractional dose. Dose delivery needs to be accurate and predictable, not in the least because current treatment planning algorithms have limited dose modeling capabilities. The purpose of this paper is to determine the dosimetric properties of a new proton eyeline. These properties are compared to those of existing systemsmore » and evaluated in the context of the specific clinical requirements of ocular treatments. Methods: The eyeline is part of a high-energy, cyclotron-based proton therapy system. The energy at the entrance of the eyeline is 105 MeV. A range modulator (RM) wheel generates the spread-out Bragg peak, while a variable range shifter system adjusts the range and spreads the beam laterally. The range can be adjusted from 0.5 up to 3.4 g/cm{sup 2}; the modulation width can be varied in steps of 0.3 g/cm{sup 2} or less. Maximum field diameter is 2.5 cm. All fields can be delivered with a dose rate of 30 Gy/min or more. The eyeline is calibrated according to the IAEA TRS-398 protocol using a cylindrical ionization chamber. Depth dose distributions and dose/MU are measured with a parallel-plate ionization chamber; lateral profiles with radiochromic film. The dose/MU is modeled as a function of range, modulation width, and instantaneous MU rate with fit parameters determined per option (RM wheel). Results: The distal fall-off of the spread-out Bragg peak is 0.3 g/cm{sup 2}, larger than for most existing systems. The lateral penumbra varies between 0.9 and 1.4 mm, except for fully modulated fields that have a larger penumbra at skin. The source-to-axis distance is found to be 169 cm. The dose/MU shows a strong dependence on range (up to 4%/mm). A linear increase in dose/MU as a function of instantaneous MU rate is observed. The dose/MU model describes the measurements with an accuracy of ±2%. Neutron dose is found to be 146 ± 102 μSv/Gy at the contralateral eye and 19 ± 13 μSv/Gy at the chest. Conclusions: Measurements show the proton eyeline meets the requirements to effectively treat ocular disease.« less

Application of physiologically based pharmacokinetic (PBPK) model of trichloroethylene in rats for estimation of internal dose

EPA Science Inventory

Potential human health risk from chemical exposure must often be assessed for conditions for which suitable human or animal data are not available, requiring extrapolation across duration and concentration. The default method for exposure-duration adjustment is based on Haber's r...

Incorporating High-Throughput Exposure Predictions with Dosimetry-Adjusted In Vitro Bioactivity to Inform Chemical Toxicity Testing

EPA Science Inventory

We previously integrated dosimetry and exposure with high-throughput screening (HTS) to enhance the utility of ToxCast™ HTS data by translating in vitro bioactivity concentrations to oral equivalent doses (OEDs) required to achieve these levels internally. These OEDs were compare...

Factors associated with higher oxytocin requirements in labor.

PubMed

Frey, Heather A; Tuuli, Methodius G; England, Sarah K; Roehl, Kimberly A; Odibo, Anthony O; Macones, George A; Cahill, Alison G

2015-09-01

To identify clinical characteristics associated with high maximum oxytocin doses in women who achieve complete cervical dilation. A retrospective nested case-control study was performed within a cohort of all term women at a single center between 2004 and 2008 who reached the second stage of labor. Cases were defined as women who had a maximum oxytocin dose during labor >20 mu/min, while women in the control group had a maximum oxytocin dose during labor of ≤20 mu/min. Exclusion criteria included no oxytocin administration during labor, multiple gestations, major fetal anomalies, nonvertex presentation, and prior cesarean delivery. Multiple maternal, fetal, and labor factors were evaluated with univariable analysis and multivariable logistic regression. Maximum oxytocin doses >20 mu/min were administered to 108 women (3.6%), while 2864 women received doses ≤20 mu/min. Factors associated with higher maximum oxytocin dose after adjusting for relevant confounders included maternal diabetes, birthweight >4000 g, intrapartum fever, administration of magnesium, and induction of labor. Few women who achieve complete cervical dilation require high doses of oxytocin. We identified maternal, fetal and labor factors that characterize this group of parturients.

Evaluation of the Pharmacokinetics and Efficacy of a Busulfan Test Dose in Adult Patients Undergoing Myeloablative Hematopoietic Cell Transplantation.

PubMed

Weil, Elizabeth; Zook, Felicia; Oxencis, Carolyn; Canadeo, Angela; Urmanski, Angela; Waggoner, Mindy; Eastwood, Daniel; Pasquini, Marcelo; Hamadani, Mehdi; Hari, Parameswaran

2017-06-01

Owing to interpatient variability in busulfan exposure, therapeutic monitoring of busulfan is often used in myeloablative allogeneic transplantation to ensure that patients are near the optimal steady-state goal of 900 ng/mL. One challenge in therapeutic monitoring of busulfan is the brief course of busulfan treatment, requiring prompt analysis and dose adjustments as needed. Pharmacokinetic evaluation of a busulfan test dose before the start of the conditioning regimen would allow for all conditioning regimen doses to be given at the calculated optimized dose. An observational study was completed to evaluate the effects of a busulfan test dose of 0.9 mg/kg administered before the start of a myeloablative intravenous busulfan-based conditioning regimen. Sixty adult patients who received a busulfan conditioning regimen were reviewed, including 30 patients prior to the implementation of the busulfan test dose (pretest dose group) and 30 patients who received the busulfan test dose (posttest dose group). The primary objective was a pharmacokinetic evaluation of the percentage of patients who achieved the desired steady-state goal using the test dose strategy. The safety and efficacy of the busulfan test dose were evaluated as well. The average busulfan steady-state level after the first dose of the conditioning regimen was significantly lower in the pre-test dose group compared with the post-test dose group (660 ng/mL versus 879.9 ng/mL; P < 0.001). Compared with the post-test dose group, significantly fewer patients in the pre-test dose group were within 10% of the busulfan steady-state goal (10% versus 73.3%; P < 0.001) or within 5% of the goal (0% versus 53%; P < 0.001). Requirements for parenteral nutrition and/or patient-controlled analgesia owing to mucositis and rates of veno-occlusive disease were not significantly different between the pre-test dose group and the post-test dose group. The rates of disease relapse, mortality, and acute graft-versus-host disease were similar in the two groups. A pretransplantation busulfan test dose of 0.9 mg/kg improved the patients' ability to reach therapeutic busulfan target levels after the first conditioning dose and resulted in fewer adjustments during conditioning. The use of a busulfan test dose did not significantly increase patients' risk of mucositis or other safety outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Dynamic Collimator Angle Adjustments During Volumetric Modulated Arc Therapy to Account for Prostate Rotations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boer, Johan de; Wolf, Anne Lisa; Szeto, Yenny Z.

2015-04-01

Purpose: Rotations of the prostate gland induce considerable geometric uncertainties in prostate cancer radiation therapy. Collimator and gantry angle adjustments can correct these rotations in intensity modulated radiation therapy. Modern volumetric modulated arc therapy (VMAT) treatments, however, include a wide range of beam orientations that differ in modulation, and corrections require dynamic collimator rotations. The aim of this study was to implement a rotation correction strategy for VMAT dose delivery and validate it for left-right prostate rotations. Methods and Materials: Clinical VMAT treatment plans of 5 prostate cancer patients were used. Simulated left-right prostate rotations between +15° and −15° weremore » corrected by collimator rotations. We compared corrected and uncorrected plans by dose volume histograms, minimum dose (D{sub min}) to the prostate, bladder surface receiving ≥78 Gy (S78) and rectum equivalent uniform dose (EUD; n=0.13). Each corrected plan was delivered to a phantom, and its deliverability was evaluated by γ-evaluation between planned and delivered dose, which was reconstructed from portal images acquired during delivery. Results: On average, clinical target volume minimum dose (D{sub min}) decreased up to 10% without corrections. Negative left-right rotations were corrected almost perfectly, whereas D{sub min} remained within 4% for positive rotations. Bladder S78 and rectum EUD of the corrected plans matched those of the original plans. The average pass rate for the corrected plans delivered to the phantom was 98.9% at 3% per 3 mm gamma criteria. The measured dose in the planning target volume approximated the original dose, rotated around the simulated left-right angle, well. Conclusions: It is feasible to dynamically adjust the collimator angle during VMAT treatment delivery to correct for prostate rotations. This technique can safely correct for left-right prostate rotations up to 15°.« less

SU-E-T-247: Multi-Leaf Collimator Model Adjustments Improve Small Field Dosimetry in VMAT Plans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Young, L; Yang, F

2014-06-01

Purpose: The Elekta beam modulator linac employs a 4-mm micro multileaf collimator (MLC) backed by a fixed jaw. Out-of-field dose discrepancies between treatment planning system (TPS) calculations and output water phantom measurements are caused by the 1-mm leaf gap required for all moving MLCs in a VMAT arc. In this study, MLC parameters are optimized to improve TPS out-of-field dose approximations. Methods: Static 2.4 cm square fields were created with a 1-mm leaf gap for MLCs that would normally park behind the jaw. Doses in the open field and leaf gap were measured with an A16 micro ion chamber andmore » EDR2 film for comparison with corresponding point doses in the Pinnacle TPS. The MLC offset table and tip radius were adjusted until TPS point doses agreed with photon measurements. Improvements to the beam models were tested using static arcs consisting of square fields ranging from 1.6 to 14.0 cm, with 45° collimator rotation, and 1-mm leaf gap to replicate VMAT conditions. Gamma values for the 3-mm distance, 3% dose difference criteria were evaluated using standard QA procedures with a cylindrical detector array. Results: The best agreement in point doses within the leaf gap and open field was achieved by offsetting the default rounded leaf end table by 0.1 cm and adjusting the leaf tip radius to 13 cm. Improvements in TPS models for 6 and 10 MV photon beams were more significant for smaller field sizes 3.6 cm or less where the initial gamma factors progressively increased as field size decreased, i.e. for a 1.6cm field size, the Gamma increased from 56.1% to 98.8%. Conclusion: The MLC optimization techniques developed will achieve greater dosimetric accuracy in small field VMAT treatment plans for fixed jaw linear accelerators. Accurate predictions of dose to organs at risk may reduce adverse effects of radiotherapy.« less

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

PubMed

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements

PubMed Central

Trujillo, Jennifer M.

2018-01-01

Background: We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. Methods: This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 (n = 95) or insulin degludec (n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1–12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Results: Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19–60 interquartile range (IQR)] units at baseline to 34.5 (19–70 IQR) units after follow up (p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different (p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 (p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Conclusions: Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different. PMID:29619208

Cost effectiveness of novel oral anticoagulants for stroke prevention in atrial fibrillation depending on the quality of warfarin anticoagulation control.

PubMed

Janzic, Andrej; Kos, Mitja

2015-04-01

Vitamin K antagonists, such as warfarin, are standard treatments for stroke prophylaxis in patients with atrial fibrillation. Patient outcomes depend on quality of warfarin management, which includes regular monitoring and dose adjustments. Recently, novel oral anticoagulants (NOACs) that do not require regular monitoring offer an alternative to warfarin. The aim of this study was to evaluate whether cost effectiveness of NOACs for stroke prevention in atrial fibrillation depends on the quality of warfarin control. We developed a Markov decision model to simulate warfarin treatment outcomes in relation to the quality of anticoagulation control, expressed as percentage of time in the therapeutic range (TTR). Standard treatment with adjusted-dose warfarin and improved anticoagulation control by genotype-guided dosing were compared with dabigatran, rivaroxaban, apixaban and edoxaban. The analysis was performed from the Slovenian healthcare payer perspective using 2014 costs. In the base case, the incremental cost-effectiveness ratio for apixaban, dabigatran and edoxaban was below the threshold of €25,000 per quality-adjusted life-years compared with adjusted-dose warfarin with a TTR of 60%. The probability that warfarin was a cost-effective option was around 1%. This percentage rises as the quality of anticoagulation control improves. At a TTR of 70%, warfarin was the preferred treatment in half the iterations. The cost effectiveness of NOACs for stroke prevention in patients with nonvalvular atrial fibrillation who are at increased risk for stroke is highly sensitive to warfarin anticoagulation control. NOACs are more likely to be cost-effective options in settings with poor warfarin management than in settings with better anticoagulation control, where they may not represent good value for money.

A search for new CYP3A4 variants as determinants of tacrolimus dose requirements in renal-transplanted patients.

PubMed

Tavira, Beatriz; Coto, Eliecer; Diaz-Corte, Carmen; Alvarez, Victoria; López-Larrea, Carlos; Ortega, Francisco

2013-08-01

The CYP3A5*3 and CYP3A4*1B alleles have been related with tacrolimus (Tac) dose requirements. The rare CYP3A4*22 variant has also been associated with a significantly lower Tac dose. We genotyped the three single-nucleotide polymorphisms in 206 kidney-transplanted patients who received Tac as the primary immunosuppressor. CYP3A5*1 and CYP3A4*1B allele carriers received a significantly higher Tac dose (P<0.01) compared with wild-type homozygotes. We did not find significant differences between the CYP3A4*22 genotypes, either nominally or according to the CYP3A5 genotype (expressers vs. nonexpressers). Sequencing of CYP3A4 coding exons in a total of 15 patients revealed only one nonreported missense change (p.P227>T) in one patient. We concluded that CYP3A5*3 and CYP3A4*1B were the main determinants of the Tac dose-adjusted blood concentration in our cohort of renal-transplanted patients.

Pharmacokinetic and pharmacodynamic considerations of antimicrobial drug therapy in cancer patients with kidney dysfunction

PubMed Central

Keller, Frieder; Schröppel, Bernd; Ludwig, Ulla

2015-01-01

Patients with cancer have a high inherent risk of infectious complications. In addition, the incidence of acute and chronic kidney dysfunction rises in this population. Anti-infective drugs often require dosing modifications based on an estimate of kidney function, usually the glomerular filtration rate (GFR). However, there is still no preferential GFR formula to be used, and in acute kidney injury there is always a considerable time delay between true kidney function and estimated GFR. In most cases, the anti-infective therapy should start with an immediate and high loading dose. Pharmacokinetic as well as pharmacodynamic principles must be applied for further dose adjustment. Anti-infective drugs with time-dependent action should be given with the target of high trough concentrations (e.g., beta lactam antibiotics, penems, vancomycin, antiviral drugs). Anti-infective drugs with concentration-dependent action should be given with the target of high peak concentrations (e.g., aminoglycosides, daptomycin, colistin, quinolones). Our group created a pharmacokinetic database, called NEPharm, hat serves as a reference to obtain reliable dosing regimens of anti-infective drugs in kidney dysfunction as well as renal replacement therapy. To avoid the risk of either too low or too infrequent peak concentrations, we prefer the eliminated fraction rule for dose adjustment calculations. PMID:26167456

Is Weight-Based Adjustment of Automatic Exposure Control Necessary for the Reduction of Chest CT Radiation Dose?

PubMed Central

Prakash, Priyanka; Gilman, Matthew D.; Shepard, Jo-Anne O.; Digumarthy, Subba R.

2010-01-01

Objective To assess the effects of radiation dose reduction in the chest CT using a weight-based adjustment of the automatic exposure control (AEC) technique. Materials and Methods With Institutional Review Board Approval, 60 patients (mean age, 59.1 years; M:F = 35:25) and 57 weight-matched patients (mean age, 52.3 years, M:F = 25:32) were scanned using a weight-adjusted AEC and non-weight-adjusted AEC, respectively on a 64-slice multidetector CT with a 0.984:1 pitch, 0.5 second rotation time, 40 mm table feed/rotation, and 2.5 mm section thickness. Patients were categorized into 3 weight categories; < 60 kg (n = 17), 60-90 kg (n = 52), and > 90 kg (n = 48). Patient weights, scanning parameters, CT dose index volumes (CTDIvol) and dose length product (DLP) were recorded, while effective dose (ED) was estimated. Image noise was measured in the descending thoracic aorta. Data were analyzed using a standard statistical package (SAS/STAT) (Version 9.1, SAS institute Inc, Cary, NC). Results Compared to the non-weight-adjusted AEC, the weight-adjusted AEC technique resulted in an average decrease of 29% in CTDIvol and a 27% effective dose reduction (p < 0.0001). With weight-adjusted AEC, the CTDIvol decreased to 15.8, 15.9, and 27.3 mGy for the < 60, 60-90 and > 91 kg weight groups, respectively, compared to 20.3, 27.9 and 32.8 mGy, with non-weight-adjusted AEC. No significant difference was observed for objective image noise between the chest CT acquired with the non-weight-adjusted (15.0 ± 3.1) and weight-adjusted (16.1 ± 5.6) AEC techniques (p > 0.05). Conclusion The results of this study suggest that AEC should be tailored according to patient weight. Without weight-based adjustment of AEC, patients are exposed to a 17 - 43% higher radiation-dose from a chest CT. PMID:20046494

Is weight-based adjustment of automatic exposure control necessary for the reduction of chest CT radiation dose?

PubMed

Prakash, Priyanka; Kalra, Mannudeep K; Gilman, Matthew D; Shepard, Jo-Anne O; Digumarthy, Subba R

2010-01-01

To assess the effects of radiation dose reduction in the chest CT using a weight-based adjustment of the automatic exposure control (AEC) technique. With Institutional Review Board Approval, 60 patients (mean age, 59.1 years; M:F = 35:25) and 57 weight-matched patients (mean age, 52.3 years, M:F = 25:32) were scanned using a weight-adjusted AEC and non-weight-adjusted AEC, respectively on a 64-slice multidetector CT with a 0.984:1 pitch, 0.5 second rotation time, 40 mm table feed/rotation, and 2.5 mm section thickness. Patients were categorized into 3 weight categories; < 60 kg (n = 17), 60-90 kg (n = 52), and > 90 kg (n = 48). Patient weights, scanning parameters, CT dose index volumes (CTDIvol) and dose length product (DLP) were recorded, while effective dose (ED) was estimated. Image noise was measured in the descending thoracic aorta. Data were analyzed using a standard statistical package (SAS/STAT) (Version 9.1, SAS institute Inc, Cary, NC). Compared to the non-weight-adjusted AEC, the weight-adjusted AEC technique resulted in an average decrease of 29% in CTDIvol and a 27% effective dose reduction (p < 0.0001). With weight-adjusted AEC, the CTDIvol decreased to 15.8, 15.9, and 27.3 mGy for the < 60, 60-90 and > 91 kg weight groups, respectively, compared to 20.3, 27.9 and 32.8 mGy, with non-weight-adjusted AEC. No significant difference was observed for objective image noise between the chest CT acquired with the non-weight-adjusted (15.0 +/- 3.1) and weight-adjusted (16.1 +/- 5.6) AEC techniques (p > 0.05). The results of this study suggest that AEC should be tailored according to patient weight. Without weight-based adjustment of AEC, patients are exposed to a 17 - 43% higher radiation-dose from a chest CT.

Pharmacokinetics of hydrocodone/acetaminophen combination product in children ages 6-17 with moderate to moderately severe postoperative pain.

PubMed

Liu, Wei; Dutta, Sandeep; Kearns, Greg; Awni, Walid; Neville, Kathleen A

2015-02-01

Lortab® Elixir, a proprietary combination product containing hydrocodone and acetaminophen, is approved in the US for the treatment of moderate to moderately severe pain in children. Despite this approval, pediatric pharmacokinetic data using this product have not been previously published. Using a single-dose open-label study approach, we evaluated the pharmacokinetics, tolerability, and safety of this product in 17 healthy children 6-17 years of age. Results showed that the body weight-normalized oral clearance (L/h/kg) of hydrocodone and acetaminophen were 42% and 27% higher, respectively when compared to data from healthy adults. This suggests that a higher mg/kg dose would be required in children to achieve exposures similar to adults. We found adjustment of hydrocodone and acetaminophen dose by body surface area to be more optimal than body weight-based dose adjustments for achieving similar systemic exposure in children and adults. However, body weight-based hydrocodone and acetaminophen dosing regimens provided close approximation of adult exposures in pediatric patients with approximately 22% to 24% lower hydrocodone and acetaminophen dose/BW-normalized AUC in pediatric patients compared to adults. Finally, the adverse event profile in our pediatric cohort was consistent with that expected of opioid-naive subjects receiving opioid-combination therapy. © 2014, The American College of Clinical Pharmacology.

Learning Difficulties of Diabetic Patients: A Survey of Educators.

ERIC Educational Resources Information Center

Bonnet, Caroline; Gagnayre, Remi; d'Ivernois, Jean-Francois

1998-01-01

Surveys 85 health care professionals on the learning difficulties of diabetic patients. Results show that educators find it easy to teach techniques: patients master procedures well and make few mistakes. In contrast, diabetic patients seem to have problems learning skills, such as insulin dose adjustment, that require complex problem-solving.…

Anesthesia for ambulatory anorectal surgery.

PubMed

Gudaityte, Jūrate; Marchertiene, Irena; Pavalkis, Dainius

2004-01-01

The prevalence of minor anorectal diseases is 4-5% of adult Western population. Operations are performed on ambulatory or 24-hour stay basis. Requirements for ambulatory anesthesia are: rapid onset and recovery, ability to provide quick adjustments during maintenance, lack of intraoperative and postoperative side effects, and cost-effectiveness. Anorectal surgery requires deep levels of anesthesia. The aim is achieved with 1) regional blocks alone or in combination with monitored anesthesia care or 2) deep general anesthesia, usually with muscle relaxants and tracheal intubation. Modern general anesthetics provide smooth, quickly adjustable anesthesia and are a good choice for ambulatory surgery. Popular regional methods are: spinal anesthesia, caudal blockade, posterior perineal blockade and local anesthesia. The trend in regional anesthesia is lowering the dose of local anesthetic, providing selective segmental block. Adjuvants potentiating analgesia are recommended. Postoperative period may be complicated by: 1) severe pain, 2) urinary retention due to common nerve supply, and 3) surgical bleeding. Complications may lead to hospital admission. In conclusion, novel general anesthetics are recommended for ambulatory anorectal surgery. Further studies to determine an optimal dose and method are needed in the group of regional anesthesia.

SU-E-T-619: Planning 131I Thyroid Treatments for Patients Requiring Hemodialysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stroud, D

Purpose: Treatment of 131I thyroid cancer patients who also require regular hemodialysis (HD) treatments requires consideration of the administered activity and the HD schedule. In this work the red bone marrow is considered the dose limiting organ and the treatment plan optimized the HD schedule with the amount of radioactivity administered. Methods: The ‘Safe’ dose was considered to be 2 Gy (200 rad) to the red bone marrow.1 131Iodine doses of 50 mCi to 100 mCi were modeled and found to require a range of HD schedules. In order to achieve the safe dose to the red marrow, more aggressivemore » HD schedules are required. 100 mCi required an aggressive HD treatment of every 24 hours for at least one week to achieve the ‘safe’ dose and an exposure appropriate for release from the hospital. A more normal schedule of HD beginning at 18 hours then every 48 hours allowed for up to 60 mCi administered dose allowed for a safe dose and expected release after less than one week.2In addition room was equipped with video cameras cameras for monitoring the patient and their vital signs from an adjacent room during HD. In this way the dialysis nurses were able to monitor the patient closely from an adjoining room. Results: Two HD patients were administered adjusted doses of about 50 mCi. The medical and nursing staff were exposed to no more than 4 mR for the entire treatment. The residual Iodine in the patient appeared to be normal after 4 to 6 days when the patient was released. Conclusion: With careful treatment planning 131Iodine treatments can be performed safely for patients needing HD and treatments appear to be as effective as those for patients with normal renal function.« less

UNUSUAL WARFARIN DOSE TO ACHIEVE THERAPEUTIC INR IN A 4-MONTH OLD CHILD: NON-GENETICS RISK FACTORS ARE STILL A CHALLENGE.

PubMed

Okumura, Lucas Miyake; Negretto, Giovanna Webster; Carvalho, Clarissa Gutiérrez

2017-01-01

To report a case of a 4-month old girl that required 0.7 mg/kg/day (5 mg) of warfarin and discuss relevant risk factors for requiring higher doses. In November 2015, a 5 kg female infant (36-week preterm) was admitted to the hospital due to status epilepticus and fever. Diazepam, phenytoin and ceftriaxone were prescribed. Cerebrospinal fluid contained 7 leukocytes, 150 mg/dL proteins, 1 mg/dL glucose and gram positive cocci were observed. Cranial tomography suggested hypodense signs in the cerebellum, right temporal lobe and left basal nuclei, which was consistent with pneumococcal meningitis-induced infectious vasculitis. She required low molecular weight heparin and warfarin for post-encephalitis thrombosis. About 10 days were required to achieve therapeutic INR, and warfarin was adjusted five times since the initial prescription. The risk factors for higher warfarin doses were age and enteral tube feeding. Phenobarbital and prednisone might also have contributed with one of the highest warfarin dose ever reported. Despite current importance given to genetics testing, clinicians should attempt to identify common contributing factors for prolonged non-therapeutic INR, to minimize the risk of coagulation, and to reduce costs of hospital stay and laboratory exams.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, P; Gang, Y; Qin, S

Purpose: Many patients with hepatocellular carcinoma (HCC) had hepatic anatomy variations as a result of inter-fraction deformation during fractionated radiotherapy, which may result in difference from the planned dose. This study aimed to investigate the relationship between adjusted dose and radiation induced liver disease (RILD) in HCC patients receiving three dimensional conformal radiotherapy (3DCRT). Methods: Twenty-three HCC patients received conventional fractionated 3DCRT were enrolled in this retrospective investigation. Among them, seven patients had been diagnosed of RILD post-radiotherapy, including 4 cases of grade 2, 3 cases of grade 3 according to the CTCAE Version 3.0. Daily cone-beam CT (CBCT) scansmore » were acquired throughout the whole treatment course for each patient. To reconstruct the daily dose to a patient considering the interfraction anatomy variations, the planned beams from each patient’s treatment plan were firstly applied to each daily modified CBCT (mCBCT). The daily doses were then summed together with the help of deformable image registration (DIR) to obtain the adjusted dose (Dadjusted) of the patient. Finally, the dose changes in normal liver between planned dose (Dplan) and Dadjusted were evaluated by V20, V30, V40 and the mean dose to normal liver (MDTNL). Univariate analysis was performed to identify the significant dose changes. Results: Among the twenty-three patients, the adjusted liver V20, V30, V40 and MDTNL showed significant changes from the planned ones (p<0.05) and averagely increased by 4.1%, 4.7%, 4.5% and 3.9Gy, respectively. And the adjusted liver dose in twenty-one patients (91%) were higher than planned value, the adjusted dose of patients with RILD (6/7) exceeds to the hepatic radiation tolerance. Conclusion: The adjusted dose of all the studied patients significantly differs from planned dose, and mCBCT-based dose reconstruction can aid in evaluating the robustness of the planning solutions, and adjusted dose has the potential to reduce the risk of RILD. The author would like to express great thanks to Lei Xing, Daniel S Kapp and Yong Yang in the Stanford University School of Medicine for their valuable suggestions to this work.This work is supported by NSFC(61471226),China Postdoctoral Science Foundation (2015T80739, 2014M551949) and research funding from Shandong Province(JQ201516).« less

Assessment of Apixaban Prescribing Patterns for Nonvalvular Atrial Fibrillation in Hospitalized Patients.

PubMed

Gibson, Caitlin M; Smith, Carmen B; Davis, Sondra; Scalese, Michael J

2018-01-01

Apixaban is a direct oral anticoagulant (DOAC) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). Other DOACs require renal dose adjustments based solely on creatinine clearance. Apixaban differs in that its dose adjustments are more complex, potentially leading to prescribing errors. To determine if adherence to Food and Drug Administration (FDA)-approved dosing for apixaban is maintained in hospitalized patients with NVAF. Patients ≥18 years old with NVAF who received apixaban during admission to 1 of 3 hospitals were evaluated. The primary outcome was to determine if providers order apixaban in accordance with FDA-approved dosages. Secondary outcomes included determining if pharmacist review increased the number of orders in accordance with FDA-approved dosing, which of the 3 criteria (age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL) were met in patients receiving off-label dosing, and the rationale for off-label prescribing. A total of 556 patients met inclusion criteria. Apixaban was dosed according to FDA labeling by providers in 83.4% (n = 464) of orders. After pharmacist review, 87.0% (n = 484) of orders were at the approved dose, 12.2% (n = 68) were underdosed, and 0.7% (n = 4) were overdosed. Most patients who were underdosed met only 1 dose reduction criterion-most commonly age ≥80 years (56.0%). Reasons for off-label dosing included home dose continuation (39.0%), history of or perceived bleeding risk (30.5%), or unspecified/other (30.5%). The majority of apixaban orders for NVAF were based on FDA-approved dosages after provider entry and pharmacist review.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.

PubMed

Katsube, Takayuki; Wajima, Toshihiro; Ishibashi, Toru; Arjona Ferreira, Juan Camilo; Echols, Roger

2017-01-01

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (T f >MIC ) for an MIC range of 0.25 to 16 μg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% T f >MIC for an MIC of ≤4 μg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect. Copyright © 2016 American Society for Microbiology.

Influence of CYP3A5 and ABCB1 gene polymorphisms and other factors on tacrolimus dosing in Caucasian liver and kidney transplant patients.

PubMed

Provenzani, Alessio; Notarbartolo, Monica; Labbozzetta, Manuela; Poma, Paola; Vizzini, Giovanni; Salis, Paola; Caccamo, Chiara; Bertani, Tullio; Palazzo, Ugo; Polidori, Piera; Gridelli, Bruno; D'Alessandro, Natale

2011-12-01

Tacrolimus is a substrate of cytochrome P4503A (CYP3A) enzymes as well as of the drug transporter ABCB1. We have investigated the possible influence of CYP3A5 and ABCB1 single nucleotide polymorphisms (SNPs) and other factors (e.g. albumin, hematocrit and steroids) on tacrolimus blood levels achieved in a population of Caucasian liver (n=51) and kidney (n=50) transplant recipients. At 1, 3 and 6 months after transplantation, tacrolimus doses (mg/kg/day) and trough blood levels (C0) were recorded and the weight-adjusted tacrolimus dosage (mg/kg/day) was calculated. Polymerase chain reaction followed by restriction fragment length polymorphism analysis was used for genotyping CYP3A5*1 and *3 [6986A>G] as well as ABCB1 at exons 21 [2677G>T/A] and 26 [3435C>T] in both liver transplant donors and recipients and in kidney transplant recipients. Of the 152 subjects studied, 84.9% showed a CYP3A5*3/*3 genotype. The total frequency of the allelic variant *3 was 93%. For the G2677T/A and C3435T polymorphisms the total frequencies of the allelic variants T/A and T were 44.7 and 46.7%, respectively. At 1, 3 and 6 months after transplantation the dose-adjusted C0 levels were significantly lower in patients with one copy of the *1 allele compared to those homozygous for the *3 allele. In the case of liver transplant patients the tacrolimus dose requirements were dominantly influenced by the polymorphisms of the CYP3A5 gene in the donors. With regard to the ABCB1 SNPs, in general they did not show any appreciable influence on tacrolimus dosing requirements; however, kidney transplant recipients carrying the 2677T/A allele required significantly higher daily tacrolimus doses than subjects homozygous for the wild-type allele. Identification of CYP3A5 single nucleotide polymorphisms prior to transplantation could contribute to evaluate the appropriate initial dosage of tacrolimus in the patients.

A Case Report of a Patient Carrying CYP2C9*3/4 Genotype with Extremely Low Warfarin Dose Requirement

PubMed Central

Lee, Soo-Youn; Nam, Myung-Hyun; Kim, June Soo

2007-01-01

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin. PMID:17596671

A case report of a patient carrying CYP2C9*3/4 genotype with extremely low warfarin dose requirement.

PubMed

Lee, Soo Youn; Nam, Myung Hyun; Kim, June Soo; Kim, Jong Won

2007-06-01

We report a case of intolerance to warfarin dosing due to impaired drug metabolism in a patient with CYP2C9*3/*4. A 73-yr-old woman with atrial fibrilation was taking warfarin. She attained a high prothrombin time international normalized ratio (INR) at the standard doses during the induction of anticoagulation and extremely low dose of warfarin (6.5 mg/week) was finally chosen to reach the target INR. Genotyping for CYP2C9 revealed that this patient had a genotype CYP2C9*3/*4. This is the first Korean compound heterozygote for CYP2C9*3 and *4. This case suggests the clinical usefulness of pharmacogenetic testing for individualized dosage adjustments of warfarin.

Dabigatran versus warfarin in patients with mechanical heart valves.

PubMed

Eikelboom, John W; Connolly, Stuart J; Brueckmann, Martina; Granger, Christopher B; Kappetein, Arie P; Mack, Michael J; Blatchford, Jon; Devenny, Kevin; Friedman, Jeffrey; Guiver, Kelly; Harper, Ruth; Khder, Yasser; Lobmeyer, Maximilian T; Maas, Hugo; Voigt, Jens-Uwe; Simoons, Maarten L; Van de Werf, Frans

2013-09-26

Dabigatran is an oral direct thrombin inhibitor that has been shown to be an effective alternative to warfarin in patients with atrial fibrillation. We evaluated the use of dabigatran in patients with mechanical heart valves. In this phase 2 dose-validation study, we studied two populations of patients: those who had undergone aortic- or mitral-valve replacement within the past 7 days and those who had undergone such replacement at least 3 months earlier. Patients were randomly assigned in a 2:1 ratio to receive either dabigatran or warfarin. The selection of the initial dabigatran dose (150, 220, or 300 mg twice daily) was based on kidney function. Doses were adjusted to obtain a trough plasma level of at least 50 ng per milliliter. The warfarin dose was adjusted to obtain an international normalized ratio of 2 to 3 or 2.5 to 3.5 on the basis of thromboembolic risk. The primary end point was the trough plasma level of dabigatran. The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding. The use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications, as compared with warfarin, thus showing no benefit and an excess risk. (Funded by Boehringer Ingelheim; ClinicalTrials.gov numbers, NCT01452347 and NCT01505881.).

198 AAAAI Survey on Immunotherapy Practice Patterns Concerning Dosing, Dose-Adjustment after Missed Doses and Duration of Immunotherapy

PubMed Central

Linnemann, Désirée Larenas; Gupta, Payel; Mithani, Sima; Ponda, Punita

2012-01-01

Background Several practical issues dealing with the exact application of allergen immunotherapy (AIT) among European and US allergists are not well known. Guidelines on AIT give recommendations and suggestions for only some of them. We present this unique survey with worldwide response. Methods The AAAAI immunotherapy committee conducted a web-based practice patterns survey (program: Survey Monkey) among all members in&outside US on dosing, dose-adjustment after missed doses and duration of AIT. Results 1201 Returned questionnaires (almost 25% response rate). 21% were non-US-Canada members. Maintenance doses in USCan are (mean/median): Dermatophagoides farinae (Df) combined with Dermatophagoides pteronyssinus (Dpt): 2155/1000AU; Df solo 2484/1000AU. Dpt when combined with Df 1937/1000AU; Dpt solo: 2183/1000AU.Cat 3224/2000BAU. Grass 11,410/4000BAU. 57-65% of the dosing falls within the recommended Practice Parameters recommended ranges. Non-USCan allergists expressed maintenance doses in many different units making analysis impossible. Dose-adjustment after missed doses is based on ‘time elapsed since the last applied dose’ by 77% of USCan and 58% of non-USCan allergists and on ‘time since missed scheduled dose’ by the rest. Doses are adjusted when a patient comes in more than 14 d/5 wk after the last administration at build-up/maintenance by both USCan and non-USCan colleagues. The mostly followed dose-adjustment schedules after 1, 2, 3 missed doses are: Build-up: repeat last dose, reduce by one dose, reduce by 2 doses; maintenance: reduce by one dose, reduce by 2 doses, reduce by 3 doses. 26% uses a different approach reducing doses by a certain percentage or volume. AIT is restarted after a gap in build-up of >30 days and of >12 weeks during maintenance in both groups (median). Outside USCan AIT is prescribed for 3 years (Median). However, 75% of USCan allergists prescribes AIT for 5 years. Main reasons why to continue AIT beyond 5 years: ‘symptoms came back after stopping’ or “patient afraid to relapse.” Conclusions These results show regional differences on some points (especially AIT duration) and they suggest in which direction to plan further research in 2 areas to establish universal dose-adjustment plans for missed applications and define the usefulness (or lack of) of long-term AIT. Moreover, there is still room for improvement in the way AIT is dosed.

Evaluation of the effect of torsemide on warfarin dosage requirements.

PubMed

Lai, Sophia; Momper, Jeremiah D; Yam, Felix K

2017-08-01

Background According to drug interaction databases, torsemide may potentiate the effects of warfarin. Evidence for this drug-drug interaction, however, is conflicting and the clinical significance is unknown. Objective The aim of this study is to evaluate the impact of torsemide initiation on warfarin dosage requirements. Setting This study was conducted at the Veterans Affairs Healthcare System in San Diego, California. Method A retrospective cohort study was conducted using Veterans Affairs data from patients who were converted from bumetanide to torsemide between March 2014 and July 2014. Patients were also prescribed and taking warfarin during the observation period. Warfarin dosage requirements were evaluated to determine if any changes occurred within the first 3 months of starting torsemide. Main outcome measure The primary outcome was the average weekly warfarin dose before and after torsemide initiation. Results Eighteen patients met study inclusion criteria. The weekly warfarin dose before and after initiation of torsemide was not significantly different (34 ± 15 and 34 ± 13 mg, p > 0.05). Of those eighteen patients, only two experienced elevations in INR that required a decrease in warfarin dosage after torsemide initiation. Between those two patients, dosage reductions ranged from 5.3 to 18%. Conclusion These results indicated that most patients did not require any warfarin dosage adjustments after torsemide was initiated. The potential for interaction, however, still exists. While empiric warfarin dosage adjustments are not recommended when initiating torsemide, increased monitoring is warranted to minimize the risk of adverse effects.

Corrigendum: direct adjustment for confounding by smoking reduces radiation-related cancer risk estimates of mortality among male nuclear workers in Japan, 1999-2010.

PubMed

Kudo, Shin'ichi; Ishida, Jun'ichi; Yoshimoto, Keiko; Mizuno, Shoichi; Ohshima, Sumio; Furuta, Hiroshige; Kasagi, Fumiyoshi

2018-05-30

We found some trivial errors which might confuse reader. The errors can be identified as the following two types. (1) The one is that misuse of "ERR" and "ERR/Sv". We denoted "Table 4 shows ERRs/Sv and 90% CIs ..." in line 7 of page 366. While we denoted "ERR and 90% CI for all cancers, excluding leukaemia, by dose category ..." in title of Table 4. The values described in Table 4 were ERR by dose category and not ERR/Sv. In addition, the explanation about the model that derived ERR by dose category is better to be added. Therefore, the description mentioned above should be changed as follows. (Misprinted) Table 4 shows ERRs/Sv and 90% CIs for all cancers excluding leukaemia by dose category. (Corrected) Table 4 shows ERRs which were defined as follow equation and 90% CIs for all cancers excluding leukaemia by dose category. λ=λ0 (a,c,y,r,s)exp(α1z1+α2z2+α3z3) (1+βi di) where di is the dose category, and βi is the ERR by dose category. The lowest dose category was set as reference. (2) The other were errors in surface caput of several tables. We described "ERR without adjustment for smoking" and "ERR with adjustment for smoking" in Table 4. These are correct description. However, "ERR with adjustment for smoking" was described as "For smoking" in Table 2. In addition, "Without adjustment" and "With adjustment" denoted in the surface caput of Table 5, 6, 7 should be denoted as "Without adjustment for smoking" and "With adjustment for smoking". The author wishes to apologies for the errors. . Creative Commons Attribution license.

Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases.

PubMed

Sorenmo, Karin; Overley, B; Krick, E; Ferrara, T; LaBlanc, A; Shofer, F

2010-09-01

A dose-intensified/dose-dense chemotherapy protocol for canine lymphoma was designed and implemented at the Veterinary Hospital of the University of Pennsylvania. In this study, we describe the clinical characteristics, prognostic factors, efficacy and toxicity in 130 dogs treated with this protocol. The majority of the dogs had advanced stage disease (63.1% stage V) and sub-stage b (58.5%). The median time to progression (TTP) and lymphoma-specific survival were 219 and 323 days, respectively. These results are similar to previous less dose-intense protocols. Sub-stage was a significant negative prognostic factor for survival. The incidence of toxicity was high; 53.9 and 45% of the dogs needed dose reductions and treatment delays, respectively. Dogs that required dose reductions and treatment delays had significantly longer TTP and lymphoma-specific survival times. These results suggest that dose density is important, but likely relative, and needs to be adjusted according to the individual patient's toxicity for optimal outcome.

COMPARISON OF THREE ALGORITHMS FOR BASAL INSULIN IN TRANSITIONING STABLE POST-CARDIOTHORACIC SURGERY PATIENTS FROM INTRAVENOUS TO SUBCUTANEOUS INSULIN

PubMed Central

Dungan, Kathleen; Hall, Christine; Schuster, Dara; Osei, Kwame

2011-01-01

Objective The objective was to determine the efficacy of an algorithim containing aspart dosed according to carbohydrate intake and one of 3 initial doses of detemir in stable cardiac surgery patients requiring intravenous (IV) insulin. Methods Patients were extubated, off pressors and otherwise stable, requiring at least 1 unit/hr of IV insulin at least 48 hours following surgery. Subjects were randomized to once daily detemir at 50, 65, or 80% of IV basal insulin requirements and received aspart according to carbohydrate intake. The dose of detemir was adjusted daily over 72 hours. Results The number of patients with an initial morning glucose 80–130 mg/dl was 36, 63, and 56% of patients at the 50, 65, and 80% doses (p=0.12) (n=82). However, the mean overall glucose at 24 and 72 hours was similar between groups, and 86, 93, and 92% achieved a mean glucose 80–180 mg/dl at 72 hours (p=0.60). Hypoglycemia (<65 mg/dl) only occurred in the 65% (21%) and 80% (12%) groups over the first 72 hours (p=0.02 in the 50% compared to the 65 and 80% groups combined) with one event <40 mg/dl in the 80% group. There was no loss of glycemic control by the end of the once daily dosing interval. Conclusions Glycemic targets can be achieved without hypoglycemia by 72 hours in most cardiac surgery patients requiring IV insulin with a regimen containing an initial detemir dose of 50% of basal IV insulin requirements and prandial and supplemental insulin. PMID:21550950

Epinephrine Dosing Period and Survival after In-Hospital Cardiac Arrest

PubMed Central

Warren, Sam A.; Huszti, Ella; Bradley, Steven M.; Chan, Paul S.; Bryson, Chris L.; Fitzpatrick, Annette L.; Nichol, Graham

2015-01-01

Background Expert guidelines for treatment of cardiac arrest recommend administration of epinephrine every three to five minutes. However, different dosing periods of epinephrine have not been systematically assessed. Objective We evaluated the association between epinephrine dosing frequency and survival to hospital discharge in adults with an in-hospital cardiac arrest (IHCA). Methods Using data from 2000–2009 in the Get With the Guidelines(GWTG)-Resuscitation IHCA registry (formerly the National Registry of Cardiopulmonary Resuscitation [NRCPR]), we examined the association between epinephrine dosing period and survival to hospital discharge. Epinephrine dosing period was defined as the time between the first epinephrine dose and the resuscitation endpoint, divided by the total number of epinephrine doses received subsequent to the first epinephrine dose. Generalized estimating equations were used to construct multivariable logistic regression models, adjusted for patient and arrest characteristics. Results Included were 20,909 eligible IHCA events from 505 GWTG-Resuscitation participating hospitals. Compared to an epinephrine dosing period of 4 to <5 minutes per dose, survival to hospital discharge was significantly higher in patients with an epinephrine dosing period of 6 to <10 minutes per dose: for 6 to <7 min/dose, adjusted odds ratio [OR], 1.41 (95% CI: 1.12, 1.78); for 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65); for 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32); for 9 to <10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92). This pattern was consistent for both shockable and non-shockable cardiac arrest rhythms. Moreover, for the majority (87%) of cardiac arrests due to non-shockable rhythms, an epinephrine dosing period of 1 to <3 minutes/dose was associated with lower rates of survival. Conclusion In this large, observational, national registry of in-hospital cardiac arrest, we found that epinephrine dosing at a less frequent dosing period than recommended by consensus guidelines was associated with improved survival of in-hospital cardiac arrest. Our findings suggest that clinical trials may be needed to determine the role and dose frequency of epinephrine in the treatment of in-hospital cardiac arrest. PMID:24252225

Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.

PubMed

1996-09-07

Adjusted-dose warfarin is highly efficacious for prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, this treatment carries a risk of bleeding and the need for frequent medical monitoring. We sought an alternative that would be safer and easier to administer to patients with AF who are at high-risk of thromboembolism. 1044 patients with AF and with at least one thromboembolic risk factor (congestive heart failure or left ventricular fractional shortening < or = 25%, previous thromboembolism, systolic blood pressure of more than 160 mm Hg at study enrollment, or being a woman aged over 75 years) were randomly assigned either a combination of low-intensity, fixed-dose warfarin (international normalised ratio [INR] 1.2-1.5 for initial dose adjustment) and aspirin (325 mg/day) or adjusted-dose warfarin (INR 2.0-3.0). Drugs were given open-labelled. The mean INR during follow-up of patients taking combination therapy (n = 521) was 1.3, compared with 2.4 for those taking adjusted-dose warfarin (n = 523). During follow-up, 54% of INRs in patients taking combination therapy were 1.2-1.5 and 34% were less than 1.2. The trial was stopped after a mean, follow-up of 1.1 years when the rate of ischaemic stroke and systemic embolism (primary events) in patients given combination therapy (7.9% per year) was significantly higher than in those given adjusted-dose warfarin (1.9% per year) at an interim analysis (p < 0.0001), an absolute reduction of 6.0% per year (95% Cl 3.4, 8.6) by adjusted-dose warfarin. The annual rates of disabling stroke (5.6% vs 1.7%, p = 0.0007) and of primary event or vascular death (11.8% vs 6.4%, p = 0.002), were also higher with combination therapy. The rates of major bleeding were similar in both treatment groups. Low-intensity, fixed-dose warfarin plus aspirin in this regimen is insufficient for stroke prevention in patients with non-valvular AF at high-risk for thromboembolism; adjusted-dose warfarin (target INR 2.0-3.0) importantly reduces stroke for high-risk patients.

Gender, body weight, disease activity, and previous radiotherapy influence the response to pegvisomant.

PubMed

Parkinson, Craig; Burman, Pia; Messig, Michael; Trainer, Peter J

2007-01-01

To effectively normalize IGF-I in patients with acromegaly, various covariates may affect dosing and plasma concentrations of pegvisomant. We assessed whether sex, age, weight, and previous radiotherapy influence dosing of pegvisomant in patients with active disease. Data from 69 men and 49 women participating in multicenter, open-label trials of pegvisomant were retrospectively evaluated using multiple regression techniques. Sixty-nine subjects (39 men, 30 women) had undergone external beam pituitary radiotherapy. Serum IGF-I was at least 30% above age-related upper limit of normal in all patients at study entry. After a loading dose of pegvisomant (80 mg), patients were commenced on 10 mg/d. Pegvisomant dose was adjusted by 5 mg every eighth week until serum IGF-I was normalized. At baseline, men had significantly higher mean serum IGF-I levels than women despite similar GH levels. After treatment with pegvisomant, IGF-I levels were similar in men and women. A significant correlation between baseline GH, IGF-I, body weight, and the dose of pegvisomant required to normalize serum IGF-I was observed (all P < 0.001). Women required an average of 0.04 mg/kg more pegvisomant than men and a mean weight-corrected dose of 19.2 mg/d to normalize serum IGF-I [14.5 mg/d (men); P < 0.001]. Patients treated with radiotherapy required less pegvisomant to normalize serum IGF-I despite similar baseline GH/IGF-I levels (15.2 vs. 18.5 mg/d for no previous radiotherapy; P = 0.002). Sex, body weight, previous radiotherapy, and baseline GH/IGF-I influence the dose of pegvisomant required to normalize serum IGF-I in patients with active acromegaly.

Evaluation of Deformable Image Coregistration in Adaptive Dose Painting by Numbers for Head-and-Neck Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olteanu, Luiza A.M., E-mail: AnaMariaLuiza.Olteanu@uzgent.be; Madani, Indira; De Neve, Wilfried

Purpose: To assess the accuracy of contour deformation and feasibility of dose summation applying deformable image coregistration in adaptive dose painting by numbers (DPBN) for head and neck cancer. Methods and Materials: Data of 12 head-and-neck-cancer patients treated within a Phase I trial on adaptive {sup 18}F-FDG positron emission tomography (PET)-guided DPBN were used. Each patient had two DPBN treatment plans: the initial plan was based on a pretreatment PET/CT scan; the second adapted plan was based on a PET/CT scan acquired after 8 fractions. The median prescription dose to the dose-painted volume was 30 Gy for both DPBN plans.more » To obtain deformed contours and dose distributions, pretreatment CT was deformed to per-treatment CT using deformable image coregistration. Deformed contours of regions of interest (ROI{sub def}) were visually inspected and, if necessary, adjusted (ROI{sub def{sub ad}}) and both compared with manually redrawn ROIs (ROI{sub m}) using Jaccard (JI) and overlap indices (OI). Dose summation was done on the ROI{sub m}, ROI{sub def{sub ad}}, or their unions with the ROI{sub def}. Results: Almost all deformed ROIs were adjusted. The largest adjustment was made in patients with substantially regressing tumors: ROI{sub def} = 11.8 {+-} 10.9 cm{sup 3} vs. ROI{sub def{sub ad}} = 5.9 {+-} 7.8 cm{sup 3} vs. ROI{sub m} = 7.7 {+-} 7.2 cm{sup 3} (p = 0.57). The swallowing structures were the most frequently adjusted ROIs with the lowest indices for the upper esophageal sphincter: JI = 0.3 (ROI{sub def}) and 0.4 (ROI{sub def{sub ad}}); OI = 0.5 (both ROIs). The mandible needed the least adjustment with the highest indices: JI = 0.8 (both ROIs), OI = 0.9 (ROI{sub def}), and 1.0 (ROI{sub def{sub ad}}). Summed doses differed non-significantly. There was a trend of higher doses in the targets and lower doses in the spinal cord when doses were summed on unions. Conclusion: Visual inspection and adjustment were necessary for most ROIs. Fast automatic ROI propagation followed by user-driven adjustment appears to be more efficient than labor-intensive de novo drawing. Dose summation using deformable image coregistration was feasible. Biological uncertainties of dose summation strategies warrant further investigation.« less

[Mechanisms of action, pharmacology and interactions of dolutegravir].

PubMed

Ribera, Esteban; Podzamczer, Daniel

2015-03-01

Dolutegravir is a second-generation integrase strand transfer inhibitor (INSTI), whose potential and binding half-life in the integrase are far superior to those of raltegravir and elvitegravir, conferring it with unique characteristics in terms of its genetic barrier to resistance and activity against viruses with one or more mutations in the integrase. The pharmacokinetic properties of dolutegravir allow once-daily dosing (50 mg), with or without food, maintaining concentrations far above those effective against wild-type viruses. If integrase resistance mutations are present, the recommended dosing regimen is 50 mg/12 h. The distribution of dolutegravir in cerebrospinal fluid is good and effective concentrations are also reached in the male and female genital tracts. Dolutegravir is metabolized by UGT1A1 and, to a lesser extent, by CYP3A4, without being an inducer or inhibitor of the usual metabolic systems. It has a very low potential for drug interactions and can be administered in routine doses with most drugs. Dose adjustment is not required, even in patients with renal insufficiency or mild or moderate liver failure. Increasing the dose of dolutegravir (50 mg/12 h) is only recommended when administered with efavirenz, nevirapine, fosamprenavir/r, tipranavir/r, rifampicin, carbamazepine, phenytoin and phenobarbital. Coadministration of dolutegravir with etravirine is not recommended without a protease inhibitor or with Hypericum perforatum. Dolutegravir should be administered 2 h before or 6 h after antacids or products with polyvalent cations. Dolutegravir can reduce renal tubule secretion of substances excreted via OCT2, with a slight initial increase in creatinine, with no risk of renal toxicity. The drug can also increase metformin concentrations and consequently monitoring is recommended in case dose adjustment is required. In summary, dolutegravir has excellent pharmacokinetic and drug interaction profiles. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Individual radiation therapy patient whole-body phantoms for peripheral dose evaluations: method and specific software.

PubMed

Alziar, I; Bonniaud, G; Couanet, D; Ruaud, J B; Vicente, C; Giordana, G; Ben-Harrath, O; Diaz, J C; Grandjean, P; Kafrouni, H; Chavaudra, J; Lefkopoulos, D; de Vathaire, F; Diallo, I

2009-09-07

This study presents a method aimed at creating radiotherapy (RT) patient-adjustable whole-body phantoms to permit retrospective and prospective peripheral dose evaluations for enhanced patient radioprotection. Our strategy involves virtual whole-body patient models (WBPM) in different RT treatment positions for both genders and for different age groups. It includes a software tool designed to match the anatomy of the phantoms with the anatomy of the actual patients, based on the quality of patient data available. The procedure for adjusting a WBPM to patient morphology includes typical dimensions available in basic auxological tables for the French population. Adjustment is semi-automatic. Because of the complexity of the human anatomy, skilled personnel are required to validate changes made in the phantom anatomy. This research is part of a global project aimed at proposing appropriate methods and software tools capable of reconstituting the anatomy and dose evaluations in the entire body of RT patients in an adapted treatment planning system (TPS). The graphic user interface is that of a TPS adapted to obtain a comfortable working process. Such WBPM have been used to supplement patient therapy planning images, usually restricted to regions involved in treatment. Here we report, as an example, the case of a patient treated for prostate cancer whose therapy planning images were complemented by an anatomy model. Although present results are preliminary and our research is ongoing, they appear encouraging, since such patient-adjusted phantoms are crucial in the optimization of radiation protection of patients and for follow-up studies.

NOTE: Individual radiation therapy patient whole-body phantoms for peripheral dose evaluations: method and specific software

NASA Astrophysics Data System (ADS)

Alziar, I.; Bonniaud, G.; Couanet, D.; Ruaud, J. B.; Vicente, C.; Giordana, G.; Ben-Harrath, O.; Diaz, J. C.; Grandjean, P.; Kafrouni, H.; Chavaudra, J.; Lefkopoulos, D.; de Vathaire, F.; Diallo, I.

2009-09-01

This study presents a method aimed at creating radiotherapy (RT) patient-adjustable whole-body phantoms to permit retrospective and prospective peripheral dose evaluations for enhanced patient radioprotection. Our strategy involves virtual whole-body patient models (WBPM) in different RT treatment positions for both genders and for different age groups. It includes a software tool designed to match the anatomy of the phantoms with the anatomy of the actual patients, based on the quality of patient data available. The procedure for adjusting a WBPM to patient morphology includes typical dimensions available in basic auxological tables for the French population. Adjustment is semi-automatic. Because of the complexity of the human anatomy, skilled personnel are required to validate changes made in the phantom anatomy. This research is part of a global project aimed at proposing appropriate methods and software tools capable of reconstituting the anatomy and dose evaluations in the entire body of RT patients in an adapted treatment planning system (TPS). The graphic user interface is that of a TPS adapted to obtain a comfortable working process. Such WBPM have been used to supplement patient therapy planning images, usually restricted to regions involved in treatment. Here we report, as an example, the case of a patient treated for prostate cancer whose therapy planning images were complemented by an anatomy model. Although present results are preliminary and our research is ongoing, they appear encouraging, since such patient-adjusted phantoms are crucial in the optimization of radiation protection of patients and for follow-up studies.

Cost-effectiveness of rotavirus vaccination in peru.

PubMed

Clark, Andrew D; Walker, Damian G; Mosqueira, N Rocio; Penny, Mary E; Lanata, Claudio F; Fox-Rushby, Julia; Sanderson, Colin F B

2009-11-01

There are plans to introduce the oral rotavirus vaccine Rotarix (GlaxoSmithKline), 1 of 2 recently developed vaccines against rotavirus, in Peru. We modeled the cost-effectiveness of adding a rotavirus vaccine to the Peruvian immunization program under 3 scenarios for the timing of vaccination: (1) strictly according to schedule, at 2 and 4 months of age (on time); (2) distributed around the target ages in the same way as the actual timings in the program (flexible); and (3) flexible but assuming vaccination is not initiated for infants >12 weeks of age (restricted). We assumed an introductory price of US $7.50 per dose, and varied the annual rate of price decrease in sensitivity analyses. The discounted cost per disability-adjusted life-year averted for restricted, flexible, and on-time schedules was $621, $615, and $581, respectively. For each of the 3 scenarios, the percentage reduction in deaths due to rotavirus infection was 53%, 66%, and 69%, respectively. The cost per disability-adjusted life-year averted for alternative "what-if" scenarios ranged from $229 (assuming a 1-dose schedule, administered on time) to $1491 (assuming a 2-dose schedule, with half the baseline vaccine efficacy rates and a restricted timing policy). On the basis of current World Health Organization guidelines, rotavirus vaccination represents a highly cost-effective intervention in Peru. Withholding the vaccine from children who present for their first dose after 12 weeks of age would reduce the number of deaths averted by approximately 20%. A single dose may be more cost-effective than 2 doses, but more evidence on the protection conferred by a single dose is required.

Oral desmopressin in central diabetes insipidus.

PubMed Central

Westgren, U; Wittström, C; Harris, A S

1986-01-01

Seven paediatric patients with central diabetes insipidus were studied in an open dose ranging study in hospital followed by a six month study on an outpatient basis to assess the efficacy and safety of peroral administration of DDAVP (desmopressin) tablets. In the dose ranging study a dose dependent antidiuretic response was observed. The response to 12.5-50 mcg was, however, less effective in correcting baseline polyuria than were doses of 100 mcg and above. Patients were discharged from hospital on a preliminary dosage regimen ranging from 100 to 400 mcg three times daily. After an initial adjustment in dosage in three patients at one week follow up, all patients were stabilised on treatment with tablets and reported an adequate water turnover at six months. As with the intranasal route of administration dosage requirements varied from patient to patient, and a dose range rather than standard doses were required. A significant correlation, however, was found for the relation between previous intranasal and present oral daily dosage. No adverse reactions were reported. No clinically significant changes were noted in blood chemistry and urinalysis. All patients expressed a preference for the oral over existing intranasal treatment. Treatment with tablets offers a beneficial alternative to the intranasal route, particularly in patients with chronic rhinitis or impaired vision. PMID:3963868

Subclinical hyperthyroidism: possible danger of overzealous thyroxine replacement therapy.

PubMed

Ross, D S

1988-12-01

Many patients taking customary doses of levothyroxine have slightly elevated serum thyroxine (T4), apparently normal serum triiodothyronine, suppressed serum thyrotropin (thyroid-stimulating hormone; TSH) concentrations, and no clinical symptoms of hyperthyroidism. Recent reports suggest that these patients may have adverse effects from subclinical hyperthyroidism, including abnormally short systolic time intervals, elevations in liver enzymes, and reductions in bone density. Controversy exists about which thyroid function tests should be used to monitor patients taking levothyroxine. A review of currently available data suggests that replacement doses of levothyroxine given to hypothyroid patients should be adjusted so that serum TSH measured by the new sensitive assays is within the normal range. Patients requiring suppressive doses of levothyroxine to shrink goitrous thyroid tissue or to prevent growth of abnormal tissue should be given the minimal dose needed to accomplish the desired clinical or biochemical response.

Early neuropsychological adverse events after switching from PI/r to dolutegravir could be related to hyperthyroidism in patients under levothyroxine.

PubMed

Berger, Jean-Luc; Nguyen, Yohan; Lebrun, Delphine; Migault, Caroline; Hentzien, Maxime; Marty, Hélène; Bani-Sadr, Firouzé

2017-01-01

We report two patients who had taken levothyroxine at the same dose for several years and who had stable thyroid stimulating hormone (TSH) levels, and who developed clinical and biological hyperthyroidism following switch from ritonavir-boosted protease inhibitors (PIs) to dolutegravir-based HAART. Levothyroxine is metabolized by deiodination and glucuronidation and the induction of glucuronidation by ritonavir leads to an increased elimination of levothyroxine and a necessity of higher daily doses. Patients who switch from ritonavir-boosted PIs to antiretroviral drugs-based HAART with minimal drug-interaction such as dolutegravir, may require an adjustment in their dose of levothyroxine in order to prevent hyperthyroidism due to impaired elimination of levothyroxine without ritonavir.

Individual dose adjustment of riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

PubMed

Hill, Nicholas S; Rahaghi, Franck F; Sood, Namita; Frey, Reiner; Ghofrani, Hossein-Ardeschir

2017-08-01

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oral vitamin C supplementation reduces erythropoietin requirement in hemodialysis patients with functional iron deficiency.

PubMed

Sultana, Tanjim; DeVita, Maria V; Michelis, Michael F

2016-09-01

Functional iron deficiency (FID) is a major cause of persistent anemia in dialysis patients and also contributes to a suboptimal response to erythropoietin (Epo) administration. Vitamin C acts as an enzyme cofactor and enhances mobilization of the ferrous form of iron to transferrin thus increasing its bioavailability. High-dose intravenous vitamin C has been shown to decrease the Epo requirement and improve hemoglobin levels in previous studies. This study assessed the effect of low-dose oral vitamin C on possible reduction in Epo dose requirements in stable hemodialysis patients with FID. This prospective study included 22 stable hemodialysis patients with FID defined as transferrin saturation (T sat) <30 % and ferritin levels of >100 mcg/L with Epo requirement of ≥4000 U/HD session. Patients received oral vitamin C 250 mg daily for 3 months. Hemoglobin, iron and T sat levels were recorded monthly. No one received iron supplementation during the study period. There was a significant reduction in median Epo dose requirement in the 15 patients who completed the study, from 203.1 U/kg/week (95 % CI 188.4-270.6) to 172.8 U/kg/week (95 % CI 160.2-214.8), (P = 0.01). In the seven responders, there was 33 % reduction in Epo dose from their baseline. Despite adjustment of Epo dose, the mean hemoglobin level was significantly increased from 10.1 ± 0.6 to 10.7 ± 0.6 mg/dL (P = 0.03). No adverse effects of oral vitamin C were observed. Daily low-dose oral vitamin C supplementation reduced Epo dose requirements in hemodialysis patients with FID. Limitations of this study include a small sample size and the lack of measurements of vitamin C and oxalate levels. Despite concerns regarding oral vitamin C absorption in dialysis patients, this study indicates vitamin C was well tolerated by all participants without reported adverse effect.

Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data.

PubMed

Warren, Sam A; Huszti, Ella; Bradley, Steven M; Chan, Paul S; Bryson, Chris L; Fitzpatrick, Annette L; Nichol, Graham

2014-03-01

Expert guidelines for treatment of cardiac arrest recommend administration of adrenaline (epinephrine) every three to five minutes. However, the effects of different dosing periods of epinephrine remain unclear. We sought to evaluate the association between epinephrine average dosing period and survival to hospital discharge in adults with an in-hospital cardiac arrest (IHCA). We performed a retrospective review of prospectively collected data on 20,909 IHCA events from 505 hospitals participating in the Get With The Guidelines-Resuscitation (GWTG-R) quality improvement registry. Epinephrine average dosing period was defined as the time between the first epinephrine dose and the resuscitation endpoint, divided by the total number of epinephrine doses received subsequent to the first epinephrine dose. Associations with survival to hospital discharge were assessed by using generalized estimating equations to construct multivariable logistic regression models. Compared to a referent epinephrine average dosing period of 4 to <5 min per dose, survival to hospital discharge was significantly higher in patients with the following epinephrine average dosing periods: for 6 to <7 min/dose, adjusted odds ratio [OR], 1.41 (95%CI: 1.12, 1.78); for 7 to <8 min/dose, adjusted OR, 1.30 (95%CI: 1.02, 1.65); for 8 to <9 min/dose, adjusted OR, 1.79 (95%CI: 1.38, 2.32); for 9 to <10 min/dose, adjusted OR, 2.17 (95%CI: 1.62, 2.92). This pattern was consistent for both shockable and non-shockable cardiac arrest rhythms. Less frequent average epinephrine dosing than recommended by consensus guidelines was associated with improved survival of in-hospital cardiac arrest. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

PubMed Central

Gambús, Pedro L; Trocóniz, Iñaki F

2015-01-01

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic–pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug–receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug–receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided. PMID:24251846

Dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation in humans

PubMed Central

Weng, Xiao-chuan; Zhou, Liang; Fu, Yin-yan; Zhu, Sheng-mei; He, Hui-liang; Wu, Jian

2005-01-01

Objective: To compare the dose requirements of continuous infusion of rocuronium and atracurium throughout orthotopic liver transplantation (OLT) in humans. Methods: Twenty male patients undergoing liver transplantation were randomly assigned to two comparable groups of 10 patients each to receive a continuous infusion of rocuronium or atracurium under intravenous balanced anesthesia. The response of adductor pollicis to train-of-four (TOF) stimulation of unlar nerve was monitored. The infusion rates of rocuronium and atracurium were adjusted to maintain T1/Tc ratio of 2%~10%. The total dose of each drug given during each of the three phases of OLT was recorded. Results: Rocuronium requirement, which were (0.468±0.167) mg/(kg·h) during the paleohepatic phase, decreased significantly during the anhepatic phase to (0.303±0.134) mg/(kg·h) and returned to the initial values at the neohepatic period ((0.429±0.130) mg/(kg·h)); whereas atracuruim requirements remained unchanged during orthotopic liver transplantation. Conclusions: This study showed that the exclusion of the liver from the circulation results in the significantly reduced requirement of rocuronium while the requirement of atracurium was not changed, which suggests that the liver is of major importance in the clearance of rocuronium. A continuous infusion of atracurium with constant rate can provide stable neuromuscular blockade during the three stages of OLT. PMID:16130187

Statistical methods for biodosimetry in the presence of both Berkson and classical measurement error

NASA Astrophysics Data System (ADS)

Miller, Austin

In radiation epidemiology, the true dose received by those exposed cannot be assessed directly. Physical dosimetry uses a deterministic function of the source term, distance and shielding to estimate dose. For the atomic bomb survivors, the physical dosimetry system is well established. The classical measurement errors plaguing the location and shielding inputs to the physical dosimetry system are well known. Adjusting for the associated biases requires an estimate for the classical measurement error variance, for which no data-driven estimate exists. In this case, an instrumental variable solution is the most viable option to overcome the classical measurement error indeterminacy. Biological indicators of dose may serve as instrumental variables. Specification of the biodosimeter dose-response model requires identification of the radiosensitivity variables, for which we develop statistical definitions and variables. More recently, researchers have recognized Berkson error in the dose estimates, introduced by averaging assumptions for many components in the physical dosimetry system. We show that Berkson error induces a bias in the instrumental variable estimate of the dose-response coefficient, and then address the estimation problem. This model is specified by developing an instrumental variable mixed measurement error likelihood function, which is then maximized using a Monte Carlo EM Algorithm. These methods produce dose estimates that incorporate information from both physical and biological indicators of dose, as well as the first instrumental variable based data-driven estimate for the classical measurement error variance.

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

PubMed

Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

2017-03-01

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

Influence of CYP3A5 genetic variation on everolimus maintenance dosing after cardiac transplantation.

PubMed

Lesche, Dorothea; Sigurdardottir, Vilborg; Setoud, Raschid; Englberger, Lars; Fiedler, Georg M; Largiadèr, Carlo R; Mohacsi, Paul; Sistonen, Johanna

2015-12-01

Everolimus (ERL) has become an alternative to calcineurin inhibitors (CNIs) due to its renal-sparing properties, especially in heart transplant (HTx) recipients with kidney dysfunction. However, ERL dosing is challenging due to its narrow therapeutic window combined with high interindividual pharmacokinetic variability. Our aim was to evaluate the effect of clinical and genetic factors on ERL dosing in a pilot cohort of 37 HTx recipients. Variants in CYP3A5, CYP3A4, CYP2C8, POR, NR1I2, and ABCB1 were genotyped, and clinical data were retrieved from patient charts. While ERL trough concentration (C0 ) was within the targeted range for most patients, over 30-fold variability in the dose-adjusted ERL C0 was observed. Regression analysis revealed a significant effect of the non-functional CYP3A5*3 variant on the dose-adjusted ERL C0 (p = 0.031). ERL dose requirement was 0.02 mg/kg/d higher in patients with CYP3A5*1/*3 genotype compared to patients with CYP3A5*3/*3 to reach the targeted C0 (p = 0.041). ERL therapy substantially improved estimated glomerular filtration rate (28.6 ± 6.6 mL/min/1.73 m(2)) in patients with baseline kidney dysfunction. Everolimus pharmacokinetics in HTx recipients is highly variable. Our preliminary data on patients on a CNI-free therapy regimen suggest that CYP3A5 genetic variation may contribute to this variability. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dose Adjustment for Normal Eating (DAFNE) in routine clinical practice: who benefits?

PubMed

Keen, A J A; Duncan, E; McKillop-Smith, A; Evans, N D; Gold, A E

2012-05-01

To explore the effectiveness of Dose Adjustment for Normal Eating in routine clinical practice in the UK. Participants were 124 adults with Type 1 diabetes who had completed a Dose Adjustment for Normal Eating course. Data were collected before the course and again 1 year later on a variety of biological, psychological and social measures. There were a range of significant benefits consistent with Dose Adjustment for Normal Eating aims, including: better control among those with baseline HbA(1c) ≥ 81 mmol/mol (9.6%) (z = -2.8, P = 0.004); reduced number of participants reporting severe hypoglycaemia (χ² = 4.27, P = 0.039); total eradication of diabetic ketoacidosis (χ² = 4.17, P = 0.041) and lower diabetes-related distress (z = -4.5, P < 0.001). The most deprived of the clinic population were significantly under-represented (χ² = 17.8, P = 0.001) and the levels of clinical depression were unusually low. These results indicate that Dose Adjustment for Normal Eating delivered in routine clinical practice is associated with a range of benefits and that certain clinical and psychosocial characteristics are associated with better outcomes. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.

Dose reduction and image quality optimizations in CT of pediatric and adult patients: phantom studies

NASA Astrophysics Data System (ADS)

Jeon, P.-H.; Lee, C.-L.; Kim, D.-H.; Lee, Y.-J.; Jeon, S.-S.; Kim, H.-J.

2014-03-01

Multi-detector computed tomography (MDCT) can be used to easily and rapidly perform numerous acquisitions, possibly leading to a marked increase in the radiation dose to individual patients. Technical options dedicated to automatically adjusting the acquisition parameters according to the patient's size are of specific interest in pediatric radiology. A constant tube potential reduction can be achieved for adults and children, while maintaining a constant detector energy fluence. To evaluate radiation dose, the weighted CT dose index (CTDIw) was calculated based on the CT dose index (CTDI) measured using an ion chamber, and image noise and image contrast were measured from a scanned image to evaluate image quality. The dose-weighted contrast-to-noise ratio (CNRD) was calculated from the radiation dose, image noise, and image contrast measured from a scanned image. The noise derivative (ND) is a quality index for dose efficiency. X-ray spectra with tube voltages ranging from 80 to 140 kVp were used to compute the average photon energy. Image contrast and the corresponding contrast-to-noise ratio (CNR) were determined for lesions of soft tissue, muscle, bone, and iodine relative to a uniform water background, as the iodine contrast increases at lower energy (i.e., k-edge of iodine is 33 keV closer to the beam energy) using mixed water-iodine contrast normalization (water 0, iodine 25, 100, 200, and 1000 HU, respectively). The proposed values correspond to high quality images and can be reduced if only high-contrast organs are assessed. The potential benefit of lowering the tube voltage is an improved CNRD, resulting in a lower radiation dose and optimization of image quality. Adjusting the tube potential in abdominal CT would be useful in current pediatric radiography, where the choice of X-ray techniques generally takes into account the size of the patient as well as the need to balance the conflicting requirements of diagnostic image quality and radiation dose optimization.

Parental language and dosing errors after discharge from the pediatric emergency department.

PubMed

Samuels-Kalow, Margaret E; Stack, Anne M; Porter, Stephen C

2013-09-01

Safe and effective care after discharge requires parental education in the pediatric emergency department (ED). Parent-provider communication may be more difficult with parents who have limited health literacy or English-language fluency. This study examined the relationship between language and discharge comprehension regarding medication dosing. We completed a prospective observational study of the ED discharge process using a convenience sample of English- and Spanish-speaking parents of children 2 to 24 months presenting to a single tertiary care pediatric ED with fever and/or respiratory illness. A bilingual research assistant interviewed parents to ascertain their primary language and health literacy and observed the discharge process. The primary outcome was parental demonstration of an incorrect dose of acetaminophen for the weight of his or her child. A total of 259 parent-child dyads were screened. There were 210 potential discharges, and 145 (69%) of 210 completed the postdischarge interview. Forty-six parents (32%) had an acetaminophen dosing error. Spanish-speaking parents were significantly more likely to have a dosing error (odds ratio, 3.7; 95% confidence interval, 1.6-8.1), even after adjustment for language of discharge, income, and parental health literacy (adjusted odds ratio, 6.7; 95% confidence interval, 1.4-31.7). Current ED discharge communication results in a significant disparity between English- and Spanish-speaking parents' comprehension of a crucial aspect of medication safety. These differences were not explained purely by interpretation, suggesting that interventions to improve comprehension must address factors beyond language alone.

Analgesia and Sedation Requirements in Mechanically Ventilated Trauma Patients With Acute, Preinjury Use of Cocaine and/or Amphetamines.

PubMed

Kram, Bridgette; Kram, Shawn J; Sharpe, Michelle L; James, Michael L; Kuchibhatla, Maragatha; Shapiro, Mark L

2017-03-01

The purpose of this study was to determine whether mechanically ventilated trauma patients with a positive urine drug screen (UDS) for cocaine and/or amphetamines have different opioid analgesic and sedative requirements compared with similar patients with a negative drug screen for these stimulants. This retrospective, single-center cohort study at a tertiary care, academic medical and level 1 trauma center in the United States included patients ≥16 years of age who were admitted to an adult intensive care unit with a diagnosis of trauma between 2009 and 2013 with a UDS documented within 24 hours of admission, and were mechanically ventilated for >24 hours. The primary end point was the daily dose of opioid received during mechanical ventilation, expressed as morphine equivalents, for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. Secondary end points included the daily benzodiazepine dose and median infusion rates of propofol and dexmedetomidine received during mechanical ventilation, duration of mechanical ventilation, intensive care unit and hospital length of stay, and in-hospital mortality. Analgesic and sedative goals were similar for the duration of the study period, and both intermittent and continuous infusions of opioids and sedatives were administered to achieve these targets, although a standardized approach was not used. A multivariate logistic regression analysis and a propensity-adjusted model evaluated patient characteristics predictive of a higher median opioid requirement. A total of 150 patients were included in the final analysis. In a univariate analysis, opioid and sedative requirements were similar for patients presenting with a positive UDS for cocaine and/or amphetamines compared with patients with a negative UDS for these stimulants. In the multivariate regression analysis, increasing age and Abbreviated Injury Scale (head and neck) were associated with decreased daily opioid requirements (odds ratio [OR], .95, 95% confidence interval [CI], .93-.97 and OR, .71, 95% CI, .65-.77, respectively), whereas preinjury stimulant use was not predictive of opioid requirements (OR, .88, 95% CI, .40-1.90). In a propensity score--adjusted model, preinjury stimulant use was similarly not predictive of opioid requirements during mechanical ventilation (OR, .97, 95% CI, .44-2.11). For trauma patients presenting with acute, preinjury use of cocaine and/or amphetamines, analgesic and sedative requirements are variables and may not be greater than those patients presenting with a stimulant-negative UDS to achieve desirable pain control and depth of sedation, although this observation should be interpreted cautiously in light of the wide CI observed in the propensity score--adjusted model. Although unexpected, these findings indicate that empirically increasing analgesic and sedative doses based on positive UDS results for these stimulants may not be necessary.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Arbique, G; Anderson, J; Guild, J

Purpose: The National Lung Screening Trial mandated manual low dose CT technique factors, where up to a doubling of radiation output could be used over a regular to large patient size range. Recent guidance from the AAPM and ACR for lung cancer CT screening recommends radiation output adjustment for patient size either through AEC or a manual technique chart. This study evaluated the use of AEC for output control and dose reduction. Methods: The study was performed on a multidetector helical CT scanner (Aquillion ONE, Toshiba Medical) equipped with iterative reconstruction (ADIR-3D), AEC was adjusted with a standard deviation (SD)more » image quality noise index. The protocol SD parameter was incrementally increased to reduce patient population dose while image quality was evaluated by radiologist readers scoring the clinical utility of images on a Likert scale. Results: Plots of effective dose vs. body size (water cylinder diameter reported by the scanner) demonstrate monotonic increase in patient dose with increasing patient size. At the initial SD setting of 19 the average CTDIvol for a standard size patient was ∼ 2.0 mGy (1.2 mSv effective dose). This was reduced to ∼1.0 mGy (0.5 mSv) at an SD of 25 with no noticeable reduction in clinical utility of images as demonstrated by Likert scoring. Plots of effective patient diameter and BMI vs body size indicate that these metrics could also be used for manual technique charts. Conclusion: AEC offered consistent and reliable control of radiation output in this study. Dose for a standard size patient was reduced to one-third of the 3 mGy CTDIvol limit required for ACR accreditation of lung cancer CT screening. Gary Arbique: Research Grant, Toshiba America Medical Systems; Cecelia Brewington: Research Grant, Toshiba America Medical Systems; Di Zhang: Employee, Toshiba America Medical Systems.« less

A Study of the Impact of Cannabis on Doses of Discharge Antipsychotic Medication in Individuals with Schizophrenia or Schizoaffective Disorder.

PubMed

Babatope, Taiwo; Chotalia, Jigar; Elkhatib, Rania; Mohite, Satyajit; Shah, Joel; Goddu, Sumana; Patel, Ruchir Arvind; Aimienwanu, Osarhiemen Ruth; Patel, Devanshu; Makanjuola, Titilayo; Okusaga, Olaoluwa O

2016-12-01

Patients with schizophrenia or schizoaffective disorder have a high prevalence of comorbid cannabis use disorder (CUD). CUD has been associated with poorer outcomes in patients. We compared doses of antipsychotic medications at the time of discharge from hospital among inpatients with schizophrenia or schizoaffective disorder with or without concurrent cannabis use. We reviewed the medical records of patients (N = 8157) with schizophrenia or schizoaffective disorder discharged from the hospital between 2008 and 2012. The patients were divided into two groups; those with urine drug tests positive for cannabis and those negative for cannabis. Doses of antipsychotic medications were converted to chlorpromazine equivalents. Bivariate analyses were done with Student's t test for continuous variables and χ 2 test for categorical variables. Linear regression was carried out to adjust for potential confounders. Unadjusted analysis revealed that the cannabis positive group was discharged on lower doses of antipsychotic medication compared with the cannabis negative group (geometric mean chlorpromazine equivalent doses 431.22 ± 2.20 vs 485.18 ± 2.21; P < 0.001). However, the difference in geometric mean chlorpromazine equivalent doses between the two groups was no longer significant after adjusting for sex, age, race, and length of stay (geometric mean difference 0.99; 95 % CI 0.92-1.10). Though limited by lack of information on duration, amount and severity of cannabis use, as well as inability to control for other non-antipsychotic medications, our study suggests that cannabis use did not significantly impact on doses of antipsychotics required during the periods of acute exacerbation in patients with schizophrenia or schizoaffective disorder.

Monte Carol-Based Dosimetry of Beta-Emitters for Intravascular Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, C.K.

2002-06-25

Monte Carlo simulations for radiation dosimetry and the experimental verifications of the simulations have been developed for the treatment geometry of intravascular brachytherapy, a form of radionuclide therapy for occluded coronary disease (restenosis). Monte Carlo code, MCNP4C, has been used to calculate the radiation dose from the encapsulated array of B-emitting seeds (Sr/Y-source train). Solid water phantoms have been fabricated to measure the dose on the radiochromic films that were exposed to the beta source train for both linear and curved coronary vessel geometries. While the dose difference for the 5-degree curved vessel at the prescription point of f+2.0 mmmore » is within the 10% guideline set by the AAPM, however, the difference increased dramatically to 16.85% for the 10-degree case which requires additional adjustment for the acceptable dosimetry planning. The experimental dose measurements agree well with the simulation results« less

International normalized ratio self-testing and self-management: improving patient outcomes.

PubMed

Pozzi, Matteo; Mitchell, Julia; Henaine, Anna Maria; Hanna, Najib; Safi, Ola; Henaine, Roland

2016-01-01

Long term oral anti-coagulation with vitamin K antagonists is a risk factor of hemorrhagic or thromebomlic complications. Periodic laboratory testing of international normalized ratio (INR) and a subsequent dose adjustment are therefore mandatory. The use of home testing devices to measure INR has been suggested as a potential way to improve the comfort and compliance of the patients and their families, the frequency of monitoring and, finally, the management and safety of long-term oral anticoagulation. In pediatric patients, increased doses to obtain and maintain the therapeutic target INR, more frequent adjustments and INR testing, multiple medication, inconstant nutritional intake, difficult venepunctures, and the need to go to the laboratory for testing (interruption of school and parents' work attendance) highlight those difficulties. After reviewing the most relevant published studies of self-testing and self-management of INR for adult patients and children on oral anticoagulation, it seems that these are valuable and effective strategies of INR control. Despite an unclear relationship between INR control and clinical effects, these self-strategies provide a better control of the anticoagulant effect, improve patients and their family quality of life, and are an appealing solution in term of cost-effectiveness. Structured education and knowledge evaluation by trained health care professionals is required for children, to be able to adjust their dose treatment safely and accurately. However, further data are necessary in order to best define those patients who might better benefit from this multidisciplinary approach.

Weight Loss and Variation of Levothyroxine Requirements in Hypothyroid Obese Patients After Bariatric Surgery.

PubMed

Fierabracci, Paola; Martinelli, Silvia; Tamberi, Anna; Piaggi, Paolo; Basolo, Alessio; Pelosini, Caterina; Ricco, Ilaria; Magno, Silvia; Querci, Giorgia; Ceccarini, Giovanni; Scartabelli, Giovanna; Salvetti, Guido; Vitti, Paolo; Santini, Ferruccio

2016-04-01

Obesity and hypothyroidism are both common disorders within the general population. Obese hypothyroid subjects require higher doses of levothyroxine (LT4) compared with normal weight individuals. Previous studies on the effects of bariatric surgery on LT4 dose requirements in hypothyroid subjects have provided conflicting results. The aim of this study was to evaluate the LT4 requirements in a group of obese subjects with acquired hypothyroidism, before and after weight loss achieved by bariatric surgery. Ninety-three obese hypothyroid subjects (mean age = 48 ± 9 years; mean body mass index = 45.9 ± 5.6 kg/m(2)), were evaluated before and 28 ± 8 months after bariatric surgery. Changes in the LT4 dose, anthropometric measures, and hormone values were evaluated. In 20 patients, data of body composition, assessed by dual energy X-ray absorptiometry, were also analyzed. On average, after weight loss, a significant reduction of the total dose of LT4 was documented (from 130.6 ± 48.5 to 116.2 ± 38.6 μg/day; p < 0.001). The LT4 dose had to be reduced in 47 patients, was unchanged in 34, and had to be increased in 12 patients affected by autoimmune thyroiditis. Reduction of the LT4 dose was proportional to reduction of the lean body mass. The weight loss achieved with modern surgical bariatric procedures is associated with a reduction of LT4 requirements in most hypothyroid subjects, which appears to be related to a decrease of the lean body mass. Occasionally, a concurrent decline of residual thyroid function, as it occurs in autoimmune thyroiditis, can counteract this phenomenon and eventually produce an increase of LT4 needs. It is believed that during the weight loss phase that follows bariatric surgery, there is no need for preventive adjustments of the LT4 dose, but serum thyroid hormones and thyrotropin should be periodically monitored in order to detect possible variations of LT4 requirements and to allow proper corrections of the therapy.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis).

PubMed

Sanchez-Migallon Guzman, David; Flammer, Keven; Papich, Mark G; Grooters, Amy M; Shaw, Shannon; Applegate, Jeff; Tully, Thomas N

2010-04-01

To determine the pharmacokinetics and safety of voriconazole administered orally in single and multiple doses in Hispaniolan Amazon parrots (Amazona ventralis). 15 clinically normal adult Hispaniolan Amazon parrots. Single doses of voriconazole (12 or 24 mg/kg) were administered orally to 15 and 12 birds, respectively; plasma voriconazole concentrations were determined at intervals via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) or water was administered orally to 6 and 4 birds, respectively, every 8 hours for 11 days (beginning day 0); trough plasma voriconazole concentrations were evaluated on 3 days. Birds were monitored daily, and clinicopathologic variables were evaluated before and after the trial. Voriconazole elimination half-life was short (0.70 to 1.25 hours). In the single-dose experiments, higher drug doses yielded proportional increases in the maximum plasma voriconazole concentration (C(max)) and area under the curve (AUC). In the multiple-dose trial, C(max), AUC, and plasma concentrations at 2 and 4 hours were decreased on day 10, compared with day 0 values; however, there was relatively little change in terminal half-life. With the exception of 1 voriconazole-treated parrot that developed polyuria, adverse effects were not evident. In Hispaniolan Amazon parrots, oral administration of voriconazole was associated with proportional kinetics following administration of single doses and a decrease in plasma concentration following administration of multiple doses. Oral administration of 18 mg of voriconazole/kg every 8 hours would require adjustment to maintain therapeutic concentrations during long-term treatment. Safety and efficacy of voriconazole treatment in this species require further investigation.

Management of early renal anaemia: diagnostic work-up, iron therapy, epoetin therapy.

PubMed

Van Wyck, D B

2000-01-01

Effective management of early anaemia in the course of chronic renal insufficiency requires the following: (i) implementing an efficient diagnostic strategy to exclude common contributing factors; (ii) initiating epoetin therapy for the majority of patients; for and (iii) ensuring adequate iron supply erythropoiesis. Diagnostic inquiry is warranted whenever the haemoglobin concentration is below the normal range adjusted for age and gender. The most efficient diagnostic approach is to assume erythropoietin deficiency, exclude iron deficiency, and pursue further diagnostic tests only when red-cell indices are abnormal or when leukopenia or thrombocytopenia are also present. Macrocytosis should prompt an inquiry into alcoholism, B12 deficiency, or folate deficiency. Microcytosis suggests iron deficiency or thalassaemia. Associated cytopenias raise the possibility of alcohol toxicity, pernicious anaemia, malignancy, or myelodysplastic syndrome. Epoetin therapy is warranted whenever the haemoglobin concentration has fallen below 10.0 g/dl. To initiate therapy prior to dialysis, epoetin should be administered at an average dose of 100 IU/kg/week (80-120 IU/kg/week, 50-150 IU/kg/ week) by subcutaneous injection. Haemoglobin concentration should be monitored every 2 weeks and the epoetin dose adjusted by increments or decrements of 25% to maintain a rate of rise of haemoglobin concentration of 0.2-0.6 g/dl (0.3 0.6 g/dl/week, 0.2-0.5 g/dl/week). When the target range is achieved, the dose of epoetin should be continually adjusted to maintain a stable haemoglobin concentration. Transferrin saturation and ferritin concentration should be monitored monthly, and sufficient iron provided to maintain transferrin saturation above 20%. The lower the haemoglobin concentration, the greater the likelihood that future intravenous iron will be required. Oral iron supplements should be avoided, since they are costly, ineffective, and troublesome to patients. Finally, a blunted therapeutic response to epoetin therapy provides important diagnostic information and gnostic inquiry.

Switch from epoetin to darbepoetin alfa in hemodialysis: dose equivalence and hemoglobin stability.

PubMed

Arrieta, Javier; Moina, Iñigo; Molina, José; Gallardo, Isabel; Muñiz, María Luisa; Robledo, Carmen; García, Oscar; Vidaur, Fernando; Muñoz, Rosa Inés; Iribar, Izaskun; Aguirre, Román; Maza, Antonio

2014-01-01

The objective of the study reported here was to describe dose equivalence and hemoglobin (Hb) stability in a cohort of unselected hemodialysis patients who were switched simultaneously from epoetin alfa to darbepoetin alfa. This was a multicenter, observational, retrospective study in patients aged ≥18 years who switched from intravenous (IV) epoetin alfa to IV darbepoetin alfa in October 2007 (Month 0) and continued on hemodialysis for at least 24 months. The dose was adjusted to maintain Hb within 1.0 g/dL of baseline. We included 125 patients (59.7% male, mean [standard deviation (SD)] age 70.4 [13.4] years). No significant changes were observed in Hb levels (mean [SD] 11.9 [1.3] g/dL, 12.0 [1.5], 12.0 [1.5], and 12.0 [1.7] at Months -12, 0, 12 and 24, respectively, P=0.409). After conversion, the erythropoiesis-stimulating agent (ESA) dose decreased significantly (P<0.0001), with an annual mean of 174.7 (88.7) international units (IU)/kg/week for epoetin versus 95.7 (43.4) (first year) and 91.4 (42.7) IU/kg/week (second year) for darbepoetin (65% and 64% reduction, respectively). The ESA resistance index decreased from 15.1 (8.5) IU/kg/week/g/dL with epoetin to 8.1 (3.9) (first year) and 7.9 (4.0) (second year) with darbepoetin (P<0.0001). The conversion rate was 354:1 in patients requiring high (>200 IU/kg/week) doses of epoetin and 291:1 in patients requiring low doses. In patients on hemodialysis receiving ESAs, conversion from epoetin alfa to darbepoetin alfa was associated with an approximate and persistent reduction of 65% of the required dose. To maintain Hb stability, a conversion rate of 300:1 seems to be appropriate for most patients receiving low doses of epoetin alfa (≤200 IU/kg/week), while 350:1 would be better for patients receiving higher doses.

Simulation-Based Evaluation of Dose-Titration Algorithms for Rapid-Acting Insulin in Subjects with Type 2 Diabetes Mellitus Inadequately Controlled on Basal Insulin and Oral Antihyperglycemic Medications.

PubMed

Ma, Xiaosu; Chien, Jenny Y; Johnson, Jennal; Malone, James; Sinha, Vikram

2017-08-01

The purpose of this prospective, model-based simulation approach was to evaluate the impact of various rapid-acting mealtime insulin dose-titration algorithms on glycemic control (hemoglobin A1c [HbA1c]). Seven stepwise, glucose-driven insulin dose-titration algorithms were evaluated with a model-based simulation approach by using insulin lispro. Pre-meal blood glucose readings were used to adjust insulin lispro doses. Two control dosing algorithms were included for comparison: no insulin lispro (basal insulin+metformin only) or insulin lispro with fixed doses without titration. Of the seven dosing algorithms assessed, daily adjustment of insulin lispro dose, when glucose targets were met at pre-breakfast, pre-lunch, and pre-dinner, sequentially, demonstrated greater HbA1c reduction at 24 weeks, compared with the other dosing algorithms. Hypoglycemic rates were comparable among the dosing algorithms except for higher rates with the insulin lispro fixed-dose scenario (no titration), as expected. The inferior HbA1c response for the "basal plus metformin only" arm supports the additional glycemic benefit with prandial insulin lispro. Our model-based simulations support a simplified dosing algorithm that does not include carbohydrate counting, but that includes glucose targets for daily dose adjustment to maintain glycemic control with a low risk of hypoglycemia.

SU-F-T-306: Validation of Mobius 3D and FX for Elekta Linear Accelerators

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nelson, C; Garcia, M; Calderon, E

2016-06-15

Purpose: Log file based IMRT and VMAT QA is a system that analyzes treatment log files and uses delivery parameters to compute the dose to the patient/phantom. This system was previously commissioned for Varian machines, the purpose of this work is to describe the process for commissioning Mobius for use with Elekta machines. Methods: Twelve IMRT and VMAT plans (6×) were planned and delivered and dose was measured using MapCheck, the results were compared to that computed by Mobius. For 10x and 18x, plans were generated, copied to a phantom and delivered, the dose was measured using a single ionmore » chamber. The difference in measured dose to computed dose (Mobius) was used to adjust the dynamic leaf gap (DLG) in Mobius to achieve optimal agreement between measurements, Mobius and treatment plans. Results: For the measured dose comparison, the average 3%/3mm gamma 97.1% of pixels passed criteria using MapCheck where Mobius computed 96.9% of voxels passing. For 10×, a DLG of −5.5 was determined to achieve optimal results for TPS and measured ion chamber data with an average 0.1% difference and −1.7% respectively. For 18×, a DLG of −3 was determined to achieve optimal results from the TPS and measured data with an average of −0.7% and −1.4% difference on average from a set of IMRT and VMAT plans. The 6x data needed no DLG correction to arrive at agreement with the TPS and the MapCheck measured data. Conclusion: We have validated with measurements for IMRT and VMAT cases the use of Mobius FX with Elekta treatment machines for IMRT and VMAT QA. For 6×, no adjustments to the DLG were required to obtain good results utilizing Mobius whereas for 10× and 18×, the DLG had to be adjusted to obtain optimum agreement with measured data and our TPS.« less

Impact of an emergency medicine pharmacist on antibiotic dosing adjustment.

PubMed

DeWitt, Kyle M; Weiss, Steven J; Rankin, Shannon; Ernst, Amy; Sarangarm, Preeyaporn

2016-06-01

Overall medication-related errors in the emergency department (ED) are 13.5 times more likely to occur in the absence of an emergency medicine pharmacist (EMP). Although the effectiveness of pharmacist-driven renal dosing adjustment has been studied in the intensive care unit, data are lacking in the ED setting. The aim of our study was to evaluate the appropriateness of antibiotic dosing when an EMP is physically present in the ED compared to when absent. This was a retrospective cohort study of patients treated in a level I trauma center with 75 adult and 12 pediatric beds and an annual census of 90000 patients. The study period was from March 1 to September 30, 2014. An EMP was physically present in the ED from 11:00 to 01:30 and absent from 01:31 to 10:59. Male and female patients 18years and older were considered for inclusion if cefazolin, cefepime, ciprofloxacin, piperacillin-tazobactam, or vancomycin was ordered. The primary outcome was the composite rate of correct antibiotic dose and frequency. Statistics included a multivariable logistic regression using age, sex, presence of EMP, and creatinine clearance as independent predictors of correct antibiotic use. A total 210 cases were randomly chosen for evaluation, half during times when EMPs were present and half when they were absent. There were 130 males (62%) with an overall mean age of 54±18years. Overall, 178 (85%) of 210 of the antibiotic orders were appropriate, with 95% appropriate when an EMP was present compared to 74% when an EMP was absent (odds ratio, 6.9; 95% confidence interval, 2.5-18.8). In a logistic regression model, antibiotic appropriateness was independently associated with the presence of the EMP and creatinine clearance. Antibiotics that require renal and/or weight dosing adjustment are 6.5 times more likely to be appropriate in the ED when an EMP is present. Prevalence of antibiotic dosing error is related to both the presence of EMPs and the degree of renal impairment. Copyright © 2016 Elsevier Inc. All rights reserved.

Retrospective study evaluating dose standards for infliximab in patients with rheumatoid arthritis at Hospital Israelita Albert Einstein, São Paulo, Brazil.

PubMed

Scheinberg, Morton; Goldenberg, José; Feldman, Daniel P; Nóbrega, João Luiz

2008-08-01

We determined, in our surrounding environment, the proportion of patients being treated with infliximab who required a therapeutic scheme escalation (an infliximab dose increase surpassing the level of 3 mg/kg every 8 weeks and/or a decrease on the current between infusions' interval). This was a study of the retrospective analysis of data from the 41 rheumatoid arthritis (RA) patients receiving an infliximab therapy at the Albert Einstein Israelita Hospital, from January 2001 up to December 2005. A questionnaire was applied to these patients, assessing their clinical and laboratory data, adverse events, and individual information regarding the infliximab administration. Therapeutic dose information was available in 68% (28/41) of the RA patients, with 46% of these (13/28) receiving a dose increase, and 30% (8/27) experiencing a shortening of the between infusions' interval. The average final infliximab dose (4.21 mg/kg) was significantly greater than their average initial dose (3.29 mg/kg). The average time intervals between the initial and final infusions, though shortened, were not significantly different. A proportion of 73% (30/41) of these patients demonstrated improvement in at least one of the assessed clinical parameters, and 50% of these patients (15/30) experienced a dose increase, while 20% (6/30) experienced shortening of the between treatments' interval. A total of 20% (8/41) of the original patients experienced adverse events. Although infliximab is effective in the control of RA, dose adjustment and/or shortening of the between treatments' interval is frequently required.

Occupational Exposure to Diesel Motor Exhaust and Lung Cancer: A Dose-Response Relationship Hidden by Asbestos Exposure Adjustment? The ICARE Study

PubMed Central

Matrat, Mireille; Guida, Florence; Cénée, Sylvie; Févotte, Joelle; Carton, Matthieu; Cyr, Diane; Menvielle, Gwenn; Paget-Bailly, Sophie; Radoï, Loredana; Schmaus, Annie; Bara, Simona; Velten, Michel; Luce, Danièle; Stücker, Isabelle; The Icare Study Group

2015-01-01

Background. In a French large population-based case-control study we investigated the dose-response relationship between lung cancer and occupational exposure to diesel motor exhaust (DME), taking into account asbestos exposure. Methods. Exposure to DME was assessed by questionnaire. Asbestos was taken into account through a global indicator of exposure to occupational carcinogens or by a specific JEM. Results. We found a crude dose response relationship with most of the indicators of DME exposure, including with the cumulative exposure index. All results were affected by adjustment for asbestos exposure. The dose response relationships between DME and lung cancer were observed among subjects never exposed to asbestos. Conclusions. Exposure to DME and to asbestos is frequently found among the same subjects, which may explain why dose-response relationships in previous studies that adjusted for asbestos exposure were inconsistent. PMID:26425123

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment

PubMed Central

Cohen, Stanley; Zwillich, Samuel H; Chow, Vincent; LaBadie, Robert R; Wilkinson, Bethanie

2010-01-01

AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug–drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15–25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX. PMID:20233177

Renal Drug Dosing

PubMed Central

Vogel, Erin A.; Billups, Sarah J.; Herner, Sheryl J.

2016-01-01

Summary Objective The purpose of this study was to compare the effectiveness of an outpatient renal dose adjustment alert via a computerized provider order entry (CPOE) clinical decision support system (CDSS) versus a CDSS with alerts made to dispensing pharmacists. Methods This was a retrospective analysis of patients with renal impairment and 30 medications that are contraindicated or require dose-adjustment in such patients. The primary outcome was the rate of renal dosing errors for study medications that were dispensed between August and December 2013, when a pharmacist-based CDSS was in place, versus August through December 2014, when a prescriber-based CDSS was in place. A dosing error was defined as a prescription for one of the study medications dispensed to a patient where the medication was contraindicated or improperly dosed based on the patient’s renal function. The denominator was all prescriptions for the study medications dispensed during each respective study period. Results During the pharmacist- and prescriber-based CDSS study periods, 49,054 and 50,678 prescriptions, respectively, were dispensed for one of the included medications. Of these, 878 (1.8%) and 758 (1.5%) prescriptions were dispensed to patients with renal impairment in the respective study periods. Patients in each group were similar with respect to age, sex, and renal function stage. Overall, the five-month error rate was 0.38%. Error rates were similar between the two groups: 0.36% and 0.40% in the pharmacist- and prescriber-based CDSS, respectively (p=0.523). The medication with the highest error rate was dofetilide (0.51% overall) while the medications with the lowest error rate were dabigatran, fondaparinux, and spironolactone (0.00% overall). Conclusions Prescriber- and pharmacist-based CDSS provided comparable, low rates of potential medication errors. Future studies should be undertaken to examine patient benefits of the prescriber-based CDSS. PMID:27466041

Safety of Single-Dose Primaquine in G6PD-Deficient and G6PD-Normal Males in Mali Without Malaria: An Open-Label, Phase 1, Dose-Adjustment Trial.

PubMed

Chen, Ingrid; Diawara, Halimatou; Mahamar, Almahamoudou; Sanogo, Koualy; Keita, Sekouba; Kone, Daouda; Diarra, Kalifa; Djimde, Moussa; Keita, Mohamed; Brown, Joelle; Roh, Michelle E; Hwang, Jimee; Pett, Helmi; Murphy, Maxwell; Niemi, Mikko; Greenhouse, Bryan; Bousema, Teun; Gosling, Roly; Dicko, Alassane

2018-03-28

The World Health Organization recommendation on the use of a single low dose of primaquine (SLD-PQ) to reduce Plasmodium falciparum malaria transmission requires more safety data. We conducted an open-label, nonrandomized, dose-adjustment trial of the safety of 3 single doses of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient adult males in Mali, followed by an assessment of safety in G6PD-deficient boys aged 11-17 years and those aged 5-10 years, including G6PD-normal control groups. The primary outcome was the greatest within-person percentage drop in hemoglobin concentration within 10 days after treatment. Fifty-one participants were included in analysis. G6PD-deficient adult males received 0.40, 0.45, or 0.50 mg/kg of SLD-PQ. G6PD-deficient boys received 0.40 mg/kg of SLD-PQ. There was no evidence of symptomatic hemolysis, and adverse events considered related to study drug (n = 4) were mild. The mean largest within-person percentage change in hemoglobin level between days 0 and 10 was -9.7% (95% confidence interval [CI], -13.5% to -5.90%) in G6PD-deficient adults receiving 0.50 mg/kg of SLD-PQ, -11.5% (95% CI, -16.1% to -6.96%) in G6PD-deficient boys aged 11-17 years, and -9.61% (95% CI, -7.59% to -13.9%) in G6PD-deficient boys aged 5-10 years. The lowest hemoglobin concentration at any point during the study was 92 g/L. SLD-PQ doses between 0.40 and 0.50 mg/kg were well tolerated in G6PD-deficient males in Mali. NCT02535767.

First month prednisone dose predicts prednisone burden during the following 11 months: an observational study from the RELES cohort

PubMed Central

Ruiz-Irastorza, G; Garcia, M; Espinosa, G; Caminal, L; Mitjavila, F; González-León, R; Sopeña, B; Canora, J; Villalba, M V; Rodríguez-Carballeira, M; López-Dupla, J M; Callejas, J L; Castro, A; Tolosa, C; Sánchez-García, M E; Pérez-Conesa, M; Navarrete-Navarrete, N; Rodríguez, A P; Herranz, M T; Pallarés, L

2016-01-01

Aim To study the influence of prednisone dose during the first month after systemic lupus erythematosus (SLE) diagnosis (prednisone-1) on glucocorticoid burden during the subsequent 11 months (prednisone-2–12). Methods 223 patients from the Registro Español de Lupus Eritematoso Sistémico inception cohort were studied. The cumulative dose of prednisone-1 and prednisone-2–12 were calculated and recoded into a four-level categorical variable: no prednisone, low dose (up to 7.5 mg/day), medium dose (up to 30 mg/day) and high dose (over 30 mg/day). The association between the cumulative prednisone-1 and prednisone-2–12 doses was tested. We analysed whether the four-level prednisone-1 categorical variable was an independent predictor of an average dose >7.5 mg/day of prednisone-2–12. Adjusting variables included age, immunosuppressives, antimalarials, methyl-prednisolone pulses, lupus nephritis and baseline SLE Disease Activity Index (SLEDAI). Results Within the first month, 113 patients (51%) did not receive any prednisone, 24 patients (11%) received average low doses, 46 patients (21%) received medium doses and 40 patients (18%) received high doses. There was a strong association between prednisone-1 and prednisone-2–12 dose categories (p<0.001). The cumulative prednisone-1 dose was directly associated with the cumulative prednisone-2–12 dose (p<0.001). Compared with patients on no prednisone, patients taking medium (adjusted OR 5.27, 95% CI 2.18 to 12.73) or high-dose prednisone-1 (adjusted OR 10.5, 95% CI 3.8 to 29.17) were more likely to receive prednisone-2–12 doses of >7.5 mg/day, while patients receiving low-dose prednisone-1 were not (adjusted OR 1.4, 95% CI 0. 0.38 to 5.2). If the analysis was restricted to the 158 patients with a baseline SLEDAI of ≥6, the model did not change. Conclusion The dose of prednisone during the first month after the diagnosis of SLE is an independent predictor of prednisone burden during the following 11 months. PMID:27547439

Poster — Thur Eve — 02: Measurement of CT radiation profile width using Fuji CR imaging plate raw data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bjarnason, T A; Department of Radiology, University of British Columbia, Vancouver; Yang, C J

2014-08-15

Measuring the CT collimation width and assessing the shape of the overall profile is a relatively straightforward quality control (QC) measure that impacts both image quality and patient dose, and is often required at acceptance and routine testing. Most CT facilities have access to computed radiography (CR) systems, so performing CT collimation profile assessments using CR plates requires no additional equipment. Previous studies have shown how to effectively use CR plates to measure the radiation profile width. However, a major limitation of the previous work is that the full dynamic range of CR detector plates are not used, since themore » CR processing technology reduces the dynamic range of the DICOM output to 2{sup 10}, requiring the sensitivity and latitude settings of CR reader to be adjusted to prevent clipping of the CT profile data. Such adjustments to CR readers unnecessarily complicate the QC procedure. These clipping artefacts hinder the ability to accurately assess CT collimation width because the full-width at half maximum value of the penumbras are not properly determined if the maximum dose of the profile is not available. Furthermore, any inconsistencies in the radiation profile shape are lost if the profile plateau is clipped off. In this work we developed an opensource Matlab script for straightforward CT profile width measurements using raw CR data that also allows assessment of the profile shape without clipping, and applied this approach during CT QC.« less

Predictive dose-based estimation of systemic exposure multiples in mouse and monkey relative to human for antisense oligonucleotides with 2'-o-(2-methoxyethyl) modifications.

PubMed

Yu, Rosie Z; Grundy, John S; Henry, Scott P; Kim, Tae-Won; Norris, Daniel A; Burkey, Jennifer; Wang, Yanfeng; Vick, Andrew; Geary, Richard S

2015-01-20

Evaluation of species differences and systemic exposure multiples (or ratios) in toxicological animal species versus human is an ongoing exercise during the course of drug development. The systemic exposure ratios are best estimated by directly comparing area under the plasma concentration-time curves (AUCs), and sometimes by comparing the dose administered, with the dose being adjusted either by body surface area (BSA) or body weight (BW). In this study, the association between AUC ratio and the administered dose ratio from animals to human were studied using a retrospective data-driven approach. The dataset included nine antisense oligonucleotides (ASOs) with 2'-O-(2-methoxyethyl) modifications, evaluated in two animal species (mouse and monkey) following single and repeated parenteral administrations. We found that plasma AUCs were similar between ASOs within the same species, and are predictable to human exposure using a single animal species, either mouse or monkey. Between monkey and human, the plasma exposure ratio can be predicted directly based on BW-adjusted dose ratios, whereas between mouse and human, the exposure ratio would be nearly fivefold lower in mouse compared to human based on BW-adjusted dose values. Thus, multiplying a factor of 5 for the mouse BW-adjusted dose would likely provide a reasonable AUC exposure estimate in human at steady-state.

Prospective analysis of principles and frequency of self-adjustment of insulin dose in people with diabetes type 1 before and after participation in a diabetes treatment and teaching programme.

PubMed

Kramer, Guido; Kuniss, Nadine; Jörgens, Viktor; Lehmann, Thomas; Müller, Nicolle; Lorkowski, Stefan; Wolf, Gunter; Müller, Ulrich A; Kloos, Christof

2016-09-01

Insulin dose self-adjustment is an essential part of intensified insulin therapy - nowadays the routine treatment of type 1 diabetes (DM1). The aim of this study was to evaluate principles and frequency of insulin dose self-adjustments in people with DM1 before and one year after participating in a structured diabetes treatment and teaching programme (DTTP) and to determine to which extent the patients followed the way they had been trained. 72 people with DM1 were interviewed before participation in our inpatient (32/72) or outpatient (40/72) DTTP. Sixty-six participants (91.7%) were followed up after one year. The number of adaptations of the insulin dose by the patients was recorded from 28days of the patients' diary. The ability to find the correct dose was tested using five different examples. Metabolic control improved significantly after one year (7.9±1.0 to 7.5±0.8%, p=0.004). The participants performed 86.0±37.1 insulin dosage adaptations per 28days before the DTTP. After one year the frequency increased significantly to 99.1±30.7 per 28days (p=0.011). Before the DTTP, 42 of 72 patients (58.3%) adjusted their insulin dose to correct high blood glucose levels by adjustment rules (factor for correction or correction scheme) and 20 of 72 people (27.8%) by personal experience/feeling. One year after the DTTP, 73% (48/66) used adjustment rules. After participating in an structured education programme, patients adjusted their insulin dosage more frequently. Metabolic control improved despite the fact that many patients did not strictly apply the rules they had been trained for. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Development of 1-year-old computational phantom and calculation of organ doses during CT scans using Monte Carlo simulation.

PubMed

Pan, Yuxi; Qiu, Rui; Gao, Linfeng; Ge, Chaoyong; Zheng, Junzheng; Xie, Wenzhang; Li, Junli

2014-09-21

With the rapidly growing number of CT examinations, the consequential radiation risk has aroused more and more attention. The average dose in each organ during CT scans can only be obtained by using Monte Carlo simulation with computational phantoms. Since children tend to have higher radiation sensitivity than adults, the radiation dose of pediatric CT examinations requires special attention and needs to be assessed accurately. So far, studies on organ doses from CT exposures for pediatric patients are still limited. In this work, a 1-year-old computational phantom was constructed. The body contour was obtained from the CT images of a 1-year-old physical phantom and the internal organs were deformed from an existing Chinese reference adult phantom. To ensure the organ locations in the 1-year-old computational phantom were consistent with those of the physical phantom, the organ locations in 1-year-old computational phantom were manually adjusted one by one, and the organ masses were adjusted to the corresponding Chinese reference values. Moreover, a CT scanner model was developed using the Monte Carlo technique and the 1-year-old computational phantom was applied to estimate organ doses derived from simulated CT exposures. As a result, a database including doses to 36 organs and tissues from 47 single axial scans was built. It has been verified by calculation that doses of axial scans are close to those of helical scans; therefore, this database could be applied to helical scans as well. Organ doses were calculated using the database and compared with those obtained from the measurements made in the physical phantom for helical scans. The differences between simulation and measurement were less than 25% for all organs. The result shows that the 1-year-old phantom developed in this work can be used to calculate organ doses in CT exposures, and the dose database provides a method for the estimation of 1-year-old patient doses in a variety of CT examinations.

Development of 1-year-old computational phantom and calculation of organ doses during CT scans using Monte Carlo simulation

NASA Astrophysics Data System (ADS)

Pan, Yuxi; Qiu, Rui; Gao, Linfeng; Ge, Chaoyong; Zheng, Junzheng; Xie, Wenzhang; Li, Junli

2014-09-01

With the rapidly growing number of CT examinations, the consequential radiation risk has aroused more and more attention. The average dose in each organ during CT scans can only be obtained by using Monte Carlo simulation with computational phantoms. Since children tend to have higher radiation sensitivity than adults, the radiation dose of pediatric CT examinations requires special attention and needs to be assessed accurately. So far, studies on organ doses from CT exposures for pediatric patients are still limited. In this work, a 1-year-old computational phantom was constructed. The body contour was obtained from the CT images of a 1-year-old physical phantom and the internal organs were deformed from an existing Chinese reference adult phantom. To ensure the organ locations in the 1-year-old computational phantom were consistent with those of the physical phantom, the organ locations in 1-year-old computational phantom were manually adjusted one by one, and the organ masses were adjusted to the corresponding Chinese reference values. Moreover, a CT scanner model was developed using the Monte Carlo technique and the 1-year-old computational phantom was applied to estimate organ doses derived from simulated CT exposures. As a result, a database including doses to 36 organs and tissues from 47 single axial scans was built. It has been verified by calculation that doses of axial scans are close to those of helical scans; therefore, this database could be applied to helical scans as well. Organ doses were calculated using the database and compared with those obtained from the measurements made in the physical phantom for helical scans. The differences between simulation and measurement were less than 25% for all organs. The result shows that the 1-year-old phantom developed in this work can be used to calculate organ doses in CT exposures, and the dose database provides a method for the estimation of 1-year-old patient doses in a variety of CT examinations.

Effect of Low (5 mg) vs. High (20-40 mg) Rosuvastatin Dose on 24h Arterial Stiffness, Central Haemodynamics, and Non-Alcoholic Fatty Liver Disease in Patients with Optimally Controlled Arterial Hypertension.

PubMed

Mitsiou, Eudoxia; Boutari, Chrysoula; Kotsis, Vasilios; Georgianou, Eleni; Doumas, Michael; Karagiannis, Asterios; Athyros, Vasilios G

2018-01-01

Arterial Stiffness (AS) and Non-Alcoholic Fatty Liver Diseases (NAFLD) are 2 related, prevalent, risk predictors of Cardiovascular Disease (CVD). We assessed the effect of low dose (5 mg/day) vs. high dose (20-40 mg/day) rosuvastatin on aortic elasticity and central haemodynamics as well as on NAFLD in patients with Arterial Hypertension (AH). Forty patients with optimally controlled AH were randomised to 2 rosuvastatin doses and followed for 6 months. 24h AS was assessed by Mobil-O-Graph, which calculates (adjusted for age and gender) Pulse Wave Velocity (PWV), adjusted for Heart Rate (HR) augmentation index (AIx75%) and central haemodynamics. The diagnosis of NAFLD was based on >5% liver steatosis on ultrasound and moderately elevated serum levels of liver enzymes. Both doses of rosuvastatin reduced Central Pulse Pressure (cPP), PWV and AIx75% (adjusted for HR) to normal values (p = NS adjusted for age, gender and HR). Liver enzymes were reduced in those with NAFLD to normal, but steatosis was reduced more by the 20-40 mg/day rosuvastatin dose (p=0.01) compared with the 5 mg/day dose. Both doses of rosuvastatin had a beneficial effect on AS; the high dose was more efficient in reducing PWVs and central haemodynamics, and also the high dose was more effective in ameliorating NAFLD. Given that AH control was optimal and lipid values attained targets, 4 other CVD predictors were also addressed. Larger and longer term studies are needed to demonstrate the clinical benefit of such treatment preference. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Adjusting insulin doses in patients with type 1 diabetes that use insulin pump and continuous glucose monitoring - Variations among countries and physicians.

PubMed

Nimri, Revital; Dassau, Eyal; Segall, Tomer; Muller, Ido; Bratina, Natasa; Kordonouri, Olga; Bello, Rachel; Biester, Torben; Dovc, Klemen; Tenenbaum, Ariel; Brener, Avivit; Šimunović, Marko; Sakka, Sophia D; Nevo Shenker, Michal; Passone, Caroline Gb; Rutigliano, Irene; Tinti, Davide; Bonura, Clara; Caiulo, Silvana; Ruszala, Anna; Piccini, Barbara; Giri, Dinesh; Stein, Ronnie; Rabbone, Ivana; Bruzzi, Patrizia; Omladič, Jasna Šuput; Steele, Caroline; Beccuti, Guglielmo; Yackobovitch-Gavan, Michal; Battelino, Tadej; Danne, Thomas; Atlas, Eran; Phillip, Moshe

2018-06-08

To evaluate physicians' adjustments of insulin pump settings based on continuous glucose monitoring (CGM) for patients with type 1 diabetes and to compare physicians' to automated insulin dose adjustments. 26 physicians from 16 centers in Europe, Israel and South-America participated in the study. All were asked to adjust insulin dosing based on insulin pump, CGM and glucometer downloads of 15 patients (mean age 16.2 ± 4.3 y, 6 females, mean A1c 8.3 ± 0.9%) gathered over a 3-week period. Recommendations were compared for the relative changes in the basal, carbohydrate-ratio (CR) and correction-factor (CF) plans among physicians, among centers and between the physicians and an automated algorithm (DreaMed Advisor Pro). Study endpoints were the percentage of comparison points for which there was full agreement on the trend of insulin dose adjustments (same trend), partial agreement (increase/decrease vs. no change) and full disagreement (opposite trend). Percentage of full agreement between physicians on the trend of insulin adjustments of the basal, CR and CF plans was 41±9%, 45±11% and 45.5±13%, and of complete disagreement was 12±7%, 9.5±7% and 10±8%, respectively. Significantly similar results were found between the physicians and the DreaMed Advisor Pro. The Advisor magnitude of insulin dose change was at least equal or less than proposed by the physicians. Physicians provide different insulin dose recommendations based on the same data sets. The automated advice of the DreaMed Advisor Pro didn't differ significantly from the advice given by the physicians in the direction or magnitude of the insulin dosing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Randomized Double-Blinded Dose Escalation Trial of Triptorelin for Ovary Protection in Childhood-Onset Systemic Lupus Erythematosus

PubMed Central

Brunner, Hermine I.; Silva, Clovis A; Reiff, Andreas; Higgins, Gloria C.; Imundo, Lisa; Williams, Calvin B.; Wallace, Carol A; Aikawa, Nadia E.; Nelson, Shannen; Klein-Gitelman, Marisa S.; Rose, Susan R.

2015-01-01

Objectives To determine for females with childhood-onset systemic lupus erythematosus (cSLE) who require cyclophosphamide the dose of triptorelin that suffices to maintain complete ovarian suppression (COS); measure the time needed to achieve ovarian suppression after triptorelin initiation, and explore the safety of triptorelin. Methods In this randomized double-blind placebo-controlled dose-escalation study females (< 21 years) were randomized 4:1 to receive triptorelin or placebo (25 triptorelin, 6 placebo). Starting doses of triptorelin between 25 and 100 microgram/kg/dose were used. Triptorelin dosage was escalated until COS was maintained. The primary outcome was the weight-adjusted dose of triptorelin that for at least 90% of the patients provides COS based on Gonadotropin-releasing-hormone Agonist Stimulation Testing. Secondary outcomes were time to ovarian suppression measured by unstimulated FSH and LH levels after study drug initiation. Results Triptorelin dosed at 120 microgram/kg bodyweight led to sustained COS in 90% of the patients. After the initial dose of triptorelin 22 days were needed for achieve COS. Rates of adverse events (AE) and serious adverse events (SAE) per 100 patient-month of follow-up were not higher in the triptorelin group as compared to the placebo group (triptorelin vs. placebo; AE: 189 vs. 362; SAE: 2.05 vs. 8.48). Conclusions For achieving and maintaining COS high doses of triptorelin are needed but appear to be well tolerated in adolescent females with cSLE. Our data suggest that a lag time of 22 days after triptorelin initiation is required before starting or continuing cyclophosphamide-therapy. Trial Registration Number clinicaltrials.gov identifier: NCT00124514 PMID:25676588

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

In vivo dose verification method in catheter based high dose rate brachytherapy.

PubMed

Jaselskė, Evelina; Adlienė, Diana; Rudžianskas, Viktoras; Urbonavičius, Benas Gabrielis; Inčiūra, Arturas

2017-12-01

In vivo dosimetry is a powerful tool for dose verification in radiotherapy. Its application in high dose rate (HDR) brachytherapy is usually limited to the estimation of gross errors, due to inability of the dosimetry system/ method to record non-uniform dose distribution in steep dose gradient fields close to the radioactive source. In vivo dose verification in interstitial catheter based HDR brachytherapy is crucial since the treatment is performed inserting radioactive source at the certain positions within the catheters that are pre-implanted into the tumour. We propose in vivo dose verification method for this type of brachytherapy treatment which is based on the comparison between experimentally measured and theoretical dose values calculated at well-defined locations corresponding dosemeter positions in the catheter. Dose measurements were performed using TLD 100-H rods (6 mm long, 1 mm diameter) inserted in a certain sequences into additionally pre-implanted dosimetry catheter. The adjustment of dosemeter positioning in the catheter was performed using reconstructed CT scans of patient with pre-implanted catheters. Doses to three Head&Neck and one Breast cancer patient have been measured during several randomly selected treatment fractions. It was found that the average experimental dose error varied from 4.02% to 12.93% during independent in vivo dosimetry control measurements for selected Head&Neck cancer patients and from 7.17% to 8.63% - for Breast cancer patient. Average experimental dose error was below the AAPM recommended margin of 20% and did not exceed the measurement uncertainty of 17.87% estimated for this type of dosemeters. Tendency of slightly increasing average dose error was observed in every following treatment fraction of the same patient. It was linked to the changes of theoretically estimated dosemeter positions due to the possible patient's organ movement between different treatment fractions, since catheter reconstruction was performed for the first treatment fraction only. These findings indicate potential for further average dose error reduction in catheter based brachytherapy by at least 2-3% in the case that catheter locations will be adjusted before each following treatment fraction, however it requires more detailed investigation. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Nonparametric methods for doubly robust estimation of continuous treatment effects.

PubMed

Kennedy, Edward H; Ma, Zongming; McHugh, Matthew D; Small, Dylan S

2017-09-01

Continuous treatments (e.g., doses) arise often in practice, but many available causal effect estimators are limited by either requiring parametric models for the effect curve, or by not allowing doubly robust covariate adjustment. We develop a novel kernel smoothing approach that requires only mild smoothness assumptions on the effect curve, and still allows for misspecification of either the treatment density or outcome regression. We derive asymptotic properties and give a procedure for data-driven bandwidth selection. The methods are illustrated via simulation and in a study of the effect of nurse staffing on hospital readmissions penalties.

Adjusted regression trend test for a multicenter clinical trial.

PubMed

Quan, H; Capizzi, T

1999-06-01

Studies using a series of increasing doses of a compound, including a zero dose control, are often conducted to study the effect of the compound on the response of interest. For a one-way design, Tukey et al. (1985, Biometrics 41, 295-301) suggested assessing trend by examining the slopes of regression lines under arithmetic, ordinal, and arithmetic-logarithmic dose scalings. They reported the smallest p-value for the three significance tests on the three slopes for safety assessments. Capizzi et al. (1992, Biometrical Journal 34, 275-289) suggested an adjusted trend test, which adjusts the p-value using a trivariate t-distribution, the joint distribution of the three slope estimators. In this paper, we propose an adjusted regression trend test suitable for two-way designs, particularly for multicenter clinical trials. In a step-down fashion, the proposed trend test can be applied to a multicenter clinical trial to compare each dose with the control. This sequential procedure is a closed testing procedure for a trend alternative. Therefore, it adjusts p-values and maintains experimentwise error rate. Simulation results show that the step-down trend test is overall more powerful than a step-down least significant difference test.

Randomized trial of a dual-hormone artificial pancreas with dosing adjustment during exercise compared with no adjustment and sensor-augmented pump therapy.

PubMed

Jacobs, P G; El Youssef, J; Reddy, R; Resalat, N; Branigan, D; Condon, J; Preiser, N; Ramsey, K; Jones, M; Edwards, C; Kuehl, K; Leitschuh, J; Rajhbeharrysingh, U; Castle, J R

2016-11-01

To test whether adjusting insulin and glucagon in response to exercise within a dual-hormone artificial pancreas (AP) reduces exercise-related hypoglycaemia. In random order, 21 adults with type 1 diabetes (T1D) underwent three 22-hour experimental sessions: AP with exercise dosing adjustment (APX); AP with no exercise dosing adjustment (APN); and sensor-augmented pump (SAP) therapy. After an overnight stay and 2 hours after breakfast, participants exercised for 45 minutes at 60% of their maximum heart rate, with no snack given before exercise. During APX, insulin was decreased and glucagon was increased at exercise onset, while during SAP therapy, subjects could adjust dosing before exercise. The two primary outcomes were percentage of time spent in hypoglycaemia (<3.9 mmol/L) and percentage of time spent in euglycaemia (3.9-10 mmol/L) from the start of exercise to the end of the study. The mean (95% confidence interval) times spent in hypoglycaemia (<3.9 mmol/L) after the start of exercise were 0.3% (-0.1, 0.7) for APX, 3.1% (0.8, 5.3) for APN, and 0.8% (0.1, 1.4) for SAP therapy. There was an absolute difference of 2.8% less time spent in hypoglycaemia for APX versus APN (p = .001) and 0.5% less time spent in hypoglycaemia for APX versus SAP therapy (p = .16). Mean time spent in euglycaemia was similar across the different sessions. Adjusting insulin and glucagon delivery at exercise onset within a dual-hormone AP significantly reduces hypoglycaemia compared with no adjustment and performs similarly to SAP therapy when insulin is adjusted before exercise. © 2016 John Wiley & Sons Ltd.

Clinical Utility of the Modified Segmental Boost Technique for Treatment of the Pelvis and Inguinal Nodes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moran, M.S., E-mail: meena.moran@yale.ed; Yale New Haven Hospital, New Haven, Connecticut and William W. Backus Hospital, Norwich, Connecticut; Castrucci, W.A.

2010-03-15

Purpose: Low-lying pelvic malignancies often require simultaneous radiation to pelvis and inguinal nodes. We previously reported improved homogeneity with the modified segmental boost technique (MSBT) compared to that with traditional methods, using phantom models. Here we report our institutional clinical experience with MSBT. Methods and Materials: MSBT patients from May 2001 to March 2007 were evaluated. Parameters analyzed included isocenter/multileaf collimation shifts, time per fraction (four fields), monitor units (MU)/fraction, femoral doses, maximal dose relative to body mass index, and inguinal node depth. In addition, a dosimetric comparison of the MSBT versus intensity modulated radiation therapy (IMRT) was conducted. Results:more » Of the 37 MSBT patients identified, 32 were evaluable. Port film adjustments were required in 6% of films. Median values for each analyzed parameter were as follows: MU/fraction, 298 (range, 226-348); delivery time, 4 minutes; inguinal depth, 4.5 cm; volume receiving 45 Gy (V45), 7%; V27.5, 87%; body mass index, 25 (range, 16.0-33.8). Inguinal dose was 100% in all cases; in-field inhomogeneity ranged from 111% to 118%. IMRT resulted in significantly decreased dose to normal tissue but required more time for treatment planning and a higher number of MUs (1,184 vs. 313 MU). Conclusions: In our clinical experience, the mono-isocentric MSBT provides a high degree of accuracy, improved homogeneity compared with traditional techniques, ease of simulation, treatment planning, treatment delivery, and acceptable femoral doses for pelvic/inguinal radiation fields requiring 45 to 50.4 Gy. In addition, the MSBT delivers a relatively uniform dose distribution throughout the treatment volume, despite varying body habitus. Clinical scenarios for the use of MSBT vs. intensity-modulated radiation therapy are discussed. To our knowledge, this is the first study reporting the utility of MSBT in the clinical setting.« less

[Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study].

PubMed

Mahner, Maria; Raus, Christina; Ludwig, Fabian; Weckmann, Gesine; Stracke, Sylvia; Chenot, Jean-François

2018-06-01

Many drugs require dose adjustment or are contraindicated in patients with chronic kidney disease (CKD) to avoid adverse events. The aims of this study were to assess if medication was appropriately dose adjusted in patients with CKD in primary care, to identify medications that were frequently prescribed inappropriately and to identify factors predicting mal-prescription. We conducted a cross-sectional observational study in 34 general practioners' offices, assessing the medication of patients with CKD stage ≥ 3 according to the corresponding pharmaceutical product information. Additional information was extracted from recommendations of scientific societies and regulatory authorities. Contraindicated and overdosed medications were identified. Predictive factors for inadequate prescribing were analyzed with multiple logistic regression. 589 patients (Ø 78 years, 63 % female) with CKD stage ≥ 3 were included. A total of 5102 medications were extracted from the medication sheets (94,6 % regular, 5,4 % "as needed"). 4,2 % were judged as being inadequate according to pharmaceutical information (2,1 % contraindicated, 2,1 % overdosed). 173 patients (29 %) had ≥ 1 inadequate prescription. The proportion of inadequate prescriptions fell to 3,5 % after adjustment for the most recent recommendations of scientific societies and regulatory authorities. Most frequent inappropriate prescriptions were ACE-inhibitors, diuretics, oral antidiabetic drugs, methotrexate and potassium supplements. Most important predictors for inadequate prescriptions were CKD stage ≥ 3b and number of medications. A quarter of all patients had a least one inadequate prescription. The overall proportion of inadequately prescribed drugs was low. Adjustment for recommendations by scientific societies and regulatory authorities further reduced the number of inadequate prescriptions. Valid data on the clinical relevance of inadequate prescriptions is scarce and further research is required. Because of the time and effort needed to assess all medications, future quality improvement projects should focus on CKD stage ≥ 3b, patients with polypharmacy and crucial medication. © Georg Thieme Verlag KG Stuttgart · New York.

Declines in Outpatient Antimicrobial Use in Canada (1995–2010)

PubMed Central

Finley, Rita; Glass-Kaastra, Shiona K.; Hutchinson, Jim; Patrick, David M.; Weiss, Karl; Conly, John

2013-01-01

Background With rising reports of antimicrobial resistance in outpatient communities, surveillance of antimicrobial use is imperative for supporting stewardship programs. The primary objective of this article is to assess the levels of antimicrobial use in Canada over time. Methods Canadian antimicrobial use data from 1995 to 2010 were acquired and assessed by four metrics: population-adjusted prescriptions, Defined Daily Doses, spending on antimicrobials (inflation-adjusted), and average Defined Daily Doses per prescription. Linear mixed models were built to assess significant differences among years and antimicrobial groups, and to account for repeated measurements over time. Measures were also compared to published reports from European countries. Results Temporal trends in antimicrobial use in Canada vary by metric and antimicrobial grouping. Overall reductions were seen for inflation-adjusted spending, population-adjusted prescription rates and Defined Daily Doses, and increases were observed for the average number of Defined Daily Doses per prescription. The population-adjusted prescription and Defined Daily Doses values for 2009 were comparable to those reported by many European countries, while the average Defined Daily Dose per prescription for Canada ranked high. A significant reduction in the use of broad spectrum penicillins occurred between 1995 and 2004, coupled with increases in macrolide and quinolone use, suggesting that replacement of antimicrobial drugs may occur as new products arrive on the market. Conclusions There have been modest decreases of antimicrobial use in Canada over the past 15 years. However, continued surveillance of antimicrobial use coupled with data detailing antimicrobial resistance within bacterial pathogens affecting human populations is critical for targeting interventions and maintaining the effectiveness of these products for future generations. PMID:24146863

Higher anti-depressant dose and major adverse outcomes in moderate chronic kidney disease: a retrospective population-based study

PubMed Central

2014-01-01

Background Many older patients have chronic kidney disease (CKD), and a lower dose of anti-depressants paroxetine, mirtazapine and venlafaxine is recommended in patients with CKD to prevent drug accumulation from reduced elimination. Using information available in large population-based healthcare administrative databases, we conducted this study to determine if ignoring the recommendation and prescribing a higher versus lower dose of anti-depressants associates with a higher risk of adverse events. Methods We conducted a population-based cohort study to describe the 30-day risk of delirium in older adults who initiated a higher vs. lower dose of these three anti-depressants in routine care. We defined delirium using the best proxy available in our data sources - hospitalization with an urgent head computed tomography (CT) scan. We determined if CKD status modified the association between anti-depressant dose and outcome, and examined the secondary outcome of 30 day all-cause mortality. We used multivariable logistic regression analyses to estimate adjusted odds ratios (relative risk (RR)) and 95% confidence intervals. Results We identified adults (mean age 75) in Ontario who started a new study anti-depressant at a higher dose (n = 36,651; 31%) or lower dose (n = 81,160; 69%). Initiating a higher vs. lower dose was not associated with an increased risk of hospitalization with head CT (1.09% vs. 1.27% (adjusted RR 0.90; 95% CI, 0.80 to 1.02), but was associated with a lower risk of all-cause mortality (0.76% vs. 0.97% RR 0.82; 95% CI, 0.71 to 0.95). Neither of these relative risks were modified by the presence of CKD (p = 0.16, 0.68, respectively). Conclusions We did not observe an increase in two adverse outcomes when study anti-depressants were initiated at a higher dose in elderly patients with moderate CKD. Contrary to our hypothesis, the 30-day risk of mortality was lower when a higher versus lower dose of anti-depressant was initiated in these patients, a finding which requires corroboration and further study. PMID:24884589

Practical applications of internal dose calculations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carbaugh, E.H.

1994-06-01

Accurate estimates of intake magnitude and internal dose are the goal for any assessment of an actual intake of radioactivity. When only one datum is available on which to base estimates, the choices for internal dose assessment become straight-forward: apply the appropriate retention or excretion function, calculate the intake, and calculate the dose. The difficulty comes when multiple data and different types of data become available. Then practical decisions must be made on how to interpret conflicting data, or how to adjust the assumptions and techniques underlying internal dose assessments to give results consistent with the data. This article describesmore » nine types of adjustments which can be incorporated into calculations of intake and internal dose, and then offers several practical insights to dealing with some real-world internal dose puzzles.« less

The Impact of AUC-Based Monitoring on Pharmacist-Directed Vancomycin Dose Adjustments in Complicated Methicillin-Resistant Staphylococcus aureus Infection.

PubMed

Stoessel, Andrew M; Hale, Cory M; Seabury, Robert W; Miller, Christopher D; Steele, Jeffrey M

2018-01-01

This study aimed to assess the impact of area under the curve (AUC)-based vancomycin monitoring on pharmacist-initiated dose adjustments after transitioning from a trough-only to an AUC-based monitoring method at our institution. A retrospective cohort study of patients treated with vancomycin for complicated methicillin-resistant Staphylococcus aureus (MRSA) infection between November 2013 and December 2016 was conducted. The frequency of pharmacist-initiated dose adjustments was assessed for patients monitored via trough-only and AUC-based approaches for trough ranges: 10 to 14.9 mg/L and 15 to 20 mg/L. Fifty patients were included: 36 in the trough-based monitoring and 14 in the AUC-based-monitoring group. The vancomycin dose was increased in 71.4% of patients when troughs were 10 to 14.9 mg/L when a trough-only approach was used and in only 25% of patients when using AUC estimation ( P = .048). In the AUC group, the dose was increased only when AUC/minimum inhibitory concentration (MIC) <400; unchanged regimens had an estimated AUC/MIC ≥400. The AUC-based monitoring did not significantly increase the frequency of dose reductions when trough concentrations were 15 to 20 mg/L (AUC: 33.3% vs trough: 4.6%; P = .107). The AUC-based monitoring resulted in fewer patients with dose adjustments when trough levels were 10 to 14.9 mg/L. The AUC-based monitoring has the potential to reduce unnecessary vancomycin exposure and warrants further investigation.

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling.

PubMed

Woodhead, Jeffrey L; Paech, Franziska; Maurer, Martina; Engelhardt, Marc; Schmitt-Hoffmann, Anne H; Spickermann, Jochen; Messner, Simon; Wind, Mathias; Witschi, Anne-Therese; Krähenbühl, Stephan; Siler, Scott Q; Watkins, Paul B; Howell, Brett A

2018-06-07

Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low. DILIsym was then used to recommend potential modifications to this dosing scheme; weight-adjusted dosing and a requirement to assay plasma alanine aminotransferase (ALT) daily and stop dosing as soon as ALT increases were observed improved the predicted safety margin of BAL30072 and decreased the predicted likelihood of severe injury. This research demonstrates a potential application for QSP modeling in improving the safety profile of candidate drugs. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Evaluation of genotype-guided acenocoumarol dosing algorithms in Russian patients.

PubMed

Sychev, Dmitriy Alexeyevich; Rozhkov, Aleksandr Vladimirovich; Ananichuk, Anna Viktorovna; Kazakov, Ruslan Evgenyevich

2017-05-24

Acenocoumarol dose is normally determined via step-by-step adjustment process based on International Normalized Ratio (INR) measurements. During this time, the risk of adverse reactions is especially high. Several genotype-based acenocoumarol dosing algorithms have been created to predict ideal doses at the start of anticoagulant therapy. Nine dosing algorithms were selected through a literature search. These were evaluated using a cohort of 63 patients with atrial fibrillation receiving acenocoumarol therapy. None of the existing algorithms could predict the ideal acenocoumarol dose in 50% of Russian patients. The Wolkanin-Bartnik algorithtm based on European population was the best-performing one with the highest correlation values (r=0.397), mean absolute error (MAE) 0.82 (±0.61). EU-PACT also managed to give an estimate within the ideal range in 43% of the cases. The two least accurate results were yielded by the Indian population-based algorithms. Among patients receiving amiodarone, algorithms by Schie and Tong proved to be the most effective with the MAE of 0.48±0.42 mg/day and 0.56±0.31 mg/day, respectively. Patient ethnicity and amiodarone intake are factors that must be considered when building future algorithms. Further research is required to find the perfect dosing formula of acenocoumarol maintenance doses in Russian patients.

The cost-effectiveness of rotavirus vaccination in Malawi.

PubMed

Berry, Stephen A; Johns, Benjamin; Shih, Chuck; Berry, Andrea A; Walker, Damian G

2010-09-01

Rotarix (GlaxoSmithKline), a newly licensed rotavirus vaccine requiring 2 doses, may have the potential to save hundreds of thousands of lives in Africa. Nations such as Malawi, where Rotarix is currently under phase III investigation, may nevertheless face difficult economic choices in considering vaccine adoption. The cost-effectiveness of implementing a Rotarix vaccine program in Malawi was estimated using published estimates of rotavirus burden, vaccine efficacy, and health care utilization and costs. With 49.5% vaccine efficacy, a Rotarix program could avert 2582 deaths annually. With GAVI Alliance cofinancing, adoption of Rotarix would be associated with a cost of $5.07 per disability-adjusted life-year averted. With market pricing, Rotarix would be associated with a base case cost of $74.73 per disability-adjusted life-year averted. Key variables influencing results were vaccine efficacy, under-2 rotavirus mortality, and program cost of administering each dose. Adopting Rotarix would likely be highly cost-effective for Malawi, particularly with GAVI support. This finding holds true across uncertainty ranges for key variables, including efficacy, for which data are becoming available.

Pharmacokinetics of drugs in pregnancy.

PubMed

Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

2015-11-01

Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. Copyright © 2015 Elsevier Inc. All rights reserved.

Influence of ABCB1 polymorphisms and haplotypes on tacrolimus nephrotoxicity and dosage requirements in children with liver transplant

PubMed Central

Hawwa, Ahmed F; McKiernan, Patrick J; Shields, Michael; Millership, Jeff S; Collier, Paul S; McElnay, James C

2009-01-01

AIMS The aim of this study was to investigate the influence of genetic polymorphisms in ABCB1 on the incidence of nephrotoxicity and tacrolimus dosage-requirements in paediatric patients following liver transplantation. METHODS Fifty-one paediatric liver transplant recipients receiving tacrolimus were genotyped for ABCB1 C1236>T, G2677>T and C3435>T polymorphisms. Dose-adjusted tacrolimus trough concentrations and estimated glomerular filtration rates (EGFR) indicative of renal toxicity were determined and correlated with the corresponding genotypes. RESULTS The present study revealed a higher incidence of the ABCB1 variant-alleles examined among patients with renal dysfunction (≥30% reduction in EGFR) at 6 months post-transplantation (1236T allele: 63.3% vs 37.5% in controls, P= 0.019; 2677T allele: 63.3% vs. 35.9%, p = 0.012; 3435T allele: 60% vs. 39.1%, P= 0.057). Carriers of the G2677->T variant allele also had a significant reduction (%) in EGFR at 12 months post-transplant (mean difference = 22.6%; P= 0.031). Haplotype analysis showed a significant association between T-T-T haplotypes and an increased incidence of nephrotoxicity at 6 months post-transplantation (haplotype-frequency = 52.9% in nephrotoxic patients vs 29.4% in controls; P= 0.029). Furthermore, G2677->T and C3435->T polymorphisms and T-T-T haplotypes were significantly correlated with higher tacrolimus dose-adjusted pre-dose concentrations at various time points examined long after drug initiation. CONCLUSIONS These findings suggest that ABCB1 polymorphisms in the native intestine significantly influence tacrolimus dosage-requirement in the stable phase after transplantation. In addition, ABCB1 polymorphisms in paediatric liver transplant recipients may predispose them to nephrotoxicity over the first year post-transplantation. Genotyping future transplant recipients for ABCB1 polymorphisms, therefore, could have the potential to individualize better tacrolimus immunosuppressive therapy and enhance drug safety. PMID:19740399

Patient preferences and willingness to pay for different options of anticoagulant therapy.

PubMed

Moia, Marco; Mantovani, Lorenzo Giovanni; Carpenedo, Monica; Scalone, Luciana; Monzini, Mara Silvia; Cesana, Giancarlo; Mannucci, Pier Mannuccio

2013-04-01

New anticoagulant drugs alternative to vitamin K antagonists are currently under clinical evaluation. Patient's preferences should be considered in the development of new therapeutic strategies. Our study aim was to elicit patient preferences, and estimate their willingness to pay for the different treatment options. A Discrete Choice Experiment was administered to patients consecutively attending an anticoagulation clinic, either on stable oral anticoagulant therapy, or during their first visit at the time of starting therapy. Six treatment characteristics were analysed: route and number of medication administrations, frequency of monitoring, risk of some minor bleeding, the amount of attention required for drug/food interactions, requirement for dose adjustment, and out-of-pocket treatment cost. Relationships between patient's preferences and their characteristics were analysed. 255 patients participated (55 % men, with a mean age 64 years; 35.7 % on stable therapy). A statistically significant importance was attributed to all but two characteristics (the amount of attention required for interaction with other drugs/food and for dose adjustment.) Monthly patient willingness to pay was 79 for tablets versus injections; 41 for once-daily versus twice-daily tablets, 25 for drugs without risk of minor bleeding events and 20 for once-monthly versus twice-monthly monitoring. Patients on stable therapy considered more important the amount of attention required for drug/food interactions than did the starters. Younger or working patients considered the reduction of monitoring frequency more important than did the older or not working patients (retired, housewives). This study elicited preferences from patients on oral anticoagulant therapy with a simple and well established method, which allows to obtain information warranted for planning optimal healthcare.

Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjögren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study.

PubMed

Papas, Athena S; Sherrer, Yvonne S; Charney, Michael; Golden, Harvey E; Medsger, Thomas A; Walsh, Bridget T; Trivedi, Madhu; Goldlust, Barry; Gallagher, Susan C

2004-08-01

: Sjögren's syndrome is characterized by the presence of xerostomia and/or xerophthalmia. Pilocarpine, a muscarinic cholinergic agonist, has been proven to be efficacious in treating radiation-induced xerostomia (up to 30 mg/day) and symptoms of dry mouth in Sjögren's patients (up to 20 mg/day). : To compare the safety and efficacy of oral pilocarpine (dose-adjusted) versus placebo in the treatment of dry eye and dry mouth symptoms in Sjögren's syndrome at 6 and 12 weeks. : In this 11-center, 256-patient placebo-controlled study, the safety and efficacy of oral pilocarpine (20 mg to 30 mg daily) for relief of Sjögren's-related dry mouth and dry eye symptoms was assessed. Changes in symptoms and salivary flow were measured over 12 weeks. : Compared with placebo, salivary flow was significantly increased in the pilocarpine group (P

Effect of 2',3'-didehydro-3'-deoxythymidine in an in vitro hollow-fiber pharmacodynamic model system correlates with results of dose-ranging clinical studies.

PubMed Central

Bilello, J A; Bauer, G; Dudley, M N; Cole, G A; Drusano, G L

1994-01-01

We sought to validate an in vitro system which could predict the minimal effect dose of antiretroviral agents. Mixtures of uninfected CEM cells and CEM cells chronically infected with human immunodeficiency virus (HIV) type 1 MN were exposed to 2',3'-didehydro-3'-deoxythymidine (D4T) in vitro in a hollow-fiber model which simulates the plasma concentration-time profile of D4T in patients. Drug concentration was adjusted to simulate continuous intravenous infusion, or an intravenous bolus administered twice daily. The effect of the dosing regimen was measured with viral infectivity, p24 antigen, and reverse transcriptase or PCR for unintegrated HIV DNA. Dose deescalation studies on a twice-daily dosing schedule predicted a minimum effect dose of 0.5 mg/kg of body weight per day which correlated with the results of a clinical trial. Antiviral effect was demonstrated to be independent of schedule for every 12-h dosing versus continuous infusion. Finally, at or near the minimal effect dose, efficacy appeared to depend on the viral load. The ability of this in vitro pharmacodynamic model to assess the response of HIV-infected cells to different doses and schedules of antiviral agents may be useful in the design of optimal dosing regimens for clinical trials but requires validation with other types of antiretroviral agents. PMID:8092842

Pharmacist-managed dose adjustment feedback using therapeutic drug monitoring of vancomycin was useful for patients with methicillin-resistant Staphylococcus aureus infections: a single institution experience

PubMed Central

Hirano, Ryuichi; Sakamoto, Yuichi; Kitazawa, Junichi; Yamamoto, Shoji; Tachibana, Naoki

2016-01-01

Background Vancomycin (VCM) requires dose adjustment based on therapeutic drug monitoring. At Aomori Prefectural Central Hospital, physicians carried out VCM therapeutic drug monitoring based on their experience, because pharmacists did not participate in the dose adjustment. We evaluated the impact of an Antimicrobial Stewardship Program (ASP) on attaining target VCM trough concentrations and pharmacokinetics (PK)/pharmacodynamics (PD) parameters in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Materials and methods The ASP was introduced in April 2012. We implemented a prospective audit of prescribed VCM dosages and provided feedback based on measured VCM trough concentrations. In a retrospective pre- and postcomparison study from April 2007 to December 2011 (preimplementation) and from April 2012 to December 2014 (postimplementation), 79 patients were treated for MRSA infection with VCM, and trough concentrations were monitored (pre, n=28; post, n=51). In 65 patients (pre, n=15; post, n=50), 24-hour area under the concentration–time curve (AUC 0–24 h)/minimum inhibitory concentration (MIC) ratios were calculated. Results Pharmacist feedback, which included recommendations for changing dose or using alternative anti-MRSA antibiotics, was highly accepted during postimplementation (88%, 29/33). The number of patients with serum VCM concentrations within the therapeutic range (10–20 μg/mL) was significantly higher during postimplementation (84%, 43/51) than during preimplementation (39%, 11/28) (P<0.01). The percentage of patients who attained target PK/PD parameters (AUC 0–24 h/MIC >400) was significantly higher during postimplementation (84%, 42/50) than during preimplementation (53%, 8/15; P=0.013). There were no significant differences in nephrotoxicity or mortality rate. Conclusion Our ASP increased the percentage of patients that attained optimal VCM trough concentrations and PK/PD parameters, which contributed to the appropriate use of VCM in patients with MRSA infections. PMID:27789965

Dose-rate-dependent damage of cerium dioxide in the scanning transmission electron microscope.

PubMed

Johnston-Peck, Aaron C; DuChene, Joseph S; Roberts, Alan D; Wei, Wei David; Herzing, Andrew A

2016-11-01

Beam damage caused by energetic electrons in the transmission electron microscope is a fundamental constraint limiting the collection of artifact-free information. Through understanding the influence of the electron beam, experimental routines may be adjusted to improve the data collection process. Investigations of CeO 2 indicate that there is not a critical dose required for the accumulation of electron beam damage. Instead, measurements using annular dark field scanning transmission electron microscopy and electron energy loss spectroscopy demonstrate that the onset of measurable damage occurs when a critical dose rate is exceeded. The mechanism behind this phenomenon is that oxygen vacancies created by exposure to a 300keV electron beam are actively annihilated as the sample re-oxidizes in the microscope environment. As a result, only when the rate of vacancy creation exceeds the recovery rate will beam damage begin to accumulate. This observation suggests that dose-intensive experiments can be accomplished without disrupting the native structure of the sample when executed using dose rates below the appropriate threshold. Furthermore, the presence of an encapsulating carbonaceous layer inhibits processes that cause beam damage, markedly increasing the dose rate threshold for the accumulation of damage. Published by Elsevier B.V.

Dose-rate-dependent damage of cerium dioxide in the scanning transmission electron microscope

PubMed Central

Johnston-Peck, Aaron C.; DuChene, Joseph S.; Roberts, Alan D.; Wei, Wei David; Herzing, Andrew A.

2016-01-01

Beam damage caused by energetic electrons in the transmission electron microscope is a fundamental constraint limiting the collection of artifact-free information. Through understanding the influence of the electron beam, experimental routines may be adjusted to improve the data collection process. Investigations of CeO2 indicate that there is not a critical dose required for the accumulation of electron beam damage. Instead, measurements using annular dark field scanning transmission electron microscopy and electron energy loss spectroscopy demonstrate that the onset of measurable damage occurs when a critical dose rate is exceeded. The mechanism behind this phenomenon is that oxygen vacancies created by exposure to a 300 keV electron beam are actively annihilated as the sample re-oxidizes in the microscope environment. As a result, only when the rate of vacancy creation exceeds the recovery rate will beam damage begin to accumulate. This observation suggests that dose-intensive experiments can be accomplished without disrupting the native structure of the sample when executed using dose rates below the appropriate threshold. Furthermore, the presence of an encapsulating carbonaceous layer inhibits processes that cause beam damage, markedly increasing the dose rate threshold for the accumulation of damage. PMID:27469265

Incidence and management of leukopenia/neutropenia in 233 kidney transplant patients following single dose alemtuzumab induction.

PubMed

Smith, A; Couvillion, R; Zhang, R; Killackey, M; Buell, J; Lee, B; Saggi, B H; Paramesh, A S

2014-12-01

The purpose of this study was to determine the incidence and management strategies for post-transplant leukopenia/neutropenia in kidney recipients receiving alemtuzumab induction during the first year following transplantation. We prospectively identified 233 adult patients who underwent kidney transplantation with alemtuzumab induction at a single institution. The incidence and severity of leukopenia (white blood cell count [WBC] ≤2500/mm(3)) and neutropenia (absolute neutrophil count [ANC] ≤500/mm(3)) were evaluated at 1, 3, 6, and 12 months post-transplantation. We determined any association with cytomegalovirus (CMV) infection, graft rejection, and infections requiring hospitalization. We also reviewed interventions performed, including medication adjustments, treatment with granulocyte stimulating factor, and hospitalization. The combined incidence of either leukopenia or neutropenia was 47.5% (n = 114/233) with an average WBC nadir of 1700 ± 50/mm(3) at 131.0 ± 8.5 days and an average ANC nadir of 1500 ± 100/mm(3) at 130.4 ± 9.6 days. No significant difference in graft rejection, CMV infection, or infections requiring hospitalization was found in the leukopenia/neutropenia group vs the normal WBC group (P = .3). The most common intervention performed for leukopenia/neutropenia group was prophylactic medication adjustment. Six patients (5.2%) required a change in >1 medication. The majority of these patients also required granulocyte stimulating factor (61.5%; 32/52), with an average of 2.5 doses given. A total of 25 patients (21.9%) required hospitalization due to leukopenia/neutropenia with an average length of stay of 6 days. Kidney transplant patients receiving alemtuzumab induction required significant interventions due to leukopenia/neutropenia in the first year post-transplantation. These results suggest the need for additional studies aimed at defining the optimum management strategies of leukopenia/neutropenia in this population. Copyright © 2014 Elsevier Inc. All rights reserved.

End-of-treatment and serial PET imaging in primary mediastinal B-cell lymphoma following dose-adjusted-EPOCH-R: A paradigm shift in clinical decision making.

PubMed

Melani, Christopher; Advani, Ranjana; Roschewski, Mark; Walters, Kelsey M; Chen, Clara C; Baratto, Lucia; Ahlman, Mark A; Miljkovic, Milos D; Steinberg, Seth M; Lam, Jessica; Shovlin, Margaret; Dunleavy, Kieron; Pittaluga, Stefania; Jaffe, Elaine S; Wilson, Wyndham H

2018-05-10

Dose-adjusted-EPOCH-R obviates the need for radiotherapy in most patients with primary mediastinal B-cell lymphoma. End-of-treatment PET, however, does not accurately identify patients at risk of treatment failure, thereby confounding clinical decision making. To define the role of PET in primary mediastinal B-cell lymphoma following dose-adjusted-EPOCH-R, we extended enrollment and follow-up on our published phase II trial and independent series. Ninety-three patients received dose-adjusted-EPOCH-R without radiotherapy. End-of-treatment PET was performed in 80 patients, of whom 57 received 144 serial scans. One nuclear medicine physician from each institution blindly reviewed all scans from their respective institution. End-of-treatment PET was negative (Deauville 1-3) in 55 (69%) patients with one treatment failure (8-year event-free and overall survival of 96.0% and 97.7%). Among 25 (31%) patients with a positive (Deauville 4-5) end-of-treatment PET, there were 5 (20%) treatment failures (8-year event-free and overall survival of 71.1% and 84.3%). Linear regression analysis of serial scans showed a significant decrease in SUVmax in positive end-of-treatment PET non-progressors compared to an increase in treatment failures. Among 6 treatment failures, the median end-of-treatment SUVmax was 15.4 (range, 1.9-21.3) and 4 achieved long-term remission with salvage therapy. Virtually all patients with a negative end-of-treatment PET following dose-adjusted-EPOCH-R achieved durable remissions and should not receive radiotherapy. Among patients with a positive end-of-treatment PET, only 5/25 (20%) had treatment-failure. Serial PET imaging distinguished end-of-treatment PET positive patients without treatment failure, thereby reducing unnecessary radiotherapy by 80%, and should be considered in all patients with an initial positive PET following dose-adjusted-EPOCH-R (NCT00001337). Copyright © 2018, Ferrata Storti Foundation.

Clinical and genetic factors affecting tacrolimus trough levels and drug-related outcomes in Korean kidney transplant recipients.

PubMed

Kim, In-Wha; Moon, Yoo Jin; Ji, Eunhee; Kim, Kyung Im; Han, Nayoung; Kim, Sung Ju; Shin, Wan Gyoon; Ha, Jongwon; Yoon, Jeong-Hyun; Lee, Hye Suk; Oh, Jung Mi

2012-05-01

The purpose of this study was to characterize the effects of clinical and genetic variables on the pharmacokinetics and complications of tacrolimus during the first year after kidney transplantation. One hundred and thirty-two Korean kidney recipients who received tacrolimus were genotyped for ABCB1 (exons 12, 21, and 26) and CYP3A5 (intron 3). Tacrolimus trough levels, dose, or dose-adjusted trough levels and complications were compared among patients during the early stage (3, 7, 14, 30, and 90 days) and up to 1 year according to the genotypes. A donor source-adjusted linear mixed model with multilevel analysis adjusting for age, body weight, hematocrit, and serum creatinine showed that CYP3A5 genotype is associated with dose-adjusted level of tacrolimus (p < 0.001). The influence of ABCB1 polymorphisms on the pharmacokinetics or complications of tacrolimus was less certain in our study. The incidence of acute rejections was significantly higher in recipients of cadaveric donor kidney (p < 0.05). A generalized estimating equation model analysis showed that alopecia and hyperlipidemia were associated with dose-adjusted level of tacrolimus (p < 0.001). Genotype of CYP3A5 variants along with significant clinical covariates may be useful in individualizing tacrolimus therapy in kidney transplantation patients.

Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects.

PubMed

Chen, Laishun; Boinpally, Ramesh; Gad, Nayra; Greenberg, William M; Wangsa, Julie; Periclou, Antonia; Ghahramani, Parviz

2015-10-01

Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39% [90% confidence interval (CI) 31-47%] and area under the concentration-time curve (AUC) by 57% (90% CI 47-67%), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26% (90% CI 22-30%) and 29% (90% CI 26-32%), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.

Derivation of mean dose tolerances for new fractionation schemes and treatment modalities

NASA Astrophysics Data System (ADS)

Perkó, Zoltán; Bortfeld, Thomas; Hong, Theodore; Wolfgang, John; Unkelbach, Jan

2018-02-01

Avoiding toxicities in radiotherapy requires the knowledge of tolerable organ doses. For new, experimental fractionation schemes (e.g. hypofractionation) these are typically derived from traditional schedules using the biologically effective dose (BED) model. In this report we investigate the difficulties of establishing mean dose tolerances that arise since the mean BED depends on the entire spatial dose distribution, rather than on the dose level alone. A formula has been derived to establish mean physical dose constraints such that they are mean BED equivalent to a reference treatment scheme. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 24 liver cancer patients for whom both proton and photon IMRT treatment plans were available. The results show that the standard BED equation—neglecting the spatial dose distribution—can overestimate mean dose tolerances for hypofractionated treatments by up to 20%. The shape difference between photon and proton dose distributions can cause 30-40% differences in mean physical dose for plans having identical mean BEDs. Converting hypofractionated, 5/15-fraction proton doses to mean BED equivalent photon doses in traditional 35-fraction regimens resulted in up to 10 Gy higher doses than applying the standard BED formula. The dose shape effect should be accounted for to avoid overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. Additionally, tolerances established for one treatment modality cannot necessarily be applied to other modalities with drastically different dose distributions, such as proton therapy. Last, protons may only allow marginal (5-10%) dose escalation if a fraction-size adjusted organ mean dose is constraining instead of a physical dose.

Is It Better to Enter a Volume CT Dose Index Value before or after Scan Range Adjustment for Radiation Dose Optimization of Pediatric Cardiothoracic CT with Tube Current Modulation?

PubMed Central

2018-01-01

Objective To determine whether the body size-adapted volume computed tomography (CT) dose index (CTDvol) in pediatric cardiothoracic CT with tube current modulation is better to be entered before or after scan range adjustment for radiation dose optimization. Materials and Methods In 83 patients, cardiothoracic CT with tube current modulation was performed with the body size-adapted CTDIvol entered after (group 1, n = 42) or before (group 2, n = 41) scan range adjustment. Patient-related, radiation dose, and image quality parameters were compared and correlated between the two groups. Results The CTDIvol after the CT scan in group 1 was significantly higher than that in group 2 (1.7 ± 0.1 mGy vs. 1.4 ± 0.3 mGy; p < 0.0001). Image noise (4.6 ± 0.5 Hounsfield units [HU] vs. 4.5 ± 0.7 HU) and image quality (1.5 ± 0.6 vs. 1.5 ± 0.6) showed no significant differences between the two (p > 0.05). In both groups, all patient-related parameters, except body density, showed positive correlations (r = 0.49–0.94; p < 0.01) with the CTDIvol before and after the CT scan. The CTDIvol after CT scan showed modest positive correlation (r = 0.49; p ≤ 0.001) with image noise in group 1 but no significant correlation (p > 0.05) in group 2. Conclusion In pediatric cardiothoracic CT with tube current modulation, the CTDIvol entered before scan range adjustment provides a significant dose reduction (18%) with comparable image quality compared with that entered after scan range adjustment.

Image perception by expert readers as a function of patient skin entrance dose levels in digital radiography

NASA Astrophysics Data System (ADS)

Lehnert, T.; Korkusuz, H.; Khan, F.; Vogl, T. J.; Mack, M. G.

2008-03-01

In this study, image quality was based on required clinical criteria, in order to investigate to what degree entrance dose could be lowered and what kind of added filtration can be used without impinging on radiologist confidence levels in diagnosing. Images were taken of extremities from a cadaver using stepwise decreasing dose levels and variation of added filtration (no filtration, aluminum, aluminum/copper) under digital projection radiography (Kodak DirectView DR7500). The starting point dose level for all body parts imaged was the current x-ray technique. Two experienced and two resident radiologists were presented the images in a blinded fashion and rated each with an image quality score from 1 to 9 indicated very satisfied and 1 as very unsatisfied indicating loss of diagnostic value. The readers were not aware of which dose level and added filtration corresponded to which image. Dose levels considered were 100%, 75%, 50% and 25% of the normal and customary x-ray techniques used for the particular body part and projection. Images were reviewed on a clinical diagnostic workstation with no time limits imposed. Readers were also able to change the image presentation by adjusting the window width and level. Without added filtration image quality mean score was rated with 6.3 (dose level 100%), 6.2 (dose level 75%), 5.3 (dose level 50%) and with 4.4 (dose level 25%). An added aluminum filtration induced an image quality mean score of 6.3 (dose level 100%), 6.0 (dose level 75%), 5.1 (dose level 50%) and of 4.2 (dose level 25%). Using aluminum/copper filtration image quality mean score was rated with 6.0 (dose level 100%), 6.1 (dose level 75%), 5.0 (dose level 50%) and with 3.8 (dose level 25%). Regardless of the added filtration a differentiation between dose levels 100% and 75% was possible in 38.9%, between dose levels 75% and 50% in 66.7%, and between dose levels 50% and 25% in 70.0% of the cases. It is possible, in the case of extremities, to lower entrance doses up to 75 % of the normal value, a reduction of 25% in dose, under simultaneous use of added aluminum or aluminum/copper filtration, without comprising the diagnostic value required.

Evaluation of an artificial intelligence guided inverse planning system: clinical case study.

PubMed

Yan, Hui; Yin, Fang-Fang; Willett, Christopher

2007-04-01

An artificial intelligence (AI) guided method for parameter adjustment of inverse planning was implemented on a commercial inverse treatment planning system. For evaluation purpose, four typical clinical cases were tested and the results from both plans achieved by automated and manual methods were compared. The procedure of parameter adjustment mainly consists of three major loops. Each loop is in charge of modifying parameters of one category, which is carried out by a specially customized fuzzy inference system. A physician prescribed multiple constraints for a selected volume were adopted to account for the tradeoff between prescription dose to the PTV and dose-volume constraints for critical organs. The searching process for an optimal parameter combination began with the first constraint, and proceeds to the next until a plan with acceptable dose was achieved. The initial setup of the plan parameters was the same for each case and was adjusted independently by both manual and automated methods. After the parameters of one category were updated, the intensity maps of all fields were re-optimized and the plan dose was subsequently re-calculated. When final plan arrived, the dose statistics were calculated from both plans and compared. For planned target volume (PTV), the dose for 95% volume is up to 10% higher in plans using the automated method than those using the manual method. For critical organs, an average decrease of the plan dose was achieved. However, the automated method cannot improve the plan dose for some critical organs due to limitations of the inference rules currently employed. For normal tissue, there was no significant difference between plan doses achieved by either automated or manual method. With the application of AI-guided method, the basic parameter adjustment task can be accomplished automatically and a comparable plan dose was achieved in comparison with that achieved by the manual method. Future improvements to incorporate case-specific inference rules are essential to fully automate the inverse planning process.

Sci-Fri AM: MRI and Diagnostic Imaging - 02: Quality Improvement: Diagnostic Reference Levels for Interior Health CT exams – L-Spine, Chest/Abdomen/pelvis, Abdomen/Pelvis, Head

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bjarnason, Thorarin

Diagnostic Reference Levels are used to optimize patient dose and image quality in the clinical setting. It is assumed that the majority of exams are of diagnostic quality, or the radiologists would request protocol adjustments. By investigating the dose indicator distributions from all scanners, the upper DRL can be set to the 75th percentile of the distribution and a lower DRL can be set to the 10th percentile. Scanners using doses consistently outside the upper/lower DRL range can be adjusted accordingly. 11 CT scanners, all contributing to the American College of Radiology Dose Index Registry (ACR DIR) were used inmore » this study. Dose indicator data were compiled from the ACR DIR data and local DRLs established. Scanners with median doses outside the upper/lower DRL were followed-up with. Using effective dose and exam volumes, collective dose was determined before and after protocol adjustments to evaluate the effect of this quality improvement effort. The quality initiative is complete for L-spine and Chest/Abdomen/Pelvis exams and only initial surveys were completed for Head and Abdomen/Pelvis examsg. Median Scanner Dose reductions were 8.8 and 4.9 % for L-spine and Chest/Abdomen/Pelvis exams, respectively, resulting with collective dose reductions of 0.7 and 3.2 person•Sv/yr. Follow-up is ongoing for Abdomen/Pelvis and Head exams.« less

Feasibility of online IMPT adaptation using fast, automatic and robust dose restoration

NASA Astrophysics Data System (ADS)

Bernatowicz, Kinga; Geets, Xavier; Barragan, Ana; Janssens, Guillaume; Souris, Kevin; Sterpin, Edmond

2018-04-01

Intensity-modulated proton therapy (IMPT) offers excellent dose conformity and healthy tissue sparing, but it can be substantially compromised in the presence of anatomical changes. A major dosimetric effect is caused by density changes, which alter the planned proton range in the patient. Three different methods, which automatically restore an IMPT plan dose on a daily CT image were implemented and compared: (1) simple dose restoration (DR) using optimization objectives of the initial plan, (2) voxel-wise dose restoration (vDR), and (3) isodose volume dose restoration (iDR). Dose restorations were calculated for three different clinical cases, selected to test different capabilities of the restoration methods: large range adaptation, complex dose distributions and robust re-optimization. All dose restorations were obtained in less than 5 min, without manual adjustments of the optimization settings. The evaluation of initial plans on repeated CTs showed large dose distortions, which were substantially reduced after restoration. In general, all dose restoration methods improved DVH-based scores in propagated target volumes and OARs. Analysis of local dose differences showed that, although all dose restorations performed similarly in high dose regions, iDR restored the initial dose with higher precision and accuracy in the whole patient anatomy. Median dose errors decreased from 13.55 Gy in distorted plan to 9.75 Gy (vDR), 6.2 Gy (DR) and 4.3 Gy (iDR). High quality dose restoration is essential to minimize or eventually by-pass the physician approval of the restored plan, as long as dose stability can be assumed. Motion (as well as setup and range uncertainties) can be taken into account by including robust optimization in the dose restoration. Restoring clinically-approved dose distribution on repeated CTs does not require new ROI segmentation and is compatible with an online adaptive workflow.

Improved sulfide mitigation in sewers through on-line control of ferrous salt dosing.

PubMed

Ganigué, Ramon; Jiang, Guangming; Liu, Yiqi; Sharma, Keshab; Wang, Yue-Cong; Gonzalez, José; Nguyen, Tung; Yuan, Zhiguo

2018-05-15

Water utilities worldwide spend annually billions of dollars to control sulfide-induced corrosion in sewers. Iron salts chemically oxidize and/or precipitate dissolved sulfide in sewage and are especially used in medium- and large-size sewers. Iron salt dosing rates are defined ad hoc, ignoring variation in sewage flows and sulfide levels. This often results in iron overdosing or poor sulfide control. Online dosing control can adjust the chemical dosing rates to current (and future) state of the sewer system, allowing high-precision, stable and cost-effective sulfide control. In this paper, we report a novel and robust online control strategy for the dosing of ferrous salt in sewers. The control considers the fluctuation of sewage flow, pH, sulfide levels and also the perturbation from rainfall. Sulfide production in the pipe is predicted using auto-regressive models (AR) based on current flow measurements, which in turn can be used to determine the dose of ferrous salt required for cost-effective sulfide control. Following comprehensive model-based assesment, the control was successfully validated and its effectiveness demonstrated in a 3-week field trial. The online control algorithm controlled sulfide below the target level (0.5 mg S/L) while reducing chemical dosing up to 30%. Copyright © 2018 Elsevier Ltd. All rights reserved.

ESR/ERS white paper on lung cancer screening

PubMed Central

Bonomo, Lorenzo; Gaga, Mina; Nackaerts, Kristiaan; Peled, Nir; Prokop, Mathias; Remy-Jardin, Martine; von Stackelberg, Oyunbileg; Sculier, Jean-Paul

2015-01-01

Lung cancer is the most frequently fatal cancer, with poor survival once the disease is advanced. Annual low dose computed tomography has shown a survival benefit in screening individuals at high risk for lung cancer. Based on the available evidence, the European Society of Radiology and the European Respiratory Society recommend lung cancer screening in comprehensive, quality-assured, longitudinal programmes within a clinical trial or in routine clinical practice at certified multidisciplinary medical centres. Minimum requirements include: standardised operating procedures for low dose image acquisition, computer-assisted nodule evaluation, and positive screening results and their management; inclusion/exclusion criteria; expectation management; and smoking cessation programmes. Further refinements are recommended to increase quality, outcome and cost-effectiveness of lung cancer screening: inclusion of risk models, reduction of effective radiation dose, computer-assisted volumetric measurements and assessment of comorbidities (chronic obstructive pulmonary disease and vascular calcification). All these requirements should be adjusted to the regional infrastructure and healthcare system, in order to exactly define eligibility using a risk model, nodule management and quality assurance plan. The establishment of a central registry, including biobank and image bank, and preferably on a European level, is strongly encouraged. PMID:25929956

The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies.

PubMed

Hernandez, Stephanie H; Howland, Maryann; Schiano, Thomas D; Hoffman, Robert S

2015-01-01

Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

Influence of Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir on Warfarin Dosing Requirements in Four Veterans.

PubMed

Britnell, Sara R; Willets, Amy E; Vanderman, Adam J; Woodard, Catherine L; Britt, Rachel B

2016-11-01

To describe international normalized ratio (INR) trends and warfarin dosage adjustments required for four veterans who were receiving warfarin therapy and started treatment for hepatitis C virus (HCV) with ledipasvir/sofosbuvir with or without ribavirin. Case series. Pharmacist-led anticoagulation clinic in a Veterans Affairs Health Care System. Four patients aged 59-66 years who were receiving warfarin and had stable, therapeutic INRs and started ledipasvir/sofosbuvir therapy with or without ribavirin for HCV infection. All four patients developed subtherapeutic INRs after the addition of ledipasvir/sofosbuvir with or without ribavirin. An increase in weekly warfarin dose ranging from 14-67% was required, with changes in warfarin doses starting 2-3 weeks after ledipasvir/sofosbuvir initiation. Two patients required dose reductions after HCV treatment completion, whereas the other two did not. Use of the Drug Interaction Probability Scale indicated that the interaction between warfarin and ledipasvir/sofosbuvir was doubtful (score of 1 [two patients]) or possible (score of 4 [two patients]). The mechanism of this interaction is unknown but may be related to improvements in hepatic function during HCV treatment. To our knowledge, this is the first case series describing a possible drug interaction between warfarin and ledipasvir/sofosbuvir (with or without ribavirin). Close monitoring is warranted when ledipasvir/sofosbuvir is initiated in patients receiving anticoagulation therapy with warfarin, especially those with evidence of cirrhosis prior to treatment. This is particularly important in the first month after starting treatment and the first month after completion. Failure to monitor and achieve therapeutic INR after HCV therapy completion may have the potential to result in adverse outcomes. © 2016 Pharmacotherapy Publications, Inc.

Control of lithium tremor with propranolol.

PubMed

Lapierre, Y D

1976-04-03

Lithium tremor is an irregular, nonrhythmic tremor of the distal extremities, variable in both intensity and frequency. It is clinically differentiated from essential tremor and tremors due to anxiety and neuroleptics. The pathophysiologic mechanisms are hypothesized to be of perpheral origin. Five patients were successfully treated with propranolol. In general, the dosage of propranolol must be individually adjusted and is usually from 30 to 40 mg daily in divided doses. This blocker of beta-adrenergic receptors remains effective with long-term administration and increases in dosage are not required.

Site-specific range uncertainties caused by dose calculation algorithms for proton therapy

NASA Astrophysics Data System (ADS)

Schuemann, J.; Dowdell, S.; Grassberger, C.; Min, C. H.; Paganetti, H.

2014-08-01

The purpose of this study was to assess the possibility of introducing site-specific range margins to replace current generic margins in proton therapy. Further, the goal was to study the potential of reducing margins with current analytical dose calculations methods. For this purpose we investigate the impact of complex patient geometries on the capability of analytical dose calculation algorithms to accurately predict the range of proton fields. Dose distributions predicted by an analytical pencil-beam algorithm were compared with those obtained using Monte Carlo (MC) simulations (TOPAS). A total of 508 passively scattered treatment fields were analyzed for seven disease sites (liver, prostate, breast, medulloblastoma-spine, medulloblastoma-whole brain, lung and head and neck). Voxel-by-voxel comparisons were performed on two-dimensional distal dose surfaces calculated by pencil-beam and MC algorithms to obtain the average range differences and root mean square deviation for each field for the distal position of the 90% dose level (R90) and the 50% dose level (R50). The average dose degradation of the distal falloff region, defined as the distance between the distal position of the 80% and 20% dose levels (R80-R20), was also analyzed. All ranges were calculated in water-equivalent distances. Considering total range uncertainties and uncertainties from dose calculation alone, we were able to deduce site-specific estimations. For liver, prostate and whole brain fields our results demonstrate that a reduction of currently used uncertainty margins is feasible even without introducing MC dose calculations. We recommend range margins of 2.8% + 1.2 mm for liver and prostate treatments and 3.1% + 1.2 mm for whole brain treatments, respectively. On the other hand, current margins seem to be insufficient for some breast, lung and head and neck patients, at least if used generically. If no case specific adjustments are applied, a generic margin of 6.3% + 1.2 mm would be needed for breast, lung and head and neck treatments. We conclude that the currently used generic range uncertainty margins in proton therapy should be redefined site specific and that complex geometries may require a field specific adjustment. Routine verifications of treatment plans using MC simulations are recommended for patients with heterogeneous geometries.

Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease.

PubMed

Qi, Hui; Li, Shixue

2014-04-01

A dose-response meta-analysis was carried out between Parkinson's disease (PD) risk, and coffee, tea and caffeine consumption. A comprehensive search was carried out to identify eligible studies. The fixed or random effect model was used based on heterogeneity test. The dose-response relationship was assessed by restricted cubic spline. A total of 13 articles involving 901 764 participants for coffee, eight articles involving 344 895 participants for tea and seven articles involving 492 724 participants for caffeine were included. A non-linear relationship was found between coffee consumption and PD risk overall, and the strength of protection reached the maximum at approximately 3 cups/day (smoking-adjusted relative risk: 0.72, 95% confidence interval 0.65-0.81). A linear relationship was found between tea and caffeine consumption, and PD risk overall, and the smoking-adjusted risk of PD decreased by 26% and 17% for every two cups/day and 200 mg/day increments, respectively. The association of coffee and tea consumption with PD risk was stronger for men than that for women, and the association of caffeine consumption with PD risk was stronger for ever users of hormones than that for never users of hormones among postmenopausal women. The aforementioned associations were weaker for USA relative to Europe or Asia. A linear dose-relationship for decreased PD risk with tea and caffeine consumption was found, whereas the strength of protection reached a maximum at approximately 3 cups/day for coffee consumption overall. Further studies are required to confirm the findings. © 2013 Japan Geriatrics Society.

Pharmacogenetics-Based Warfarin Dosing in Patients With Cardiac Valve Replacement: The Effects of CYP2C9 and VKORC1 Gene Polymorphisms.

PubMed

Farzamikia, Negin; Sakhinia, Ebrahim; Afrasiabirad, Abbas

2017-12-22

Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study. Genotyping of CYP2C9 and VKORC1 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The demographic and clinical data were collected using a precodified questionnaire and clinical examination and then were analyzed.Our findings revealed that the prevalence of CYP2C9 *2, *3 and VKORC1 -1639A alleles in patients were 10.5%, 39%, and 48%, respectively. We also found that patients with CYP2C9 *1 and VKORC1 -1639G alleles required the highest dosages of warfarin, while the carriers of CYP2C9 variant *2 and *3 alleles and VKORC1 -1639A required less warfarin. Univariate regression analysis showed that age and presence of CYP2C9 *2 allele significantly influenced the daily warfarin dose requirement. Our findings provide additional evidence to support the hypothesis that CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms explain a considerable proportion of interindividual variability in warfarin dose. Therefore, testing for these variants might be helpful for adjusting patient warfarin dosage to an effective and safe level. © American Society for Clinical Pathology 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments.

PubMed

Agarwal, Suresh K; DiNardo, Courtney D; Potluri, Jalaja; Dunbar, Martin; Kantarjian, Hagop M; Humerickhouse, Rod A; Wong, Shekman L; Menon, Rajeev M; Konopleva, Marina Y; Salem, Ahmed Hamed

2017-02-01

The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m 2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax C max and AUC 0-24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax C max and AUC 0-24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax C max and AUC 0-24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Impact of Uncertainties in Exposure Assessment on Thyroid Cancer Risk among Persons in Belarus Exposed as Children or Adolescents Due to the Chernobyl Accident.

PubMed

Little, Mark P; Kwon, Deukwoo; Zablotska, Lydia B; Brenner, Alina V; Cahoon, Elizabeth K; Rozhko, Alexander V; Polyanskaya, Olga N; Minenko, Victor F; Golovanov, Ivan; Bouville, André; Drozdovitch, Vladimir

2015-01-01

The excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of 131I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error. We examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996-2004, who had direct thyroid 131I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied. There was a statistically significant (p<0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy- (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy- (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy- (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy- (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053-0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2). In summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.

Initial fluid resuscitation following adjusted body weight dosing is associated with improved mortality in obese patients with suspected septic shock.

PubMed

Taylor, Stephanie Parks; Karvetski, Colleen H; Templin, Megan A; Heffner, Alan C; Taylor, Brice T

2018-02-01

The optimal initial fluid resuscitation strategy for obese patients with septic shock is unknown. We evaluated fluid resuscitation strategies across BMI groups. Retrospective analysis of 4157 patients in a multicenter activation pathway for treatment of septic shock between 2014 and 2016. 1293 (31.3%) patients were obese (BMI≥30). Overall, higher BMI was associated with lower mortality, however this survival advantage was eliminated in adjusted analyses. Patients with higher BMI received significantly less fluid per kilogram at 3h than did patients with lower BMI (p≤0.001). In obese patients, fluid given at 3h mimicked a dosing strategy based on actual body weight (ABW) in 780 (72.2%), adjusted body weight (AdjBW) in 95 (8.8%), and ideal body weight (IBW) in 205 (19.0%). After adjusting for condition- and treatment-related variables, dosing based on AdjBW was associated with improved mortality compared to ABW (OR 0.45; 95% CI [0.19, 1.07]) and IBW (OR 0.29; 95% CI [0.11,0.74]). Using AdjBW to calculate initial fluid resuscitation volume for obese patients with suspected shock may improve outcomes compared to other weight-based dosing strategies. The optimal fluid dosing strategy for obese patients should be a focus of future prospective research. Copyright © 2017 Elsevier Inc. All rights reserved.

Blood purification in the critically ill patient. Prescription tailored to the indication (including the pediatric patient).

PubMed

Sanchez-Izquierdo Riera, J A; Montoiro Allué, R; Tomasa Irriguible, T; Palencia Herrejón, E; Cota Delgado, F; Pérez Calvo, C

2016-10-01

We maintain a dynamic position on extracorporeal blood purification therapies (EBPT). Continuous therapies are of choice in the hemodynamically unstable patient. We recommend their early introduction in the course of the disease, and starting with a dose of 30-35mL/kg/h. Above all, however, daily re-evaluation is required of the hemodynamic and metabolic situation and water balance of our patients in order to allow dynamic dose adjustment. Some data suggest that continuous EBPT can favorably influence the clinical course of our patients, even in the absence of acute kidney injury. The potential usefulness of hemofiltration at doses higher than the conventional doses (continuous ultrafiltration >50mL/kg/h or pulses of at least 4h a day to more than 100dosesmL/kg/h) for achieving blood purification has also been commented. We review the possible indications of this technique, together with the peculiarities of implementing these therapies in children. Copyright © 2016 Elsevier España, S.L.U. y SEMICYUC. All rights reserved.

An information and communication technology-based centralized clinical trial to determine the efficacy and safety of insulin dose adjustment education based on a smartphone personal health record application: a randomized controlled trial.

PubMed

Kim, Gyuri; Bae, Ji Cheol; Yi, Byoung Kee; Hur, Kyu Yeon; Chang, Dong Kyung; Lee, Moon-Kyu; Kim, Jae Hyeon; Jin, Sang-Man

2017-07-18

A Personal Health Record (PHR) is an online application that allows patients to access, manage, and share their health data. PHRs not only enhance shared decision making with healthcare providers, but also enable remote monitoring and at-home-collection of detailed data. The benefits of PHRs can be maximized in insulin dose adjustment for patients starting or intensifying insulin regimens, as frequent self-monitoring of glucose, self-adjustment of insulin dose, and precise at-home data collection during the visit-to-visit period are important for glycemic control. The aim of this study is to examine the efficacy and safety of insulin dose adjustment based on a smartphone PHR application in patients with diabetes mellitus (DM) and to confirm the validity and stability of an information and communication technology (ICT)-based centralized clinical trial monitoring system. This is a 24-week, open-label, randomized, multi-center trial. There are three follow-up measures: baseline, post-intervention at week 12, and at week 24. Subjects diagnosed with type 1 DM, type 2 DM, and/or post-transplant DM who initiate basal insulin or intensify their insulin regimen to a basal-bolus regimen are included. After education on insulin dose titration and prevention for hypoglycemia and a 1-week acclimation period, subjects are randomized in a 1:1 ratio to either an ICT-based intervention group or a conventional intervention group. Subjects in the conventional intervention group will save and send their health information to the server via a PHR application, whereas those in ICT-based intervention group will receive additional algorithm-based feedback messages. The health information includes level of blood glucose, insulin dose, details on hypoglycemia, food diary, and step count. The primary outcome will be the proportion of patients who reach an optimal insulin dose within 12 weeks of study enrollment, without severe hypoglycemia or unscheduled clinic visits. This clinical trial will reveal whether insulin dose adjustment based on a smartphone PHR application can facilitate the optimization of insulin doses in patients with DM. In addition, the process evaluation will provide information about the validity and stability of the ICT-based centralized clinical trial monitoring system in this research field. Clinicaltrials.gov NCT 03112343 . Registered on 12 April 2017.

Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population.

PubMed

Lee, Soo-Chin; Ng, Swee-Siang; Oldenburg, Johannes; Chong, Pei-Yi; Rost, Simone; Guo, Jia-Yi; Yap, Hui-Ling; Rankin, Sheila Clare; Khor, Hui-Boon; Yeo, Tiong-Cheng; Ng, Kheng-Siang; Soong, Richie; Goh, Boon-Cher

2006-03-01

Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements. We sequenced the coding regions of CYP2C9 and VKORC1 and inferred VKORC1 haplotype from 10 intronic variants in 147 Chinese, 85 Malay, and 43 Indian patients receiving maintenance warfarin. The mean weight-normalized warfarin dose was lower for Chinese and Malays than for Indians (0.058 +/- 0.025 mg/kg, 0.059 +/- 0.023 mg/kg, and 0.089 +/- 0.036 mg/kg, respectively; P < .001 for comparisons between Chinese and Malays with Indians). CYP2C9*2 and VKORC1 coding region variants were rare (<2%), whereas CYP2C9*3 associated with lower warfarin requirements was less common in Chinese and Malays (7% and 9%, respectively) than in Indians (18%) and could not account for their lower warfarin requirements. VKORC1 H1 and H7/H8/H9 haplotypes were associated with lower and higher warfarin requirements, respectively (0.050 +/- 0.019 mg/kg and 0.092 +/- 0.057 mg/kg, respectively; P < .001). VKORC1 H1 haplotype (requiring low warfarin doses) was common in Chinese (87%) and Malays (65%) but uncommon in Indians (12%), whereas H7, H8, and H9 haplotypes (requiring high warfarin doses) were rare in Chinese (9%), intermediate in Malays (30%), and common in Indians (82%). The interethnic difference in warfarin requirements became nonsignificant when adjusted for VKORC1 haplotype. Interethnic difference in VKORC1 haplotypes accounts for the difference in warfarin requirements between Chinese, Malays, and Indians, providing interesting insights into genetic variation between ethnogeographically distinct Asian groups.

Efficacy and safety of continuous every-2-week dosing of ixekizumab over 52 weeks in patients with moderate-to-severe plaque psoriasis in a randomized phase III trial (IXORA-P).

PubMed

Langley, R G; Papp, K; Gooderham, M; Zhang, L; Mallinckrodt, C; Agada, N; Blauvelt, A; Foley, P; Polzer, P

2018-06-01

Ixekizumab is an interleukin-17A antagonist approved for treatment of moderate-to-severe plaque psoriasis with a recommended 160-mg starting dose, then 80 mg every 2 weeks (Q2W) to week 12, and every 4 weeks (Q4W) thereafter. To evaluate continuous Q2W dosing over 52 weeks. In this phase III, multicentre, double-blinded, parallel-group trial, three ixekizumab dosing regimens were assessed for efficacy and safety at week 52 in patients with moderate-to-severe plaque psoriasis randomized at a 2 : 1 : 1 ratio to continuous Q2W (n = 611), continuous Q4W (n = 310) or dose adjustment per protocol (Q4W/Q2W, n = 306), each with a 160-mg starting dose. Dose adjustment was determined by predefined criteria to which investigators were blinded; 72 (23?5%) patients in the Q4W/Q2W group adjusted dose. Efficacy outcomes were evaluated using logistic regression. Co-primary end points were met at week 52: Psoriasis Area and Severity Index 75 responses for Q2W and Q4W dose groups were 85·9% and 79·0%, respectively (P = 0·006), and static patient global assessment 0/1 responses for Q2W and Q4W dose groups were 78·6% and 70·6%, respectively (P = 0·005). Treatment-emergent and serious adverse events were comparable across dose groups. Ixekizumab Q2W had higher efficacy at week 52 than ixekizumab Q4W, with no increase in safety events. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Ceftazidime dosing in the elderly: economic implications.

PubMed

Vlasses, P H; Bastion, W A; Behal, R; Sirgo, M A

1993-01-01

This study evaluated the prevalence and resulting costs of ceftazidime dosing in excess of product labeling recommendations in elderly hospitalized patients. Ceftazidime is a beta-lactam antibiotic excreted via glomerular filtration. According to product labeling, ceftazidime dosing can frequently be decreased in the elderly because glomerular filtration declines with age. A multicenter, retrospective utilization audit involving 11 US academic medical centers examined 221 medical records of patients 65 years of age or older receiving ceftazidime (any brand, any indication). The creatinine clearance of each patient was estimated using the Cockcroft-Gault formula. Renal insufficiency, defined as an estimated creatinine clearance of less than 50 mL/min, was present in 111 of the patients (50 percent). Ceftazidime dosing in excess of product labeling recommendations was noted in 75 of those 111 (68 percent). The cost of excess ceftazidime dosing for those 75 patients (i.e., extra drug acquisition, preparation, administration) was $13,822.50. Although the dosage of ceftazidime required in a specific patient is based on many factors, ceftazidime is frequently overdosed in the elderly because renal function is not considered. Ceftazidime dose-adjustment in the elderly, based on the estimated creatinine clearance, can lead to cost savings. In the US, where hospital reimbursement by Medicare is based on diagnosis, institutions can realize direct cost savings.

Social aspects in additive manufacturing of pharmaceutical products.

PubMed

Lind, Johanna; Kälvemark Sporrong, Sofia; Kaae, Susanne; Rantanen, Jukka; Genina, Natalja

2017-08-01

Additive manufacturing (AM) techniques, such as drug printing, represent a new engineering approach that can implement the concept of personalized medicine via on-demand manufacturing of dosage forms with individually adjusted doses. Implementation of AM principles, such as pharmacoprinting, will challenge the entire drug distribution chain and affect the society at different levels. Areas covered: This work summarizes the concept of personalized medicine and gives an overview of possibilities for monitoring patients' health. The most recent activities in the field of printing technologies for fabrication of dosage forms and 'polypills' with flexible doses and tailored release profiles are reviewed. Different scenarios for the drug distribution chain with the required adjustments in drug logistics, quality systems and environmental safety are discussed, as well as whether AM will be used for production of on-demand medicine. The impact of such changes in the distribution chain on regulation, healthcare professionals and patients are highlighted. Expert opinion: Drug manufacturing by traditional methods is well-established, but it lacks the possibility for on-demand personalized drug production. With the recent approval of the first printed medicine, society should be prepared for the changes that will follow the introduction of printed pharmaceuticals.

Linagliptin: farmacology, efficacy and safety in type 2 diabetes treatment

PubMed Central

2013-01-01

Type 2 diabetes mellitus (T2DM) has a high prevalence and incidence around the world. The complex pathophysiology mechanism is among the barriers for diabetes treatment. Type 2 diabetes patients have dysfunction in incretin hormones (as glucagon-like peptide-1 or GLP-1, and glucose-dependent insulinotropic polypeptide or GIP). By inhibiting the dipeptidyl peptidase-4 (DPP-4) enzyme, it is possible to slow the inactivation of GLP-1 and GIP, promoting blood glucose level reduction in a glucose-dependent manner. Linagliptin is a highly specific and potent inhibitor of DPP-4 that is currently indicated for the treatment of type 2 diabetes. Clinical studies with linagliptin demonstrated efficacy in reducing glycated hemoglobin (HbA1c) levels in type 2 diabetes patients, while maintaining a placebo-like safety and tolerability profile. Linagliptin has an interesting pharmacokinetic profile in terms of its predominantly non-renal elimination and the main implication of this characteristic is that no dose adjustment is necessary in patients with renal disease. Also, no dose adjustment is required in patients with hepatic insufficiency, as well in elderly or obese patients. This article will review the pharmacokinetic profile, efficacy data and safety aspects of linagliptin in type 2 diabetes patients. PMID:23697612

Clinical pharmacology of lumiracoxib: a selective cyclo-oxygenase-2 inhibitor.

PubMed

Rordorf, Christiane M; Choi, Les; Marshall, Paul; Mangold, James B

2005-01-01

Lumiracoxib (Prexige) is a selective cyclo-oxygenase (COX)-2 inhibitor developed for the treatment of osteoarthritis, rheumatoid arthritis and acute pain. Lumiracoxib possesses a carboxylic acid group that makes it weakly acidic (acid dissociation constant [pKa] 4.7), distinguishing it from other selective COX-2 inhibitors. Lumiracoxib has good oral bioavailability (74%). It is rapidly absorbed, reaching maximum plasma concentrations 2 hours after dosing, and is highly plasma protein bound. Lumiracoxib has a short elimination half-life from plasma (mean 4 hours) and demonstrates dose-proportional plasma pharmacokinetics with no accumulation during multiple dosing. In patients with rheumatoid arthritis, peak lumiracoxib synovial fluid concentrations occur 3-4 hours later than in plasma and exceed plasma concentrations from 5 hours after dosing to the end of the 24-hour dosing interval. These data suggest that lumiracoxib may be associated with reduced systemic exposure, while still reaching sites where COX-2 inhibition is required for pain relief. Lumiracoxib is metabolised extensively prior to excretion, with only a small amount excreted unchanged in urine or faeces. Lumiracoxib and its metabolites are excreted via renal and faecal routes in approximately equal amounts. The major metabolic pathways identified involve oxidation of the 5-methyl group of lumiracoxib and/or hydroxylation of its dihaloaromatic ring. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX-2 selective. In vitro, the major oxidative pathways are catalysed primarily by cytochrome P450 (CYP) 2C9 with very minor contribution from CYP1A2 and CYP2C19. However, in patients genotyped as poor CYP2C9 metabolisers, exposure to lumiracoxib (area under the plasma concentration-time curve) is not significantly increased compared with control subjects, indicating no requirement for adjustment of lumiracoxib dose in these subjects. Lumiracoxib is selective for COX-2 compared with COX-1 in the human whole blood assay with a ratio of 515 : 1 in healthy subjects and in patients with osteoarthritis or rheumatoid arthritis. COX-2 selectivity was confirmed by a lack of inhibition of arachidonic acid and collagen-induced platelet aggregation. COX-2 selectivity of lumiracoxib is associated with a reduced incidence of gastroduodenal erosions compared with naproxen and a lack of effect on both small and large bowel permeability. Lumiracoxib does not exhibit any clinically meaningful interactions with a range of commonly used medications including aspirin (acetylsalicylic acid), fluconazole, an ethinylestradiol- and levonorgestrel-containing oral contraceptive, omeprazole, the antacid Maalox, methotrexate and warfarin (although, as in common practice, routine monitoring of coagulation is recommended when lumiracoxib is co-administered with warfarin). As such, dose adjustments are not required when co-administering these agents with lumiracoxib. In addition, moderate hepatic impairment and mild to moderate renal impairment do not appear to influence lumiracoxib exposure.

Similar clinical benefits from below-target and target dose enalapril in patients with heart failure in the SOLVD Treatment trial.

PubMed

Lam, Phillip H; Dooley, Daniel J; Fonarow, Gregg C; Butler, Javed; Bhatt, Deepak L; Filippatos, Gerasimos S; Deedwania, Prakash; Forman, Daniel E; White, Michel; Fletcher, Ross D; Arundel, Cherinne; Blackman, Marc R; Adamopoulos, Chris; Kanonidis, Ioannis E; Aban, Inmaculada B; Patel, Kanan; Aronow, Wilbert S; Allman, Richard M; Anker, Stefan D; Pitt, Bertram; Ahmed, Ali

2018-02-01

To examine associations of below-target and target dose of enalapril, an angiotensin-converting enzyme (ACE) inhibitor, with outcomes in patients with heart failure and reduced ejection fraction (HFrEF) in the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial. Two thousand five hundred and sixty-nine patients with HFrEF (ejection fraction ≤35%) were randomized to below-target (5-10 mg/day) dose placebo (n = 1284) or enalapril (n = 1285). One month post-randomization, blind up-titration to target (20 mg/day) dose was attempted for both study drugs in 2458 patients. Among the 1444 patients who achieved dose up-titration (placebo, n = 748; enalapril, n = 696; mean dose for both groups, 20.0 mg/day), target dose enalapril (vs. target dose placebo) was associated with a 9% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality [adjusted hazard ratio (HR) 0.70; 95% confidence interval (CI) 0.60-0.81; P < 0.001] during 4 years of follow-up. Among the 1014 patients who could not achieve target dose (placebo, n = 486; enalapril, n = 528; mean dose for both groups, 8.8 mg/day), below-target dose enalapril (vs. below-target dose placebo) was associated with a 12% absolute lower risk of the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 0.68; 95% CI 0.57-0.81; P < 0.001). Among the 1224 patients receiving enalapril, target (vs. below-target) dose had no association with the combined endpoint of heart failure hospitalization or all-cause mortality (adjusted HR 1.04; 95% CI 0.87-1.23; P = 0.695). In patients with HFrEF, the clinical benefits of ACE inhibitors appear to be similar at both below-target and target doses. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

The effect of low-dose dexmedetomidine on hemodynamics and anesthetic requirement during bis-spectral index-guided total intravenous anesthesia.

PubMed

Park, Hee Yeon; Kim, Jong Yeop; Cho, Sang Hyun; Lee, Dongchul; Kwak, Hyun Jeong

2016-08-01

The purpose of this study was to evaluate the effects of low-dose dexmedetomidine on hemodynamics and anesthetic requirements during propofol and remifentanil anesthesia for laparoscopic cholecystectomy. Thirty adult patients were randomly allocated to receive dexmedetomidine infusion of 0.3 μg/kg/h (dexmedetomidine group, n = 15) or comparable volumes of saline infusion (control group, n = 15). Target controlled infusion of propofol and remifentanil was used for anesthetic induction and maintenance, and adjusted in order to maintain a bispectral index of 40-55 and hemodynamic stability. We measured hemodynamics and recorded total and mean infused dosages of propofol and remifentanil. For anesthesia induction and maintenance, mean infused doses of propofol (121 ± 27 vs. 144 ± 29 μg/kg/min, P = 0.04) and remifentanil (118 ± 27 vs. 150 ± 36 ng/kg/min, P = 0.01) were lower in the dexmedetomidine group than in the control group, respectively. The dexmedetomidine group required 16 % less propofol and 23 % less remifentanil. During anesthetic induction and maintenance, the dexmedetomidine group required fewer total doses of propofol (9.6 ± 2.3 vs. 12.4 ± 3.3 mg/kg, P = 0.01) and remifentanil (9.6 ± 3.4 vs. 12.7 ± 2.6 μg/kg, P = 0.01). The change in mean arterial pressure over time differed between the groups (P < 0.05). Significantly lower mean arterial pressure was observed in the dexmedetomidine group than in the control group at immediately and 5 min after pneumoperitoneum. The time to extubation after completion of drug administration did not differ between the groups (P = 0.25). This study demonstrated that a low-dose dexmedetomidine infusion of 0.3 μg/kg/h reduced propofol and remifentanil requirements as well as hemodynamic change by pneumoperitoneum without delayed recovery during propofol-remifentanil anesthesia for laparoscopic cholecystectomy.

Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.

PubMed

Gulløv, A L; Koefoed, B G; Petersen, P; Pedersen, T S; Andersen, E D; Godtfredsen, J; Boysen, G

1998-07-27

Despite the efficacy of warfarin sodium therapy for stroke prevention in atrial fibrillation, many physicians hesitate to prescribe it to elderly patients because of the risk for bleeding complications and because of inconvenience for the patients. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study was a randomized, controlled trial examining the following therapies: warfarin sodium, 1.25 mg/d; warfarin sodium, 1.25 mg/d, plus aspirin, 300 mg/d; and aspirin, 300 mg/d. These were compared with adjusted-dose warfarin therapy (international normalized ratio of prothrombin time [INR], 2.0-3.0). Stroke or a systemic thromboembolic event was the primary outcome event. Transient ischemic attack, acute myocardial infarction, and death were secondary events. Data were handled as survival data, and risk factors were identified using the Cox proportional hazards model. The trial was scheduled for 6 years from May 1, 1993, but due to scientific evidence of inefficiency of low-intensity warfarin plus aspirin therapy from another study, our trial was prematurely terminated on October 2, 1996. We included 677 patients (median age, 74 years). The cumulative primary event rate after 1 year was 5.8% in patients receiving minidose warfarin; 7.2%, warfarin plus aspirin; 3.6%, aspirin; and 2.8%, adjusted-dose warfarin (P = .67). After 3 years, no difference among the groups was seen. Major bleeding events were rare. Although the difference was insignificant, adjusted-dose warfarin seemed superior to minidose warfarin and to warfarin plus aspirin after 1 year of treatment. The results do not justify a change in the current recommendation of adjusted-dose warfarin (INR, 2.0-3.0) for stroke prevention in atrial fibrillation.

Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma

PubMed Central

Calhoun, William J.; Ameredes, Bill T.; King, Tonya S.; Icitovic, Nikolina; Bleecker, Eugene R.; Castro, Mario; Cherniack, Reuben M.; Chinchilli, Vernon M.; Craig, Timothy; Denlinger, Loren; DiMango, Emily A.; Engle, Linda L.; Fahy, John V.; Grant, J. Andrew; Israel, Elliot; Jarjour, Nizar; Kazani, Shamsah D.; Kraft, Monica; Kunselman, Susan J.; Lazarus, Stephen C.; Lemanske, Robert F.; Lugogo, Njira; Martin, Richard J.; Meyers, Deborah A.; Moore, Wendy C.; Pascual, Rodolfo; Peters, Stephen P.; Ramsdell, Joe; Sorkness, Christine A.; Sutherland, E. Rand; Szefler, Stanley J.; Wasserman, Stephen I.; Walter, Michael J.; Wechsler, Michael E.; Boushey, Homer A.

2013-01-01

Context No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. Objective To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma. Design, Setting, and Participants A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. Interventions For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. Main Outcome Measure The primary outcome was time to treatment failure. Results There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). Conclusion Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure. Trial Registration clinicaltrials.gov Identifier: NCT00495157 PMID:22968888

Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.

PubMed

Macha, Sreeraj; Sennewald, Regina; Rose, Peter; Schoene, Katja; Pinnetti, Sabine; Woerle, Hans J; Broedl, Uli C

2013-03-01

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug-drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug-drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2-5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0-∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87-107.20; Cmax: GMR, 92.39%; 90% CI, 85.38-99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05-100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65-111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51-116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73-119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00-101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67-104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0-∞ (GMR, 106.11%; 90% CI, 96.71-116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33-130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril). Copyright © 2013 Elsevier HS Journals, Inc. All rights reserved.

Unilateral Versus Bilateral Laparoscopic Ovarian Drilling Using Thermal Dose Adjusted According to Ovarian Volume in CC-Resistant PCOS, A Randomized Study.

PubMed

El-Sayed, Mohamed Lotfy Mohamed; Ahmed, Mostafa Abdo; Mansour, Marwa Abdel Azim; Mansour, Shymma Abdel Azim

2017-10-01

This study aimed to evaluate the efficacy of unilateral laparoscopic ovarian drilling versus bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume in clomiphene citrate (CC)-resistant PCOS patients in terms of endocrine changes, menstrual cycle resumption, ovulation and pregnancy rates. This study was conducted in the Department of Obstetrics and Gynecology, Zagazig university hospitals. One hundred CC-resistant PCOS patients were divided into two groups. Group (I) (50 patients) underwent unilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume (60 J/cm 3 of ovarian tissue), and group (II) (50 patients) underwent bilateral laparoscopic ovarian drilling using the same previously mentioned thermal dose. Endocrinal changes and menstrual cycle resumption were assessed within 8 weeks postoperatively, but the ovulation and pregnancy rates were estimated after 6-month follow-up period. There was no statistically significant difference between the two groups as regards demographic data ( p  > 0.05). As regards menstruation cycle resumption (62.5 vs. 81%) ( p  = 0.047), total ovulation rate (54.2 vs. 78.7%) ( p  = 0.011) and cumulative pregnancy rate (33.3 vs. 55.3%) ( p  = 0.031), there was statistically significant difference between both groups. After drilling, there were highly statistically significant decrease in the mean serum levels of luteinizing hormone (LH) and significant decrease in the mean serum levels of testosterone in both groups. Mean serum level of follicle stimulating hormone (FSH) did not change significantly in both groups after drilling. Bilateral laparoscopic ovarian drilling with thermal dose adjusted according to ovarian volume is more effective than the right-sided unilateral technique with thermal dose adjusted according to ovarian volume in terms of menstrual cycle resumption, ovulation and cumulative pregnancy rates in CC-resistant PCOS patients.

Characterizing Potentially Inappropriate Prescribing of Proton Pump Inhibitors in Older People in Primary Care in Ireland from 1997 to 2012.

PubMed

Moriarty, Frank; Bennett, Kathleen; Cahir, Caitriona; Fahey, Tom

2016-12-01

To characterize prescribing of proton pump inhibitors (PPIs) and medicines that increase gastrointestinal bleeding risk (ulcerogenic) in older people from 1997 to 2012 and assess factors associated with maximal-dose prescribing in long-term PPI users. Repeated cross-sectional study of pharmacy claims data. Eastern Health Board region of Ireland. Individuals aged 65 and older from a means-tested health plan in 1997, 2002, 2007, and 2012 (range 78,489-133,884 individuals). PPI prescribing prevalence was determined per study year, categorized according to duration (≤8 or >8 weeks), dosage (maximal or maintenance), and co-prescribed drugs. Logistic regression in long-term PPI users was used to determine whether age, sex, polypharmacy, and ulcerogenic medicine use were associated with being prescribed a maximal dose rather than a maintenance dose. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are presented. Half of this older population received a PPI in 2007 and 2012. Long-term use (>8 weeks) of maximal doses rose from 0.8% of individuals in 1997 to 23.6% in 2012. Although some ulcerogenic medicines and polypharmacy were significantly associated with maximal PPI doses, any nonsteroidal anti-inflammatory drug use was significantly associated with lower odds of maximal PPI dose (adjusted OR = 0.87, 95% CI = 0.85-0.89), as were aspirin use and older age. Adjusting for medication and demographic factors, odds of being prescribed a maximal PPI dose were significantly higher in 2012 than in 1997 (adjusted OR = 6.30, 95% CI = 5.76-6.88). Long-term maximal-dose PPI prescribing is highly prevalent in older adults and is not consistently associated with gastrointestinal bleeding risk factors. Interventions involving prescribers and patients may promote appropriate PPI use, reducing costs and adverse effects of PPI overprescribing. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Single-center evaluation of the single-dose pharmacokinetics of the angiotensin II receptor antagonist azilsartan medoxomil in renal impairment.

PubMed

Preston, Richard A; Karim, Aziz; Dudkowski, Caroline; Zhao, Zhen; Garg, Dyal; Lenz, Oliver; Sica, Domenic A

2013-05-01

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a pro-drug and not detected in blood after oral administration because of rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite M-II and minor metabolites. The objective of this study was to determine the effect of renal impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase I parallel-group study which examined the single-dose (40-mg) pharmacokinetics of AZL and M-II in 24 subjects with mild, moderate, or severe renal impairment or end-stage renal disease requiring hemodialysis (n = 6 per group), respectively, and healthy matched subjects (n = 24). Renal impairment/disease did not cause clinically meaningful increases in exposure to AZL. M-II exposure was higher in all renally impaired subjects and highest in those with severe impairment (approx fivefold higher vs. control). M-II is pharmacologically inactive; increased exposure was not considered important in dose selection for AZL-M in subjects with renal impairment. Hemodialysis did not significantly remove AZL or M-II. Renal impairment had no clinically meaningful effect on the plasma protein binding of AZL or M-II. Single doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with any degree of renal impairment, including end-stage renal disease.

Reduction of severe visual loss and complications following intra-arterial chemotherapy (IAC) for refractory retinoblastoma.

PubMed

Reddy, M Ashwin; Naeem, Zishan; Duncan, Catriona; Robertson, Fergus; Herod, Jane; Rennie, Adam; Liasis, Alki; Thompson, Dorothy Ann; Sagoo, Mandeep

2017-12-01

Intra-arterial chemotherapy (IAC) for retinoblastoma has been documented as causing visual loss and ocular motility problems. A lack of safety data has precluded its acceptance in all centres. Retrospective cohort study of patients with retinoblastoma from 2013 to 2015 who had a healthy foveola and relapsed following systemic chemotherapy. All required IAC. The correlation of complications with doses of melphalan +/- topotecan used and putative catheterisation complications was assessed. Ocular complications were determined using vision, macular (including pattern visual evoked potentials (PVEPs)), retinal electroretinograms (ERGs) and ocular motility functions. Efficacy (tumour control) was also assessed. All eyes had age appropriate doses of melphalan with five having additional doses of topotecan. Severe physiological reactions requiring adrenaline were seen in six patients during the catheterisation procedure. Difficulty was documented in accessing the ophthalmic artery in 7/27 catheterisations. The median/mean number of courses of chemotherapy was three. No child had severe visual loss as assessed by age appropriate tests (median follow-up 20.9 months, range 3.7-35.2 months). One child had nasal choroidal ischaemia and a sixth nerve palsy. Post-IAC PVEPs were performed in eight and reported as normal. All post-IAC ERGs were normal apart from one (total dose 20 mg melphalan 0.8 mg topotecan). Tumour control was achieved in six of nine cases. The proportion of visual and ocular motility complications may be reduced by providing age-adjusted doses of melphalan. Dose rather than complications from catheterisation is the most important risk factor for ocular injury. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Efficacy and optimal dose of daily polyethylene glycol 3350 for treatment of constipation and encopresis in children.

PubMed

Pashankar, D S; Bishop, W P

2001-09-01

To determine efficacy, safety, and optimal dose of a laxative, polyethylene glycol (PEG) 3350, in children with chronic constipation. Children with chronic constipation (n = 24) were treated with PEG for 8 weeks at an initial dose of 1 g/kg/d. The dose was adjusted every 3 days as required to achieve 2 soft stools per day. A diary was kept to monitor dose, stool frequency and consistency, soiling, and other symptoms. Stool consistency was rated from 1 (hard) to 5 (watery). Subjects were examined for fecal retention. The Student t test and the Fisher exact test were used for data analysis. All 20 children who completed the study found PEG to be palatable and were satisfied with the treatment. There were no significant adverse effects. Weekly stool frequency increased from 2.3 +/- 0.4 to 16.9 +/- 1.6 (P <.0001) during treatment and stool consistency from 1.2 +/- 0.1 to 3.3 +/- 0.1 (P <.0001). In 9 children with soiling, weekly soiling events declined from 10.0 +/- 2.4 to 1.3 +/- 0.7 (P =.003). The mean effective dose was 0.84 g/kg/d (range, 0.27-1.42 g/kg/d). Daily administration of PEG at a mean dose of 0.8 g/kg is an effective, safe, and palatable treatment for constipation.

Room model based Monte Carlo simulation study of the relationship between the airborne dose rate and the surface-deposited radon progeny.

PubMed

Sun, Kainan; Field, R William; Steck, Daniel J

2010-01-01

The quantitative relationships between radon gas concentration, the surface-deposited activities of various radon progeny, the airborne radon progeny dose rate, and various residential environmental factors were investigated through a Monte Carlo simulation study based on the extended Jacobi room model. Airborne dose rates were calculated from the unattached and attached potential alpha-energy concentrations (PAECs) using two dosimetric models. Surface-deposited (218)Po and (214)Po were significantly correlated with radon concentration, PAECs, and airborne dose rate (p-values <0.0001) in both non-smoking and smoking environments. However, in non-smoking environments, the deposited radon progeny were not highly correlated to the attached PAEC. In multiple linear regression analysis, natural logarithm transformation was performed for airborne dose rate as a dependent variable, as well as for radon and deposited (218)Po and (214)Po as predictors. In non-smoking environments, after adjusting for the effect of radon, deposited (214)Po was a significant positive predictor for one dose model (RR 1.46, 95% CI 1.27-1.67), while deposited (218)Po was a negative predictor for the other dose model (RR 0.90, 95% CI 0.83-0.98). In smoking environments, after adjusting for radon and room size, deposited (218)Po was a significant positive predictor for one dose model (RR 1.10, 95% CI 1.02-1.19), while a significant negative predictor for the other model (RR 0.90, 95% CI 0.85-0.95). After adjusting for radon and deposited (218)Po, significant increases of 1.14 (95% CI 1.03-1.27) and 1.13 (95% CI 1.05-1.22) in the mean dose rates were found for large room sizes relative to small room sizes in the different dose models.

Effectiveness of a Third Dose of MMR Vaccine for Mumps Outbreak Control.

PubMed

Cardemil, Cristina V; Dahl, Rebecca M; James, Lisa; Wannemuehler, Kathleen; Gary, Howard E; Shah, Minesh; Marin, Mona; Riley, Jacob; Feikin, Daniel R; Patel, Manisha; Quinlisk, Patricia

2017-09-07

The effect of a third dose of the measles-mumps-rubella (MMR) vaccine in stemming a mumps outbreak is unknown. During an outbreak among vaccinated students at the University of Iowa, health officials implemented a widespread MMR vaccine campaign. We evaluated the effectiveness of a third dose for outbreak control and assessed for waning immunity. Of 20,496 university students who were enrolled during the 2015-2016 academic year, mumps was diagnosed in 259 students. We used Fisher's exact test to compare unadjusted attack rates according to dose status and years since receipt of the second MMR vaccine dose. We used multivariable time-dependent Cox regression models to evaluate vaccine effectiveness, according to dose status (three vs. two doses and two vs. no doses) after adjustment for the number of years since the second dose. Before the outbreak, 98.1% of the students had received at least two doses of MMR vaccine. During the outbreak, 4783 received a third dose. The attack rate was lower among the students who had received three doses than among those who had received two doses (6.7 vs. 14.5 cases per 1000 population, P<0.001). Students had more than nine times the risk of mumps if they had received the second MMR dose 13 years or more before the outbreak. At 28 days after vaccination, receipt of the third vaccine dose was associated with a 78.1% lower risk of mumps than receipt of a second dose (adjusted hazard ratio, 0.22; 95% confidence interval, 0.12 to 0.39). The vaccine effectiveness of two doses versus no doses was lower among students with more distant receipt of the second vaccine dose. Students who had received a third dose of MMR vaccine had a lower risk of mumps than did those who had received two doses, after adjustment for the number of years since the second dose. Students who had received a second dose of MMR vaccine 13 years or more before the outbreak had an increased risk of mumps. These findings suggest that the campaign to administer a third dose of MMR vaccine improved mumps outbreak control and that waning immunity probably contributed to propagation of the outbreak. (Funded by the Centers for Disease Control and Prevention.).

Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency

PubMed Central

Midgley, John E M; Larisch, Rolf; Dietrich, Johannes W; Hoermann, Rudolf

2015-01-01

Several influences modulate biochemical responses to a weight-adjusted levothyroxine (l-T4) replacement dose. We conducted a secondary analysis of the relationship of l-T4 dose to TSH and free T3 (FT3), using a prospective observational study examining the interacting equilibria between thyroid parameters. We studied 353 patients on steady-state l-T4 replacement for autoimmune thyroiditis or after surgery for malignant or benign thyroid disease. Peripheral deiodinase activity was calculated as a measure of T4–T3 conversion efficiency. In euthyroid subjects, the median l-T4 dose was 1.3 μg/kg per day (interquartile range (IQR) 0.94,1.60). The dose was independently associated with gender, age, aetiology and deiodinase activity (all P<0.001). Comparable FT3 levels required higher l-T4 doses in the carcinoma group (n=143), even after adjusting for different TSH levels. Euthyroid athyreotic thyroid carcinoma patients (n=50) received 1.57 μg/kg per day l-T4 (IQR 1.40, 1.69), compared to 1.19 μg/kg per day (0.85,1.47) in autoimmune thyroiditis (P<0.01, n=76) and 1.08 μg/kg per day (0.82, 1.44) in patients operated on for benign disease (P< 0.01, n=80). Stratifying patients by deiodinase activity categories of <23, 23–29 and >29 nmol/s revealed an increasing FT3–FT4 dissociation; the poorest converters showed the lowest FT3 levels in spite of the highest dose and circulating FT4 (P<0.001). An l-T4-related FT3–TSH disjoint was also apparent; some patients with fully suppressed TSH failed to raise FT3 above the median level. These findings imply that thyroid hormone conversion efficiency is an important modulator of the biochemical response to l-T4; FT3 measurement may be an additional treatment target; and l-T4 dose escalation may have limited success to raise FT3 appropriately in some cases. PMID:26335522

The dose of hydroxyethyl starch 6% 130/0.4 for fluid therapy and the incidence of acute kidney injury after cardiac surgery: A retrospective matched study

PubMed Central

Nkoy Ena, Lompoli; Van Dyck, Michel; Matta, Amine; Kahn, David; Thiry, Dominique; Grégoire, André; Watremez, Christine

2017-01-01

The safety of hydroxyethyl starches (HES) is still under debate. No studies have compared different dosing regimens of HES in cardiac surgery. We analyzed whether the incidence of Acute Kidney Injury (AKI) differed taking into account a weight-adjusted cumulative dose of HES 6% 130/0.4 for perioperative fluid therapy. This retrospective cohort study included all adult patients undergoing elective or emergency cardiac surgery with or without cardiopulmonary bypass. Exclusion criteria were patients on renal replacement therapy (RRT), cardiac trauma surgery, heart transplantation, patients with ventricular assist devices, subjects who required a surgical revision for bleeding and those whose medical records were incomplete. Primary endpoint was AKI following the creatinine based RIFLE classification. Secondary endpoints were 30-day mortality and RRT. Patients were divided into 2 groups whether they had received a cumulative HES dose of < 30 mL/kg (Low HES) or ≥ 30 mL/kg (High HES) during the intra- and postoperative period. A total of 1501 patients were analyzed with 983 patients in the Low HES and 518 subjects in the High HES group. 185 (18.8%) patients in the Low HES and 119 (23.0%) patients in the High HES group developed AKI (P = 0.06). In multivariable regression analysis the dose of HES administered per weight was not associated with AKI. After case-control matching 217 patients were analyzed in each group. AKI occurred in 39 (18.0%) patients in the Low HES and 50 (23.0%) patients in the High HES group (P = 0.19). In conditional regression analysis performed on the matched groups a lower weight-adjusted dose of HES was significantly associated with a reduced incidence of AKI [(Odds Ratio (95% CI) = 0.825 (0.727–0.936); P = 0.003]. In the absence of any safety study the cumulative dose of modern HES in cardiac surgery should be kept less than 30 mL/kg. PMID:29045467

Adaptive intensity modulated radiotherapy for advanced prostate cancer

NASA Astrophysics Data System (ADS)

Ludlum, Erica Marie

The purpose of this research is to develop and evaluate improvements in intensity modulated radiotherapy (IMRT) for concurrent treatment of prostate and pelvic lymph nodes. The first objective is to decrease delivery time while maintaining treatment quality, and evaluate the effectiveness and efficiency of novel one-step optimization compared to conventional two-step optimization. Both planning methods are examined at multiple levels of complexity by comparing the number of beam apertures, or segments, the amount of radiation delivered as measured by monitor units (MUs), and delivery time. One-step optimization is demonstrated to simplify IMRT planning and reduce segments (from 160 to 40), MUs (from 911 to 746), and delivery time (from 22 to 7 min) with comparable plan quality. The second objective is to examine the capability of three commercial dose calculation engines employing different levels of accuracy and efficiency to handle high--Z materials, such as metallic hip prostheses, included in the treatment field. Pencil beam, convolution superposition, and Monte Carlo dose calculation engines are compared by examining the dose differences for patient plans with unilateral and bilateral hip prostheses, and for phantom plans with a metal insert for comparison with film measurements. Convolution superposition and Monte Carlo methods calculate doses that are 1.3% and 34.5% less than the pencil beam method, respectively. Film results demonstrate that Monte Carlo most closely represents actual radiation delivery, but none of the three engines accurately predict the dose distribution when high-Z heterogeneities exist in the treatment fields. The final objective is to improve the accuracy of IMRT delivery by accounting for independent organ motion during concurrent treatment of the prostate and pelvic lymph nodes. A leaf-shifting algorithm is developed to track daily prostate position without requiring online dose calculation. Compared to conventional methods of adjusting patient position, adjusting the multileaf collimator (MLC) leaves associated with the prostate in each segment significantly improves lymph node dose coverage (maintains 45 Gy compared to 42.7, 38.3, and 34.0 Gy for iso-shifts of 0.5, 1 and 1.5 cm). Altering the MLC portal shape is demonstrated as a new and effective solution to independent prostate movement during concurrent treatment.

Azathioprine-Induced Warfarin Resistance

PubMed Central

Vazquez, Sara R; Rondina, Matthew T; Pendleton, Robert C

2011-01-01

OBJECTIVE To describe a case of azathioprine-induced warfarin resistance, present a literature review on warfarin–azathioprine interactions, and provide recommendations on appropriate management of this clinically significant interaction. CASE SUMMARY A 29-year-old female with Cogan’s syndrome experienced thrombosis of the left internal carotid artery. She was treated with an average weekly warfarin dose of 39 mg (5.5 mg daily) prior to beginning azathioprine therapy. Three weeks following initiation of azathioprine 150 mg daily, the international normalized ratio (INR) decreased from 1.9 (prior to the medication change) to 1.0 without any change in the warfarin dose or other relevant factors. Over several weeks, the patient’s warfarin dose was titrated up to 112 mg weekly (16 mg daily) to achieve an INR of 2.5 (a 188%, or 2.9-fold dose increase). Because of elevated liver enzyme levels, the azathioprine dosage was decreased to 100 mg daily. Within 2 weeks following that decrease, warfarin requirements decreased to 105 mg weekly (15 mg daily). DISCUSSION Azathioprine was the probable causative agent of warfarin resistance according to the Naranjo probability scale, and a possible causative agent according to the Drug Interaction Probability Scale. A literature search (PubMed, 1966–December 2007) revealed 8 case reports of this drug interaction and 2 cases involving a similar effect with 6-mercaptopurine, the active metabolite of azathioprine. The exact mechanism of the interaction remains unknown. Previously published case reports point to a rapid onset and offset of the warfarin–azathioprine interaction and a dose-dependent increase of at least 2.5-fold in warfarin dose requirement with the initiation of azathioprine 75–200 mg daily. CONCLUSIONS This case report and several others point toward azathioprine as a clinically significant inducer of warfarin resistance. Providers should anticipate the need for higher warfarin doses, warfarin dose adjustment, and close INR monitoring in patients receiving azathioprine or its active metabolite, 6-mercaptopurine. PMID:18505911

Ischaemic heart disease incidence and mortality in an extended cohort of Mayak workers first employed in 1948–1982

PubMed Central

Grigoryeva, Evgeniya S; Haylock, Richard G E; Pikulina, Maria V; Moseeva, Maria B

2015-01-01

Objective: Incidence and mortality from ischaemic heart disease (IHD) was studied in an extended cohort of 22,377 workers first employed at the Mayak Production Association during 1948–82 and followed up to the end of 2008. Methods: Relative risks and excess relative risks per unit dose (ERR/Gy) were calculated based on the maximum likelihood using Epicure software (Hirosoft International Corporation, Seattle, WA). Dose estimates used in analyses were provided by an updated “Mayak Worker Dosimetry System—2008”. Results: A significant increasing linear trend in IHD incidence with total dose from external γ-rays was observed after having adjusted for non-radiation factors and dose from internal radiation {ERR/Gy = 0.10 [95% confidence interval (CI): 0.04 to 0.17]}. The pure quadratic model provided a better fit of the data than did the linear one. No significant association of IHD mortality with total dose from external γ-rays after having adjusted for non-radiation factors and dose from internal alpha radiation was observed in the study cohort [ERR/Gy = 0.06 (95% CI: <0 to 0.15)]. A significant increasing linear trend was observed in IHD mortality with total absorbed dose from internal alpha radiation to the liver after having adjusted for non-radiation factors and dose from external γ-rays in both the whole cohort [ERR/Gy = 0.21 (95% CI: 0.01 to 0.58)] and the subcohort of workers exposed at alpha dose <1.00 Gy [ERR/Gy = 1.08 (95% CI: 0.34 to 2.15)]. No association of IHD incidence with total dose from internal alpha radiation to the liver was found in the whole cohort after having adjusted for non-radiation factors and external gamma dose [ERR/Gy = 0.02 (95% CI: not available to 0.10)]. Statistically significant dose effect was revealed in the subcohort of workers exposed to internal alpha radiation at dose to the liver <1.00 Gy [ERR/Gy = 0.44 (95% CI: 0.09 to 0.85)]. Conclusion: This study provides strong evidence of IHD incidence and mortality association with external γ-ray exposure and some evidence of IHD incidence and mortality association with internal alpha-radiation exposure. Advances in knowledge: It is the first time the validity of internal radiation dose estimates has been shown to affect the risk of IHD incidence. PMID:26224431

Impact of multiple-dose versus single-dose inhaler devices on COPD patients’ persistence with long-acting β2-agonists: a dispensing database analysis

PubMed Central

van Boven, Job FM; van Raaij, Joost J; van der Galiën, Ruben; Postma, Maarten J; van der Molen, Thys; Dekhuijzen, PN Richard; Vegter, Stefan

2014-01-01

Background: With a growing availability of different devices and types of medication, additional evidence is required to assist clinicians in prescribing the optimal medication in relation to chronic obstructive pulmonary disease (COPD) patients’ persistence with long-acting β2-agonists (LABAs). Aims: To assess the impact of the type of inhaler device (multiple-dose versus single-dose inhalers) on 1-year persistence and switching patterns with LABAs. Methods: A retrospective observational cohort study was performed comparing a cohort of patients initiating multiple-dose inhalers and a cohort initiating single-dose inhalers. The study population consisted of long-acting bronchodilator naive COPD patients, initiating inhalation therapy with mono-LABAs (formoterol, indacaterol or salmeterol). Analyses were performed using pharmacy dispensing data from 1994 to 2012, obtained from the IADB.nl database. Study outcomes were 1-year persistence and switching patterns. Results were adjusted for initial prescriber, initial medication, dosing regimen and relevant comorbidities. Results: In all, 575 patients initiating LABAs were included in the final study cohort. Among them, 475 (83%) initiated a multiple-dose inhaler and 100 (17%) a single-dose inhaler. Further, 269 (47%) initiated formoterol, 9 (2%) indacaterol and 297 (52%) salmeterol. There was no significant difference in persistence between users of multiple-dose or single-dose inhalers (hazard ratio: 0.98, 95% confidence interval: 0.76–1.26, P=0.99). Over 80% re-started or switched medication. Conclusions: There seems no impact of inhaler device (multiple-dose versus single-dose inhalers) on COPD patients’ persistence with LABAs. Over 80% of patients who initially seemed to discontinue LABAs, re-started their initial medication or switched inhalers or medication within 1 year. PMID:25274453

Hospital morphine preparation for abstinence syndrome in newborns exposed to buprenorphine or methadone.

PubMed

Colombini, Nathalie; Elias, Riad; Busuttil, Muriel; Dubuc, Myriam; Einaudi, Marie-Ange; Bues-Charbit, Martine

2008-06-01

This study was undertaken to evaluate the adequacy of a hospital formulated oral morphine preparation for management of neonatal abstinence syndrome (NAS) and to compare clinical features in infants exposed to methadone or buprenorphine in utero. Between October 1998 and October 2004 all infants born to mothers treated with buprenorphine or methadone during pregnancy were enrolled into this prospective study. Morphine hydrochloride solution (0.2 mg/ml) was prepared without preservatives under a flow laminar air box (class 100). Morphine solution: quantitative and qualitative HPLC analysis and microbiological study at regular intervals during storage at 4 degrees C for 6 months. Maternal characteristics: age, opiate dose during pregnancy. Neonatal characteristics: gestational age at delivery, birth weight, Lipsitz scores. Morphine dose: daily morphine dose, maximum morphine dose, duration of NAS, and duration of treatment required to achieve stable Lipsitz scores below 4. Kruskal-Wallis test for comparison of median values. Microbiological and HPLC analysis showed that the morphine preparation remained stable for 6 months at 4 degrees C. Nine methadone-exposed infants and 13 buprenorphine-exposed infants were included in the study. All infants presented NAS requiring treatment with the morphine solution. Lipsitz scores at birth were significantly different in the methadone and buprenorphine groups (P < 0.05). The methadone group required significantly higher doses of morphine preparation than the buprenorphine group during the first 38 days of treatment (P < 0.05): 0.435 +/- 0.150 mg/kg/day vs. 0.257 +/- 0.083 mg/kg/day. This hospital morphine solution is adequate for management of NAS. Preparations showed good stability and doses could be adjusted with a margin of 0.02 mg. The onset of NAS occurred within 24 h after birth in methadone-exposed infants (range 6-24 h) and within 48 h after birth in buprenorphine-exposed infants (range 24-168 h). Due to the possibility of delayed onset of NAS up to 7 days, infants born to mothers treated with buprenorphine should be kept in the hospital for an appropriate surveillance period. Treatment time was significantly longer (45 vs. 28 days) and the mean morphine doses were higher (1.7 fold) in methadone-exposed than buprenorphine-exposed infants.

Pitfalls of insulin pump clocks: technical glitches that may potentially affect medical care in patients with diabetes.

PubMed

Aldasouqi, Saleh A; Reed, Amy J

2014-11-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients' visits, and should remind their patients to always verify these settings. © 2014 Diabetes Technology Society.

Pitfalls of Insulin Pump Clocks

PubMed Central

Reed, Amy J.

2014-01-01

The objective was to raise awareness about the importance of ensuring that insulin pumps internal clocks are set up correctly at all times. This is a very important safety issue because all commercially available insulin pumps are not GPS-enabled (though this is controversial), nor equipped with automatically adjusting internal clocks. Special attention is paid to how basal and bolus dose errors can be introduced by daylight savings time changes, travel across time zones, and am-pm clock errors. Correct setting of insulin pump internal clock is crucial for appropriate insulin delivery. A comprehensive literature review is provided, as are illustrative cases. Incorrect setting can potentially result in incorrect insulin delivery, with potential harmful consequences, if too much or too little insulin is delivered. Daylight saving time changes may not significantly affect basal insulin delivery, given the triviality of the time difference. However, bolus insulin doses can be dramatically affected. Such problems may occur when pump wearers have large variations in their insulin to carb ratio, especially if they forget to change their pump clock in the spring. More worrisome than daylight saving time change is the am-pm clock setting. If this setting is set up incorrectly, both basal rates and bolus doses will be affected. Appropriate insulin delivery through insulin pumps requires correct correlation between dose settings and internal clock time settings. Because insulin pumps are not GPS-enabled or automatically time-adjusting, extra caution should be practiced by patients to ensure correct time settings at all times. Clinicians and diabetes educators should verify the date/time of insulin pumps during patients’ visits, and should remind their patients to always verify these settings. PMID:25355713

Proton therapy of prostate cancer by anterior-oblique beams: implications of setup and anatomy variations

NASA Astrophysics Data System (ADS)

Moteabbed, M.; Trofimov, A.; Sharp, G. C.; Wang, Y.; Zietman, A. L.; Efstathiou, J. A.; Lu, H.-M.

2017-03-01

Proton therapy of prostate by anterior beams could offer an attractive option for treating patients with hip prosthesis and limiting the high-dose exposure to the rectum. We investigated the impact of setup and anatomy variations on the anterior-oblique (AO) proton plan dose, and strategies to manage these effects via range verification and adaptive delivery. Ten patients treated by bilateral (BL) passive-scattering proton therapy (79.2 Gy in 44 fractions) who underwent weekly verification CT scans were selected. Plans with AO beams were additionally created. To isolate the effect of daily variations, initial AO plans did not include range uncertainty margins. The use of fixed planning margins and adaptive range adjustments to manage these effects was investigated. For each case, the planned dose was recalculated on weekly CTs, and accumulated on the simulation CT using deformable registration to approximate the delivered dose. Planned and accumulated doses were compared for each scenario to quantify dose deviations induced by variations. The possibility of estimating the necessary range adjustments before each treatment was explored by simulating the procedure of a diode-based in vivo range verification technique, which would potentially be used clinically. The average planned rectum, penile bulb and femoral heads mean doses were smaller for initial AO compared to BL plans (by 8.3, 16.1 and 25.9 Gy, respectively). After considering interfractional variations in AO plans, the target coverage was substantially reduced. The maximum reduction of V 79.2/D 95/D mean/EUD for AO (without distal margins) (25.3%/10.7/1.6/4.9 Gy, respectively) was considerably larger than BL plans. The loss of coverage was mainly related to changes in water equivalent path length of the prostate after fiducial-based setup, caused by discrepancies in patient anterior surface and bony-anatomy alignment. Target coverage was recovered partially when using fixed planning margins, and fully when applying adaptive range adjustments. The accumulated organs-at-risk dose for AO beams after range adjustment demonstrated full sparing of femoral heads and superior sparing of penile bulb and rectum compared to the conventional BL cases. Our study indicates that using AO beams makes prostate treatment more susceptible to target underdose induced by interfractional variations. Adaptive range verification/adjustment may facilitate the use of anterior beam approaches, and ensure adequate target coverage in every fraction of the treatment.

Risk-adjusted antibiotic consumption in 34 public acute hospitals in Ireland, 2006 to 2014

PubMed Central

Oza, Ajay; Donohue, Fionnuala; Johnson, Howard; Cunney, Robert

2016-01-01

As antibiotic consumption rates between hospitals can vary depending on the characteristics of the patients treated, risk-adjustment that compensates for the patient-based variation is required to assess the impact of any stewardship measures. The aim of this study was to investigate the usefulness of patient-based administrative data variables for adjusting aggregate hospital antibiotic consumption rates. Data on total inpatient antibiotics and six broad subclasses were sourced from 34 acute hospitals from 2006 to 2014. Aggregate annual patient administration data were divided into explanatory variables, including major diagnostic categories, for each hospital. Multivariable regression models were used to identify factors affecting antibiotic consumption. Coefficient of variation of the root mean squared errors (CV-RMSE) for the total antibiotic usage model was very good (11%), however, the value for two of the models was poor (> 30%). The overall inpatient antibiotic consumption increased from 82.5 defined daily doses (DDD)/100 bed-days used in 2006 to 89.2 DDD/100 bed-days used in 2014; the increase was not significant after risk-adjustment. During the same period, consumption of carbapenems increased significantly, while usage of fluoroquinolones decreased. In conclusion, patient-based administrative data variables are useful for adjusting hospital antibiotic consumption rates, although additional variables should also be employed. PMID:27541730

An educational program for insulin self-adjustment associated with structured self-monitoring of blood glucose significantly improves glycemic control in patients with type 2 diabetes mellitus after 12 weeks: a randomized, controlled pilot study.

PubMed

Silva, Daniel Dutra Romualdo; Bosco, Adriana Aparecida

2015-01-01

Self-monitoring of blood glucose (SMBG) has been recommended as a useful tool for improving glycemic control, but is still an underutilized strategy and most diabetic patients are not aware of the actions that must be taken in response to its results and do not adjust their treatment. The purpose of this study was to evaluate the effectiveness and safety of an educational program for insulin self-adjustment based on SMBG in poorly controlled patients with type 2 diabetes (T2DM). A prospective, randomized, controlled 12-week intervention study was conducted on poorly controlled insulin-requiring patients with T2DM. Twenty-three subjects were randomized to two educational programs: a 2-week basic program with guidance about SMBG and types and techniques of insulin administration (group A, n = 12) and a 6-week program including the basic one and additional instructions about self-titration of insulin doses according to a specific protocol (group B, n = 11). Patients were reviewed after 12 weeks and baseline to endpoint changes in glycated hemoglobin (A1C), insulin doses, body weight and incidence of hypoglycemia were compared by paired and independent Student t-tests. After 12 weeks, there was a significant reduction in A1C only in group B, but group comparison showed no significant difference (p = 0.051). A higher percentage of subjects in group B achieved an A1C near the treatment target (<7.5%) than in group A. Daily insulin dose increased non-significantly in the two groups and there was no significant difference in the incidence of hypoglycemia or body weight changes between groups. Training for self-titrating insulin doses combined with structured SMBG can safely improve glycemic control in poorly controlled insulin-treated T2DM patients. This strategy may facilitate effective insulin therapy in routine medical practice, compensating for any reluctance on the part of physicians to optimize insulin therapy and thus to improve the achievement of recommended targets of diabetes care.

Control of lithium tremor with propranolol.

PubMed Central

Lapierre, Y. D.

1976-01-01

Lithium tremor is an irregular, nonrhythmic tremor of the distal extremities, variable in both intensity and frequency. It is clinically differentiated from essential tremor and tremors due to anxiety and neuroleptics. The pathophysiologic mechanisms are hypothesized to be of perpheral origin. Five patients were successfully treated with propranolol. In general, the dosage of propranolol must be individually adjusted and is usually from 30 to 40 mg daily in divided doses. This blocker of beta-adrenergic receptors remains effective with long-term administration and increases in dosage are not required. PMID:1260604

Thyrotoxic atrial fibrillation.

PubMed

Parmar, Malvinder S

2005-01-04

Atrial fibrillation is the most common cardiac complication of hyperthyroidism and occurs in 15% of patients with hyperthyroidism. It is associated with a higher risk of thromboembolism that often involves the central nervous system. Oral anticoagulation is important in the majority of these patients to prevent thromboembolic complications. These patients require adjustment in the dose of various rate-controlling agents because of increased clearance associated with hyperthyroidism and a decrease in warfarin dosage because of increased clearance of vitamin K-dependent clotting factors. The management of thyrotoxic atrial fibrillation is summarized in this clinical review.

Pediatric Obesity: Pharmacokinetic Alterations and Effects on Antimicrobial Dosing.

PubMed

Natale, Stephanie; Bradley, John; Nguyen, William Huy; Tran, Tri; Ny, Pamela; La, Kirsten; Vivian, Eva; Le, Jennifer

2017-03-01

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight (TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. © 2017 Pharmacotherapy Publications, Inc.

Identification of factors associated with sedation tolerance in 5000 patients undergoing outpatient colonoscopy: Canadian tertiary center experience.

PubMed

Shingina, Alexandra; Ou, George; Takach, Oliver; Svarta, Sigrid; Kwok, Ricky; Tong, Jessica; Donaldson, Kieran; Lam, Eric; Enns, Robert

2016-12-16

To develop a prediction model aimed at identifying patients that may require higher than usual sedation doses during colonoscopy. A retrospective chart review on 5000 patients who underwent an outpatient colonoscopy at St. Paul's Hospital from 2009 to 2010 was conducted in order to develop a model for identifying patients who will require increased doses of sedatives. Potential predictor variables including age, gender, endoscopy indication, high sedation requirements during previous endoscopies, difficulty of the procedure, bowel preparation quality, interventions, findings as well as current use of benzodiazepines, opioids and alcohol were analyzed. The outcome of study was the use of high dose of sedation agents for the procedure. In particular, the high dose of sedation was defined as fentanyl greater than 50 mcg and midazolam greater than 3 mg. Analysis of 5282 patients (mean age 57 ± 12, 49% female) was performed. Most common indication for the procedure was screening colonoscopy (57%). Almost half of our patients received doses exceeding Fentanyl 50 mcg and Midazolam 3 mg. Logistic regression models identified the following variables associated with high sedation: Younger age (OR = 0.95 95%CI: 0.94-0.95; P < 0.0001); abdominal pain (OR = 1.45, 95%CI: 1.08-1.96); P = 0.01) and Inflammatory Bowel Disease (OR = 1.45, 95%CI: 1.04-2.03; P = 0.02) as indications for the procedure; difficult procedure as defined by gastroenterologist (OR = 1.73, 95%CI: 1.48-2.03; P < 0.0001); past history of abdominal surgery (OR = 1.33, 95%CI: 1.17-1.52; P <0.0001) and previous colonoscopy (OR = 1.39, 95%CI: 1.21-1.60; P = 0.0001) and alcohol use (OR = 1.26, 95%CI: 1.03-1.54; P = 0.02). Age and gender adjusted analysis yielded inflammatory bowel disease as an indication (OR = 3.17, 95%CI: 1.58-6.37; P = 0.002); difficult procedure as defined by an endoscopist (OR = 5.13 95%CI: 2.97-8.85; P = 0.0001) and current use of opioids, benzodiazepines or antidepressants (OR = 2.88, 95%CI: 1.74-4.77; P = 0.001) having the highest predictive value of high sedation requirements. Our prediction model using the following pre-procedural variables including age, gender, indication for the procedure, medication/substance use, previous surgeries, previous high sedation requirements for colonoscopy yielded an area under the curve of 0.76 for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg. Pre-procedural planning is the key in conducting successful, efficient colonoscopy. Logistic regression analysis of 5000 patients who underwent out-patient colonoscopy revealed the following factors associated with increased sedation requirement: Younger age, female gender, difficult endoscopy, specific indications as well as cardiopulmonary complications and current use of opioids/benzodiazepines. Age and gender adjusted analysis yielded similar results. These patients are more likely to need a longer recovery periods post-endoscopy, which could result in additional time and personnel requirements. The final predictive model has good predictive ability for Fentanyl ≥ 100 mcg and Midazolam ≥ 3 mg and fair predictive ability for Fentanyl ≥ 50 mcg and Midazolam ≥ 2 mg. The external validity of this model is planned to be tested in another center.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

PubMed

Jutkowitz, Eric; Choi, Hyon K; Pizzi, Laura T; Kuntz, Karen M

2014-11-04

Gout is the most common inflammatory arthritis in the United States. To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. Markov model. Published literature and expert opinion. Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. Lifetime. Health care payer. 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. Long-term outcome data for patients with gout, including medication adherence, are limited. Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. Agency for Healthcare Research and Quality.

Renal function in atrial fibrillation patients switched from warfarin to a direct oral anticoagulant.

PubMed

Minhas, Anum S; Jiang, Qingmei; Gu, Xiaokui; Haymart, Brian; Kline-Rogers, Eva; Almany, Steve; Kozlowski, Jay; Krol, Gregory D; Kaatz, Scott; Froehlich, James B; Barnes, Geoffrey D

2016-11-01

All available direct oral anticoagulants (DOACs) are at least partially eliminated by the kidneys. These agents are increasingly being used as alternatives to warfarin for stroke prevention in patients with atrial fibrillation. The aim of this study was to identify changes in renal function and associated DOAC dosing implications in a multicenter cohort of atrial fibrillation patients switched from warfarin to DOAC treatment. We included all patients in the Michigan Anticoagulation Quality Improvement Initiative cohort who switched from warfarin to a DOAC with atrial fibrillation as their anticoagulant indication between 2009 and 2014, and who had at least two creatinine values. Compliance with FDA-recommended dosing based on renal function was assessed. Of the 189 patients switched from warfarin to a DOAC, 34 (18.0 %) had a baseline creatinine clearance <50 mL/min and 23 (12.2 %) experienced important fluctuations in renal function. Of these 23 patients, 6 (26.1 %) should have impacted the DOAC dosing, but only 1 patient actually received an appropriate dose adjustment. Additionally, 15 (7.9 %) of patients on DOACs had a dose change performed, but only one patient demonstrated a change in renal function to justify the dose adjustment. Most atrial fibrillation patients who switched from warfarin to a DOAC had stable renal function. However, the majority of patients who had a change in renal function did not receive the indicated dose change. As the use of DOACs expands, monitoring of renal function and appropriate dose adjustments are critical.

Panobinostat plus bortezomib and dexamethasone: impact of dose intensity and administration frequency on safety in the PANORAMA 1 trial.

PubMed

San-Miguel, Jesús F; Hungria, Vania T M; Yoon, Sung-Soo; Beksac, Meral; Dimopoulos, Meletios A; Elghandour, Ashraf; Jedrzejczak, Wieslaw W; Guenther, Andreas; Na Nakorn, Thanyaphong; Siritanaratkul, Noppadol; Schlossman, Robert L; Hou, Jian; Moreau, Philippe; Lonial, Sagar; Lee, Jae-Hoon; Einsele, Hermann; Salwender, Hans; Sopala, Monika; Redhu, Suman; Paul, Sofia; Corrado, Claudia; Richardson, Paul G

2017-10-01

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events (AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study (TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes. © 2017 John Wiley & Sons Ltd.

Palliative sedation at home for terminally ill children with cancer.

PubMed

Korzeniewska-Eksterowicz, Aleksandra; Przysło, Łukasz; Fendler, Wojciech; Stolarska, Małgorzata; Młynarski, Wojciech

2014-11-01

The presence of symptoms that are difficult to control always requires adjustment of treatment, and palliative sedation (PS) should be considered. We analyzed our experience in conducting PS at home for terminally ill children with cancer during a seven-year period. We performed a retrospective analysis of medical records of children with cancer treated at home between the years 2005 and 2011. We analyzed the data of 42 cancer patients (18% of all patients); in 21 cases, PS was initiated (solid tumors n = 11, brain tumors [5], bone tumors [4], leukemia [1]). Sedation was introduced because of pain (n = 13), dyspnea (9), anxiety (5), or two of those symptoms (6). The main drug used for sedation was midazolam; all patients received morphine. There were no significant differences in the dose of morphine or midazolam depending on the patient's sex; age was correlated with an increase of midazolam dose (R = 0.68; P = 0.005). Duration of sedation (R = 0.61; P = 0.003) and its later initiation (R = 0.43; P = 0.05) were correlated with an increase of the morphine dose. All patients received adjuvant treatment; in patients who required a morphine dose increase, metoclopramide was used more often (P = 0.0002). Patients did not experience any adverse reactions. Later introduction of sedation was associated with a marginally higher number of intervention visits and a significantly higher number of planned visits (R = 0.53; P = 0.013). Sedation may be safely used at home. It requires close monitoring and full cooperation between the family and hospice team. Because of the limited data on home PS in pediatric populations, further studies are needed. Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

PubMed

Koch, Gilbert; Datta, Alexandre N; Jost, Kerstin; Schulzke, Sven M; van den Anker, John; Pfister, Marc

2017-12-01

To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of adjusting the combination of budesonide/formoterol on the alleviation of asthma symptoms.

PubMed

Souma, Ryosuke; Sugiyama, Kumiya; Masuda, Hiroyuki; Arifuku, Hajime; Nakano, Kentaro; Watanabe, Hiroyoshi; Wakayama, Tomoshige; Tokita, Shingo; Tatewaki, Masamitsu; Satoh, Hideyuki; Koyama, Kenya; Hayashi, Yumeko; Fukushima, Fumiya; Hirata, Hirokuni; Arima, Masafumi; Kurasawa, Kazuhiro; Fukuda, Takeshi; Fukushima, Yasutsugu

2018-01-01

The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p  < 0.05) and when they had only one symptom compared with two or three symptoms (1.3 vs. 5.7 or 10.5, p  < 0.01). The relationship between PEF (% of personal best) when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = - 0.591X + 89.2 (r 2  = 0.299, p  < 0.001). As a guide for increasing the BFC dose when patients with mild asthma have asthma symptoms, the dose should be increased when cough is present or PEF is decreased to 88.9% (i.e., X = 0.5).

Managing iron overload in patients with myelodysplastic syndromes with oral deferasirox therapy.

PubMed

Jabbour, Elias; Garcia-Manero, Guillermo; Taher, Ali; Kantarjian, Hagop M

2009-05-01

Patients with myelodysplastic syndromes (MDS) often require chronic RBC transfusions, which can lead to iron overload. Without adequate management, this may cause progressive damage to hepatic, endocrine, and cardiac organs, significantly affecting overall survival. Recent retrospective analyses have suggested that iron chelation provides a survival advantage in iron-overloaded patients with MDS who are given chelation therapy compared with those who are not. Nonetheless, it is evident that iron overload in many patients with MDS is not adequately managed. Clinical evaluation of the once-daily, oral iron chelator deferasirox in MDS populations has indicated that it provides dose-dependent reductions in body iron burden and is generally well tolerated, with a manageable safety profile in adult and pediatric patients. The most common treatment-related adverse events (AEs) included transient, mild-to-moderate gastrointestinal disturbances and skin rash, which rarely required drug discontinuation and resolved spontaneously in most cases. Adequate management of AEs and practical approaches such as patient education and counseling are necessary to ensure that patients remain compliant with therapy. Regular monitoring of serum ferritin levels is key to identifying patients who require iron chelation therapy, and to ensure maintenance of iron levels below the critical level of 1,000 microg/l. The flexible dosing regimen of deferasirox allows dose adjustments to be made in response to trends in serum ferritin, to changes in a patient's transfusional iron intake, and to the objectives of treatment, allowing the full benefit of transfusion therapy without the risks associated with iron overload.

Automated estimation of abdominal effective diameter for body size normalization of CT dose.

PubMed

Cheng, Phillip M

2013-06-01

Most CT dose data aggregation methods do not currently adjust dose values for patient size. This work proposes a simple heuristic for reliably computing an effective diameter of a patient from an abdominal CT image. Evaluation of this method on 106 patients scanned on Philips Brilliance 64 and Brilliance Big Bore scanners demonstrates close correspondence between computed and manually measured patient effective diameters, with a mean absolute error of 1.0 cm (error range +2.2 to -0.4 cm). This level of correspondence was also demonstrated for 60 patients on Siemens, General Electric, and Toshiba scanners. A calculated effective diameter in the middle slice of an abdominal CT study was found to be a close approximation of the mean calculated effective diameter for the study, with a mean absolute error of approximately 1.0 cm (error range +3.5 to -2.2 cm). Furthermore, the mean absolute error for an adjusted mean volume computed tomography dose index (CTDIvol) using a mid-study calculated effective diameter, versus a mean per-slice adjusted CTDIvol based on the calculated effective diameter of each slice, was 0.59 mGy (error range 1.64 to -3.12 mGy). These results are used to calculate approximate normalized dose length product values in an abdominal CT dose database of 12,506 studies.

Examining the Starting Dose of Glyburide in Gestational Diabetes.

PubMed

Glover, Angelica V; Tita, Alan; Biggio, Joseph R; Harper, Lorie M

2016-01-01

The aim of this study was to determine the impact of initial glyburide dosing on pregnancy outcomes. STUDY DESign: Retrospective cohort of singleton pregnancies complicated by gestational diabetes mellitus (GDM) from 2007 to 2013. Women who received glyburide were compared by initial dose: 2.5 mg (n = 170) versus 5 mg (n = 154) total daily dose. The primary maternal outcome was hypoglycemia, defined as a blood glucose < 60 mg/dL. The primary neonatal outcome was birth weight. Secondary maternal outcomes included time to blood glucose control, preeclampsia, and cesarean delivery. Secondary neonatal outcomes included macrosomia (>4,000 g), hypoglycemia (<40 mg/dL), shoulder dystocia, and preterm delivery. The 5 mg/day glyburide dose did not increase maternal hypoglycemia (26% in the 2.5 mg/day group vs. 27% in the 5 mg/day group; adjusted odds ratio [AOR] 0.67; confidence interval [CI] 0.30-1.49). An increase in macrosomia in the 5 mg/day group was not significant after adjusting for maternal obesity (AOR 2.16; CI 0.96-4.88). Differences in preterm birth and large for gestational age were not significant after adjusting for prior preterm birth and maternal obesity, respectively. A higher starting dose of glyburide for the management of GDM was not associated with increased maternal hypoglycemia or decreased adverse neonatal outcomes. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Non-Targeted Effects and the Dose Response for Heavy Ion Tumorigenesis

NASA Technical Reports Server (NTRS)

Chappelli, Lori J.; Cucinotta, Francis A.

2010-01-01

BACKGROUND: There is no human epidemiology data available to estimate the heavy ion cancer risks experienced by astronauts in space. Studies of tumor induction in mice are a necessary step to estimate risks to astronauts. Previous experimental data can be better utilized to model dose response for heavy ion tumorigenesis and plan future low dose studies. DOSE RESPONSE MODELS: The Harderian Gland data of Alpen et al.[1-3] was re-analyzed [4] using non-linear least square regression. The data set measured the induction of Harderian gland tumors in mice by high-energy protons, helium, neon, iron, niobium and lanthanum with LET s ranging from 0.4 to 950 keV/micron. We were able to strengthen the individual ion models by combining data for all ions into a model that relates both radiation dose and LET for the ion to tumor prevalence. We compared models based on Targeted Effects (TE) to one motivated by Non-targeted Effects (NTE) that included a bystander term that increased tumor induction at low doses non-linearly. When comparing fitted models to the experimental data, we considered the adjusted R2, the Akaike Information Criteria (AIC), and the Bayesian Information Criteria (BIC) to test for Goodness of fit.In the adjusted R2test, the model with the highest R2values provides a better fit to the available data. In the AIC and BIC tests, the model with the smaller values of the summary value provides the better fit. The non-linear NTE models fit the combined data better than the TE models that are linear at low doses. We evaluated the differences in the relative biological effectiveness (RBE) and found the NTE model provides a higher RBE at low dose compared to the TE model. POWER ANALYSIS: The final NTE model estimates were used to simulate example data to consider the design of new experiments to detect NTE at low dose for validation. Power and sample sizes were calculated for a variety of radiation qualities including some not considered in the Harderian Gland data set and with different background tumor incidences. We considered different experimental designs with varying number of doses and varying low doses dependant on the LET of the radiation. The optimal design to detect a NTE for an individual ion had 4 doses equally spaced below a maximal dose where bending due to cell sterilization was < 2%. For example at 100 keV/micron we would irradiate at 0.03 Gy, 0.065 Gy, 0.13 Gy, and 0.26 Gy and require 850 mice including a control dose for a sensitivity to detect NTE with 80% power. Sample sizes could be improved by combining ions similar to the methods used with the Harderian Gland data.

Levothyroxine Tablet Malabsorption Associated with Gastroparesis Corrected with Gelatin Capsule Formulation.

PubMed

Reardon, David P; Yoo, Peter S

2016-01-01

Treatment of hypothyroidism with levothyroxine sodium often requires multiple dose adjustments and can be complicated by patients with gastric and intestinal dysfunction that limits absorption. In these cases, doses are often titrated higher than commonly used in clinical practice. Multiple formulations of levothyroxine are currently available and some may be preferred in cases of malabsorption. We report a case of a 42-year-old female who presented with a living unrelated kidney transplant evaluation with myxedema while being treated with levothyroxine sodium tablets. She was noted to have gastroparesis secondary to Type I diabetes mellitus which may have contributed to levothyroxine malabsorption. Changing to a gelatin capsule formulation quickly corrected her thyroid function assays. This case suggests that gastroparesis may affect absorption of levothyroxine tablets and the gelatin capsules may be an effective alternative therapy.

45 CFR 153.610 - Risk adjustment issuer requirements.

Code of Federal Regulations, 2014 CFR

2014-10-01

... HHS on behalf of the State. (b) Risk adjustment data storage. An issuer that offers risk adjustment... adjustment issuer requirements. (a) Data requirements. An issuer that offers risk adjustment covered plans must submit or make accessible all required risk adjustment data for those risk adjustment covered...

45 CFR 153.610 - Risk adjustment issuer requirements.

Code of Federal Regulations, 2012 CFR

2012-10-01

... HHS on behalf of the State. (b) Risk adjustment data storage. An issuer that offers risk adjustment... adjustment issuer requirements. (a) Data requirements. An issuer that offers risk adjustment covered plans must submit or make accessible all required risk adjustment data for those risk adjustment covered...

45 CFR 153.610 - Risk adjustment issuer requirements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... HHS on behalf of the State. (b) Risk adjustment data storage. An issuer that offers risk adjustment... adjustment issuer requirements. (a) Data requirements. An issuer that offers risk adjustment covered plans must submit or make accessible all required risk adjustment data for those risk adjustment covered...

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

PubMed

Furlanetto, J; Eiermann, W; Marmé, F; Reimer, T; Reinisch, M; Schmatloch, S; Stickeler, E; Thomssen, C; Untch, M; Denkert, C; von Minckwitz, G; Lederer, B; Nekljudova, V; Weber, K; Loibl, S; Möbus, V

2016-11-01

In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m 2 or adjusted to an ideal weight for obese patients due to safety reasons. Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m 2 . A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Management of rivaroxaban in relation to bodyweight and body mass index

PubMed Central

Uprichard, James

2016-01-01

Being overweight or obese is associated with a higher individual risk of venous thromboembolism and poorer postprocedural outcomes after hip or knee replacement surgery. In addition, there is evidence that obesity represents a significant driving factor for the current and projected prevalence of atrial fibrillation. Rivaroxaban and other direct oral anticoagulants offer fixed-dose regimens for these indications. They do not require therapeutic drug monitoring or dose adjustment according to the weight of the patient. However, primary care physicians seem to be hesitant to accept the concept of a fixed-dose regimen for patients at extremes of weight, perhaps because of familiarity with weight-based dosing of other drugs including low molecular weight heparins. The main concerns related to unadjusted dosing are increased exposure in underweight patients leading to a risk of excessive bleeding and conversely to underanticoagulation of overweight patients. Rivaroxaban has shown similar efficacy and a similar or better safety profile compared with standard treatment for several venous and arterial indications, including venous thromboembolism, nonvalvular atrial fibrillation, and acute coronary syndrome. Prespecified subgroup analyses of patients stratified by weight or body mass index demonstrated outcomes that were consistent with the overall analysis and within each weight and body mass index group. The results suggest that standard-dose rivaroxaban can be safely prescribed in adult patients of all weights. PMID:27090286

A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis

PubMed Central

2011-01-01

Background Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid-sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements. Methods The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2-years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG. Results Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019). Conclusions This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems. Trial registration SANCTR:DOH-27-0411-2436 PMID:21819556

A BMI-adjusted ultra-low-dose CT angiography protocol for the peripheral arteries-Image quality, diagnostic accuracy and radiation exposure.

PubMed

Schreiner, Markus M; Platzgummer, Hannes; Unterhumer, Sylvia; Weber, Michael; Mistelbauer, Gabriel; Loewe, Christian; Schernthaner, Ruediger E

2017-08-01

To investigate radiation exposure, objective image quality, and the diagnostic accuracy of a BMI-adjusted ultra-low-dose CT angiography (CTA) protocol for the assessment of peripheral arterial disease (PAD), with digital subtraction angiography (DSA) as the standard of reference. In this prospective, IRB-approved study, 40 PAD patients (30 male, mean age 72 years) underwent CTA on a dual-source CT scanner at 80kV tube voltage. The reference amplitude for tube current modulation was personalized based on the body mass index (BMI) with 120 mAs for [BMI≤25] or 150 mAs for [2570%) was assessed by two readers independently and compared to subsequent DSA. Radiation exposure was assessed with the computed tomography dose index (CTDIvol) and the dosis-length product (DLP). Objective image quality was assessed via contrast- and signal-to-noise ratio (CNR and SNR) measurements. Radiation exposure and image quality were compared between the BMI groups and between the BMI-adjusted ultra-low-dose protocol and the low-dose institutional standard protocol (ISP). The BMI-adjusted ultra-low-dose protocol reached high diagnostic accuracy values of 94% for Reader 1 and 93% for Reader 2. Moreover, in comparison to the ISP, it showed significantly (p<0.001) lower CTDIvol (1.97±0.55mGy vs. 4.18±0.62 mGy) and DLP (256±81mGy x cm vs. 544±83mGy x cm) but similar image quality (p=0.37 for CNR). Furthermore, image quality was similar between BMI groups (p=0.86 for CNR). A CT protocol that incorporates low kV settings with a personalized (BMI-adjusted) reference amplitude for tube current modulation and iterative reconstruction enables very low radiation exposure CTA, while maintaining good image quality and high diagnostic accuracy in the assessment of PAD. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacokinetics of Intranasal Scopolamine Gel Formation During Antiorthostatic Bedrest - A Microgravity Analog

NASA Technical Reports Server (NTRS)

Lakshmi, Putcha; Singh, R. P.; Crady, V. A.; Derendorf, H.

2011-01-01

Space Motion sickness (SMS) is an age old problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is the most frequently used drug for the treatment of motion sickness (MS) which is currently available in transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability thus allowing precise and reduced dosing options in addition to offering rescue and treatment options. As such, an intranasal gel dosage formulation of scopolamine (INSCOP) was developed and Pharmacokinetics (PK) and bioavailability were determined under IND guidelines. The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostatic bedrest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 and 0.4 mg doses of INSCOP during AMB and ABR in a four-way crossover design. Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose. Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration versus time curve (AUC) during ABR after the 0.4 mg dose. This difference in AUC and Cls at the higher but not the lower dose during ABR may suggest that ABR may affect metabolism and/or clearance at higher doses of INSCOP. These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

Unified approach for extrapolation and bridging of adult information in early-phase dose-finding paediatric studies.

PubMed

Petit, Caroline; Samson, Adeline; Morita, Satoshi; Ursino, Moreno; Guedj, Jérémie; Jullien, Vincent; Comets, Emmanuelle; Zohar, Sarah

2018-06-01

The number of trials conducted and the number of patients per trial are typically small in paediatric clinical studies. This is due to ethical constraints and the complexity of the medical process for treating children. While incorporating prior knowledge from adults may be extremely valuable, this must be done carefully. In this paper, we propose a unified method for designing and analysing dose-finding trials in paediatrics, while bridging information from adults. The dose-range is calculated under three extrapolation options, linear, allometry and maturation adjustment, using adult pharmacokinetic data. To do this, it is assumed that target exposures are the same in both populations. The working model and prior distribution parameters of the dose-toxicity and dose-efficacy relationships are obtained using early-phase adult toxicity and efficacy data at several dose levels. Priors are integrated into the dose-finding process through Bayesian model selection or adaptive priors. This calibrates the model to adjust for misspecification, if the adult and pediatric data are very different. We performed a simulation study which indicates that incorporating prior adult information in this way may improve dose selection in children.

Real-World Treatment Patterns for Golimumab and Concomitant Medications in Japanese Rheumatoid Arthritis Patients.

PubMed

Okazaki, Masateru; Kobayashi, Hisanori; Ishii, Yutaka; Kanbori, Masayoshi; Yajima, Tsutomu

2018-06-01

The aim of this study was to investigate real-world treatment patterns for use of golimumab and concomitant medications in Japanese patients with rheumatoid arthritis. This study was a post hoc retrospective analysis from post-marketing surveillance data on 2350 Japanese patients with moderate/severe rheumatoid arthritis who received golimumab for 24 weeks. The study population was divided based on initiation treatment or dose adjustment patterns with golimumab, methotrexate, or oral glucocorticoids. Logistic regression analysis revealed that the baseline factors associated with administration of golimumab (100 mg) were higher body weight, failure of prior biological therapy (bio-failure), no previous methotrexate use, and respiratory disease, while previous methotrexate use and absence of renal impairment or respiratory disease were associated with concomitant methotrexate therapy, and previous glucocorticoid use was associated with concomitant glucocorticoid therapy. The following associations were identified with regard to dose adjustment during treatment: bio-failure, no previous methotrexate use, previous csDMARDs use, presence of respiratory disease, allergy history, and higher CRP for golimumab dose escalation; shorter disease duration, previous GC, and no previous methotrexate use for methotrexate dose escalation; no prior biological therapy and renal impairment for methotrexate dose reduction; no previous GC use for glucocorticoid dose escalation; and absence of Steinbrocker's stage II/III/IV, absence of Steinbrocker's class II, no bio-failure, and no previous csDMARDs use for glucocorticoid dose reduction. This study revealed that various baseline factors were associated with initiation of treatment and dose adjustment of golimumab, methotrexate, or oral glucocorticoids, reflecting both the treatment strategies of physicians for improving RA symptoms and/or reducing adverse events. Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation.

A longitudinal study of depression among middle-aged and senior patients initiating chronic opioid therapy.

PubMed

Von Korff, Michael; Shortreed, Susan M; LeResche, Linda; Saunders, Kathleen; Thielke, Stephen; Thakral, Manu; Rosenberg, Dori; Turner, Judith A

2017-03-15

Improved understanding how depressive symptoms change with sustained opioid use is needed. We prospectively assessed patients 45 years or older initiating chronic opioid therapy (COT) at baseline and at 4 and 12 months, differentiating recent COT initiators (n=748) and continuing users (n=468). Level of opioid use before 12-month follow-up was classified as regular/higher-dose, intermittent/lower-dose, or minimal/no use. Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8). Depressive symptoms decreased, on average, from baseline to 12 months regardless of level of opioid use. COT patients with regular/higher-dose compared to those with intermittent/lower-dose opioid use (who had similar pain outcomes) did not differ in PHQ-8 scores at 12 months (adjusted mean difference -0.14, 95% CI, -1.07, 0.78 for COT initiators). At 12 months, COT patients with intermittent/lower-dose use had higher adjusted PHQ-8 scores than did those with minimal/no opioid use (adjusted mean difference 0.77, 95% CI, 0.03-1.52 for COT initiators). However, 77% of patients who discontinued opioids cited improved pain as a reason for discontinuation, while 21% cited negative emotional effects of opioids as a reason for discontinuation. Discontinuation was more common among persons who, at baseline, attributed 3 or more depressive symptoms to opioid use. Results are relevant to older COT patients receiving low to moderate opioid doses. Depressive symptoms did not increase with sustained opioid use. Depressive symptoms were not higher with regular/higher-dose compared to intermittent/lower-dose use. Persons who perceived negative effects of opioids on emotions more often discontinued their use. Copyright © 2017. Published by Elsevier B.V.

The safety and efficacy of dexmedetomidine-remifentanil in children undergoing flexible bronchoscopy

PubMed Central

Li, Xia; Wang, Xue; Jin, Shuguang; Zhang, Dongsheng; Li, Yanuo

2017-01-01

Abstract Flexible bronchoscopy is more and more used for diagnosis and management of various pulmonary diseases in pediatrics. As poor coordination of children, the procedure is usually performed under general anesthesia with spontaneous or controlled ventilation to increase children and bronchoscopists’ safety and comfort. Previous studies have reported that dexmedetomidine (DEX) could be safely and effectively used for flexible bronchoscopy in both adulate and children. However, there is no trial to evaluate the dose-finding of safety and efficacy of dexmedetomidine-remifentanil (DEX-RF) in children undergoing flexible bronchoscopy. The objective of this study is to evaluate the dose-finding of safety and efficacy of DEX-RF in children undergoing flexible bronchoscopy. One hundred thirty-five children undergoing flexible bronchoscopy with DEX-RF were divided into 3 groups: Group DR1 (n = 47, DEX infusion at 0.5 μg·kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 0.5 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR2 (n = 43, DEX infusion at 1 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR3 (n = 45, DEX infusion at 1.5 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1). Ramsay sedation scale of the 3 groups was maintained 3. Anesthesia onset time, total number of intraoperative children movements, hemodynamics (heart rate, arterial pressure, pulse oxygen saturation (SpO2), respiratory rate), total cumulative dose of dexmedetomidine and remifentanil, the amount of midazolam and lidocaine, time to first dose of rescue midazolam and lidocaine, postoperative recovery time, adverse events, bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DR3 group (14.23 ± 5.45 vs 14.45 ± 5.12 vs 11.13 ± 4.51 minutes, respectively, of DR1, DR2, DR3, P = 0.003). Additionally, the perioperative hemodynamic profile was more stable in group DR3 than that in the other 2 groups. Total number of children movements during flexible bronchoscopy was higher in DR1 group than the other 2 groups (46.81% 22/47 vs 34.88% 15/43 vs 17.78% 8/45, respectively, of DR1, DR2, DR3, P = 0.012). Total doses of rescue midazolam and lidocaine were significantly higher in DR1 and DR2 groups than that of DR3 group (P = 0.000). The time to first dose of rescue midazolam and lidocaine was significantly longer in DR3 group than DR1 and DR2 groups (P = 0.000). Total cumulative dose of dexmedetomidine was more in DR2 and DR3 groups (P = 0.000), while the amount of remifentanil was more in DR1 and DR2 groups (P = 0.000). The time to recovery for discharge from the PACU was significantly shorter in DR1 group compared with the other 2 groups (P = 0.000). Results from bronchoscopist satisfaction score showed significantly higher in DR2 and DR3 groups than that of DR1 group (P = 0.025). There were significant differences among the 3 groups in terms of the overall incidence of hypertension, tachycardia, hypoxemia, and cough (P < 0.05). Though it required longer recovery time, high dose of DEX-RF, which provided better stable hemodynamic profiles and bronchoscopist satisfaction score, less amount of rescue scheme, and children movements, could be safely and efficacy used in children undergoing flexible bronchoscopy. PMID:28296782

Fluorine magnetic resonance spectroscopy measurement of brain fluvoxamine and fluoxetine in pediatric patients treated for pervasive developmental disorders.

PubMed

Strauss, Wayne L; Unis, Alan S; Cowan, Charles; Dawson, Geraldine; Dager, Stephen R

2002-05-01

Pediatric populations, including those with autistic disorder or other pervasive developmental disorders, increasingly are being prescribed selective serotonin reuptake inhibitors (SSRIs). Little is known about the age-related brain pharmacokinetics of SSRIs; there is a lack of data regarding optimal dosing of medications for children. The authors used fluorine magnetic resonance spectroscopy ((19)F MRS) to evaluate age effects on whole-brain concentrations of fluvoxamine and fluoxetine in children taking SSRIs. Twenty-one pediatric subjects with diagnoses of autistic disorder or other pervasive developmental disorders, 6-15 years old and stabilized with a consistent dose of fluvoxamine or fluoxetine, were recruited for the study; 16 successfully completed the imaging protocol. Whole-brain drug levels in this group were compared to similarly acquired data from 28 adults. A significant relationship between dose and brain drug concentration was observed for both drugs across the age range studied. Brain fluvoxamine concentration in the children was lower, consistent with a lower dose/body mass drug prescription; when brain concentration was adjusted for dose/mass, age effects were no longer significant. Brain fluoxetine concentration was similar between age groups; no significant age effects on brain fluoxetine drug levels remained after adjustment for dose/mass. Observations of brain fluoxetine bioavailability and elimination half-life also were similar between age groups. These findings suggest that fluvoxamine or fluoxetine prescriptions adjusted for dose/mass are an acceptable treatment approach for medicating children with autistic disorder or other pervasive developmental disorders. It must be determined whether these findings can be generalized to other pediatric populations.

Maternal characteristics and hospital policies as risk factors for nonreceipt of hepatitis B vaccine in the newborn nursery.

PubMed

O'Leary, Sean T; Nelson, Christina; Duran, Julie

2012-01-01

A birth dose of hepatitis B vaccine (HBV) is a primary focus of the Advisory Committee on Immunization Practices' strategy to eliminate transmission of hepatitis B virus in the United States. We sought to assess the impact of maternal characteristics and hospital policy on the receipt of a birth dose of HBV. A retrospective cohort study was performed using data from the 2008 Colorado birth registry. Hospital policy was assessed by state health department personnel. Univariate and multivariate logistic regression analyses were used to examine the association of maternal characteristics and hospital policy with nonreceipt of HBV. A total of 64,425 infants were identified in the birth cohort, of whom 61.6% received a birth dose of HBV. Higher maternal education and income were associated with nonreceipt of HBV (master's degree vs. eighth grade or less: adjusted odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.49-1.85; >$75,000 vs. <$15,000: adjusted OR = 1.21, 95% CI = 1.13-1.30). Lack of a hospital policy stipulating a universal birth dose strongly predicted nonreceipt of a birth dose of HBV (policy with no birth dose vs. policy with a birth dose: adjusted OR = 2.21, 95% CI = 2.13-2.30). Maternal characteristics such as higher education and income are associated with nonreceipt of the HBV during the perinatal period. To effectively reduce risk of perinatal hepatitis B transmission, hospitals should stipulate that all infants are offered HBV and ensure that these policies are implemented and followed.

Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants?

PubMed

Chan, Noel; Sager, Philip T; Lawrence, Jack; Ortel, Thomas's; Reilly, Paul; Berkowitz, Scott; Kubitza, Dagmar; Eikelboom, John; Florian, Jeffry; Stockbridge, Norman; Rose, Martin; Temple, Robert; Seltzer, Jonathan H

2018-05-01

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. Copyright © 2017. Published by Elsevier Inc.

Ventilator-associated pneumonia: the influence of bacterial resistance, prescription errors, and de-escalation of antimicrobial therapy on mortality rates.

PubMed

Souza-Oliveira, Ana Carolina; Cunha, Thúlio Marquez; Passos, Liliane Barbosa da Silva; Lopes, Gustavo Camargo; Gomes, Fabiola Alves; Röder, Denise Von Dolinger de Brito

2016-01-01

Ventilator-associated pneumonia is the most prevalent nosocomial infection in intensive care units and is associated with high mortality rates (14-70%). This study evaluated factors influencing mortality of patients with Ventilator-associated pneumonia (VAP), including bacterial resistance, prescription errors, and de-escalation of antibiotic therapy. This retrospective study included 120 cases of Ventilator-associated pneumonia admitted to the adult adult intensive care unit of the Federal University of Uberlândia. The chi-square test was used to compare qualitative variables. Student's t-test was used for quantitative variables and multiple logistic regression analysis to identify independent predictors of mortality. De-escalation of antibiotic therapy and resistant bacteria did not influence mortality. Mortality was 4 times and 3 times higher, respectively, in patients who received an inappropriate antibiotic loading dose and in patients whose antibiotic dose was not adjusted for renal function. Multiple logistic regression analysis revealed the incorrect adjustment for renal function was the only independent factor associated with increased mortality. Prescription errors influenced mortality of patients with Ventilator-associated pneumonia, underscoring the challenge of proper Ventilator-associated pneumonia treatment, which requires continuous reevaluation to ensure that clinical response to therapy meets expectations. Copyright © 2016. Published by Elsevier Editora Ltda.

Process change evaluation framework for allogeneic cell therapies: impact on drug development and commercialization.

PubMed

Hassan, Sally; Huang, Hsini; Warren, Kim; Mahdavi, Behzad; Smith, David; Jong, Simcha; Farid, Suzanne S

2016-04-01

Some allogeneic cell therapies requiring a high dose of cells for large indication groups demand a change in cell expansion technology, from planar units to microcarriers in single-use bioreactors for the market phase. The aim was to model the optimal timing for making this change. A development lifecycle cash flow framework was created to examine the implications of process changes to microcarrier cultures at different stages of a cell therapy's lifecycle. The analysis performed under assumptions used in the framework predicted that making this switch earlier in development is optimal from a total expected out-of-pocket cost perspective. From a risk-adjusted net present value view, switching at Phase I is economically competitive but a post-approval switch can offer the highest risk-adjusted net present value as the cost of switching is offset by initial market penetration with planar technologies. The framework can facilitate early decision-making during process development.

Safety of allergen immunotherapy: a review of premedication and dose adjustment.

PubMed

Morris, A Erika; Marshall, Gailen D

2012-03-01

From the first allergen immunotherapy proposed in the early 1900s to the present day, numerous studies have proven the efficacy of allergen immunotherapy for the treatment of allergic rhinitis, allergic conjunctivitis, allergic asthma and stinging insect hypersensitivity. The major risk, however small, with allergen immunotherapy is anaphylaxis. There has been considerable interest and debate regarding risk factors for immunotherapy reactions (local and systemic) and interventions to reduce the occurrence of these reactions. One of these interventions that is especially debated regards dose adjustment for various reasons, but in particular for local reactions. In this review, we discuss the safety of immunotherapy and provide a comprehensive review of the literature regarding immunotherapy schedules and doses.

Sex Differences in Dose Escalation and Overdose Death during Chronic Opioid Therapy: A Population-Based Cohort Study

PubMed Central

Kaplovitch, Eric; Gomes, Tara; Camacho, Ximena; Dhalla, Irfan A.; Mamdani, Muhammad M.; Juurlink, David N.

2015-01-01

Background The use of opioids for noncancer pain is widespread, and more than 16,000 die of opioid-related causes in the United States annually. The patients at greatest risk of death are those receiving high doses of opioids. Whether sex influences the risk of dose escalation or opioid-related mortality is unknown. Methods and Findings We conducted a cohort study using healthcare records of 32,499 individuals aged 15 to 64 who commenced chronic opioid therapy for noncancer pain between April 1, 1997 and December 31, 2010 in Ontario, Canada. Patients were followed from their first opioid prescription until discontinuation of therapy, death from any cause or the end of the study period. Among patients receiving chronic opioid therapy, 589 (1.8%) escalated to high dose therapy and n = 59 (0.2%) died of opioid-related causes while on treatment. After multivariable adjustment, men were more likely than women to escalate to high-dose opioid therapy (adjusted hazard ratio 1.44; 95% confidence interval 1.21 to 1.70) and twice as likely to die of opioid-related causes (adjusted hazard ratio 2.04; 95% confidence interval 1.18 to 3.53). These associations were maintained in a secondary analysis of 285,520 individuals receiving any opioid regardless of the duration of therapy. Conclusions Men are at higher risk than women for escalation to high-dose opioid therapy and death from opioid-related causes. Both outcomes were more common than anticipated. PMID:26291716

Pharmacokinetics and Safety of Bortezomib in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction: Phase 1 NCI Organ Dysfunction Working Group Study NCI-6432

PubMed Central

LoRusso, Patricia M; Venkatakrishnan, Karthik; Ramanathan, Ramesh K; Sarantopoulos, John; Mulkerin, Daniel; Shibata, Stephen I; Hamilton, Anne; Dowlati, Afshin; Mani, Sridhar; Rudek, Michelle A; Takimoto, Chris H; Neuwirth, Rachel; Esseltine, Dixie-Lee; Ivy, Percy

2013-01-01

Purpose The proteasome inhibitor bortezomib undergoes oxidative hepatic metabolism. This study (NCI-6432; NCT00091117) was conducted to evaluate bortezomib pharmacokinetics and safety in patients with varying degrees of hepatic impairment, to inform dosing recommendations in these special populations. Methods Patients received bortezomib on days 1, 4, 8, and 11 of 21-day cycles. Patients were assigned to four hepatic function groups based on the National Cancer Institute Organ Dysfunction Working Group classification. Those with normal function received bortezomib at the 1.3 mg/m2 standard dose. Patients with severe, moderate, and mild impairment received escalating doses from 0.5, 0.7, and 1.0 mg/m2, respectively, up to a 1.3 mg/m2 maximum. Serial blood samples were collected for 24 hours post-dose on days 1 and 8, cycle 1, for bortezomib plasma concentration measurements. Results Sixty-one patients were treated, including 14 with normal hepatic function and 17, 12, and 18 with mild, moderate, and severe impairment, respectively. Mild hepatic impairment did not alter dose-normalized bortezomib exposure (AUC0-tlast) or Cmax compared with patients with normal function. Mean dose-normalized AUC0-tlast was increased by approximately 60% on day 8 in patients with moderate or severe impairment. Conclusions Patients with mild hepatic impairment do not require a starting dose adjustment of bortezomib. Patients with moderate or severe hepatic impairment should be started at a reduced dose of 0.7 mg/m2. PMID:22394984

Effect of Idalopirdine as Adjunct to Cholinesterase Inhibitors on Change in Cognition in Patients With Alzheimer Disease: Three Randomized Clinical Trials.

PubMed

Atri, Alireza; Frölich, Lutz; Ballard, Clive; Tariot, Pierre N; Molinuevo, José Luis; Boneva, Neli; Windfeld, Kristian; Raket, Lars L; Cummings, Jeffrey L

2018-01-09

New therapeutic approaches for Alzheimer disease (AD) are needed. To assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD. Three randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017. Idalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3). Primary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded. Among 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups. In patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD. clinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

The EU(7)-PIM list: a list of potentially inappropriate medications for older people consented by experts from seven European countries.

PubMed

Renom-Guiteras, Anna; Meyer, Gabriele; Thürmann, Petra A

2015-07-01

The aim of the study was to develop a European list of potentially inappropriate medications (PIM) for older people, which can be used for the analysis and comparison of prescribing patterns across European countries and for clinical practice. A preliminary PIM list was developed, based on the German PRISCUS list of potentially inappropriate medications and other PIM lists from the USA, Canada and France. Thirty experts on geriatric prescribing from Estonia, Finland, France, the Netherlands, Spain and Sweden participated; eight experts performed a structured expansion of the list, suggesting further medications; twenty-seven experts participated in a two-round Delphi survey assessing the appropriateness of drugs and suggesting dose adjustments and therapeutic alternatives. Finally, twelve experts completed a brief final survey to decide upon issues requiring further consensus. Experts reached a consensus that 282 chemical substances or drug classes from 34 therapeutic groups are PIM for older people; some PIM are restricted to a certain dose or duration of use. The PIM list contains suggestions for dose adjustments and therapeutic alternatives. The European Union (EU)(7)-PIM list is a screening tool, developed with participation of experts from seven European countries, that allows identification and comparison of PIM prescribing patterns for older people across European countries. It can also be used as a guide in clinical practice, although it does not substitute the decision-making process of individualised prescribing for older people. Further research is needed to investigate the feasibility and applicability and, finally, the clinical benefits of the newly developed list.

Chronic use of low-dose aspirin is not associated with lower bone mineral density in the general population.

PubMed

Bonten, T N; de Mutsert, R; Rosendaal, F R; Jukema, J W; van der Bom, J G; de Jongh, R T; den Heijer, M

2017-10-01

Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD). Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n=329) was conducted. After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI -0.027 to 0.100) g/cm 2 ) and femoral BMD (adjusted mean difference: 0.001 (-0.067 to 0.069) g/cm 2 ). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (-0.046 to 0.184) g/cm 2 ) or femoral BMD (adjusted mean difference: -0.055 (-0.139;0.029) g/cm 2 ). Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Transitioning Patients With Iron Overload From Exjade to Jadenu.

PubMed

Tinsley, Sara M; Hoehner-Cooper, Christine M

Iron overload is a concern for patients who require chronic transfusions as a result of inherited or acquired anemias, including sickle cell disease, thalassemia, and myelodysplastic syndromes. Iron chelation therapy (ICT) is the primary treatment for iron overload in these patients. The ICT deferasirox, which has been available as an oral dispersible tablet for liquid suspension, is now also available as a once-daily, film-coated tablet (FCT). Deferasirox FCT allows greater convenience and may be associated with fewer gastrointestinal side effects versus the original formulation. Dose adjustment increments, determined by titration monitoring, are lower for the FCT because of greater bioavailability.

A RANKL Wrinkle: Denosumab-Induced Hypocalcemia.

PubMed

Laskowski, Larissa K; Goldfarb, David S; Howland, Mary Ann; Kavcsak, Kelly; Lugassy, Danny M; Smith, Silas W

2016-09-01

The human monoclonal antibody denosumab inhibits osteoclast-mediated bone resorption by binding to receptor activator of nuclear factor κB ligand (RANKL), which is upregulated by tumor cells. Denosumab is indicated to prevent skeletal-related events (SREs) from osteoporosis and metastatic bone disease. We report a case of denosumab-induced hypocalcemia to highlight potential toxicity and treatment considerations. A 66-year-old man with prostate cancer, small cell lung cancer, and bone metastases presented with fatigue, weakness, and muscle spasm. Sixteen days prior, he received cycle 6 of cisplatin and etoposide, leuprolide, and denosumab (120 mg subcutaneously). His examination demonstrated a slight resting tremor, normal strength, and negative Chvostek sign. Laboratory analysis revealed hemoglobin, 8.0 g/dL; total calcium, 5.2 mg/dL (pre-denosumab, 8.9 mg/dL); and magnesium, 0.7 mg/dL. He initially received two units packed red blood cells, intravenous calcium and magnesium, and vitamin D. During his hospitalization, he required multiple doses of intravenous and oral calcium, magnesium, and vitamin D. Despite ongoing oral supplementation, his post-discharge serum calcium fluctuated significantly, requiring close monitoring and frequent dose adjustments. Denosumab's unique antiresorptive properties yield fewer SREs. The trade-off is increased hypocalcemia risk, which may be severe and require aggressive, prolonged supplementation and monitoring.

Daily short message service surveys to measure sexual behavior and pre-exposure prophylaxis use among Kenyan men and women.

PubMed

Curran, Kathryn; Mugo, Nelly R; Kurth, Ann; Ngure, Kenneth; Heffron, Renee; Donnell, Deborah; Celum, Connie; Baeten, Jared M

2013-11-01

Pre-exposure prophylaxis (PrEP) is a novel HIV prevention strategy which requires high adherence. We tested the use of daily short message service (i.e., SMS/text message) surveys to measure sexual behavior and PrEP adherence in Kenya. Ninety-six HIV-uninfected adult individuals, taking daily oral PrEP in a clinical trial, received daily SMS surveys for 60 days. Most participants (96.9 %) reported taking PrEP on ≥80 % days, but 69.8 % missed at least one dose. Unprotected sex was reported on 4.9 % of days; however, 47.9 % of participants reported unprotected sex at least once. Unprotected sex was not correlated with PrEP use (OR = 0.95). Participants reporting more sex were less likely to report PrEP non-adherence and those reporting no sex were most likely to report missing a PrEP dose (adjusted OR = 1.87). PrEP adherence was high, missed doses were correlated with sexual abstinence, and unprotected sex was not associated with decreased PrEP adherence.

Effect of gamma irradiation on Burkholderia thailandensis ( Burkholderia pseudomallei surrogate) survival under combinations of pH and NaCl

NASA Astrophysics Data System (ADS)

Yoon, Yohan; Kim, Jae-Hun; Byun, Myung-Woo; Choi, Kyoung-Hee; Lee, Ju-Woon

2010-04-01

This study evaluated the effect of gamma irradiation on Burkholderia thailandensis ( Burkholderia pseudomallei surrogate; potential bioterrorism agent) survival under different levels of NaCl and pH. B. thailandensis in Luria Bertani broth supplemented with NaCl (0-3%), and pH-adjusted to 4-7 was treated with gamma irradiation (0-0.5 kGy). Surviving cell counts of bacteria were then enumerated on tryptic soy agar. Data for the cell counts were also used to calculate D10 values (the dose required to reduce 1 log CFU/mL of B. thailandensis). Cell counts of B. thailandensis were decreased ( P<0.05) as irradiation dose increased, and no differences ( P≥0.05) in cell counts of the bacteria were observed among different levels of NaCl and pH. D10 values ranged from 0.04 to 0.07 kGy, regardless of NaCl and pH level. These results indicate that low doses of gamma irradiation should be a useful treatment in decreasing the potential bioterrorism bacteria, which may possibly infect humans through foods.

Clinical Pharmacokinetics and Pharmacodynamics of Atezolizumab in Metastatic Urothelial Carcinoma.

PubMed

Stroh, M; Winter, H; Marchand, M; Claret, L; Eppler, S; Ruppel, J; Abidoye, O; Teng, S L; Lin, W T; Dayog, S; Bruno, R; Jin, J; Girish, S

2017-08-01

Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Heparin in acute ischemic stroke revisited.

PubMed

Chamorro, A

2008-10-01

The evidence gathered in clinical trials of low molecular weight heparins (LMWHs) or with unfractionated heparin (UH) given subcutaneously at low or medium doses to patients with acute stroke cannot be extrapolated to the insufficiently tested effects of intravenous, weight-adjusted UH. Recent small studies have provided encouraging results but are potentially confounded and deserve confirmation in larger randomized controlled trials. In accordance with the current understanding of the biology of acute ischemic stroke and the pharmacology of UH, the new randomized controlled trials on heparin should give appropriate credit to the importance of a short therapeutic window, adequate dose adjustment of the drug, intravenous administration, and close monitoring of biological effects. UH is an orphan drug and only an academic driven trial would be able to face such an enterprise. Meanwhile, recommendations against the value of "early" anticoagulation with full dose of weight adjusted UH in the setting of acute ischemic stroke are not based on direct evidence but on extrapolations.

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF

PubMed Central

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (≥120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy. PMID:23194486

Cardioembolic vs. noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies.

PubMed

Hart, R G; Pearce, L A; Miller, V T; Anderson, D C; Rothrock, J F; Albers, G W; Nasco, E

2000-01-01

While atrial fibrillation (AF) increases the risk of cardioembolic stroke, some ischemic strokes in AF patients are noncardioembolic. To assess ischemic stroke mechanisms in AF and to compare their responses to antithrombotic therapies. On-therapy analyses of ischemic strokes occurring in 3,950 participants in the Stroke Prevention in Atrial Fibrillation I-III clinical trials. Strokes were classified by presumed mechanism according to specified neurologic features by neurologists unaware of antithrombotic therapy. Of 217 ischemic strokes, 52% were classified as probably cardioembolic, 24% as noncardioembolic, and 24% as of uncertain cause (i.e., 68% of classifiable infarcts were deemed cardioembolic). Compared to those receiving placebo or no antithrombotic therapy, the proportion of cardioembolic stroke was lower in patients taking adjusted-dose warfarin (p = 0.02), while the proportion of noncardioembolic stroke was lower in those taking aspirin (p = 0.06). Most (56%) ischemic strokes occurring in AF patients taking adjusted-dose warfarin were noncardioembolic vs. 16% of strokes in those taking aspirin. Adjusted-dose warfarin reduced cardioembolic strokes by 83% (p < 0.001) relative to aspirin. Cardioembolic strokes were particularly disabling (p = 0.05). Most ischemic strokes in AF patients are probably cardioembolic, and these are sharply reduced by adjusted-dose warfarin. Aspirin in AF patients appears to primarily reduce noncardioembolic strokes. AF patients at highest risk for stroke have the highest rates of cardioembolic stroke and have the greatest reduction in stroke by warfarin. Copyright 2000 S. Karger AG, Basel

Automated size-specific CT dose monitoring program: assessing variability in CT dose.

PubMed

Christianson, Olav; Li, Xiang; Frush, Donald; Samei, Ehsan

2012-11-01

The potential health risks associated with low levels of ionizing radiation have created a movement in the radiology community to optimize computed tomography (CT) imaging protocols to use the lowest radiation dose possible without compromising the diagnostic usefulness of the images. Despite efforts to use appropriate and consistent radiation doses, studies suggest that a great deal of variability in radiation dose exists both within and between institutions for CT imaging. In this context, the authors have developed an automated size-specific radiation dose monitoring program for CT and used this program to assess variability in size-adjusted effective dose from CT imaging. The authors radiation dose monitoring program operates on an independent health insurance portability and accountability act compliant dosimetry server. Digital imaging and communication in medicine routing software is used to isolate dose report screen captures and scout images for all incoming CT studies. Effective dose conversion factors (k-factors) are determined based on the protocol and optical character recognition is used to extract the CT dose index and dose-length product. The patient's thickness is obtained by applying an adaptive thresholding algorithm to the scout images and is used to calculate the size-adjusted effective dose (ED(adj)). The radiation dose monitoring program was used to collect data on 6351 CT studies from three scanner models (GE Lightspeed Pro 16, GE Lightspeed VCT, and GE Definition CT750 HD) and two institutions over a one-month period and to analyze the variability in ED(adj) between scanner models and across institutions. No significant difference was found between computer measurements of patient thickness and observer measurements (p = 0.17), and the average difference between the two methods was less than 4%. Applying the size correction resulted in ED(adj) that differed by up to 44% from effective dose estimates that were not adjusted by patient size. Additionally, considerable differences were noted in ED(adj) distributions between scanners, with scanners employing iterative reconstruction exhibiting significantly lower ED(adj) (range: 9%-64%). Finally, a significant difference (up to 59%) in ED(adj) distributions was observed between institutions, indicating the potential for dose reduction. The authors developed a robust automated size-specific radiation dose monitoring program for CT. Using this program, significant differences in ED(adj) were observed between scanner models and across institutions. This new dose monitoring program offers a unique tool for improving quality assurance and standardization both within and across institutions.

Automated size-specific CT dose monitoring program: Assessing variability in CT dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Christianson, Olav; Li Xiang; Frush, Donald

2012-11-15

Purpose: The potential health risks associated with low levels of ionizing radiation have created a movement in the radiology community to optimize computed tomography (CT) imaging protocols to use the lowest radiation dose possible without compromising the diagnostic usefulness of the images. Despite efforts to use appropriate and consistent radiation doses, studies suggest that a great deal of variability in radiation dose exists both within and between institutions for CT imaging. In this context, the authors have developed an automated size-specific radiation dose monitoring program for CT and used this program to assess variability in size-adjusted effective dose from CTmore » imaging. Methods: The authors radiation dose monitoring program operates on an independent health insurance portability and accountability act compliant dosimetry server. Digital imaging and communication in medicine routing software is used to isolate dose report screen captures and scout images for all incoming CT studies. Effective dose conversion factors (k-factors) are determined based on the protocol and optical character recognition is used to extract the CT dose index and dose-length product. The patient's thickness is obtained by applying an adaptive thresholding algorithm to the scout images and is used to calculate the size-adjusted effective dose (ED{sub adj}). The radiation dose monitoring program was used to collect data on 6351 CT studies from three scanner models (GE Lightspeed Pro 16, GE Lightspeed VCT, and GE Definition CT750 HD) and two institutions over a one-month period and to analyze the variability in ED{sub adj} between scanner models and across institutions. Results: No significant difference was found between computer measurements of patient thickness and observer measurements (p= 0.17), and the average difference between the two methods was less than 4%. Applying the size correction resulted in ED{sub adj} that differed by up to 44% from effective dose estimates that were not adjusted by patient size. Additionally, considerable differences were noted in ED{sub adj} distributions between scanners, with scanners employing iterative reconstruction exhibiting significantly lower ED{sub adj} (range: 9%-64%). Finally, a significant difference (up to 59%) in ED{sub adj} distributions was observed between institutions, indicating the potential for dose reduction. Conclusions: The authors developed a robust automated size-specific radiation dose monitoring program for CT. Using this program, significant differences in ED{sub adj} were observed between scanner models and across institutions. This new dose monitoring program offers a unique tool for improving quality assurance and standardization both within and across institutions.« less

The Influence of Hepatic and Renal Impairment on the Pharmacokinetics of a Treatment for Herpes Zoster, Amenamevir (ASP2151): Phase 1, Open-Label, Single-Dose, Parallel-Group Studies.

PubMed

Kusawake, Tomohiro; Kowalski, Donna; Takada, Akitsugu; Kato, Kota; Katashima, Masataka; Keirns, James J; Lewand, Michaelene; Lasseter, Kenneth C; Marbury, Thomas C; Preston, Richard A

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside human herpesvirus helicase-primase inhibitor that was approved in Japan for the treatment of herpes zoster (shingles) in 2017. This article reports the results of two clinical trials that investigated the effects of renal and hepatic impairment on the pharmacokinetics of amenamevir. These studies were phase 1, open-label, single-dose (oral 400 mg), parallel-group studies evaluating the pharmacokinetics, safety, and tolerability of amenamevir in healthy participants and participants with moderate hepatic impairment and mild, moderate, and severe renal impairment. In the hepatic impairment study, the pharmacokinetic profile of amenamevir in participants with moderate hepatic impairment was generally similar to that of participants with normal hepatic function. In the renal impairment study, the area under the amenamevir concentration versus time curve from the time of dosing up to the time of the last sample with extrapolation to infinity of the terminal phase was increased by 78.1% in participants with severe renal impairment. There was a positive relationship between creatinine clearance and oral and renal clearance for amenamevir in the renal impairment study. In both studies, amenamevir was safe and well tolerated. The findings of the hepatic impairment study indicate that no dosing adjustment is required in patients with moderate hepatic impairment. In the renal impairment study, systemic amenamevir exposure was increased by renal impairment. However, it is unlikely that renal impairment will have a significant effect on the safety of amenamevir given that in previous pharmacokinetic and safety studies in healthy individuals amenamevir was safe and well tolerated after a single dose (5-2400 mg, fasted condition) and repeated doses for 7 days (300 or 600 mg, fed condition), and the amount of amenamevir exposure in the renal impairment study was covered by those studies. These findings suggest that amenamevir does not require dosage reduction in accordance with the creatinine clearance FUNDING: Astellas Pharma.

Impact of Body Habitus on Phenytoin Levels Following Fosphenytoin Loading Dose in Pediatric Patients.

PubMed

Messinger, Mindl M; Moffett, Brady S; Wilfong, Angus

2015-12-01

Obesity has been shown to affect the disposition of water-soluble medications in pediatric patients. There are no published data describing serum phenytoin concentrations in obese pediatric patients. A retrospective descriptive study was designed that included patients from 2011 to 2013 between 2 and 19 years of age who received a dose of fosphenytoin with a subsequent serum phenytoin concentration, drawn 2-4 hours postloading dose. Body mass index (BMI) was calculated and patients were categorized by BMI percentiles into underweight (<5th percentile), normal weight (5th-84th percentile), overweight (85th-94th percentile), and obese (≥95th percentile). Descriptive statistical analysis and comparisons between groups occurred to determine differences in serum phenytoin concentrations. Multivariable linear regression analysis was performed to determine the effect of body habitus on serum phenytoin concentrations. One hundred ten patients met study criteria (male 51.8%, mean age: 8.3 ± 4.9 years). Patients were normal weight (47.3%), underweight (20.9%), overweight (14.6%), and obese (17.3%). No significant differences were identified between groups in regard to patient demographics, with the exception of weight (P < 0.05). The mean fosphenytoin dose was 23.4 ± 5.7 mg Phenytoin Equivalents (PE)/kg and the serum phenytoin concentration was 22.4 ± 6.8 mg/L measured at 2.9 ± 0.6 hours after dose, and this did not vary significantly across groups (P > 0.05). Multivariable linear regression identified body habitus as a nonsignificant predictor of serum phenytoin concentrations (P > 0.05). Patients of higher BMI did not require further antiepileptic therapy as compared with patients with lower BMI (P > 0.05). Contrary to the adult population, loading dose adjustments do not seem to be required in pediatric patients. Obesity does not affect serum phenytoin concentrations in pediatric patients after intravenous bolus fosphenytoin administration.

CURRENT USE AND FUTURE NEEDS OF BIODOSIMETRY IN STUDIES OF LONG-TERM HEALTH RISK FOLLOWING RADIATION EXPOSURE

PubMed Central

Simon, Steven L.; Bouville, André; Kleinerman, Ruth

2009-01-01

Biodosimetry measurements can potentially be an important and integral part of the dosimetric methods used in long-term studies of health risk following radiation exposure. Such studies rely on accurate estimation of doses to the whole body or to specific organs of individuals in order to derive reliable estimates of cancer risk. However, dose estimates based on analytical dose reconstruction (i.e., models) or personnel monitoring measurements, e.g., film-badges, can have substantial uncertainty. Biodosimetry can potentially reduce uncertainty in health risk studies by corroboration of model-based dose estimates or by using them to assess bias in dose models. While biodosimetry has begun to play a more significant role in long-term health risk studies, its use is still generally limited in that context due to one or more factors including, inadequate limits of detection, large inter-individual variability of the signal measured, high per-sample cost, and invasiveness. Presently, the most suitable biodosimetry methods for epidemiologic studies are chromosome aberration frequencies from fluorescence in situ hybridization (FISH) of peripheral blood lymphocytes and electron paramagnetic resonance (EPR) measurements made on tooth enamel. Both types of measurements, however, are usually invasive and require difficult to obtain biological samples. Moreover, doses derived from these methods are not always directly relevant to the tissues of interest. To increase the value of biodosimetry to epidemiologic studies, a number of issues need to be considered including limits of detection, effects of inhomogenous exposure of the body, how to extrapolate from the tissue sampled to the tissues of interest, and how to adjust dosimetry models applied to large populations based on sparse biodosimetry measurements. The requirements of health risk studies suggest a set of characteristics that, if satisfied by new biodosimetry methods, would increase the overall usefulness of biodosimetry to determining radiation health risks. PMID:20065672

Preemptive warfarin dose reduction after initiation of sulfamethoxazole-trimethoprim or metronidazole.

PubMed

Powers, Anna; Loesch, Erin B; Weiland, Anthony; Fioravanti, Nicole; Lucius, David

2017-07-01

To evaluate the utility of a preemptive warfarin dose reduction at the time of initiation of either sulfamethoxazole-trimethoprim or metronidazole, a retrospective chart review of patients who received an outpatient prescription for warfarin and either sulfamethoxazole-trimethoprim and/or metronidazole from July 1, 2011 to July 1, 2015 was conducted. Clinical outcomes compared Veterans who had a warfarin dose reduction and those who did not within 120 h (5 days) of antibiotic initiation. The primary outcome compared the pre-and post-antibiotic International Normalized Ratio (INR) of patients in the intervention group (warfarin dose reduction) with those in the control group (no intervention). Secondary outcomes assessed incidence of thromboembolic and major bleeding events within 30 days of antibiotic completion. Fifty patients were assessed. Forty-nine patients had at least one follow-up appointment; 126 follow-up visits were evaluated. There was a statistically significant difference for the change in therapeutic INR at the first follow-up appointment (p = 0.029) for those patients in the control group. On average, the patients in the intervention group required fewer follow-up visits (p = 0.019). There were no statistically significant differences for the overall rate of therapeutic INR values between groups, as well as no instances of a thromboembolic or major bleeding events during the follow-up period. Clinically significant differences were observed for patients who received a preemptive warfarin dose reduction upon initiation of sulfamethoxazole-trimethoprim or metronidazole. Patients in the intervention group required fewer follow-up appointments and were more likely maintain a therapeutic INR within the 30 days following the antibiotic course. Results of this study will be presented the at Pharmacy and Therapeutics committee in an effort to seek approval for policy development to initiate a local preemptive warfarin dose adjustment as a standard of practice.

Unit of Measurement Used and Parent Medication Dosing Errors

PubMed Central

Dreyer, Benard P.; Ugboaja, Donna C.; Sanchez, Dayana C.; Paul, Ian M.; Moreira, Hannah A.; Rodriguez, Luis; Mendelsohn, Alan L.

2014-01-01

BACKGROUND AND OBJECTIVES: Adopting the milliliter as the preferred unit of measurement has been suggested as a strategy to improve the clarity of medication instructions; teaspoon and tablespoon units may inadvertently endorse nonstandard kitchen spoon use. We examined the association between unit used and parent medication errors and whether nonstandard instruments mediate this relationship. METHODS: Cross-sectional analysis of baseline data from a larger study of provider communication and medication errors. English- or Spanish-speaking parents (n = 287) whose children were prescribed liquid medications in 2 emergency departments were enrolled. Medication error defined as: error in knowledge of prescribed dose, error in observed dose measurement (compared to intended or prescribed dose); >20% deviation threshold for error. Multiple logistic regression performed adjusting for parent age, language, country, race/ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease; site. RESULTS: Medication errors were common: 39.4% of parents made an error in measurement of the intended dose, 41.1% made an error in the prescribed dose. Furthermore, 16.7% used a nonstandard instrument. Compared with parents who used milliliter-only, parents who used teaspoon or tablespoon units had twice the odds of making an error with the intended (42.5% vs 27.6%, P = .02; adjusted odds ratio=2.3; 95% confidence interval, 1.2–4.4) and prescribed (45.1% vs 31.4%, P = .04; adjusted odds ratio=1.9; 95% confidence interval, 1.03–3.5) dose; associations greater for parents with low health literacy and non–English speakers. Nonstandard instrument use partially mediated teaspoon and tablespoon–associated measurement errors. CONCLUSIONS: Findings support a milliliter-only standard to reduce medication errors. PMID:25022742

Unit of measurement used and parent medication dosing errors.

PubMed

Yin, H Shonna; Dreyer, Benard P; Ugboaja, Donna C; Sanchez, Dayana C; Paul, Ian M; Moreira, Hannah A; Rodriguez, Luis; Mendelsohn, Alan L

2014-08-01

Adopting the milliliter as the preferred unit of measurement has been suggested as a strategy to improve the clarity of medication instructions; teaspoon and tablespoon units may inadvertently endorse nonstandard kitchen spoon use. We examined the association between unit used and parent medication errors and whether nonstandard instruments mediate this relationship. Cross-sectional analysis of baseline data from a larger study of provider communication and medication errors. English- or Spanish-speaking parents (n = 287) whose children were prescribed liquid medications in 2 emergency departments were enrolled. Medication error defined as: error in knowledge of prescribed dose, error in observed dose measurement (compared to intended or prescribed dose); >20% deviation threshold for error. Multiple logistic regression performed adjusting for parent age, language, country, race/ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease; site. Medication errors were common: 39.4% of parents made an error in measurement of the intended dose, 41.1% made an error in the prescribed dose. Furthermore, 16.7% used a nonstandard instrument. Compared with parents who used milliliter-only, parents who used teaspoon or tablespoon units had twice the odds of making an error with the intended (42.5% vs 27.6%, P = .02; adjusted odds ratio=2.3; 95% confidence interval, 1.2-4.4) and prescribed (45.1% vs 31.4%, P = .04; adjusted odds ratio=1.9; 95% confidence interval, 1.03-3.5) dose; associations greater for parents with low health literacy and non-English speakers. Nonstandard instrument use partially mediated teaspoon and tablespoon-associated measurement errors. Findings support a milliliter-only standard to reduce medication errors. Copyright © 2014 by the American Academy of Pediatrics.

Low-dose aspirin use and survival in breast cancer patients: A nationwide cohort study.

PubMed

Mc Menamin, Úna C; Cardwell, Chris R; Hughes, Carmel M; Murray, Liam J

2017-04-01

Preclinical evidence from breast cancer cell lines and animal models suggest that aspirin could have anti-cancer properties. In a large breast cancer patient cohort, we investigated whether post-diagnostic low-dose aspirin use was associated with a reduction in the risk of breast cancer-specific mortality. We identified 15,140 newly diagnosed breast cancer patients within the Scottish Cancer Registry. Linkages to the Scottish Prescribing Information System provided data on dispensed medications and breast cancer-specific deaths were identified from National Records of Scotland Death Records. Time-dependent Cox regression models were used to calculate hazard ratios (HR) and 95% CIs for breast cancer-specific and all-cause mortality by post-diagnostic low-dose aspirin use. HRs were adjusted for a range of potential confounders including age at diagnosis, year of diagnosis, cancer stage, grade, cancer treatments received, comorbidities, socioeconomic status and use of statins. Secondary analysis investigated the association between pre-diagnostic low-dose aspirin use and breast cancer-specific and all-cause mortality. Post-diagnostic users of low-dose aspirin appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.44, 95% CI 1.26, 1.65) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.92, 95% CI 0.75, 1.14). Findings were similar in analysis by increasing duration of use and in analysis of pre-diagnostic low-dose aspirin use. In this large nationwide study of breast cancer patients, we found little evidence of an association between post-diagnostic low-dose aspirin use and cancer-specific mortality. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics.

PubMed

Duconge, Jorge; Ramos, Alga S; Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y; Cadilla, Carmen L; Cruz, Iadelisse; Feliu, Juan F; Vergara, Cunegundo; Ruaño, Gualberto

2016-01-01

This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Results supported our rationale to incorporate individual's genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. ClinicalTrials.gov NCT01318057.

ICRP publication 121: radiological protection in paediatric diagnostic and interventional radiology.

PubMed

Khong, P-L; Ringertz, H; Donoghue, V; Frush, D; Rehani, M; Appelgate, K; Sanchez, R

2013-04-01

Paediatric patients have a higher average risk of developing cancer compared with adults receiving the same dose. The longer life expectancy in children allows more time for any harmful effects of radiation to manifest, and developing organs and tissues are more sensitive to the effects of radiation. This publication aims to provide guiding principles of radiological protection for referring clinicians and clinical staff performing diagnostic imaging and interventional procedures for paediatric patients. It begins with a brief description of the basic concepts of radiological protection, followed by the general aspects of radiological protection, including principles of justification and optimisation. Guidelines and suggestions for radiological protection in specific modalities - radiography and fluoroscopy, interventional radiology, and computed tomography - are subsequently covered in depth. The report concludes with a summary and recommendations. The importance of rigorous justification of radiological procedures is emphasised for every procedure involving ionising radiation, and the use of imaging modalities that are non-ionising should always be considered. The basic aim of optimisation of radiological protection is to adjust imaging parameters and institute protective measures such that the required image is obtained with the lowest possible dose of radiation, and that net benefit is maximised to maintain sufficient quality for diagnostic interpretation. Special consideration should be given to the availability of dose reduction measures when purchasing new imaging equipment for paediatric use. One of the unique aspects of paediatric imaging is with regards to the wide range in patient size (and weight), therefore requiring special attention to optimisation and modification of equipment, technique, and imaging parameters. Examples of good radiographic and fluoroscopic technique include attention to patient positioning, field size and adequate collimation, use of protective shielding, optimisation of exposure factors, use of pulsed fluoroscopy, limiting fluoroscopy time, etc. Major paediatric interventional procedures should be performed by experienced paediatric interventional operators, and a second, specific level of training in radiological protection is desirable (in some countries, this is mandatory). For computed tomography, dose reduction should be optimised by the adjustment of scan parameters (such as mA, kVp, and pitch) according to patient weight or age, region scanned, and study indication (e.g. images with greater noise should be accepted if they are of sufficient diagnostic quality). Other strategies include restricting multiphase examination protocols, avoiding overlapping of scan regions, and only scanning the area in question. Up-to-date dose reduction technology such as tube current modulation, organ-based dose modulation, auto kV technology, and iterative reconstruction should be utilised when appropriate. It is anticipated that this publication will assist institutions in encouraging the standardisation of procedures, and that it may help increase awareness and ultimately improve practices for the benefit of patients. Copyright © 2012. Published by Elsevier Ltd.

X-ray mask and method for making

DOEpatents

Morales, Alfredo M.

2004-10-26

The present invention describes a method for fabricating an x-ray mask tool which is a contact lithographic mask which can provide an x-ray exposure dose which is adjustable from point-to-point. The tool is useful in the preparation of LIGA plating molds made from PMMA, or similar materials. In particular the tool is useful for providing an ability to apply a graded, or "stepped" x-ray exposure dose across a photosensitive substrate. By controlling the x-ray radiation dose from point-to-point, it is possible to control the development process for removing exposed portions of the substrate; adjusting it such that each of these portions develops at a more or less uniformly rate regardless of feature size or feature density distribution.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

PubMed

Leuchter, Russia Ha-Vinh; Gui, Laura; Poncet, Antoine; Hagmann, Cornelia; Lodygensky, Gregory Anton; Martin, Ernst; Koller, Brigitte; Darqué, Alexandra; Bucher, Hans Ulrich; Hüppi, Petra Susan

2014-08-27

Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. clinicaltrials.gov Identifier: NCT00413946.

Phantom-derived estimation of effective dose equivalent from X rays with and without a lead apron.

PubMed

Mateya, C F; Claycamp, H G

1997-06-01

Organ dose equivalents were measured in a humanoid phantom in order to estimate effective dose equivalent (H(E)) and effective dose (E) from low-energy x rays and in the presence or absence of a protective lead apron. Plane-parallel irradiation conditions were approximated using direct x-ray beams of 76 and 104 kVp and resulting dosimetry data was adjusted to model exposures conditions in fluoroscopy settings. Values of H(E) and E estimated under-shielded conditions were compared to the results of several recent studies that used combinations of measured and calculated dosimetry to model exposures to radiologists. While the estimates of H(E) and E without the lead apron were within 0.2 to 20% of expected values, estimates based on personal monitors worn at the (phantom) waist (underneath the apron) underestimated either H(E) or E while monitors placed at the neck (above the apron) significantly overestimated both quantities. Also, the experimentally determined H(E) and E were 1.4 to 3.3 times greater than might be estimated using recently reported "two-monitor" algorithms for the estimation of effective dose quantities. The results suggest that accurate estimation of either H(E) or E from personal monitors under conditions of partial body exposures remains problematic and is likely to require the use of multiple monitors.

Microchips and controlled-release drug reservoirs.

PubMed

Staples, Mark

2010-01-01

This review summarizes and updates the development of implantable microchip-containing devices that control dosing from drug reservoirs integrated with the devices. As the expense and risk of new drug development continues to increase, technologies that make the best use of existing therapeutics may add significant value. Trends of future medical care that may require advanced drug delivery systems include individualized therapy and the capability to automate drug delivery. Implantable drug delivery devices that promise to address these anticipated needs have been constructed in a variety of ways using micro- and nanoelectromechanical systems (MEMS or NEMS)-based technology. These devices expand treatment options for addressing unmet medical needs related to dosing. Within the last few years, advances in several technologies (MEMS or NEMS fabrication, materials science, polymer chemistry, and data management) have converged to enable the construction of miniaturized implantable devices for controlled delivery of therapeutic agents from one or more reservoirs. Suboptimal performance of conventional dosing methods in terms of safety, efficacy, pain, or convenience can be improved with advanced delivery devices. Microchip-based implantable drug delivery devices allow localized delivery by direct placement of the device at the treatment site, delivery on demand (emergency administration, pulsatile, or adjustable continuous dosing), programmable dosing cycles, automated delivery of multiple drugs, and dosing in response to physiological and diagnostic feedback. In addition, innovative drug-medical device combinations may protect labile active ingredients within hermetically sealed reservoirs. Copyright (c) 2010 John Wiley & Sons, Inc.

Effects of Age, Sex, and Race on the Safety and Pharmacokinetics of Single and Multiple Doses of Azilsartan Medoxomil in Healthy Subjects.

PubMed

Harrell, Robert E; Karim, Aziz; Zhang, Wencan; Dudkowski, Caroline

2016-05-01

Azilsartan medoxomil (AZL-M) is an angiotensin II receptor blocker approved to treat hypertension. After oral dosing, AZL-M is quickly hydrolyzed to azilsartan (AZL). The aims of this study were to assess the effects of age, sex, and race on the pharmacokinetics of AZL-M in healthy subjects, as well as safety and tolerability. Sixty-one healthy adults were enrolled in this phase I, single-blind, randomized placebo-controlled study (placebo control was for assessment of safety/tolerability only). Subjects were stratified by age (18-45 vs. 65-85 years), sex, and race (black vs. white) and given oral AZL-M 60 mg (3 × 20 mg capsules) or placebo as a single dose (Day 1) and consecutive daily doses (Days 4-8) (6:2 ratio for AZL-M:placebo per group). Pharmacokinetics were evaluated (AZL-M patients only) on Days 1-3 and 8-9 and safety/tolerability was monitored. Age, sex, and race had no clinically meaningful effect on AZL exposures after single or multiple dosing. Pharmacokinetic parameters remained similar between Days 1 and 8 for each age, sex, and race subgroup. The frequency of adverse events was similar for AZL-M (32%) and placebo (29%). No discontinuations or serious adverse events occurred. Based on these pharmacokinetic and safety/tolerability findings, no AZL-M dose adjustments are required based on age, sex, or race (black/white).

The Use of the Kurtosis-Adjusted Cumulative Noise Exposure Metric in Evaluating the Hearing Loss Risk for Complex Noise.

PubMed

Xie, Hong-Wei; Qiu, Wei; Heyer, Nicholas J; Zhang, Mei-Bian; Zhang, Peng; Zhao, Yi-Ming; Hamernik, Roger P

2016-01-01

To test a kurtosis-adjusted cumulative noise exposure (CNE) metric for use in evaluating the risk of hearing loss among workers exposed to industrial noises. Specifically, to evaluate whether the kurtosis-adjusted CNE (1) provides a better association with observed industrial noise-induced hearing loss, and (2) provides a single metric applicable to both complex (non-Gaussian [non-G]) and continuous or steady state (Gaussian [G]) noise exposures for predicting noise-induced hearing loss (dose-response curves). Audiometric and noise exposure data were acquired on a population of screened workers (N = 341) from two steel manufacturing plants located in Zhejiang province and a textile manufacturing plant located in Henan province, China. All the subjects from the two steel manufacturing plants (N = 178) were exposed to complex noise, whereas the subjects from textile manufacturing plant (N = 163) were exposed to a G continuous noise. Each subject was given an otologic examination to determine their pure-tone HTL and had their personal 8-hr equivalent A-weighted noise exposure (LAeq) and full-shift noise kurtosis statistic (which is sensitive to the peaks and temporal characteristics of noise exposures) measured. For each subject, an unadjusted and kurtosis-adjusted CNE index for the years worked was created. Multiple linear regression analysis controlling for age was used to determine the relationship between CNE (unadjusted and kurtosis adjusted) and the mean HTL at 3, 4, and 6 kHz (HTL346) among the complex noise-exposed group. In addition, each subject's HTLs from 0.5 to 8.0 kHz were age and sex adjusted using Annex A (ISO-1999) to determine whether they had adjusted high-frequency noise-induced hearing loss (AHFNIHL), defined as an adjusted HTL shift of 30 dB or greater at 3.0, 4.0, or 6.0 kHz in either ear. Dose-response curves for AHFNIHL were developed separately for workers exposed to G and non-G noise using both unadjusted and adjusted CNE as the exposure matric. Multiple linear regression analysis among complex exposed workers demonstrated that the correlation between HTL3,4,6 and CNE controlling for age was improved when using the kurtosis-adjusted CNE compared with the unadjusted CNE (R = 0.386 versus 0.350) and that noise accounted for a greater proportion of hearing loss. In addition, although dose-response curves for AHFNIHL were distinctly different when using unadjusted CNE, they overlapped when using the kurtosis-adjusted CNE. For the same exposure level, the prevalence of NIHL is greater in workers exposed to complex noise environments than in workers exposed to a continuous noise. Kurtosis adjustment of CNE improved the correlation with NIHL and provided a single metric for dose-response effects across different types of noise. The kurtosis-adjusted CNE may be a reasonable candidate for use in NIHL risk assessment across a wide variety of noise environments.

What is the best diagnostic and therapeutic management strategy for an Addison patient during pregnancy?

PubMed

Lebbe, Marie; Arlt, Wiebke

2013-04-01

A new diagnosis of primary adrenal insufficiency (PAI) during pregnancy is extremely rare and difficult to recognize as signs and symptoms such as nausea, fatigue and hypotension may resemble features of normal pregnancy. However, if the diagnosis is overlooked and steroid replacement delayed, subsequent adrenal crisis triggered by hyperemesis gravidarum, fever or delivery can cause severe maternal and foetal morbidity and even mortality. In case of clinical suspicion of PAI, we recommend to measure paired samples of cortisol and ACTH and, if clinically feasible, a short synacthen test. We propose trimester-specific pass cut-offs for the short synacthen test that take into account the rise of total and also free cortisol during pregnancy. Empirical hydrocortisone treatment should never be delayed if the clinical suspicion is high. All pregnant women with PAI should be monitored by a team of endocrine and obstetric specialists. The third trimester is physiologically associated with a rise not only in total but also free cortisol and thus requires regular adjustment of the glucocorticoid dose. Mineralocorticoid requirements may change during pregnancy due to the anti-mineralocorticoid properties of progesterone. As plasma renin physiologically increases in pregnancy, monitoring is limited to clinical assessment including blood pressure and serum electrolytes. It is crucial that a pregnant woman with PAI and her partner are well educated regarding the adjustment of glucocorticoid dose in intercurrent illness and that both are trained in hydrocortisone emergency injection techniques. The obstetric staff should be provided with clear and written guidance for hydrocortisone cover during labour and delivery. With the appropriate replacement therapy, PAI patients can expect to have an uneventful pregnancy and deliver a healthy infant. © 2012 Blackwell Publishing Ltd.

Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients.

PubMed

Shuker, Nauras; de Man, Femke M; de Weerd, Annelies E; van Agteren, Madelon; Weimar, Willem; Betjes, Michiel G H; van Gelder, Teun; Hesselink, Dennis A

2016-04-01

The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes.

SU-E-J-33: Comparison Between Soft Tissue Alignment and Bony Alignment for Pancreatic Cancer Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Suh, Y; Crane, C; Krishnan, S

Purpose An IGRT modality for pancreatic cancer treatment with dose escalation at our institution is in-room daily CT imaging. The purpose of this study is to assess the difference between soft tissue alignment and bony alignment for pancreatic tumor localization. Methods Eighteen patients with pancreatic tumors who underwent IMRT treatment with an inspiration breath-hold technique between July 2012 and February 2015 are included in this study. Prior to each treatment, a CT scan was acquired. The CT image guidance started with auto-alignment to either the bony anatomy (vertebral bodies) or fiducials (for the six patients with the stent in/near themore » tumor) and then, when necessary, manual adjustments were made based on soft tissue alignment using clinical software (CT-Assisted Targeting system). The difference between soft tissue alignment and bony/fiducial alignment was evaluated. Results Of all 380 treatments, manual adjustment was made in 225 treatments, ranging from 11% (3 treatments out of 28) to 96% (27 treatments out of 28) per patient. The mean of the difference between soft tissue alignment and bony/fiducial alignment per patient ranged from −3.6 to 0.3 mm, −1.5 to 2.8 mm, and −3.3 to 3.4 mm in the AP, SI, and RL directions, respectively. The maximum difference over all treatments was −9.5, −14.6, and −14.6 mm in the AP, SI, and RL directions, respectively. Conclusion About 60% of the time, manual adjustment based on soft tissue alignment was required. The extent of manual adjustment was usually small but varied significantly from patient to patient. The ultimate goal of the IGRT modality using daily CT imaging is not to fully cover the target but to spare organs-at-risk as much as possible to avoid them moving into higher dose gradients than accepted in the treatment plan. To this end, manual adjustment based on soft tissue alignment is critically important.« less

Field Investigation of the Surface-deposited Radon Progeny as a Possible Predictor of the Airborne Radon Progeny Dose Rate

PubMed Central

Sun, Kainan; Steck, Daniel J.; Field, R. William

2009-01-01

The quantitative relationships between radon gas concentration, the surface-deposited activities of various radon progeny, the airborne radon progeny dose rate, and various residential environmental factors were investigated through actual field measurements in 38 selected Iowa houses occupied by either smokers or nonsmokers. Airborne dose rate was calculated from unattached and attached potential alpha energy concentrations (PAECs) using two dosimetric models with different activity-size weighting factors. These models are labeled Pdose and Jdose, respectively. Surface-deposited 218Po and 214Po were found significantly correlated to radon, unattached PAEC, and both airborne dose rates (p < 0.0001) in nonsmoking environments. However, deposited 218Po was not significantly correlated to the above parameters in smoking environments. In multiple linear regression analysis, natural logarithm transformation was performed for airborne dose rate as the dependent variable, as well as for radon and deposited 218Po and 214Po as predictors. An interaction effect was found between deposited 214Po and an obstacle in front of the Retrospective Reconstruction Detector (RRD) in predicting dose rate (p = 0.049 and 0.058 for Pdose and Jdose, respectively) for nonsmoking environments. After adjusting for radon and deposited radon progeny effects, the presence of either cooking, usage of a fireplace, or usage of a ceiling fan significantly, or marginal significantly, reduced the Pdose to 0.65 (90% CI 0.42–0.996), 0.54 (90% CI 0.28–1.02) and 0.66 (90% CI 0.45–0.96), respectively. For Jdose, only the usage of a ceiling fan significantly reduced the dose rate to 0.57 (90% CI 0.39–0.85). In smoking environments, deposited 218Po was a significant negative predictor for Pdose (RR 0.68, 90% CI 0.55–0.84) after adjusting for long-term 222Rn and environmental factors. A significant decrease of 0.72 (90% CI 0.64–0.83) in the mean Pdose was noted, after adjusting for the radon and radon progeny effects and other environmental factors, for every 10 increasing cigarettes smoked in the room. A significant increase of 1.71 in the mean Pdose was found for large room size relative to small room size (90% CI 1.08–2.79) after adjusting for the radon and radon progeny effects as well as other environmental factors. Fireplace usage was found to significantly increase the mean Pdose to 1.71 (90% CI 1.20–2.45) after adjusting for other factors. PMID:19590273

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

PubMed Central

Damle, Bharat; LaBadie, Robert; Crownover, Penelope; Glue, Paul

2008-01-01

AIMS Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug. METHODS This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h). RESULTS Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUCτ) and maximum concentration (Cmax), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUCτ (−7%; 90% CI −23, 13) and increased Cmax (23%; 90% CI −1, 53), while increasing efavirenz AUCτ (17%; 90% CI 6, 29) and not changing Cmax when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz. CONCLUSIONS When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.Furthermore, voriconazole increases the systemic exposure of efavirenz.Co-administration was therefore initially contraindicated. WHAT THIS STUDY ADDS The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication. PMID:18294336

Dosing of antirheumatic drugs in renal disease and dialysis.

PubMed

Swarup, Areena; Sachdeva, Namita; Schumacher, H Ralph

2004-08-01

Many patients with rheumatic diseases have their management complicated by renal problems. Renal failure modifies the metabolism of many drugs, especially by retention. Questions often arise about the effects of renal failure on the handling of drugs commonly used in rheumatology. For which drugs must we be especially concerned about increased toxicity? Patients on chronic dialysis may also need a variety of drugs for rheumatic disease. How are our drugs dialyzed, and which of these can be safety used and how best to use them?Decisions about dosing of rheumatic drugs are often required for the patients with chronic renal insufficiency or on long-term dialysis, although many drugs have not been formally studied in these settings. Patients with renal insufficiency are excluded from most drug trials. Data for some of these drugs have to be extrapolated based on the information available about the pharmacokinetics of the drug.This review addresses dosing of commonly used drugs in rheumatology in patients with chronic renal insufficiency or failure. It is compiled from a MEDLINE search of papers dealing with renal handling of antirheumatic drugs and suggestions for dose adjustments for these drugs. Drugs reviewed include commonly used disease-modifying antirheumatic drugs (DMARDS), drugs used for treatment of gout, commonly used nonsteroidal antnflammatory drugs (NSAIDS) and the newer COX-2 inhibitors.

Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy: the influence of light color and irradiance on the treatment outcome in vitro.

PubMed

Helander, Linda; Krokan, Hans E; Johnsson, Anders; Gederaas, Odrun A; Plaetzer, Kristjan

2014-08-01

Hexyl 5-aminolevulinate (HAL) is a lipophilic derivative of 5-aminolevulinate, a key intermediate in biosynthesis of the photosensitizer protoporphyrin IX (PpIX). The photodynamic efficacy and cell death mode after red versus blue light illumination of HAL-induced PpIX have been examined and compared using five different cancer cell lines. LED arrays emitting at 410 and 624 nm served as homogenous and adjustable light sources. Our results show that the response after HAL-PDT is cell line specific, both regarding the shape of the dose-survival curve, the overall dose required for efficient cell killing, and the relative amount of apoptosis. The ratio between 410 and 624 nm in absorption coefficient correlates well with the difference in cell killing at the same wavelengths. In general, the PDT efficacy was several folds higher for blue light as compared with red light, as expected. However, HAL-PDT₆₂₄ induced more apoptosis than HAL-PDT₄₁₀ and illumination with low irradiance resulted in more apoptosis than high irradiance at the same lethal dose. This indicates differences in death modes after low and high irradiance after similar total light doses. From a treatment perspective, these differences may be important.

Red versus blue light illumination in hexyl 5-aminolevulinate photodynamic therapy: the influence of light color and irradiance on the treatment outcome in vitro

NASA Astrophysics Data System (ADS)

Helander, Linda; Krokan, Hans E.; Johnsson, Anders; Gederaas, Odrun A.; Plaetzer, Kristjan

2014-08-01

Hexyl 5-aminolevulinate (HAL) is a lipophilic derivative of 5-aminolevulinate, a key intermediate in biosynthesis of the photosensitizer protoporphyrin IX (PpIX). The photodynamic efficacy and cell death mode after red versus blue light illumination of HAL-induced PpIX have been examined and compared using five different cancer cell lines. LED arrays emitting at 410 and 624 nm served as homogenous and adjustable light sources. Our results show that the response after HAL-PDT is cell line specific, both regarding the shape of the dose-survival curve, the overall dose required for efficient cell killing, and the relative amount of apoptosis. The ratio between 410 and 624 nm in absorption coefficient correlates well with the difference in cell killing at the same wavelengths. In general, the PDT efficacy was several folds higher for blue light as compared with red light, as expected. However, HAL-PDT624 induced more apoptosis than HAL-PDT410 and illumination with low irradiance resulted in more apoptosis than high irradiance at the same lethal dose. This indicates differences in death modes after low and high irradiance after similar total light doses. From a treatment perspective, these differences may be important.

Insulin Requirements in Non-Critically Ill Hospitalized Patients With Diabetes and Steroid-Induced Hyperglycemia

PubMed Central

Spanakis, Elias K.; Shah, Nina; Malhotra, Keya; Kemmerer, Terri; Yeh, Hsin-Chieh; Golden, Sherita Hill

2014-01-01

Objective Steroid-induced hyperglycemia is common in hospitalized patients with diabetes mellitus. Guidelines for glucose management in this setting are lacking. Methods We conducted a retrospective chart review of non-critically ill patients with diabetes receiving steroids, hospitalized from January 2009 to October 2012. Fifty-eight patients were identified from 247 consults. Multivariable linear regression was used to assess median daily insulin requirements of normoglycemic patients compared with hyperglycemic patients. Results Of the 58 total patients included in our study, 20 achieved normoglycemia during admission (patient-day weighted mean blood glucose [PDWMBG] level = 154 ± 16 mg/dL) and 38 remained hyperglycemic (PDWMBG level= 243 ± 39 mg/dL; P < 0.001). There were no differences between the 2 patient groups in age, sex, race, body weight, renal function, HbA1c level, glucose-altering medications, diabetes type, or disease duration. Following multivariable adjustment, compared with hyperglycemic patients, normoglycemic patients required similar units of basal insulin (median [interquartile range])(23.6 [17.9, 31.2] vs 20.1 [16.5, 24.4]; P = 0.35); higher units of nutritional insulin (45.5 [34.2, 60.4] vs 20.1 [16.4, 24.5]; P < 0.001]; and lower units of correctional insulin (5.8 [4.1, 8.1] vs 13.0 [10.2, 16.5]; P < 0.001]). Patients achieving normoglycemia required a significantly lower percentage of correction insulin (total daily dose [TDD]: 7.4% vs 23.4%; P < 0.001) and a higher percentage of nutritional insulin (TDD: 58.1% vs 36.2%; P < 0.001) than hyperglycemic patients. There was no difference in the TDD per kilogram, TDD per milligram hydrocortisone dose, or TDD per milligram hydrocortisone dose per kilogram weight between the 2 groups. Conclusion The data suggest that non-critically ill patients with hyperglycemia receiving steroids require a higher percentage of TDD insulin therapy as nutritional insulin to achieve normoglycemia. PMID:24769781

Insulin requirements in non-critically ill hospitalized patients with diabetes and steroid-induced hyperglycemia.

PubMed

Spanakis, Elias K; Shah, Nina; Malhotra, Keya; Kemmerer, Terri; Yeh, Hsin-Chieh; Golden, Sherita Hill

2014-04-01

Steroid-induced hyperglycemia is common in hospitalized patients with diabetes mellitus. Guidelines for glucose management in this setting are lacking. We conducted a retrospective chart review of non-critically ill patients with diabetes receiving steroids, hospitalized from January 2009 to October 2012. Fifty-eight patients were identified from 247 consults. Multivariable linear regression was used to assess median daily insulin requirements of normoglycemic patients compared with hyperglycemic patients. Of the 58 total patients included in our study, 20 achieved normoglycemia during admission (patient-day weighted mean blood glucose [PDWMBG] level = 154 ± 16 mg/dL) and 38 remained hyperglycemic (PDWMBG level = 243 ± 39 mg/dL; P < 0.001). There were no differences between the 2 patient groups in age, sex, race, body weight, renal function, HbA1c level, glucose-altering medications, diabetes type, or disease duration. Following multivariable adjustment, compared with hyperglycemic patients, normoglycemic patients required similar units of basal insulin (median interquartile range [IQR])(23.6 [17.9, 31.2] vs 20.1 [16.5, 24.4]; P = 0.35); higher units of nutritional insulin (45.5 [34.2, 60.4] vs 20.1 [16.4, 24.5]; P < 0.001]; and lower units of correctional insulin (5.8 [4.1, 8.1] vs 13.0 [10.2, 16.5]; P < 0.001]). Patients achieving normoglycemia required a significantly lower percentage of correction insulin (total daily dose [TDD]: 7.4% vs 23.4%; P < 0.001) and a higher percentage of nutritional insulin (TDD: 58.1% vs 36.2%; P <0.001) than hyperglycemic patients. There was no difference in the TDD per kilogram, TDD per milligram hydrocortisone dose, or TDD per milligram hydrocortisone dose per kilogram weight between the 2 groups. The data suggest that non-critically ill patients with hyperglycemia receiving steroids require a higher percentage of TDD insulin therapy as nutritional insulin to achieve normoglycemia.

Case-control study of urinary bladder cancer in metropolitan Nagoya.

PubMed

Ohno, Y; Aoki, K; Obata, K; Morrison, A S

1985-12-01

We conducted a population-based case-control study of patients with bladder cancer and of controls drawn randomly from the general population of Metropolitan Nagoya and interviewed both groups. The incidence rates of bladder cancer were 2.42 and 7.05/100,000 for females and males, respectively. The analysis, based on 293 patients and 589 controls who were frequency matched for age, sex, and residence, provided the following major findings. Age-adjusted relative risks of 1.89 (1.15-3.10) and 3.53 (1.71-7.27) were found in male and female cigarette smokers, respectively. Significant relative risk was also found in males who drank cocoa. Elevated risk with a dose-response relationship was observed among women who used hair dye and who smoke, but this risk was insignificant, with the disappearance of a dose-response relationship, when it was adjusted for smoking. Age- and smoking-adjusted relative risk of coffee drinking was insignificant with no dose-response relationship. Relative risk of artificial sweetener use was below 1 with adjustment for age and smoking. Intake of alcoholic beverages and cola was insignificantly associated. Reduced risk of significance was suggested for the intake of black tea and matcha (powdered green tea) in females and of fruit juice in males.

Warfarin Dosing Algorithms Underpredict Dose Requirements in Patients Requiring ≥7 mg Daily: A Systematic Review and Meta-analysis.

PubMed

Saffian, S M; Duffull, S B; Wright, Dfb

2017-08-01

There is preliminary evidence to suggest that some published warfarin dosing algorithms produce biased maintenance dose predictions in patients who require higher than average doses. We conducted a meta-analysis of warfarin dosing algorithms to determine if there exists a systematic under- or overprediction of dose requirements for patients requiring ≥7 mg/day across published algorithms. Medline and Embase databases were searched up to September 2015. We quantified the proportion of over- and underpredicted doses in patients whose observed maintenance dose was ≥7 mg/day. The meta-analysis included 47 evaluations of 22 different warfarin dosing algorithms from 16 studies. The meta-analysis included data from 1,492 patients who required warfarin doses of ≥7 mg/day. All 22 algorithms were found to underpredict warfarin dosing requirements in patients who required ≥7 mg/day by an average of 2.3 mg/day with a pooled estimate of underpredicted doses of 92.3% (95% confidence interval 90.3-94.1, I 2 = 24%). © 2017 American Society for Clinical Pharmacology and Therapeutics.

Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide.

PubMed

Cawello, Willi; Fuhr, Uwe; Hering, Ursula; Maatouk, Haidar; Halabi, Atef

2013-10-01

The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis. This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis). Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients. In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore, dose supplementation following hemodialysis should be considered.

Rotating and translating anthropomorphic head voxel models to establish an horizontal Frankfort plane for dental CBCT Monte Carlo simulations: a dose comparison study

NASA Astrophysics Data System (ADS)

Stratis, A.; Zhang, G.; Jacobs, R.; Bogaerts, R.; Bosmans, H.

2016-12-01

In order to carry out Monte Carlo (MC) dosimetry studies, voxel phantoms, modeling human anatomy, and organ-based segmentation of CT image data sets are applied to simulation frameworks. The resulting voxel phantoms preserve patient CT acquisition geometry; in the case of head voxel models built upon head CT images, the head support with which CT scanners are equipped introduces an inclination to the head, and hence to the head voxel model. In dental cone beam CT (CBCT) imaging, patients are always positioned in such a way that the Frankfort line is horizontal, implying that there is no head inclination. The orientation of the head is important, as it influences the distance of critical radiosensitive organs like the thyroid and the esophagus from the x-ray tube. This work aims to propose a procedure to adjust head voxel phantom orientation, and to investigate the impact of head inclination on organ doses in dental CBCT MC dosimetry studies. The female adult ICRP, and three in-house-built paediatric voxel phantoms were in this study. An EGSnrc MC framework was employed to simulate two commonly used protocols; a Morita Accuitomo 170 dental CBCT scanner (FOVs: 60  ×  60 mm2 and 80  ×  80 mm2, standard resolution), and a 3D Teeth protocol (FOV: 100  ×  90 mm2) in a Planmeca Promax 3D MAX scanner. Result analysis revealed large absorbed organ dose differences in radiosensitive organs between the original and the geometrically corrected voxel models of this study, ranging from  -45.6% to 39.3%. Therefore, accurate dental CBCT MC dose calculations require geometrical adjustments to be applied to head voxel models.

Effect of ketoconazole on cyclosporine dose in healthy dogs.

PubMed

Dahlinger, J; Gregory, C; Bea, J

1998-01-01

To determine the degree to which the dose of oral cyclosporine (CyA), in healthy dogs, can be decreased by concurrent oral administration of ketoconazole. Dogs in this study were observed for physical or biochemical side effects that might have been caused by the administration of CyA and ketoconazole. Prospective research study. Five healthy, intact female Beagle dogs. CyA was administered orally twice daily to achieve stable whole blood trough levels of 400 to 600 ng/mL. Ketoconazole was added at a low therapeutic dose (average dose: 13.6 mg/kg/d) then at a subtherapeutic dose (average dose: 4.7 mg/kg/d). CyA whole blood trough levels were monitored every 3 to 4 days and maintained at 400 to 600 ng/mL by adjusting CyA doses accordingly. Physical examination, CBC, biochemical profile, and urinalysis were performed at 2-week intervals throughout the study period. The initial mean dose of CyA required to achieve target blood levels was 14.5 mg/ kg/d. With concurrent ketoconazole (low therapeutic dose, average dose: 13.6 mg/kg/d) and CyA administration, the CyA dose declined to 3.4 mg/kg/day (range: 1.2 to 5.2 mg/kg/d), representing a 75% reduction in CyA dose and monetary savings of 57.8%. At a subtherapeutic dose of ketoconazole (average dose: 4.7 mg/kg/d), combination therapy resulted in a CyA dose of 10.1 mg/kg/day (4.9 to 10.6 mg/kg/d), representing a 38% reduction in CyA dose and monetary savings of 23.8%. Weight loss and transient hypoalbuminemia of unknown clinical significance were observed. Other physical and biochemical evaluations were unremarkable over the 12-week study period. The oral administration of ketoconazole can be used to reduce substantially the oral CyA dose needed to maintain selected blood levels in healthy dogs. The oral administration of ketoconazole can result in substantial cost savings to owners of dogs receiving CyA after renal allograft transplantation or for the treatment of autoimmune disease.

Demonstration of electronic design automation flow for massively parallel e-beam lithography

NASA Astrophysics Data System (ADS)

Brandt, Pieter; Belledent, Jérôme; Tranquillin, Céline; Figueiro, Thiago; Meunier, Stéfanie; Bayle, Sébastien; Fay, Aurélien; Milléquant, Matthieu; Icard, Beatrice; Wieland, Marco

2014-07-01

For proximity effect correction in 5 keV e-beam lithography, three elementary building blocks exist: dose modulation, geometry (size) modulation, and background dose addition. Combinations of these three methods are quantitatively compared in terms of throughput impact and process window (PW). In addition, overexposure in combination with negative bias results in PW enhancement at the cost of throughput. In proximity effect correction by over exposure (PEC-OE), the entire layout is set to fixed dose and geometry sizes are adjusted. In PEC-dose to size (DTS) both dose and geometry sizes are locally optimized. In PEC-background (BG), a background is added to correct the long-range part of the point spread function. In single e-beam tools (Gaussian or Shaped-beam), throughput heavily depends on the number of shots. In raster scan tools such as MAPPER Lithography's FLX 1200 (MATRIX platform) this is not the case and instead of pattern density, the maximum local dose on the wafer is limiting throughput. The smallest considered half-pitch is 28 nm, which may be considered the 14-nm node for Metal-1 and the 10-nm node for the Via-1 layer, achieved in a single exposure with e-beam lithography. For typical 28-nm-hp Metal-1 layouts, it was shown that dose latitudes (size of process window) of around 10% are realizable with available PEC methods. For 28-nm-hp Via-1 layouts this is even higher at 14% and up. When the layouts do not reach the highest densities (up to 10∶1 in this study), PEC-BG and PEC-OE provide the capability to trade throughput for dose latitude. At the highest densities, PEC-DTS is required for proximity correction, as this method adjusts both geometry edges and doses and will reduce the dose at the densest areas. For 28-nm-hp lines critical dimension (CD), hole&dot (CD) and line ends (edge placement error), the data path errors are typically 0.9, 1.0 and 0.7 nm (3σ) and below, respectively. There is not a clear data path performance difference between the investigated PEC methods. After the simulations, the methods were successfully validated in exposures on a MAPPER pre-alpha tool. A 28-nm half pitch Metal-1 and Via-1 layouts show good performance in resist that coincide with the simulation result. Exposures of soft-edge stitched layouts show that beam-to-beam position errors up to ±7 nm specified for FLX 1200 show no noticeable impact on CD. The research leading to these results has been performed in the frame of the industrial collaborative consortium IMAGINE.

No regional difference in cisatracurium dose-response and time-course-of-action between patients in China and Bosnia.

PubMed

Dahaba, A A; Suljevic, I; Bornemann, H; Wu, X-M; Metzler, H

2011-03-01

Variability in drug response could result from a variety of genetic and environmental factors that are often hard to define or quantify. A number of studies demonstrated regional geographic variations in potency of neuromuscular blocking agents (NMBAs). The aim of our study was to compare dose-response and time-course-of-action of cisatracurium besylate, an NMBA eliminated via the Hoffman degradation, in two countries with different life habits, diet, and ambient conditions; being Han Chinese in China and Caucasians in Bosnia. Neuromuscular block of cisatracurium 20 µg kg(-1), followed by four incremental 10 µg kg(-1) doses, and the remainder of 100 µg kg(-1) was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, The Netherlands). Dose-response curves were created using log-dose-probit-response transformation. There were no significant differences in cisatracurium mean (95% confidence intervals) ED(50), ED(90), and ED(95) (effective doses for 50%, 90%, and 95% first twitch depression) in Caucasian [39.1 (35.7-42.3), 50.6 (45.5-54.3), and 54.4 (49.8-58.9) µg kg(-1)] compared with Chinese patients [39.2 (35.1-43.1), 52.4 (47.9-56.8), and 56.9 (52.8-61.9) µg kg(-1)], respectively. There were no significant differences in mean (sd) Dur(25) and Dur(0.9) (time until 25% first twitch and 0.9 train-of-four ratio recoveries) in Caucasian [47.1 (6.4) and 77.5 (9.1) min)] compared with Chinese patients [(45.9 (4.7) and 72.3 (9.1) min)], respectively. Cisatracurium dose-response relationship and time-course-of-action were not influenced by geographic location. Thus, cisatracurium would not require dose adjustments between patients living in the two geographic locations.

Comprehensive clinical commissioning and validation of the RayStation treatment planning system for proton therapy with active scanning and passive treatment techniques.

PubMed

Bäumer, C; Geismar, D; Koska, B; Kramer, P H; Lambert, J; Lemke, M; Plaude, S; Pschichholz, L; Qamhiyeh, S; Schiemann, A; Timmermann, B; Vermeren, X

2017-11-01

To commission the treatment planning system (TPS) RayStation for proton therapy including beam models for spot scanning and for uniform scanning. Tests consist of procedures from ESTRO booklet number 7, the German DIN for constancy checks of TPSs, and extra tests checking the dose perturbation function. The dose distributions within patients were verified in silico by a comparison of 65 clinical treatment plans with the TPS XiO. Dose-volume parameters, dose differences, and three-dimensional gamma-indices serve as measures of similarity. The monthly constancy checks of Raystation have been automatized with a script. The basic functionality of the software complies with ESTRO booklet number 7. For a few features minor enhancements are suggested. The dose distribution in RayStation agrees with the calculation in XiO. This is supported by a gamma-index (3mm/3%) pass rate of >98.9% (median over 59 plans) for the volume within the 20% isodose line and a difference of <0.3% of V 95 of the PTV (median over 59 plans). If spot scanning is used together with a range shifter, the dose level calculated by RayStation can be off by a few percent. RayStation can be used for the creation of clinical proton treatment plans. Compared to XiO RayStation has an improved modelling of the lateral dose fall-off in passively delivered fields. For spot scanning fields with range shifter blocks an empirical adjustment of monitor units is required. The computation of perturbed doses also allows the evaluation of the robustness of a treatment plan. Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study.

PubMed

Reiss, Kim A; Yu, Shun; Mamtani, Ronac; Mehta, Rajni; D'Addeo, Kathryn; Wileyto, E Paul; Taddei, Tamar H; Kaplan, David E

2017-11-01

Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HR adj ], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.

SU-F-BRA-14: Optimization of Dosimetric Guidelines for Accelerated Partial Breast Irradiation (APBI) Using the Strut-Adjusted Volume Implant (SAVI)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mooney, K; Altman, M; Garcia-Ramirez, J

Purpose: Treatment planning guidelines for accelerated partial breast irradiation (ABPI) using the strut-adjusted volume implant (SAVI) are inconsistent between the manufacturer and NSABP B-39/RTOG 0413 protocol. Furthermore neither set of guidelines accounts for different applicator sizes. The purpose of this work is to establish guidelines specific to the SAVI that are based on clinically achievable dose distributions. Methods: Sixty-two consecutive patients were implanted with a SAVI and prescribed to receive 34 Gy in 10 fractions twice daily using high dose-rate (HDR) Ir-192 brachytherapy. The target (PTV-EVAL) was defined per NSABP. The treatments were planned and evaluated using a combination ofmore » dosimetric planning goals provided by the NSABP, the manufacturer, and our prior clinical experience. Parameters evaluated included maximum doses to skin and ribs, and volumes of PTV-EVAL receiving 90%, 95%, 100%, 150%, and 200% of the prescription (V90, etc). All target parameters were evaluated for correlation with device size using the Pearson correlation coefficient. Revised dosimetric guidelines for target coverage and heterogeneity were determined from this population. Results: Revised guidelines for minimum target coverage (ideal in parentheses): V90≥95%(97%), V95≥90%(95%), V100≥88%(91%). The only dosimetric parameters that were significantly correlated (p<0.05) with device size were V150 and V200. Heterogeneity criteria were revised for the 6–1 Mini/6-1 applicators to V150≤30cc and V200≤15cc, and unchanged for the other sizes. Re-evaluation of patient plans showed 90% (56/62) met the revised minimum guidelines and 76% (47/62) met the ideal guidelines. All and 56/62 patients met our institutional guidelines for maximum skin and rib dose, respectively. Conclusions: We have optimized dosimetric guidelines for the SAVI applicators, and found that implementation of these revised guidelines for SAVI treatment planning yielded target coverage exceeding that required by existing guidelines while preserving heterogeneity constraints and minimizing dose to organs at risk.« less

Automated IMRT planning with regional optimization using planning scripts

PubMed Central

Wong, Eugene; Bzdusek, Karl; Lock, Michael; Chen, Jeff Z.

2013-01-01

Intensity‐modulated radiation therapy (IMRT) has become a standard technique in radiation therapy for treating different types of cancers. Various class solutions have been developed for simple cases (e.g., localized prostate, whole breast) to generate IMRT plans efficiently. However, for more complex cases (e.g., head and neck, pelvic nodes), it can be time‐consuming for a planner to generate optimized IMRT plans. To generate optimal plans in these more complex cases which generally have multiple target volumes and organs at risk, it is often required to have additional IMRT optimization structures such as dose limiting ring structures, adjust beam geometry, select inverse planning objectives and associated weights, and additional IMRT objectives to reduce cold and hot spots in the dose distribution. These parameters are generally manually adjusted with a repeated trial and error approach during the optimization process. To improve IMRT planning efficiency in these more complex cases, an iterative method that incorporates some of these adjustment processes automatically in a planning script is designed, implemented, and validated. In particular, regional optimization has been implemented in an iterative way to reduce various hot or cold spots during the optimization process that begins with defining and automatic segmentation of hot and cold spots, introducing new objectives and their relative weights into inverse planning, and turn this into an iterative process with termination criteria. The method has been applied to three clinical sites: prostate with pelvic nodes, head and neck, and anal canal cancers, and has shown to reduce IMRT planning time significantly for clinical applications with improved plan quality. The IMRT planning scripts have been used for more than 500 clinical cases. PACS numbers: 87.55.D, 87.55.de PMID:23318393

Childhood thyroid radioiodine exposure and subsequent infertility in the intermountain fallout cohort.

PubMed

Stone, Mary Bishop; Stanford, Joseph B; Lyon, Joseph L; VanDerslice, James A; Alder, Stephen C

2013-01-01

Above-ground and underground nuclear weapon detonation at the Nevada Test Site (1951-1992) has resulted in radioiodine exposure for nearby populations. Although the long-term effect of environmental radioiodine exposure on thyroid disease has been well studied, little is known regarding the effect of childhood radioiodine exposure on subsequent fertility. We investigated early childhood thyroid radiation exposure from nuclear testing fallout (supplied predominantly by radioactive isotopes of iodine) and self-reported lifetime incidence of male or female infertility or sterility. Participants were members of the 1965 Intermountain Fallout Cohort, schoolchildren at the time of exposure who were reexamined during two subsequent study phases to collect dietary and reproductive histories. Thyroid radiation exposure was calculated via an updated dosimetry model. We used multivariable logistic regression with robust sandwich estimators to estimate odds ratios for infertility, adjusted for potential confounders and (in separate models) for a medically confirmed history of thyroid disease. Of 1,389 participants with dosimetry and known fertility history, 274 were classified as infertile, including 30 classified as sterile. Childhood thyroid radiation dose was possibly associated with infertility [adjusted odds ratio (AOR) = 1.17; 95% CI: 0.82, 1.67 and AOR = 1.35; 95% CI: 0.96, 1.90 for the middle and upper tertiles vs. the first tertile of exposure, respectively]. The odds ratios were attenuated (AOR = 1.08; 95% CI: 0.75, 1.55 and AOR = 1.29; 95% CI: 0.91, 1.83 for the middle and upper tertiles, respectively) after adjusting for thyroid disease. There was no association of childhood radiation dose and sterility. Our findings suggest that childhood radioiodine exposure from nuclear testing may be related to subsequent adult infertility. Further research is required to confirm this.

Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.

PubMed

Sturgeon, Kathleen; Digiovanni, Laura; Good, Jerene; Salvatore, Domenick; Fenderson, Desiré; Domchek, Susan; Stopfer, Jill; Galantino, Mary Lou; Bryan, Cathy; Hwang, Wei-Ting; Schmitz, Kathryn

2016-08-01

Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose). In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR. ©2016 American Association for Cancer Research.

Goal directed enoxaparin dosing provides superior chemoprophylaxis against deep vein thrombosis.

PubMed

Kopelman, Tammy R; Walters, Jarvis W; Bogert, James N; Basharat, Usmaan; Pieri, Paola G; Davis, Karole M; Quan, Asia N; Vail, Sydney J; Pressman, Melissa A

2017-05-01

Optimal enoxaparin dosing for deep venous thrombosis (DVT) prophylaxis remains elusive. Prior research demonstrated that trauma patients at increased risk for DVT based upon Greenfield's risk assessment profile (RAP) have DVT rates of 10.8% despite prophylaxis. The aim of this study was to determine if goal directed prophylactic enoxaparin dosing to achieve anti-Xa levels of 0.3-0.5IU/ml would decrease DVT rates without increased complications. Retrospective review of trauma patients having received prophylactic enoxaparin and appropriately timed anti-Xa levels was performed. Dosage was adjusted to maintain an anti-Xa level of 0.3-0.5IU/ml. RAP was determined on each patient. A score of ≥5 was considered high risk for DVT. Sub-analysis was performed on patients who received duplex examinations subsequent to initiation of enoxaparin therapy to determine the incidence of DVT. 306 patients met inclusion criteria. Goal anti-Xa levels were met initially in only 46% of patients despite dosing of >40mg twice daily in 81% of patients; however, with titration, goal anti-Xa levels were achieved in an additional 109 patients (36%). An average enoxaparin dosage of 0.55mg/kg twice daily was required for adequacy. Bleeding complications were identified in five patients (1.6%) with three requiring intervention. There were no documented episodes of HIT. Subsequent duplex data was available in 197 patients with 90% having a RAP score >5. Overall, five DVTs (2.5%) were identified and all occurred in the high-risk group. All patients were asymptomatic at the time of diagnosis. An increased anti-Xa range of 0.3-0.5IU/ml was attainable but frequently required titration of enoxaparin dosage. This produced a lower rate of DVT than previously published without increased complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Influence of apixaban on antifactor Xa levels in a patient with acute kidney injury.

PubMed

Wendte, Jodi; Voss, Glenn; VanOverschelde, Beau

2016-04-15

The case of a patient requiring conversion from apixaban to heparin in the setting of acute kidney injury is reported. A 70-year-old man was initiated on apixaban 5 mg twice daily for new-onset, nonvalvular atrial fibrillation with a CHA2DS2-VASc score of 4, indicating a high risk of stroke. Soon after starting apixaban, he experienced pulmonary edema with pneumonia requiring hospitalization. During the course of hospitalization, the patient developed acute kidney injury requiring hemodialysis, and apixaban was stopped due to concerns about altered pharmacokinetics and impaired drug elimination in this setting. A heparin infusion was started 36 hours after the last dose of apixaban was administered. Antifactor Xa levels were monitored consistent with the hospital's standard practice protocols. The initial and repeat antifactor Xa concentrations were elevated (1.8-4.4 IU/mL) for up 72 hours after stopping the heparin infusion. Given the suspected interference of apixaban with standard antifactor Xa level monitoring, the heparin protocol was modified to reflect drip-rate adjustments based on activated partial thromboplastin times (aPTTs). The hospital protocol for heparin infusions was reinstituted on hospital day 7, with dosage adjustments based on antifactor Xa levels. The patient remained on a continuous heparin infusion for atrial fibrillation for the remainder of his hospitalization without complications or bleeding events. A 70-year-old man with new-onset nonvalvular atrial fibrillation and receiving apixaban discontinued this therapy and was given heparin instead due to acute kidney injury. His heparin dosage was successfully adjusted based on antifactor Xa levels and aPPTs. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

PubMed

Tsuchimine, Shoko; Ochi, Shinichiro; Tajiri, Misuzu; Suzuki, Yutaro; Sugawara, Norio; Inoue, Yoshimasa; Yasui-Furukori, Norio

2018-06-01

Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

The dexmedetomidine concentration required after remifentanil anesthesia is three-fold higher than that after fentanyl anesthesia or that for general sedation in the ICU

PubMed Central

Kunisawa, Takayuki; Fujimoto, Kazuhiro; Kurosawa, Atsushi; Nagashima, Michio; Matsui, Koji; Hayashi, Dai; Yamamoto, Kunihiko; Goto, Yuya; Akutsu, Hiroaki; Iwasaki, Hiroshi

2014-01-01

Purpose The general dexmedetomidine (DEX) concentration required for sedation of intensive care unit patients is considered to be approximately 0.7 ng/mL. However, higher DEX concentrations are considered to be required for sedation and/or pain management after major surgery using remifentanil. We determined the DEX concentration required after major surgery by using a target-controlled infusion (TCI) system for DEX. Methods Fourteen patients undergoing surgery for abdominal aortic aneurysms (AAA) were randomly, double-blindly assigned to two groups and underwent fentanyl- or remifentanil-based anesthetic management. DEX TCI was started at the time of closing the peritoneum and continued for 12 hours after stopping propofol administration (M0); DEX TCI was adjusted according to the sedation score and complaints of pain. The doses and concentrations of all anesthetics and postoperative conditions were investigated. Results Throughout the observation period, the predicted plasma concentration of DEX in the fentanyl group was stable at approximately 0.7 ng/mL. In contrast, the predicted plasma concentration of DEX in the remifentanil group rapidly increased and stabilized at approximately 2 ng/mL. The actual DEX concentration at 540 minutes after M0 showed a similar trend (0.54±0.14 [fentanyl] versus 1.57±0.39 ng/mL [remifentanil]). In the remifentanil group, the dopamine dose required and the duration of intubation decreased, and urine output increased; however, no other outcomes improved. Conclusion The DEX concentration required after AAA surgery with remifentanil was three-fold higher than that required after AAA surgery with fentanyl or the conventional DEX concentration for sedation. High DEX concentration after remifentanil affords some benefits in anesthetic management. PMID:25328395

Cost-effectiveness comparison of current proton-pump inhibitors to treat gastro-oesophageal reflux disease in the UK.

PubMed

Remák, E; Brown, R E; Yuen, C; Robinson, A

2005-10-01

Gastro-oesophageal reflux disease (GORD) is a recurring condition with many patients requiring long-term maintenance therapy. Therefore initial choice of treatment has long-term cost implications. The aim was to compare the costs and effectiveness of treatment of GORD the (unconfirmed by endoscopy) with seven proton pump inhibitors (PPIs: esomeprazole, lansoprazole (capsules and oro-dispersible tablets), omeprazole (generic and branded), pantoprazole and rabeprazole), over one year. A treatment model was developed of 13 interconnected Markov models incorporating acute treatment of symptoms, long-term therapy and subsequent decisions to undertake endoscopy to confirm diagnosis. Patients were allowed to stop treatment or to receive maintenance treatment either continuously or on-demand depending on response to therapy. Long-term dosing schedule (high dose or step-down dose) was based on current market data. Efficacy of treatments was based on clinical trials and follow-up studies, while resource use patterns were determined by a panel of physicians. The model predicts total expected annual costs, number of symptom-free days and quality-adjusted life-years (QALY). Generic omeprazole and rabeprazole dominated (i.e. cost less and resulted in more symptom-free days and higher QALY gains) the other PPIs. Rabeprazole had a favourable cost-effectiveness ratio of 3.42 pounds per symptom-free day and 8308 pounds/quality-adjusted life-year gained when compared with generic omeprazole. Rabeprazole remained cost-effective independent of choice of maintenance treatment (i.e. proportion of patients remaining on continuous treatment versus on-demand treatment). Economic models provide a useful framework to evaluate PPIs in realistic clinical scenarios. Our findings show that rabeprazole is cost-effective for the treatment of GORD.

The Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support improves HbA1c in poorly controlled type 1 diabetic patients: a 6-month, randomized, open-label, parallel-group, multicenter trial (TeleDiab 1 Study).

PubMed

Charpentier, Guillaume; Benhamou, Pierre-Yves; Dardari, Dured; Clergeot, Annie; Franc, Sylvia; Schaepelynck-Belicar, Pauline; Catargi, Bogdan; Melki, Vincent; Chaillous, Lucy; Farret, Anne; Bosson, Jean-Luc; Penfornis, Alfred

2011-03-01

To demonstrate that Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support significantly improves HbA(1c) in poorly controlled type 1 diabetic patients. In a six-month open-label parallel-group, multicenter study, adult patients (n = 180) with type 1 diabetes (>1 year), on a basal-bolus insulin regimen (>6 months), with HbA(1c) ≥ 8%, were randomized to usual quarterly follow-up (G1), home use of a smartphone recommending insulin doses with quarterly visits (G2), or use of the smartphone with short teleconsultations every 2 weeks but no visit until point end (G3). Six-month mean HbA(1c) in G3 (8.41 ± 1.04%) was lower than in G1 (9.10 ± 1.16%; P = 0.0019). G2 displayed intermediate results (8.63 ± 1.07%). The Diabeo system gave a 0.91% (0.60; 1.21) improvement in HbA(1c) over controls and a 0.67% (0.35; 0.99) reduction when used without teleconsultation. There was no difference in the frequency of hypoglycemic episodes or in medical time spent for hospital or telephone consultations. However, patients in G1 and G2 spent nearly 5 h more than G3 patients attending hospital visits. The Diabeo system gives a substantial improvement to metabolic control in chronic, poorly controlled type 1 diabetic patients without requiring more medical time and at a lower overall cost for the patient than usual care.

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule.

PubMed

Gatault, Philippe; Brachet, Guillaume; Ternant, David; Degenne, Danielle; Récipon, Guillaume; Barbet, Christelle; Gyan, Emmanuel; Gouilleux-Gruart, Valérie; Bordes, Cécile; Farrell, Alexandra; Halimi, Jean Michel; Watier, Hervé

2015-01-01

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic-uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R(2) = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration.

Therapeutic drug monitoring of eculizumab: Rationale for an individualized dosing schedule

PubMed Central

Gatault, Philippe; Brachet, Guillaume; Ternant, David; Degenne, Danielle; Récipon, Guillaume; Barbet, Christelle; Gyan, Emmanuel; Gouilleux-Gruart, Valérie; Bordes, Cécile; Farrell, Alexandra; Halimi, Jean Michel; Watier, Hervé

2015-01-01

The annual cost of eculizumab maintenance therapy in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic–uremic syndrome (aHUS) exceeds $300,000 per patient. A better understanding of eculizumab pharmacokinetics and subsequent individual dose adjustment could reduce this cost. We measured the trough eculizumab concentration in 9 patients with maintenance therapy (aHUS, n = 7; PNH, n = 2) and determined: 1) the intra- and inter-individual variability; 2) the influence of weight on eculizumab pharmacokinetics; and 3) the rate of elimination of eculizumab following discontinuation. A one-compartment model was developed to describe the pharmacokinetics of eculizumab and predicted complement activity by body weight. Trough eculizumab concentrations were >50 µg/mL in 9/9, >100 µg/mL in 8/9, and >300 µg/mL in 5/9 of patients. Intra-individual variability was low but eculizumab concentrations, closely correlated with patient weight (R2 = 0.66, p = 0.034), varied broadly (55 ± 12 to 733 ± 164 µg/mL). Pharmacokinetic modeling showed that the elimination half-life varied greatly, with an increase from 7.8 d in a patient weighing 100 kg to 19.5 d in a 40 kg patient. We predicted that infusions of 1200 mg could be spaced every 4 or 6 weeks in patients weighing <90 and <70 kg, respectively. In this pilot study, the current recommended use of a fixed eculizumab dose for maintenance therapy is associated with excessively high trough concentrations in many patients. Further prospective larger studies are now required to support an individualized schedule adjusted for patient weight and based on the observed trough serum eculizumab concentration. PMID:26337866

Implementation of telehealth support for patients with type 2 diabetes using insulin treatment: an exploratory study.

PubMed

Turner, Jane; Larsen, Mark; Tarassenko, Lionel; Neil, Andrew; Farmer, Andrew

2009-01-01

Initiating and adjusting insulin treatment for people with type 2 diabetes (T2D) requires frequent clinician contacts both face-to-face and by telephone. We explored the use of a telehealth system to offer additional support to these patients. Twenty-three patients with uncontrolled T2D were recruited from nine general practices to assess the feasibility and acceptability of telehealth monitoring and support for insulin initiation and adjustment. The intervention included a standard algorithm for self-titration of insulin dose, a Bluetooth enabled glucose meter linked to a mobile phone, an integrated diary to record insulin dose, feedback of charted blood glucose data and telehealth nurse review with telephone follow-up. Additional contact with patients was initiated when no readings were transmitted for >3 days or when persistent hyper- or hypoglycaemia was identified. Reponses of patients and clinicians to the system were assessed informally. The mean (SD) patient age was 58 years (12) with 78% male. The mean (SD) diabetes duration was 6.4 years (4.5), HbA1c at baseline was 9.5% (2.2), and the decrease in HbA1c at three months was 0.52% (0.91) with an insulin dose increase of 9 units (26). A mean (SD) of 160 (93) blood glucose readings was transmitted per patient in these three months. Practice nurses and general practitioners (GPs) viewed the technology as having the potential to improve patient care. Most patients were able to use the equipment with training and welcomed review of their blood glucose readings by a telehealth nurse. Although the concept of telehealth monitoring is unfamiliar to most patients and practice nurses, the technology improved the support available for T2D patients commencing insulin treatment.

Improving contraceptive choice: fidelity of implementation and the gap between effectiveness and efficacy.

PubMed

Garbers, Samantha; Flandrick, Kathleen; Bermudez, Dayana; Meserve, Allison; Chiasson, Mary Ann

2014-11-01

Interventions to reduce unintended pregnancy through improved contraceptive use are a public health priority. A comprehensive process evaluation of a contraceptive assessment module intervention with demonstrated efficacy was undertaken. The 12-month process evaluation goal was to describe the extent to which the intervention was implemented as intended over time, and to identify programmatic adjustments to improve implementation fidelity. Quantitative and qualitative methods included staff surveys, electronic health record data, usage monitoring, and observations. Fidelity of implementation was low overall (<10% of eligible patients completed the entire module [dose received]). Although a midcourse correction making the module available in clinical areas led to increased dose delivered (23% vs. 30%, chi-square test p = .006), dose received did not increase significantly after this adjustment. Contextual factors including competing organizational and staff priorities and staff buy-in limited the level of implementation and precluded adoption of some strategies such as adjusting patient flow. Using a process evaluation framework enabled the research team to identify and address complexities inherent in effectiveness studies and facilitated the alignment of program and context. © 2014 Society for Public Health Education.

A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I.

PubMed

Roth, Eli M; Moriarty, Patrick M; Bergeron, Jean; Langslet, Gisle; Manvelian, Garen; Zhao, Jian; Baccara-Dinet, Marie T; Rader, Daniel J

2016-11-01

In previous phase III studies, the PCSK9 monoclonal antibody alirocumab was administered at doses of 75 or 150 mg every 2 weeks (Q2W). CHOICE I (NCT01926782) evaluated 300 mg every 4 weeks (Q4W) in patients on either maximally tolerated statin or no statin, both ± other lipid-lowering therapies. CHOICE I included patients with hypercholesterolemia at moderate-to-very-high cardiovascular risk. Patients were randomized to alirocumab 300 mg Q4W, 75 mg Q2W (calibrator arm), or placebo for 48 weeks, with dose adjustment for either alirocumab arm to 150 mg Q2W at Week (W) 12 if at W8 LDL-C levels were >70/100 mg/dL (1.8/2.6 mmol/L) depending on cardiovascular risk or LDL-C reduction was <30% from baseline. Co-primary endpoints were percent LDL-C change from baseline to W24, and to time-averaged LDL-C over W21-24. Approximately two-thirds of randomized patients were receiving statins. At W12, 14.7% (no statin) and 19.3% (statin) of patients receiving alirocumab 300 mg Q4W required dose adjustment. At W24, significant LDL-C reductions from baseline were observed with alirocumab 300 mg Q4W: mean differences were -52.7% (no statin; placebo: -0.3%) and -58.8% (statin; placebo: -0.1%). Average LDL-C reductions from baseline to W21-24 were also significantly greater with alirocumab 300 mg Q4W vs. placebo in patients not receiving (-56.9% vs. -1.6%) and receiving statin (-65.8% vs. -0.8%). Treatment-emergent adverse event rates ranged from 61.1 to 75.0% (placebo) and 71.5 to 78.1% (alirocumab 300 mg Q4W). Alirocumab 300 mg Q4W is a viable additional treatment option in patients requiring LDL-C-lowering. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Weight-based dosing in medication use: what should we know?

PubMed Central

Pan, Sheng-dong; Zhu, Ling-ling; Chen, Meng; Xia, Ping; Zhou, Quan

2016-01-01

Background Weight-based dosing strategy is still challenging due to poor awareness and adherence. It is necessary to let clinicians know of the latest developments in this respect and the correct circumstances in which weight-based dosing is of clinical relevance. Methods A literature search was conducted using PubMed. Results Clinical indications, physiological factors, and types of medication may determine the applicability of weight-based dosing. In some cases, the weight effect may be minimal or the proper dosage can only be determined when weight is combined with other factors. Medications within similar therapeutic or structural class (eg, anticoagulants, antitumor necrosis factor medications, P2Y12-receptor antagonists, and anti-epidermal growth factor receptor antibodies) may exhibit differences in requirements on weight-based dosing. In some cases, weight-based dosing is superior to currently recommended fixed-dose regimen in adult patients (eg, hydrocortisone, vancomycin, linezolid, and aprotinin). On the contrary, fixed dosing is noninferior to or even better than currently recommended weight-based regimen in adult patients in some cases (eg, cyclosporine microemulsion, recombinant activated Factor VII, and epoetin α). Ideal body-weight-based dosing may be superior to the currently recommended total body-weight-based regimen (eg, atracurium and rocuronium). For dosing in pediatrics, whether weight-based dosing is better than body surface-area-based dosing is dependent on the particular medication (eg, methotrexate, prednisone, prednisolone, zidovudine, didanosine, growth hormone, and 13-cis-retinoic acid). Age-based dosing strategy is better than weight-based dosing in some cases (eg, intravenous busulfan and dalteparin). Dosing guided by pharmacogenetic testing did not show pharmacoeconomic advantage over weight-adjusted dosing of 6-mercaptopurine. The common viewpoint (ie, pediatric patients should be dosed on the basis of body weight) is not always correct. Effective weight-based dosing interventions include standardization of weight estimation, documentation and dosing determination, dosing chart, dosing protocol, order set, pharmacist participation, technological information, and educational measures. Conclusion Although dosing methods are specified in prescribing information for each drug and there are no principal pros and cons to be elaborated, this review of weight-based dosing strategy will enrich the knowledge of medication administration from the perspectives of safety, efficacy, and pharmacoeconomics, and will also provide research opportunities in clinical practice. Clinicians should be familiar with dosage and administration of the medication to be prescribed as well as the latest developments. PMID:27110105

In vivo thermoluminescence dosimetry for total body irradiation.

PubMed

Palkosková, P; Hlavata, H; Dvorák, P; Novotný, J; Novotný, J

2002-01-01

An improvement in the clinical results obtained using total body irradiation (TBI) with photon beams requires precise TBI treatment planning, reproducible irradiation, precise in vivo dosimetry, accurate documentation and careful evaluation. In vivo dosimetry using LiF Harshaw TLD-100 chips was used during the TBI treatments performed in our department. The results of in vivo thermoluminescence dosimetry (TLD) show that using TLD measurements and interactive adjustment of some treatment parameters based on these measurements, like monitor unit calculations, lung shielding thickness and patient positioning, it is possible to achieve high precision in absorbed dose delivery (less than 0.5%) as well as in homogeneity of irradiation (less than 6%).

A Novel Admixture-Based Pharmacogenetic Approach to Refine Warfarin Dosing in Caribbean Hispanics

PubMed Central

Claudio-Campos, Karla; Rivera-Miranda, Giselle; Bermúdez-Bosch, Luis; Renta, Jessicca Y.; Cadilla, Carmen L.; Cruz, Iadelisse; Feliu, Juan F.; Vergara, Cunegundo; Ruaño, Gualberto

2016-01-01

Aim This study is aimed at developing a novel admixture-adjusted pharmacogenomic approach to individually refine warfarin dosing in Caribbean Hispanic patients. Patients & Methods A multiple linear regression analysis of effective warfarin doses versus relevant genotypes, admixture, clinical and demographic factors was performed in 255 patients and further validated externally in another cohort of 55 individuals. Results The admixture-adjusted, genotype-guided warfarin dosing refinement algorithm developed in Caribbean Hispanics showed better predictability (R2 = 0.70, MAE = 0.72mg/day) than a clinical algorithm that excluded genotypes and admixture (R2 = 0.60, MAE = 0.99mg/day), and outperformed two prior pharmacogenetic algorithms in predicting effective dose in this population. For patients at the highest risk of adverse events, 45.5% of the dose predictions using the developed pharmacogenetic model resulted in ideal dose as compared with only 29% when using the clinical non-genetic algorithm (p<0.001). The admixture-driven pharmacogenetic algorithm predicted 58% of warfarin dose variance when externally validated in 55 individuals from an independent validation cohort (MAE = 0.89 mg/day, 24% mean bias). Conclusions Results supported our rationale to incorporate individual’s genotypes and unique admixture metrics into pharmacogenetic refinement models in order to increase predictability when expanding them to admixed populations like Caribbean Hispanics. Trial Registration ClinicalTrials.gov NCT01318057 PMID:26745506

The comparative short-term effectiveness of iron dosing and formulations in US hemodialysis patients.

PubMed

Kshirsagar, Abhijit V; Freburger, Janet K; Ellis, Alan R; Wang, Lily; Winkelmayer, Wolfgang C; Brookhart, M Alan

2013-06-01

Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 μg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized. Copyright © 2013 Elsevier Inc. All rights reserved.

Dosing algorithm to target a predefined AUC in patients with primary central nervous system lymphoma receiving high dose methotrexate.

PubMed

Joerger, Markus; Ferreri, Andrés J M; Krähenbühl, Stephan; Schellens, Jan H M; Cerny, Thomas; Zucca, Emanuele; Huitema, Alwin D R

2012-02-01

There is no consensus regarding optimal dosing of high dose methotrexate (HDMTX) in patients with primary CNS lymphoma. Our aim was to develop a convenient dosing algorithm to target AUC(MTX) in the range between 1000 and 1100 µmol l(-1) h. A population covariate model from a pooled dataset of 131 patients receiving HDMTX was used to simulate concentration-time curves of 10,000 patients and test the efficacy of a dosing algorithm based on 24 h MTX plasma concentrations to target the prespecified AUC(MTX) . These data simulations included interindividual, interoccasion and residual unidentified variability. Patients received a total of four simulated cycles of HDMTX and adjusted MTX dosages were given for cycles two to four. The dosing algorithm proposes MTX dose adaptations ranging from +75% in patients with MTX C(24) < 0.5 µmol l(-1) up to -35% in patients with MTX C(24) > 12 µmol l(-1). The proposed dosing algorithm resulted in a marked improvement of the proportion of patients within the AUC(MTX) target between 1000 and 1100 µmol l(-1) h (11% with standard MTX dose, 35% with the adjusted dose) and a marked reduction of the interindividual variability of MTX exposure. A simple and practical dosing algorithm for HDMTX has been developed based on MTX 24 h plasma concentrations, and its potential efficacy in improving the proportion of patients within a prespecified target AUC(MTX) and reducing the interindividual variability of MTX exposure has been shown by data simulations. The clinical benefit of this dosing algorithm should be assessed in patients with primary central nervous system lymphoma (PCNSL). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

SU-E-T-561: Monte Carlo-Based Organ Dose Reconstruction Using Pre-Contoured Human Model for Hodgkins Lymphoma Patients Treated by Cobalt-60 External Beam Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jung, J; Pelletier, C; Lee, C

Purpose: Organ doses for the Hodgkin’s lymphoma patients treated with cobalt-60 radiation were estimated using an anthropomorphic model and Monte Carlo modeling. Methods: A cobalt-60 treatment unit modeled in the BEAMnrc Monte Carlo code was used to produce phase space data. The Monte Carlo simulation was verified with percent depth dose measurement in water at various field sizes. Radiation transport through the lung blocks were modeled by adjusting the weights of phase space data. We imported a precontoured adult female hybrid model and generated a treatment plan. The adjusted phase space data and the human model were imported to themore » XVMC Monte Carlo code for dose calculation. The organ mean doses were estimated and dose volume histograms were plotted. Results: The percent depth dose agreement between measurement and calculation in water phantom was within 2% for all field sizes. The mean organ doses of heart, left breast, right breast, and spleen for the selected case were 44.3, 24.1, 14.6 and 3.4 Gy, respectively with the midline prescription dose of 40.0 Gy. Conclusion: Organ doses were estimated for the patient group whose threedimensional images are not available. This development may open the door to more accurate dose reconstruction and estimates of uncertainties in secondary cancer risk for Hodgkin’s lymphoma patients. This work was partially supported by the intramural research program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.« less

OPTIMIZING LENVATINIB THERAPY IN PATIENTS WITH METASTATIC RADIOACTIVE IODINE-RESISTANT DIFFERENTIATED THYROID CANCERS.

PubMed

Jasim, Sina; Iniguez-Ariza, Nicole M; Hilger, Crystal R; Chintakuntlawar, Ashish V; Ryder, Mabel M; Morris, John C; Bible, Keith C

2017-10-01

Lenvatinib is approved for use in advanced radioactive iodine-resistant differentiated thyroid cancers (RAIR-DTCs). Its efficacy is indisputable, but toxicities are great, creating daunting challenges for patients and providers. Few data regarding early adverse events and impact on quality of life (QOL) exist; we sought to clarify these issues by analyzing our initial postapproval lenvatinib experience. Standardized patient education was implemented, providing detailed instructions and expert provider contacts to facilitate timely reporting of toxicities and guide responsive actions. Early adverse events, QOL outcomes, and response data from 25 consecutively treated DTC patients (02/2015 and 05/2016) were retrospectively analyzed. The median age was 55 years (range 27-81); 52% were female. Fourteen (56%) were on antihypertensive medication(s) at baseline. Most patients (21/25, 84%) developed adverse events during the first month of therapy. Hypertension arose in 16/25 (64%), requiring antihypertensive dose adjustment/addition in 6 (24%)/12 (48%) patients, respectively, during the first month of therapy. Dose reduction was required in 11 (44%) due to multiple adverse events; the median time to first dose reduction was 33 days (range 11-84); 8 (32%) required multiple dose reductions. Therapy interruption >3 weeks occurred in 4 (16%). The median change in patient-reported fatigue score was +2 (worsening, range -2 to +10, P<.007; 0-10 scales), but the median QOL change was 0 (range +4 to -9, P = .57). The mean duration of lenvatinib therapy was 6.5 months (range 1-12); median overall and progression-free survival have not yet been reached. Lenvatinib was discontinued in 7 (28%) patients; among 20 patients with available RECIST (Response Evaluation Criteria In Solid Tumors) measurements, 10 (50%) achieved partial response. Lenvatinib has promising efficacy in RAIR-DTC, but toxicities require frequent early interventions. QOL can be maintained on lenvatinib therapy. DTC = differentiated thyroid cancer; LASA = linear analog self-assessment; PR = partial response; QOL = quality of life; RAI = radioactive iodine; RAIR = RAI-resistant; RECIST = Response Evaluation Criteria In Solid Tumors; Tg = thyroglobulin; VEGFR = vascular endothelial growth factor receptor.

Protective effect of vaccination against mumps complications, Czech Republic, 2007-2012.

PubMed

Orlíková, Hana; Malý, Marek; Lexová, Pavla; Šebestová, Helena; Limberková, Radomíra; Jurzykowská, Lucie; Kynčl, Jan

2016-04-01

In the Czech Republic, two-dose immunization against mumps achieves 98% coverage. The routine reporting detects mumps cases, clinical complications, and hospital admissions in unvaccinated but also in vaccinated individuals. Using surveillance data of patients with mumps we assessed the effectiveness of mumps vaccination on mumps clinical complications and hospitalization need. We also investigated the effect of the time since immunization. We analysed data on incident mumps cases reported to the Czech national surveillance system in 2007-2012. Using a logistic regression model with adjustment for age, sex, year of onset, and the administrative region, the association between vaccination and the most frequent mumps complications and hospitalization was evaluated. The adjusted odds ratios (ORa) for mumps complications were compared between the vaccinated and non-vaccinated groups, reflecting the vaccine effectiveness (VEa) computed as VEa = (1-ORa) × 100. We estimated the risk of mumps complications by the time from vaccination. From total of 9663 mumps analysed cases 5600 (58%) occurred in males. The mean age at the disease onset was 17.3, median 16 years. Ninety percent of the study patients had no complications, while 1.6% developed meningitis, 0.2% encephalitis, and 0.6% pancreatitis. Mumps orchitis occurred in 659 (11.8%) male cases. In total, 1192 (12.3%) patients required hospitalization. Two doses of vaccine received by 81.8% cases significantly reduced the risk of hospitalization: ORa 0.29 (95% CI: 0.24, 0.35). Two doses showed statistically significant VEa 64% (95% CI: 46, 79) for meningitis, 93% (95% CI: 66, 98) for encephalitis in all cases, and 72% (95% CI: 64, 78) for orchitis in males. Vaccine effectiveness for orchitis declined from 81 to 74% and 56% in the most affected age groups 10-14, 15-19, and 20-24 years, respectively. Among 7850 two-dose recipients, the rate of complications rose from below 1 to 16% in categories up to 6 years and 24 and more years after the second dose, respectively. This study demonstrates a significant preventive effect of two-dose vaccination against mumps complications (orchitis, meningitis, or encephalitis) and hospitalization for mumps. The risk of complications increases with time interval from vaccination. Teenagers and young adults were the most affected age groups.

Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity.

PubMed

Murthy, Bindu; Schmitt-Hoffmann, Anne

2008-01-01

Ceftobiprole, a beta-lactam, is the first of a new generation of broad-spectrum cephalosporins in late-stage development with activity against methicillin-resistant Staphylococcus aureus (MRSA) in addition to broad-spectrum bactericidal activity against other Gram-positive and Gram-negative pathogens. The prodrug, ceftobiprole medocaril, is converted rapidly and almost completely to the active drug, ceftobiprole, upon infusion by type A esterases. In humans, ceftobiprole binds minimally (16%) to plasma proteins, and binding is independent of the drug and protein concentrations. Its steady-state volume of distribution (18.4 L) approximates the extracellular fluid volume in humans. Ceftobiprole undergoes minimal hepatic metabolism, and the primary metabolite is the beta-lactam ring-opened hydrolysis product (open-ring metabolite). Systemic exposure of the open-ring metabolite accounts for 4% of ceftobiprole exposure following single-dose administration; approximately 5% of the dose is excreted in the urine as the metabolite. Ceftobiprole does not significantly induce or inhibit relevant cytochrome P450 enzymes and is neither a substrate nor an inhibitor of P-glycoprotein. Ceftobiprole is rapidly eliminated, primarily unchanged, by renal excretion, with a terminal elimination half-life of 3 hours; the predominant mechanism responsible for elimination is glomerular filtration, with approximately 89% of the dose being excreted as the prodrug, active drug (ceftobiprole) and open-ring metabolite. The pharmacokinetics of ceftobiprole are linear following single and multiple infusions of 125-1000 mg. Steady-state drug concentrations are attained on the first day of dosing, with no appreciable accumulation when administered three times daily (every 8 hours) and twice daily (every 12 hours) in subjects with normal renal function. Low intersubject variability has been seen across studies. Ceftobiprole exposure is slightly higher (~15%) in females than in males; this difference has been attributed to bodyweight. However, the pharmacodynamics of ceftobiprole are similar in males and females, and dosing adjustments are not required based on gender. In patients with moderate to severe renal impairment, systemic clearance of ceftobiprole correlated well with creatinine clearance. For these patients, dose adjustments for the treatment of infections caused by target pathogens, including MRSA, should be based on creatinine clearance. Ceftobiprole is undergoing clinical evaluation in phase III trials in patients with complicated skin and skin structure infections, patients with nosocomial pneumonia, and community-acquired pneumonia in hospitalized patients.

LACK OF CORRELATION BETWEEN OPIOID DOSE ADJUSTMENT AND PAIN SCORE CHANGE IN A GROUP OF CHRONIC PAIN PATIENTS

PubMed Central

Chen, Lucy; Vo, Trang; Seefeld, Lindsey; Malarick, Charlene; Houghton, Mary; Ahmed, Shihab; Zhang, Yi; Cohen, Abigail; Retamozo, Cynthia; Hilaire, Kristen St.; Zhang, Vivian; Mao, Jianren

2013-01-01

Despite the increasing use of opioid analgesics for chronic pain management, it is unclear whether opioid dose escalation leads to better pain relief during chronic opioid therapy. In this study, we retrospectively analyzed clinical data collected from the Massachusetts General Hospital (MGH) Center for Pain Medicine over a 7-year period. We examined 1) the impact of opioid dose adjustment (increase or decrease) on clinical pain score, 2) gender and age differences in response to opioid therapy, and 3) the influence of clinical pain conditions on the opioid analgesic efficacy. A total of 109 subjects met the criteria for data collection. We found that neither opioid dose increase, nor decrease, correlated with point changes in clinical pain score in a subset of chronic pain patients over a prolonged course of opioid therapy (an average of 704 days). This lack of correlation was consistent regardless of the type of chronic pain including neuropathic, nociceptive, or mixed pain conditions. Neither gender nor age differences showed a significant influence on the clinical response to opioid therapy in these subjects. These results suggest that dose adjustment during opioid therapy may not necessarily alter long-term clinical pain score in a group of chronic pain patients and that individualized opioid therapy based on the clinical effectiveness should be considered to optimize the treatment outcome. Perspectives The study reports a relationship, or lack thereof, between opioid dose change and clinical pain score in a group of chronic pain patients. The study also calls for further investigation into the effectiveness of opioid therapy in the management of chronic non-malignant pain conditions. PMID:23452826

IV busulfan dose individualization in children undergoing hematopoietic stem cell transplant: limited sampling strategies.

PubMed

Dupuis, L Lee; Sibbald, Cathryn; Schechter, Tal; Ansari, Marc; Gassas, Adam; Théorêt, Yves; Kassir, Nastya; Champagne, Martin A; Doyle, John

2008-05-01

We currently calculate area under the busulfan concentration time curve (AUC) using 7 plasma busulfan concentrations (AUC7) drawn after the first of 16 i.v. busulfan doses given as a 2-hour infusion every 6 hours. The aim of this study was to develop and validate limited sampling strategies (LSSs) using 3 or fewer busulfan concentration values with which to reliably calculate AUC in children undergoing hematopoietic stem cell transplant (HSCT). Children in the development group (44) received i.v. busulfan at Sick Kids; the validation group consisted of 35 children who received care at CHU Ste-Justine. Busulfan doses given and subsequent plasma busulfan concentrations were recorded. LSSs using 1 to 3 concentration-time points were developed using multiple linear regression. LSS were considered to be acceptable when adjusted r(2) > 0.9, mean bias <15% and precision <15%. Extent of agreement between the AUC7 values and the LSS AUC was assessed by the intraclass correlation coefficient (ICC) and Bland-Altman (BA) analysis. Agreement was considered to be excellent when the lower limit of the 95% confidence limit of the ICC exceeded 0.9 and when the limits of agreement in the BA analysis were +/-15% for both AUC and dose. Administration of the theoretic adjusted busulfan doses based on each LSS was simulated and cases where the resulting AUC was >1500 or <900 microM x min were noted. LSSs using 1, 2, or 3 plasma busulfan concentrations were developed that showed excellent agreement with AUC7 and adjusted busulfan doses. In the validation sample, only the 2- and 3-point LSSs demonstrated acceptable precision and lack of bias. LSSs using 2 or 3 plasma busulfan concentrations can be used to reliably estimate busulfan AUC after IV administration in children undergoing HSCT.

Cost Effectiveness of a Shingles Vaccine Booster for Currently Vaccinated Adults in the U.S.

PubMed

Le, Phuc; Rothberg, Michael B

2017-12-01

The Advisory Committee on Immunization Practices recommends a single dose of the live attenuated herpes zoster vaccine in people aged ≥60 years. Because vaccine-induced protection decreases to zero after 10 years, many vaccinated people will soon be subject to an increased risk of the disease. The study objective was to determine the cost effectiveness of a herpes zoster vaccine booster and its optimal timing among immunocompetent adults first vaccinated at aged ≥60 years. A Markov model was built to follow vaccinated individuals for a lifetime. From the societal perspective, costs and quality-adjusted life years were compared between no booster versus booster options. A booster was given any time between 1 and 20 years after the first dose, and for those who had the first dose at different ages: 60, 70, and 80 years. Because people entered the model already vaccinated, costs and side effects of the first dose were not included. The booster was assumed to have the same efficacy and waning rate as the initial vaccination. Model inputs were based on published literature. A cost effectiveness threshold of $100,000/quality-adjusted life year was used. The analysis was conducted in 2016. Cost effectiveness of a booster varied by age and time since vaccination. The booster cost <$100,000/quality-adjusted life year if given >5 years after the initial dose, but was most cost effective at around 10 years. The finding was robust to wide variations in model inputs. Under current assumptions, a booster dose of herpes zoster vaccine would be cost effective for all vaccinated people 10 years after initial vaccination. Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System.

PubMed

Eser, Alexander; Primas, Christian; Reinisch, Sieglinde; Vogelsang, Harald; Novacek, Gottfried; Mould, Diane R; Reinisch, Walter

2018-01-30

Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard. We assessed long-term infliximab retention in patients being dosed concordantly versus discordantly with Bayesian dashboard recommendations. Three hundred eighty-two serum samples from 117 adult IBD patients on infliximab maintenance therapy were analyzed by 3 commercially available assays. Data from each assay was modeled using NONMEM and a Bayesian dashboard. PK parameter precision and residual variability were assessed. Forecast concentrations from both systems were compared with observed concentrations. Infliximab retention was assessed by prediction for dose intensification via Bayesian dashboard versus real-life practice. Forecast precision of SICs varied between detection assays. At least 3 SICs from a reliable assay are needed for an accurate forecast. The Bayesian dashboard performed similarly to NONMEM to predict SICs. Patients dosed concordantly with Bayesian dashboard recommendations had a significantly longer median drug survival than those dosed discordantly (51.5 versus 4.6 months, P < .0001). The Bayesian dashboard helps to assess the diagnostic performance of infliximab detection assays. Three, not single, SICs provide sufficient information for individualized dose adjustment when incorporated into the Bayesian dashboard. Treatment adjusted to forecasted SICs is associated with longer drug retention of infliximab. © 2018, The American College of Clinical Pharmacology.

Comparison of the effectiveness of brand-name and generic antipsychotic drugs for treating patients with schizophrenia in Taiwan.

PubMed

Hsu, Chih-Wei; Lee, Sheng-Yu; Wang, Liang-Jen

2018-03-01

The purpose of this nationwide population-based study is to compare the long-term effectiveness of brand-name antipsychotics with generic antipsychotics for treating schizophrenia. We identified patients with schizophrenia who were prescribed antipsychotics from a random sample of one million records from Taiwan's National Health Insurance database, observed between January 1, 2000 and December 31, 2012. Only those with no prior use of antipsychotics for at least 180days were included. We selected patients who were prescribed brand-name risperidone (N=404), generic risperidone (N=145), brand-name sulpiride (N=334), or generic sulpiride (N=991). The effectiveness of the treatments researched in this study consisted of average daily doses, rates of treatment discontinuation, augmentation therapy, and psychiatric hospitalization. We found that compared to patients treated with generic risperidone, those treated with brand-name risperidone required lower daily doses (2.14mg vs. 2.61mg). However, the two groups demonstrated similar rates of treatment discontinuation, augmentation, and psychiatric hospitalization. On the other hand, in comparison with patients prescribed generic sulpiride, those treated with brand-name sulpiride not only required lower daily doses (302.72mg vs. 340.71mg) but also had lower psychiatric admission rates (adjusted hazard ratio: 0.24, 95% confidence interval: 0.10-0.56). In conclusion, for both risperidone and sulpiride, higher daily doses of the respective generic drugs were prescribed than with brand-name drugs in clinical settings. Furthermore, the brand-name sulpiride is more effective at preventing patients from hospitalization than generic sulpiride. These findings can serve as an important reference for clinical practices and healthcare economics for treating schizophrenic patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function.

PubMed

Cawello, Willi; Ahrweiler, Sascha; Sulowicz, Wladyslaw; Szymczakiewicz-Multanowska, Agnieszka; Braun, Marina

2012-01-01

To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODS All subjects received a single transdermal 10 cm² patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h⁻¹). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,t(last) ) and C(max) for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for C(max) for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis. © 2011 UCB Biosciences GmbH. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function

PubMed Central

Cawello, Willi; Ahrweiler, Sascha; Sulowicz, Wladyslaw; Szymczakiewicz-Multanowska, Agnieszka; Braun, Marina

2012-01-01

AIM To evaluate the influence of different stages of chronic renal insufficiency on the pharmacokinetics and safety/tolerability of the transdermally applied dopamine agonist rotigotine in an open label group comparison including 32 subjects (healthy, mild, moderate or severe impairment of renal function and patients with end-stage renal insufficiency requiring haemodialysis). METHODS All subjects received a single transdermal 10 cm2 patch (24 h patch-on period) containing 4.5 mg rotigotine (nominal drug release 2 mg 24 h−1). Main evaluations included relative bioavailability and renal elimination of rotigotine and its metabolites. RESULTS Point estimates for the ratios between the groups with moderate to severe renal impairment and healthy subjects for the pharmacokinetic parameters AUC(0,tlast) and Cmax for the active substance unconjugated rotigotine were near 1:0.88 for AUC and 0.93 for Cmax for moderate renal impairment, 1.14 and 1.18 for severe renal impairment and 1.05 and 1.25 for end-stage renal insufficiency requiring haemodialysis. There was no correlation of these parameters with creatinine clearance. The amount of unconjugated rotigotine excreted into urine and renal clearance decreased with increasing severity of renal insufficiency but had no observable effect on total clearance as the amounts excreted were below 1% of the administered dose. Occurrence of adverse events did not increase with the degree of renal insufficiency. CONCLUSIONS The pharmacokinetic profiles of unconjugated rotigotine were similar in healthy subjects and subjects with impaired renal function indicating that no dose adjustments are required for transdermal rotigotine in patients with different stages of chronic renal insufficiency including patients on haemodialysis. PMID:21707699

Half-Unit Insulin Pens: Disease Management in Patients With Diabetes Who Are Sensitive to Insulin.

PubMed

Klonoff, David C; Nayberg, Irina; Stauder, Udo; Oualali, Hamid; Domenger, Catherine

2017-05-01

Insulin pens represent a significant technological advancement in diabetes management. While the vast majority have been designed with 1U-dosing increments, improved accuracy and precision facilitated by half-unit increments may be particularly significant in specific patients who are sensitive to insulin. These include patients with low insulin requirements and in those requiring more precise dose adjustments, such as the pediatric patient population. This review summarized functional characteristics of insulin half-unit pens (HUPs) and their effect on user experience. The literature search was restricted to articles published in English between January 1, 2000, and January 1, 2015. A total of 17 publications met the set criteria and were included in the review. Overall, studies outlined characteristics for 4 insulin HUPs. Based on their functionality, the pens were generally similar and all met the ISO 11608-1 criteria for accuracy. However, some had specific advantageous features in terms of size, weight, design, dialing torque, and injection force. Although limited, the currently available user preference studies in children and adolescents with diabetes and their carers suggest that the selection of an HUP is likely to be influenced by a combination of factors such as these, in addition to the prescribed insulin and dosing regimen. Insulin HUPs are likely to be a key diabetes management tool for patients who are sensitive to insulin; specific pen features may further advance diabetes management in these populations.

The effects of organizational stress on inpatient psychiatric medication patterns.

PubMed

Gouse, A S

1984-07-01

The effect of organizational stress on the antipsychotic medication levels of patients was assessed over a 1-year period. Through the use of autocorrelational techniques, medication use was shown to function as a dynamic homeostasis: Continuous adjustments and counter-adjustments resulted in an approximation of equilibrium centering around an idealized dose level. Graphically, these homeostatic oscillations resembled a sinusoidal function with distinct amplitude and periodicity. Organizational stress significantly increased the amplitude of dose level oscillations and shortened the periodicity of each oscillation. Uncontrolled, this situation could lead to a state of extreme overmedication followed sharply by extreme undermedication .

Effectiveness of monovalent human rotavirus vaccine against admission to hospital for acute rotavirus diarrhoea in South African children: a case-control study.

PubMed

Groome, Michelle J; Page, Nicola; Cortese, Margaret M; Moyes, Jocelyn; Zar, Heather J; Kapongo, Constant N; Mulligan, Christine; Diedericks, Ralph; Cohen, Cheryl; Fleming, Jessica A; Seheri, Mapaseka; Mphahlele, Jeffrey; Walaza, Sibongile; Kahn, Kathleen; Chhagan, Meera; Steele, A Duncan; Parashar, Umesh D; Zell, Elizabeth R; Madhi, Shabir A

2014-11-01

The effectiveness of the rotavirus vaccine under conditions of routine use in an African setting with a high prevalence of HIV infection needs to be established. We assessed the vaccine effectiveness of monovalent human rotavirus vaccine in preventing admission to hospital for acute rotavirus diarrhoea, after its introduction at age 6 and 14 weeks into South Africa's national immunisation programme. This case-control study was done at seven hospitals in South Africa between April 19, 2010, and Oct 31, 2012. The hospitals were located in a range of urban, peri-urban, and rural settings, with varying rates of population HIV infection. Cases were children aged from 18 weeks to 23 months who were age-eligible to have received at least one dose of the human rotavirus vaccine (ie, those born after June 14, 2009) admitted to hospital with laboratory-confirmed acute rotavirus diarrhoea, and the primary control group was children admitted to hospital with diarrhoea testing negative for rotavirus. A second control group comprised children admitted to a subset of three of the seven hospitals with respiratory illness. The primary endpoint was adjusted vaccine effectiveness (1 - adjusted odds ratio × 100%) in children aged from 18 weeks to 23 months and was calculated by unconditional logistic regression. This study is registered on the South African National Clinical Trial Register, number DOH-27-0512-3247. Of 540 rotavirus-positive cases, 278 children (52%) received two doses, 126 (23%) one dose, and 136 (25%) no doses of human rotavirus vaccine, compared with 1434 rotavirus-negative controls of whom 856 (60%) received two doses, 334 (23%) one dose, and 244 (17%) no doses. Adjusted vaccine effectiveness using rotavirus-negative controls was 57% (95% CI 40-68) for two doses and 40% (16-57) for one dose; estimates were similar when respiratory controls were used as the control group. Adjusted vaccine effectiveness for two doses was similar between age groups 18 weeks-11 months (54%, 95% CI 32-68) and 12-23 months (61%, 35-77), and was similar in HIV-exposed-uninfected (64%, 95% CI 34-80) and HIV-unexposed-uninfected children (54%, 31-69). Human rotavirus vaccine provided sustained protection against admission to hospital for acute rotavirus diarrhoea during the first and second years of life. This finding is encouraging and establishes the public health value of rotavirus vaccine in an African setting, especially as rotavirus vaccines are introduced into an increasing number of African countries. GAVI Alliance (with support from PATH). Copyright © 2014 Elsevier Ltd. All rights reserved.

40 CFR 63.92 - Approval of State requirements that adjust a section 112 rule.

Code of Federal Regulations, 2010 CFR

2010-07-01

... adjust a section 112 rule. 63.92 Section 63.92 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... requirements that adjust a section 112 rule. Under this section a State may seek approval of State requirements that make pre-approved adjustments to a Federal section 112 rule, emission standard, or requirement...

26 CFR 1.9001-4 - Adjustments required in computing excess-profits credit.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Adjustments required in computing excess... Adjustments required in computing excess-profits credit. (a) In general. Subsection (f) of the Act provides adjustments required to be made in computing the excess-profits credit for any taxable year under the Excess...

Small Versus Large-Sized Drug-Eluting Beads (DEBIRI) for the Treatment of Hepatic Colorectal Metastases: A Propensity Score Matching Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akinwande, Olaguoke K., E-mail: gokeakin@gmail.com; Philips, Prejesh, E-mail: prejesh.philips@louisville.edu; Duras, Petr, E-mail: durasp@seznam.cz

2015-04-15

PurposeTo compare the feasibility, safety, and efficacy with small and large irinotecan drug-eluting beads (DEBIRI) for treating hepatic colorectal metastases.MethodsUsing our prospectively maintained, multi-center, intra-arterial therapy registry, we identified 196 patients treated with a combination of large beads (100–300 to 500–700 μm) and patients treated with a combination of small beads (70–150 to 100–300 μm). To minimize selection bias, a propensity score analysis was performed to compare both groups.ResultsUnadjusted analysis consisted of 196 and 30 patients treated with large and small beads, respectively. The adjusted analysis consisted of 19 patients each. Unadjusted analysis showed decreased all-grade (p = <0.001) and high-grade adverse effects (p = 0.02)more » in the small bead group, with a persisting trend toward decreased overall side effects in the adjusted analysis favoring small beads (p = 0.09) The adjusted analysis showed the percentage dose delivered (delivered dose/intended dose) was significantly greater in the small bead group compared to the large bead group (96 vs 79 %; p = 0.005). There were also a lower percentage of treatments terminating in complete stasis in the adjusted analysis (0.0035). Adjusted analysis also showed increased objective response rate (ORR) at 12 months (p = 0.04), with a corresponding trend also seen in the unadjusted analysis (0.09).ConclusionSmaller beads result in increased dose delivery probably due to less propensity to reach complete stasis. It may also lead to more durable long-term efficacy. Smaller beads also demonstrate similarly low toxicity compared to large-sized beads with a trend toward less toxicity.« less

Maintenance therapy of childhood acute lymphoblastic leukemia revisited-Should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts?

PubMed

Schmiegelow, Kjeld; Nersting, Jacob; Nielsen, Stine Nygaard; Heyman, Mats; Wesenberg, Finn; Kristinsson, Jon; Vettenranta, Kim; Schrøeder, Henrik; Weinshilboum, Richard; Jensen, Katrine Lykke; Grell, Kathrine; Rosthoej, Susanne

2016-12-01

6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10 9 /l. After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10 9 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 10 9 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, r s  = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy. © 2016 Wiley Periodicals, Inc.

Awareness and Knowledge Among Internal Medicine Resident Trainees for Dose Adjustment of Analgesics and Neuropsychotropic Medications in CKD.

PubMed

Saad, Chadi Y; Fogel, Joshua; Rubinstein, Sofia

2018-03-01

Errors in drug dosing lead to poor patient outcomes and are common in patients with chronic kidney disease (CKD). Because the majority of patients with CKD are being treated by physicians specializing in internal medicine, we studied the awareness and knowledge that internal medicine resident trainees (IMRTs) have regarding the correct dosage of commonly used analgesic and neuropsychotropic medications for patients with CKD. We surveyed 353 IMRTs about their awareness of whether a medication needs dose adjustment in patients with CKD and knowledge for medication adjustment by level of glomerular filtration rate. There were high percentages for lack of awareness and knowledge. For analgesics, this lack of awareness/knowledge was highest for acetaminophen (awareness 83.0%, knowledge 90.9%). For neuropsychotropics, this was highest for paroxetine (awareness 74.5%, knowledge 91.5%). Analyses for postgraduate year (PGY) -1 trainees and PGY-2 trainees for analgesics showed higher odds for lack of awareness for tramadol (PGY-1 odds ratio [OR] 2.37, 95% confidence interval [CI] 1.2-4.62, P < 0.05; PGY-2 OR 2.34, 95% CI 1.16-4.72, P < 0.05) and for lack of knowledge for meperedine (PGY-1 OR 4.01, 95% CI 1.81-8.89, P < 0.05; PGY-2 OR 3.30, 95% CI 1.44-7.59, P < 0.05). Nephrology residency rotation for the neuropsychotropic medication of gabapentin showed lower odds for both lack of awareness (OR 0.56, 95% CI 0.32-0.97, P < 0.05) and knowledge (OR 0.52, 95% CI 0.27-0.997, P < 0.05). Awareness and knowledge are poor among IMRTs for dose adjustments of analgesics and neuropsychotropic medication classes in patients with CKD. There should be a renewed focus during IMRTs' residency on additional nephrology exposure and formal didactic educational training to help them better manage complex treatment regimens to prevent medication dosing errors.

Effects of Altering Levothyroxine (L-T4) Doses on Quality of Life, Mood, and Cognition in L-T4 Treated Subjects.

PubMed

Samuels, Mary H; Kolobova, Irina; Niederhausen, Meike; Janowsky, Jeri S; Schuff, Kathryn G

2018-05-01

The brain is a critical target organ for thyroid hormone, but it is unclear whether variations in thyroid function within and near the reference range affect quality of life, mood, or cognition. A total of 138 subjects with levothyroxine (L-T4)-treated hypothyroidism and normal thyrotropin (TSH) levels underwent measures of quality of life (36-Item Short Form Health Survey, Underactive Thyroid-Dependent Quality of Life Questionnaire), mood (Profile of Mood States, Affective Lability Scale), and cognition (executive function, memory). They were then randomly assigned to receive an unchanged, higher, or lower L-T4 dose in double-blind fashion, targeting one of three TSH ranges (0.34 to 2.50, 2.51 to 5.60, or 5.61 to 12.0 mU/L). Doses were adjusted every 6 weeks based on TSH levels. Baseline measures were reassessed at 6 months. At the end of the study, by intention to treat, mean L-T4 doses were 1.50 ± 0.07, 1.32 ± 0.07, and 0.78 ± 0.08 μg/kg (P < 0.001), and mean TSH levels were 1.85 ± 0.25, 3.93 ± 0.38, and 9.49 ± 0.80 mU/L (P < 0.001), respectively, in the three arms. There were minor differences in a few outcomes between the three arms, which were no longer significant after correction for multiple comparisons. Subjects could not ascertain how their L-T4 doses had been adjusted (P = 0.55) but preferred L-T4 doses they perceived to be higher (P < 0.001). Altering L-T4 doses in hypothyroid subjects to vary TSH levels in and near the reference range does not affect quality of life, mood, or cognition. L-T4-treated subjects prefer perceived higher L-T4 doses despite a lack of objective benefit. Adjusting L-T4 doses in hypothyroid patients based on symptoms in these areas may not result in significant clinical improvement.

Resistance of neonates and field-collected garter snakes (Thamnophis spp.) to tetrodotoxin.

PubMed

Ridenhour, Benjamin J; Brodie, Edmund D; Brodie, Edmund D

2004-01-01

Prior studies of tetrodotoxin (TTX) resistance in garter snakes (Thamnophis spp.) have used laboratory-reared neonates as subjects, but the use of field-caught individuals would reduce cost and effort. We compared estimates of TTX resistance in field-caught and laboratory-born garter snakes. We found that a mass-adjusted dose of TTX administered to field-caught garter snakes produces an estimate of a population 50% dose that is comparable and unbiased with respect to those previously reported using laboratory-born neonates. Dose-response curves estimated for three field-caught populations closely matched the curves estimated from neonate data. The method was tested using populations with levels of TTX resistance ranging between approximately 5-90 mass-adjusted mouse units for their respective 50% doses. The technique of using field-caught snakes as test subjects provides larger genetically independent data sets that are more easily obtained. Our results indicate that changes in mass during development parallel ontogenetic shifts in TTX resistance.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucconi, G; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA; Bentefour, E

Purpose: The clinical commissioning of a workflow for pre-treatment range verification/adjustment for the head treatment of pediatric medulloblastoma patients, including dose monitoring during treatment. Methods: An array of Si-diodes (DIODES Incorporated) is placed on the patient skin on the opposite side to the beam entrance. A “scout” SOBP beam, with a longer beam range to cover the diodes in its plateau, is delivered; the measured signal is analyzed and the extracted water equivalent path lengths (WEPL) are compared to the expected values, revealing if a range correction is needed. Diodes stay in place during treatment to measure dose. The workflowmore » was tested in solid water and head phantoms and validated against independent WEPL measurements. Both measured WEPL and skin doses were compared to computed values from the TPS (XiO); a Markus chamber was used for reference dose measurements. Results: The WEPL accuracy of the method was verified by comparing it with the dose extinction method. It resulted, for both solid water and head phantom, in the sub-millimeter range, with a deviation less than 1% to the value extracted from the TPS. The accuracy of dose measurements in the fall-off part of the dose profile was validated against the Markus chamber. The entire range verification workflow was successfully tested for the mock-treatment of head phantom with the standard delivery of 90 cGy per field per fraction. The WEPL measurement revealed no need for range correction. The dose measurements agreed to better than 4% with the prescription dose. The robustness of the method and workflow, including detector array, hardware set and software functions, was successfully stress-tested with multiple repetitions. Conclusion: The performance of the in-vivo range verification system and related workflow meet the clinical requirements in terms of the needed WEPL accuracy for pretreatment range verification with acceptable dose to the patient.« less

Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis.

PubMed

Carr, Susan J; Wang, Xia; Olavarria, Veronica V; Lavados, Pablo M; Rodriguez, Jorge A; Kim, Jong S; Lee, Tsong-Hai; Lindley, Richard I; Pontes-Neto, Octavio M; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay K; Woodward, Mark; Chalmers, John; Anderson, Craig S; Robinson, Thompson G

2017-09-01

Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m 2 ) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. Compared with patients with normal renal function (>90 mL/min per 1.73 m 2 ), those with severe RD (<30 mL/min per 1.73 m 2 ) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P =0.04 for trend); every 10 mL/min per 1.73 m 2 lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P =0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P =0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616. © 2017 American Heart Association, Inc.

Methadone dosage and its relationship to quality of life, satisfaction, psychopathology, cognitive performance and additional consumption of non-prescribed drugs.

PubMed

Pedrero-Pérez, Eduardo J; MethaQoL, Grupo

2016-06-14

The effectiveness of methadone maintenance treatment is beyond any doubt, but there remains some incertitude about the appropriate and effective dosage and the objectives that should be achieved by this therapy. Some authors maintain that only doses higher than 50-60 mg/day ought to be considered effective, since only these block all the opioid receptors. But others propose the use of doses adjusted to the needs of the patient, based on their recovery process. Quality of life, satisfaction with treatment, psychopathological symptoms, cognitive performance and additional intake of illegal and unprescribed drugs were evaluated in a representative sample of all patients treated with opioid agonists in the Addiction Institute of Madrid (N = 1898, n = 450) and the Junta de Extremadura (N = 100, n = 65). The results revealed a negative relationship between dose and quality of life, psychopathological symptoms and cognitive performance. Satisfaction with treatment, based on doses negotiated together by doctor and patient, was very high, regardless of the dose. To establish hypothetical causal dependencies among the studied variables structural equation modelling was performed. The results reject the need for high dosage if not required by the patient, and highlight the benefits of other psychosocial interventions that lead to recovery, despite the chronification that could imply the use of high doses. Whereas high dosage programmes provide better indicators of social control, the patient's quality of life must be one of the main indicators of a successful treatment, as in any other health problem.

Dose-Dependent Negative Effects of Prior Multiple Vaccinations against Influenza A and Influenza B among School Children: A Study of Kamigoto Island in Japan during the 2011/12, 2012/13 and 2013/14 Influenza Seasons.

PubMed

Saito, Nobuo; Komori, Kazuhiro; Suzuki, Motoi; Kishikawa, Takayuki; Yasaka, Takahiro; Ariyoshi, Koya

2018-03-08

We investigated the negative effects of prior multiple vaccinations on influenza vaccine effectiveness (VE) and analysed the association of VE with prior vaccine doses. Patients aged 9-18 years presenting with influenza-like illness at a community hospital on a Japanese remote island during the 2011/12, 2012/13 and 2013/14 seasons were tested for influenza using a rapid diagnostic test (RDT). A test-negative case-control study design was used to estimate the VEs of trivalent inactivated influenza vaccine (TIV). Histories of vaccination and medically-attended influenza (MA-flu) A and B during three previous seasons were collected from registry systems. VE was calculated using multi-level mixed-effects logistic regression models adjusted for the history of RDT-confirmed MA-flu. During three influenza seasons, 1668 influenza-like illness episodes were analysed, including 421 and 358 episodes of MA-fluA and MA-fluB, respectively. The adjusted VE yielded significant dose-dependent attenuations by prior vaccinations against both MA-fluA [0 doses during previous three seasons: 96% (95% CI: 69%-100%), 1 dose: 48% (-7% to 74%), 2 doses: 52% (11%-74%), 3 doses: 21% (-25% to 51%); P for trend <0.05] and MA-fluB [0 doses: 66% (-5% to 89%), 1 dose: 48% (-14% to 76%), 2 doses: 34% (-33% to 67%), 3 doses: -7% (-83% to 37%); P for trend <0.05]. After excluding episodes of MA-flu during prior three seasons, similar trends were observed. Repeated previous vaccinations over multiple seasons had significant dose-dependent negative impacts on VE against both MA-fluA and MA-fluB. Further studies to confirm this finding are necessary.

Phaeochromocytoma with hypercortisolism and hypercalcaemia.

PubMed

Edafe, Ovie; Webster, Jonathan; Fernando, Malee; Vinayagam, Ragu; Balasubramanian, Sabapathy P

2015-10-07

We report a case of phaeochromocytoma associated with hypercortisolism and hypercalcaemia in a 62-year-old man. The patient presented to clinic, with a 3-year history of exertional headaches, and a 4-month history of increasing fatigue, sweating and palpitations, loss of appetite and weight, and sleepiness. He did not have a medical, family or social history that could account for these symptoms. 24 h urinary catecholamines, plasma metanephrines, 24 h urinary cortisol and adjusted serum calcium, were elevated. Overnight low-dose dexamethasone suppression test did not suppress morning plasma cortisol. Serum intact parathyroid hormone and parathyroid hormone-related peptide were low, and adrenocorticotropic hormone was normal. The patient was treated with intravenous 0.9% sodium chloride and disodium pamidronate to control hypercalcaemia. CT showed a 10 cm left adrenal mass. Following inpatient treatment with phenoxybenzamine, he underwent a left adrenectomy and histology confirmed a phaeochromocytoma. Postoperatively, he required long-term steroids for contralateral adrenal suppression. Adjusted serum calcium returned to normal postoperatively. 2015 BMJ Publishing Group Ltd.

Pharmacokinetics of Intranasal Scopolamine Gel Formulation During Antiorthostatic Bed Rest, a Microgravity Analog

NASA Technical Reports Server (NTRS)

Singh, Rajendra P.; Daniels, Vernie R.; Crady, Camille J.; Derendorf, H.; Putcha, L.

2011-01-01

Statement of Purpose, Innovation or Hypothesis: Space Motion sickness (SMS) is a long-standing problem for astronauts on both short and long duration space flights. Scopolamine (SCOP) is frequently used for the treatment of motion sickness (MS), and is available as transdermal patch and tablet dosage forms. These formulations of SCOP are ineffective for the treatment of SMS. Intranasal dosage forms are noninvasive with rapid absorption and enhanced bioavailability, thus allowing precise and reduced dosing in addition to offering rescue and treatment options. An intranasal gel dosage formulation of scopolamine (INSCOP) was developed and pharmacokinetics (PK) and bioavailability were determined in clinical trials with human subjects under IND guidelines.Description of Methods and Materials: The present clinical trial compares PK and bioavailability of INSCOP in 12 normal, healthy subjects (6 male/ 6 female) during ambulation (AMB) and antiorthostaticbed rest (ABR) used as a ground-based microgravity analog. Subjects received 0.2 mg and 0.4 mg doses of INSCOP during AMB and ABR in a 4-way crossover design.Data and Results: Results indicated no difference between AMB and ABR in PK parameters after 0.2 mg dose, Clearance (Cls) decreased with a concomitant increase in maximum concentration and area under concentration-versus-time curve (AUC) during ABR after the 0.4 mg dose.Interpretation, Conclusion or Significance: The difference in AUC and Cls at the higher (0.4 mg) but not the lower dose (0.2 mg) during ABR suggests that ABR may affect metabolism and/or clearance of INSCOP at higher doses . These results indicate that dosing adjustment may be required for treatment of SMS with INSCOP in space.

Flexible meal-related dosing with repaglinide facilitates glycemic control in therapy-naive type 2 diabetes.

PubMed

Moses, R G; Gomis, R; Frandsen, K B; Schlienger, J L; Dedov, I

2001-01-01

This double-blind randomized placebo-controlled parallel group study assessed the efficacy and safety (with particular regard to body weight and hypoglycemia) of repaglinide when used in a flexible mealtime dosing regimen in a situation close to everyday clinical practice. A total of 408 patients with type 2 diabetes considered poorly controlled by diet, but without a history of previous antidiabetic medication, were randomized to receive 0.5 mg repaglinide at mealtimes (increased to 1 mg after 4 weeks depending on blood glucose response) or placebo for 16 weeks. Patients were free to choose a flexible meal pattern, adjusting the dosing schedule from two to four preprandial doses per day in accordance with a "one meal, one dose; no meal, no dose" principle. Additional snacks were not a requirement of the treatment schedule. Treatment with repaglinide significantly improved glycemic control with respect to baseline and placebo, reducing HbA1c by 1.14% from baseline and fasting plasma glucose by 1.8 mmol/l. Improvement in glycemic control was independent of the meal pattern adopted by patients, including those most commonly taking two or four meals daily, with no correlation between meal pattern and risk of hypoglycemia. The improvement in glycemic control was also independent of degree of obesity and age < or =65 or >65 years. There was no significant body weight increase in the repaglinide group. Mealtime dosing with repaglinide is effective in improving overall glycemic control in type 2 diabetic patients for which control is suboptimal using diet alone. Patients are able to vary their meal pattern from a conventional regimen of three meals daily without compromising control or increasing the risk of adverse events.

Exploration of approaches to adjusting brand-name drug prices in Mainland of China: based on comparison and analysis of some brand-name drug prices of Mainland and Taiwan, China.

PubMed

Weng, Geng; Han, Sheng; Pu, Run; Pan, Wynn H T; Shi, Luwen

2014-01-01

Under the circumstance of the New Medical Reform in Mainland of China, lowering drug prices has become an approach to relieving increase of medical expenses, and lowering brand-name medication price is a key strategy. This study, by comparing and analyzing brand-name medication prices between Mainland of China and Taiwan, explores how to adjust brand-name medication prices in Mainland of China in the consideration of the drug administrative strategies in Taiwan. By selecting brand-name drug with generic name and dose types matched in Mainland and Taiwan, calculate the average unit price and standard deviation and test it with the paired t-test. In the mean time, drug administrative strategies between Mainland and Taiwan are also compared systematically. Among the 70 brand-name medications with generic names and matched dose types, 54 are at higher prices in Mainland of China than Taiwan, which is statistically significant in t-test. Also, among the 47 medications with all of matched generic names, dose types, and manufacturing enterprises, 38 are at higher prices in Mainland than Taiwan, and the gap is also statistically significant in t-test. In Mainland of China, brand-name medication took cost-plus pricing and price-based price adjustment, while in Taiwan, brand-name medication took internal and external reference pricing and market-based price adjustment. Brand-name drug prices were higher in Mainland of China than in Taiwan. The adjustment strategies of drug prices are scientific in Taiwan and are worth reference by Mainland of China.

Image-guided high dose rate endorectal brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devic, Slobodan; Vuong, Te; Moftah, Belal

2007-11-15

Fractionated high dose rate endorectal brachytherapy (HDR-EBT) using CT-based treatment planning is an alternative method for preoperative down-sizing and down-staging of advanced rectal adeno-carcinomas. The authors present an image guidance procedure that was developed to ensure daily dose reproducibility for the four brachytherapy treatment fractions. Since the applicator might not be placed before each treatment fraction inside the rectal lumen in the same manner as it was placed during the 3D CT volume acquisition used for treatment planning, there is a shift along the catheter axis that may have to be performed. The required shift is determined by comparison ofmore » a daily radiograph with the treatment planning digitally-reconstructed radiograph (DRR). A procedure is developed for DRR reconstruction from the 3D data set used for the treatment planning, and two possible daily longitudinal shifts are illustrated: above and below the planning dose distribution. The authors also describe the procedure for rotational alignment illustrated on a clinical case. Reproduction of the treatment planned dose distribution on a daily basis is crucial for the success of fractionated 3D based brachytherapy treatments. Due to the cylindrical symmetry of the applicator used for preoperative HDR-EBT, two types of adjustments are necessary: applicator rotation and dwell position shift along the applicator's longitudinal axis. The impact of the longitudinal applicator shift prior to treatment delivery for 62 patients treated in our institution is also assessed.« less

Development and validation of a questionnaire to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes.

PubMed

Koontz, Michaela B; Cuttler, Leona; Palmert, Mark R; O'Riordan, Maryann; Borawski, Elaine A; McConnell, Judy; Kern, Elizabeth O

2010-03-01

OBJECTIVE The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach alpha and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen. RESULTS PCQ mean score was 87 +/- 9.7% (range 42-98%). Cronbach alpha was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = -0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003). CONCLUSIONS The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ.

Overdosing of benzodiazepines/Z-drugs and falls in older adults: Costs for the health system.

PubMed

Díaz-Gutiérrez, María José; Cengotitabengoa, Mónica Martínez; Bermúdez-Ampudia, Cristina; García, Sainza; López, Purificación; Martínez-Cengotitabengoa, Mayte; González-Pinto, Ana

2018-05-08

Benzodiazepines and Z drugs (BZD/Z drugs) are commonly used for the treatment of insomnia and anxiety in older adults for long periods of time. Given the physiological and metabolic characteristics of this group of patients, they are more prone to the adverse effects of these drugs which include falls. The recommendations for use of BZD/Z drugs include the need to adjust the dose and select those with a short half-life, to avoid adverse events, which as well as potentially affecting patient outcome, increase healthcare costs. In this study, we have evaluated the hospital-related costs associated with falls in older adults who use BZD/Z drugs at doses higher than recommended for this age group. We conducted a cross-sectional observational study assessing the BZD/Z drug prescriptions of older adults attending the emergency department after a fall. Cost analysis was performed for cases in which the prescriptions exceeded the maximum recommended dose for this age group. A total of 40.6% of the prescriptions recorded were higher than the defined daily dose in older adults (DDD olderadults ). Of the 57 patients who used BZD/Z drugs at higher-than-recommended doses, 53 experienced trauma and 33 required hospitalisation. The costs associated with emergency department services, tests performed and hospitalisation amounted to €1850/patient. Appropriate dosage of BZD/Z drugs in older adults could reduce both patient suffering and costs for the health system. Copyright © 2017. Published by Elsevier Inc.

Targeting higher ferritin concentrations with intravenous iron dextran lowers erythropoietin requirement in hemodialysis patients.

PubMed

DeVita, M V; Frumkin, D; Mittal, S; Kamran, A; Fishbane, S; Michelis, M F

2003-11-01

Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of < or = 33% were enrolled. Subjects were divided as follows: Group 1: target SFer of 200 ng/ml, Group 2: target SFer of 400 ng/ml. Each subject below the target level received IVFe in up to 10 divided doses during consecutive dialysis sessions as needed to reach the target. HCT was maintained between 32.5% and 36% by adjusting rHuEPO dosage. Mean SFer concentration at the study conclusion in Group 1: 261 ng/ml; Group 2: 387 ng/ml. The mean decrease in rHuEPO dose for Group 1 was 31 U/kg body weight/week (250 - 219 U/kg bw/wk) while in Group 2 it was 154 U/kg body weight/week (312 - 158 U/kg bw/wk) (p < 0.001). There was no difference in HCT between groups. Our results suggest that higher target serum ferritin concentrations can be well tolerated and lower rHuEPO requirements.

Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.

PubMed

Vassal, G; Michel, G; Espérou, H; Gentet, J C; Valteau-Couanet, D; Doz, F; Mechinaud, F; Galambrun, C; Neven, B; Zouabi, H; Nguyen, L; Puozzo, C

2008-01-01

Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years). No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

Distribution, variability, and predictors of urinary bisphenol A levels in 50 North Carolina adults over a six-week monitoring period.

PubMed

Morgan, Marsha K; Nash, Maliha; Barr, Dana Boyd; Starr, James M; Scott Clifton, M; Sobus, Jon R

2018-03-01

Bisphenol A (BPA) is commonly manufactured to make polycarbonate plastics and epoxy resins for use in consumer products and packaged goods. BPA has been found in several different types of environmental media (e.g., food, dust, and air). Many cross-sectional studies have frequently detected BPA concentrations in adult urine samples. However, limited data are available on the temporal variability and important predictors of urinary BPA concentrations in adults. In this work, the major objectives were to: 1) quantify BPA levels in duplicate-diet solid food, drinking water, hard floor surface wipe, and urine samples (first-morning void [FMV], bedtime, and 24-h) collected from adults over a six-week monitoring period; 2) determine the temporal variability of urinary BPA levels using concentration, specific gravity (SG) adjusted, creatinine (CR) adjusted, and excretion rate values, and; 3) examine associations between available study factors and urinary BPA concentrations. In 2009-2011, a convenience sample of 50 adults was recruited from residential settings in North Carolina. The participants completed diaries and collected samples during weeks 1, 2, and/or 6 of a six-week monitoring period. BPA was detected in 38%, 4%, and 99% of the solid food (n=775), drinking water (n=50), and surface wipe samples (n=138), respectively. Total BPA (free plus conjugated) was detected in 98% of the 2477 urine samples. Median urinary BPA levels were 2.07ng/mL, 2.20ng/mL-SG, 2.29ng/mg, and 2.31ng/min for concentration, SG-adjusted, CR-adjusted, and excretion rate values, respectively. The intraclass correlation coefficient (ICC) estimates for BPA showed poor reproducibility (≤0.35) for all urine sample types and methods over a day, week, and six weeks. CR-adjusted bedtime voids collected over six-weeks required the fewest, realistic number of samples (n=11) to obtain a reliable biomarker estimate (ICC=0.80). Results of linear mixed-effects models showed that sex, race, season, and CR-level were all significant predictors (p<0.05) of the adults' urinary BPA concentrations. BPA levels in the solid food and surface wipe samples did not contribute significantly to the participants' urinary BPA concentrations. However, a significant positive relationship was observed between solid food intake and urine-based estimates of BPA dose, when aggregated over 24-h periods. Ingestion of BPA via solid food explained only about 20% of the total dose (at the median of the dose distribution), suggesting that these adults were likely exposed to other major unknown (non-dietary) sources of BPA in their everyday environments. Published by Elsevier Ltd.

An Increased Risk of Reversible Dementia May Occur After Zolpidem Derivative Use in the Elderly Population

PubMed Central

Shih, Hsin-I; Lin, Che-Chen; Tu, Yi-Fang; Chang, Chia-Ming; Hsu, Hsiang-Chin; Chi, Chih-Hsien; Kao, Chia-Hung

2015-01-01

Abstract We evaluate the effects of zolpidem use to develop dementia or Alzheimer disease from the Taiwan National Health Insurance Research Database (NHIRD). A retrospective population-based nested case–control study. Newly diagnosed dementia patients 65 years and older and controls were sampled. A total of 8406 dementia and 16,812 control subjects were enrolled from Taiwan NHIRD during 2006 to 2010. The relationships between zolpidem use and dementia were measured using odds and adjusted odds ratios. The relationship between the average cumulative doses for zolpidem and dementia was also analyzed. Zolpidem alone or with other underlying diseases, such as hypertension, diabetes, and stroke, was significantly associated with dementia after controlling for potential confounders, such as age, sex, coronary artery disease, diabetes, anti-hypertension drugs, stroke, anticholesterol statin drugs, depression, anxiety, benzodiazepine, anti-psychotic, and anti-depressant agents’ use (Adjusted OR = 1.33, 95% CI 1.24–1.41). Zolpidem use also has significant dose–response effects for most of the types of dementia. In patient with Alzheimer diseases, the effects of zolpidem among patients with Alzheimer's disease remained obscure. The adjusted OR for patients whose cumulative exposure doses were between 170 and 819 mg/year (adjusted OR: 1.65, 95% CI 1.08–2.51, P = 0.0199) was significant; however, the effects for lower and higher cumulative dose were not significant. Zolpidem used might be associated with increased risk for dementia in elderly population. Increased accumulative dose might have higher risk to develop dementia, especially in patients with underlying diseases such as hypertension, diabetes, and stroke. PMID:25929937

Pharmacokinetics of fixed-dose combinations of empagliflozin/metformin compared with individual tablets in healthy subjects.

PubMed

Rojas, Christina; Link, Jasmin; Meinicke, Thomas; Macha, Sreeraj

2016-04-01

To compare the pharmacokinetics of fixed-dose combination (FDC) tablets of empagliflozin/metformin with individual tablets taken together. In 3 randomized, open-label studies, healthy subjects received a single FDC tablet of empagliflozin/metformin in 1 of 6 dose combinations (empagliflozin 12.5 mg or 5 mg; metformin 500 mg, 850 mg, or 1,000 mg) in 1 period and the individual tablets taken together under fed conditions in another period. Empagliflozin 12.5 mg/metformin 1,000 mg FDC and individual tablets were also given under fasted conditions. Adjusted geometric mean ratios (GMRs) of empagliflozin area under the plasma concentration-time curve (AUC(0-∞)) for the FDCs vs. individual tablets ranged from 97.92 to 106.00%, and 90% CIs ranged from 93.53 to 109.39%. Adjusted GMRs of empagliflozin maximum plasma concentrations (C(max)) for the FDCs vs. individual tablets ranged from 100.97 to 106.52%, and 90% CIs ranged from 95.86 to 118.35%. Adjusted GMRs of metformin AUC(0-∞) for the FDCs vs. individual tablets ranged from 96.25 to 101.61%, and 90% CIs ranged from 88.54 to 106.62%. Adjusted GMRs of metformin C(max) for the FDCs vs. individual tablets ranged from 93.83 to 102.95%, and 90% CIs ranged from 88.01 to 109.08%. Bioequivalence was also established under fasted conditions for empagliflozin 12.5 mg/metformin 1,000 mg FDC vs. individual tablets taken together. All treatments were well tolerated. Empagliflozin/metformin FDC tablets were found to be bioequivalent to individual tablets taken together at all tested dose strengths.

Comparison of Aspirin and Naoxintong Capsule () with Adjusted-Dose Warfarin in Elderly Patients with High-Risk of Non-Valvular Atrial Fibrillation and Genetic Variants of Vitamin K Epoxide Reductase.

PubMed

Wang, Huan; Zhou, Xiao-Kai; Zheng, Li-Fan; Wu, Xiao-Ying; Chen, Hui

2018-04-01

To compared the therapeutic effect of a Chinese patent medicine Naoxintong Capsule (, NXT) and aspirin with adjusted-dose warfarin in Chinese elderly patients (over 65 years) with nonvalvular atrial fibrillation (NVAF) and genetic variants of vitamin K epoxide reductase (VKORC1), who are at high-risk of thromboembolism. A total of 151 patients, with NVAF and AA genotype of VKORC1-1639 (a sensitive genotype to warfarin) and a CHA 2 DS 2 -VASc clinical risk score of 2 or above, were chosen for this study. Patients were randomized into two groups and orally treated with a combination of aspirin (100 mg/day) and NXT (1.6 g thrice a day) or adjusted-dose warfarin [international normalized ratio 2.0-3.0). The primary end points including ischemic stroke and death as well as the secondary end points including hemorrhage events were followed up for at least 1 year. Baseline clinical data and the rates of primary end points were similar between groups. However, the rate of serious bleeding (secondary event) in the combination therapy group was lower than that in the adjusted-dose warfarin group (0% vs. 7.9%, odds ratio: 0.921, 95% confidence interval: 0.862-0.984, P=0.028). Aspirin combined with NXT and warfarin displayed comparable rates of primary end point including ischemic stroke and all-cause death during the 1-year follow-up. However, as compared with warfarin, the combination therapy reduced the rate of serious bleeding. Therefore, aspirin combined with NXT might provide an alternative pharmacotherapy in preventing ischemic stroke for elderly patients with NAVF who cannot tolerate warfarin. (No. ChiCTR-TRC-13003596).

Association of cumulative dose of haloperidol with next-day delirium in older medical ICU patients.

PubMed

Pisani, Margaret A; Araujo, Katy L B; Murphy, Terrence E

2015-05-01

To evaluate the association between cumulative dose of haloperidol and next-day diagnosis of delirium in a cohort of older medical ICU patients, with adjustment for its time-dependent confounding with fentanyl and intubation. Prospective, observational study. Medical ICU at an urban, academic medical center. Age 60 years and older admitted to the medical ICU who received at least one dose of haloperidol (n = 93). Of these, 72 patients were intubated at some point in their medical ICU stay, whereas 21 were never intubated. None. Detailed data were collected concerning time, dosage, route of administration of all medications, as well as for important clinical covariates, and daily status of intubation and delirium using the confusion assessment method for the ICU and a chart-based algorithm. Among nonintubated patients, and after adjustment for time-dependent confounding and important covariates, each additional cumulative milligram of haloperidol was associated with 5% higher odds of next-day delirium with odds ratio of 1.05 (credible interval [CI], 1.02-1.09). After adjustment for time-dependent confounding and covariates, intubation was associated with a five-fold increase in odds of next-day delirium with odds ratio of 5.66 (CI, 2.70-12.02). Cumulative dose of haloperidol among intubated patients did not change their already high likelihood of next-day delirium. After adjustment for time-dependent confounding, the positive associations between indicators of intubation and of cognitive impairment and next-day delirium became stronger. These results emphasize the need for more studies regarding the efficacy of haloperidol for treatment of delirium among older medical ICU patients and demonstrate the value of assessing nonintubated patients.

Allopurinol, benzbromarone and risk of coronary heart disease in gout patients: A population-based study.

PubMed

Lin, Hsiu-Chen; Daimon, Masao; Wang, Ching-Hung; Ho, Yi; Uang, Yow-Shieng; Chiang, Shuo-Ju; Wang, Li-Hsuan

2017-04-15

The effect of gout on the risk of developing coronary artery disease (CAD) is uncertain. Some studies have found that gout is a risk factor for acute myocardial infarction. This study examined the changes in risk of CAD in gout patients taking allopurinol and/or benzbromarone, and analyzed the dose-response relationship of both drugs with CAD incidence. The medical records of one million subjects from 2000 to 2011 were provided by the Taiwan National Health Insurance Research Database. Cox proportional hazard ratio was used to compare the risk of CAD in gout patients taking allopurinol or/and benzbromarone with those taking neither drug. Hazard ratios (HR) were adjusted for possible confounding factors, including age, gender, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and relevant medications. Of 8047 gout patients, 1422 were treated with allopurinol (Group A), 4141 with benzbromarone (Group B), and 2484 with both drugs (Group A/B) during the follow-up period. Our results showed the incidence of CAD after adjusting for covariates for Group A, Group B, and Group A/B did not significantly differ from the comparison group. However, after adjustment for covariates in dose-response analyses, treatment with over 270 defined daily doses (DDDs) of allopurinol, and over 360 DDDs of benzbromarone, was associated with a significantly reduced risk of CAD. We found that the use of allopurinol and benzbromarone, whether alone or in combination, had a linear dose-response relationship between the numbers of defined daily doses and the risk of CAD, especially in higher DDDs. Copyright © 2017 Elsevier B.V. All rights reserved.

Optimizing the Anti-VEGF Treatment Strategy for Neovascular Age-Related Macular Degeneration: From Clinical Trials to Real-Life Requirements.

PubMed

Mantel, Irmela

2015-06-01

This Perspective discusses the pertinence of variable dosing regimens with anti-vascular endothelial growth factor (VEGF) for neovascular age-related macular degeneration (nAMD) with regard to real-life requirements. After the initial pivotal trials of anti-VEGF therapy, the variable dosing regimens pro re nata (PRN), Treat-and-Extend, and Observe-and-Plan, a recently introduced regimen, aimed to optimize the anti-VEGF treatment strategy for nAMD. The PRN regimen showed good visual results but requires monthly monitoring visits and can therefore be difficult to implement. Moreover, application of the PRN regimen revealed inferior results in real-life circumstances due to problems with resource allocation. The Treat-and-Extend regimen uses an interval based approach and has become widely accepted for its ease of preplanning and the reduced number of office visits required. The parallel development of the Observe-and-Plan regimen demonstrated that the future need for retreatment (interval) could be reliably predicted. Studies investigating the observe-and-plan regimen also showed that this could be used in individualized fixed treatment plans, allowing for dramatically reduced clinical burden and good outcomes, thus meeting the real life requirements. This progressive development of variable dosing regimens is a response to the real-life circumstances of limited human, technical, and financial resources. This includes an individualized treatment approach, optimization of the number of retreatments, a minimal number of monitoring visits, and ease of planning ahead. The Observe-and-Plan regimen achieves this goal with good functional results. Translational Relevance: This perspective reviews the process from the pivotal clinical trials to the development of treatment regimens which are adjusted to real life requirements. The article discusses this translational process which- although not the classical interpretation of translation from fundamental to clinical research, but a subsequent process after the pivotal clinical trials - represents an important translational step from the clinical proof of efficacy to optimization in terms of patients' and clinics' needs. The related scientific procedure includes the exploration of the concept, evaluation of security, and finally proof of efficacy.

Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Chronic Lymphocytic Leukemia: Ibrutinib, Idelalisib, and Venetoclax.

PubMed

Waldron, Madeline; Winter, Allison; Hill, Brian T

2017-11-01

Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents. Unique treatment-related adverse events including bleeding and atrial fibrillation with ibrutinib, hepatotoxicity with idelalisib, and tumor lysis syndrome with venetoclax can be severe and dose limiting. Furthermore, dose adjustments for organ dysfunction may also be warranted. Here, we review the available literature on the pharmacokinetic and pharmacodynamic properties of these novel agents to guide the reader in the appropriate use of ibrutinib, idelalisib, and venetoclax.

Low human papillomavirus (HPV) vaccine knowledge among Latino parents in Utah.

PubMed

Kepka, Deanna; Warner, Echo L; Kinney, Anita Y; Spigarelli, Michael G; Mooney, Kathi

2015-02-01

Latinas have the highest incidence of cervical cancer, yet Latino parents/guardians' knowledge about and willingness to have their children receive the human papillomavirus (HPV) vaccine is unknown. Latino parents/guardians (N = 67) of children aged 11-17 were recruited from two community organizations to complete a survey, including HPV vaccine knowledge, child's uptake, demographic characteristics, and acculturation. Descriptive statistics and correlates of parents' HPV knowledge and uptake were calculated using Chi square tests and multivariable logistic regression. Receipt of at least one dose of the HPV vaccine was moderate for daughters (49.1%) and low for sons (23.4%). Parents/guardians reported limited knowledge as the main barrier to vaccine receipt. Among parents/guardians with vaccinated daughters, 92.6% did not know the vaccine requires three doses. Adjusting for income, low-acculturated parents were more likely than high-acculturated parents to report inadequate information (OR 8.59, 95% CI 2.11-34.92). Interventions addressing low knowledge and children's uptake of the HPV vaccine are needed among Latino parents/guardians.

The Mobile Insulin Titration Intervention (MITI) for Insulin Adjustment in an Urban, Low-Income Population: Randomized Controlled Trial.

PubMed

Levy, Natalie; Moynihan, Victoria; Nilo, Annielyn; Singer, Karyn; Bernik, Lidia S; Etiebet, Mary-Ann; Fang, Yixin; Cho, James; Natarajan, Sundar

2015-07-17

Diabetes patients are usually started on a low dose of insulin and their dose is adjusted or "titrated" according to their blood glucose levels. Insulin titration administered through face-to-face visits with a clinician can be time consuming and logistically burdensome for patients, especially those of low socioeconomic status (SES). Given the wide use of mobile phones among this population, there is the potential to use short message service (SMS) text messaging and phone calls to perform insulin titration remotely. The goals of this pilot study were to (1) evaluate if our Mobile Insulin Titration Intervention (MITI) intervention using text messaging and phone calls was effective in helping patients reach their optimal insulin glargine dose within 12 weeks, (2) assess the feasibility of the intervention within our clinic setting and patient population, (3) collect data on the cost savings associated with the intervention, and (4) measure patient satisfaction with the intervention. This was a pilot study evaluating an intervention for patients requiring insulin glargine titration in the outpatient medical clinic of Bellevue Hospital Center in New York City. Patients in the intervention arm received weekday SMS text messages from a health management platform requesting their fasting blood glucose values. The clinic's diabetes nurse educator monitored the texted responses on the platform website each weekday for alarm values. Once a week, the nurse reviewed the glucose values, consulted the MITI titration algorithm, and called patients to adjust their insulin dose. Patients in the usual care arm continued to receive their standard clinic care for insulin titration. The primary outcome was whether a patient reached his/her optimal insulin glargine dose within 12 weeks. A total of 61 patients consented and were randomized into the study. A significantly greater proportion of patients in the intervention arm reached their optimal insulin glargine dose than patients in the usual care arm (88%, 29/33 vs 37%, 10/27; P<.001). Patients responded to 84.3% (420/498) of the SMS text messages requesting their blood glucose values. The nurse reached patients within 2 attempts or by voicemail 91% of the time (90/99 assigned calls). When patients traveled to the clinic, they spent a median of 45 minutes (IQR 30-60) on travel and 39 minutes (IQR 30-64) waiting prior to appointments. A total of 61% (37/61) of patients had appointment copays. After participating in the study, patients in the intervention arm reported higher treatment satisfaction than those in the usual care arm. MITI is an effective way to help low-SES patients reach their optimal insulin glargine dose using basic SMS text messaging and phone calls. The intervention was feasible and patients were highly satisfied with their treatment. The intervention was cost saving in terms of time for patients, who were able to have their insulin titrated without multiple clinic appointments. Similar interventions should be explored to improve care for low-SES patients managing chronic disease. Clinicaltrials.gov NCT01879579; https://clinicaltrials.gov/ct2/show/NCT01879579 (Archived by WebCite at http://www.webcitation.org/6YZik33L3).

A new Monte Carlo-based treatment plan optimization approach for intensity modulated radiation therapy.

PubMed

Li, Yongbao; Tian, Zhen; Shi, Feng; Song, Ting; Wu, Zhaoxia; Liu, Yaqiang; Jiang, Steve; Jia, Xun

2015-04-07

Intensity-modulated radiation treatment (IMRT) plan optimization needs beamlet dose distributions. Pencil-beam or superposition/convolution type algorithms are typically used because of their high computational speed. However, inaccurate beamlet dose distributions may mislead the optimization process and hinder the resulting plan quality. To solve this problem, the Monte Carlo (MC) simulation method has been used to compute all beamlet doses prior to the optimization step. The conventional approach samples the same number of particles from each beamlet. Yet this is not the optimal use of MC in this problem. In fact, there are beamlets that have very small intensities after solving the plan optimization problem. For those beamlets, it may be possible to use fewer particles in dose calculations to increase efficiency. Based on this idea, we have developed a new MC-based IMRT plan optimization framework that iteratively performs MC dose calculation and plan optimization. At each dose calculation step, the particle numbers for beamlets were adjusted based on the beamlet intensities obtained through solving the plan optimization problem in the last iteration step. We modified a GPU-based MC dose engine to allow simultaneous computations of a large number of beamlet doses. To test the accuracy of our modified dose engine, we compared the dose from a broad beam and the summed beamlet doses in this beam in an inhomogeneous phantom. Agreement within 1% for the maximum difference and 0.55% for the average difference was observed. We then validated the proposed MC-based optimization schemes in one lung IMRT case. It was found that the conventional scheme required 10(6) particles from each beamlet to achieve an optimization result that was 3% difference in fluence map and 1% difference in dose from the ground truth. In contrast, the proposed scheme achieved the same level of accuracy with on average 1.2 × 10(5) particles per beamlet. Correspondingly, the computation time including both MC dose calculations and plan optimizations was reduced by a factor of 4.4, from 494 to 113 s, using only one GPU card.

Short-term reproducibility of computed tomography-based lung density measurements in alpha-1 antitrypsin deficiency and smokers with emphysema.

PubMed

Shaker, S B; Dirksen, A; Laursen, L C; Maltbaek, N; Christensen, L; Sander, U; Seersholm, N; Skovgaard, L T; Nielsen, L; Kok-Jensen, A

2004-07-01

To study the short-term reproducibility of lung density measurements by multi-slice computed tomography (CT) using three different radiation doses and three reconstruction algorithms. Twenty-five patients with smoker's emphysema and 25 patients with alpha1-antitrypsin deficiency underwent 3 scans at 2-week intervals. Low-dose protocol was applied, and images were reconstructed with bone, detail, and soft algorithms. Total lung volume (TLV), 15th percentile density (PD-15), and relative area at -910 Hounsfield units (RA-910) were obtained from the images using Pulmo-CMS software. Reproducibility of PD-15 and RA-910 and the influence of radiation dose, reconstruction algorithm, and type of emphysema were then analysed. The overall coefficient of variation of volume adjusted PD-15 for all combinations of radiation dose and reconstruction algorithm was 3.7%. The overall standard deviation of volume-adjusted RA-910 was 1.7% (corresponding to a coefficient of variation of 6.8%). Radiation dose, reconstruction algorithm, and type of emphysema had no significant influence on the reproducibility of PD-15 and RA-910. However, bone algorithm and very low radiation dose result in overestimation of the extent of emphysema. Lung density measurement by CT is a sensitive marker for quantitating both subtypes of emphysema. A CT-protocol with radiation dose down to 16 mAs and soft or detail reconstruction algorithm is recommended.

Examining the Starting Dose of Glyburide in Gestational Diabetes

PubMed Central

GLOVER, Angelica V.; TITA, Alan; BIGGIO, Joseph R.; HARPER, Lorie M.

2016-01-01

OBJECTIVE The aim of this study was to determine the impact of initial glyburide dosing on pregnancy outcomes. STUDY DESIGN Retrospective cohort of singleton pregnancies complicated by gestational diabetes (GDM) from 2007-2013. Women who received glyburide were compared by initial dose: 2.5mg (n=170) versus 5mg (n=154) total daily dose. The primary maternal outcome was hypoglycemia, defined as a blood glucose <60 mg/dL. The primary neonatal outcome was birth weight. Secondary maternal outcomes included time to blood glucose control, preeclampsia, and cesarean delivery. Secondary neonatal outcomes included macrosomia (>4000g), hypoglycemia (<40 mg/dL), shoulder dystocia, and preterm delivery. RESULTS The 5 mg/day glyburide dose did not increase maternal hypoglycemia (26% in the 2.5 mg/day group versus 27% in the 5 mg/day group, AOR 0.67 (CI 0.30-1.49)). An increase in macrosomia in the 5 mg/day group was not significant after adjusting for maternal obesity (AOR 2.16 (CI 0.96-4.88)). Differences in preterm birth and large for gestational age were not significant after adjusting for prior preterm birth and maternal obesity, respectively. CONCLUSIONS A higher starting dose of glyburide for the management of GDM was not associated with increased maternal hypoglycemia or decreased adverse neonatal outcomes. PMID:26368915

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Risk of Subsequent Leukemia After a Solid Tumor in Childhood: Impact of Bone Marrow Radiation Therapy and Chemotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Allodji, Rodrigue S., E-mail: rodrigue.allodji@gustaveroussy.fr; Gustave Roussy, Villejuif; Paris Sud University, Orsay

Purpose: To investigate the roles of radiation therapy and chemotherapy in the occurrence of subsequent leukemia after childhood cancer. Methods and Materials: We analyzed data from a case-control study with 35 cases and 140 controls. The active bone marrow (ABM) was segmented into 19 compartments, and the radiation dose was estimated in each. The chemotherapy drug doses were also estimated to enable adjustments. Models capable of accounting for radiation dose heterogeneity were implemented for analysis. Results: Univariate analysis showed a significant trend in the increase of secondary leukemia risk with radiation dose, after accounting for dose heterogeneity (P=.046). This trendmore » became nonsignificant after adjustment for doses of epipodophyllotoxins, alkylating agents, and platinum compounds and the first cancer on multivariate analysis (P=.388). The role of the radiation dose appeared to be dwarfed, mostly by the alkylating agents (odds ratio 6.9, 95% confidence interval 1.9-25.0). Among the patients who have received >16 Gy to the ABM, the radiogenic risk of secondary leukemia was about 4 times greater in the subgroup with no alkylating agents than in the subgroup receiving ≥10 g/m{sup 2}. Conclusions: Notwithstanding the limitations resulting from the size of our study population and the quite systematic co-treatment with chemotherapy, the use of detailed information on the radiation dose distribution to ABM enabled consideration of the role of radiation therapy in secondary leukemia induction after childhood cancer.« less

Increasing alkali supplementation decreases urinary nitrogen excretion when adjusted for same day nitrogen intake

USDA-ARS?s Scientific Manuscript database

Summary: We examined whether escalating doses of potassium bicarbonate (KHCO3) supplements alter urinary nitrogen excretion expressed as a ratio to same day nitrogen intake (measure of muscle-protein breakdown). The ratio declined significantly from placebo to low to high dose of KHCO3 supplementati...

Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects.

PubMed

Krösser, Sonja; Marquet, Anne; Gallemann, Dieter; Wolna, Peter; Fauchoux, Nicolas; Hermann, Robert; Johne, Andreas

2012-12-01

The purpose of this mechanistic drug interaction study was to investigate the effects of ketoconazole on the pharmacokinetics of safinamide. Ketoconazole was applied as a potent prototypic inhibitor of cytochrome CYP3A4, to determine the role of CYP3A4 in the metabolic clearance of safinamide. In an open-label, randomized, two-period, two-sequence cross-over study, 14 healthy adult subjects (7 males/7 females) received two single doses of 100 mg safinamide: alone and on top of multiple doses of ketoconazole (200 mg b.i.d.) given over 6 days. Serial blood samples were collected over 240 h post dose to quantify safinamide parent drug and metabolite concentrations for pharmacokinetic evaluation. Safinamide exposure was essentially unchanged when administered with and without ketoconazole: C(max) and AUC(0-∞) point estimates (90% CIs) for the treatment comparison were 106.6 (101.0; 112.4) and 112.9 (109.8; 116.03), respectively. Similarly, ketoconazole did not influence the formation and clearance of safinamide metabolites to a clinically relevant extent. Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo. Therefore, safinamide can be administered together with potent CYP3A4 inhibitors without any requirement for dose adjustment. Copyright © 2012 John Wiley & Sons, Ltd.

Assessing pediatrics residents' mathematical skills for prescribing medication: a need for improved training.

PubMed

Glover, Mark L; Sussmane, Jeffrey B

2002-10-01

To evaluate residents' skills in performing basic mathematical calculations used for prescribing medications to pediatric patients. In 2001, a test of ten questions on basic calculations was given to first-, second-, and third-year residents at Miami Children's Hospital in Florida. Four additional questions were included to obtain the residents' levels of training, specific pediatrics intensive care unit (PICU) experience, and whether or not they routinely double-checked doses and adjusted them for each patient's weight. The test was anonymous and calculators were permitted. The overall score and the score for each resident class were calculated. Twenty-one residents participated. The overall average test score and the mean test score of each resident class was less than 70%. Second-year residents had the highest mean test scores, although there was no significant difference between the classes of residents (p =.745) or relationship between the residents' PICU experiences and their exam scores (p =.766). There was no significant difference between residents' levels of training and whether they double-checked their calculations (p =.633) or considered each patient's weight relative to the dose prescribed (p =.869). Seven residents committed tenfold dosing errors, and one resident committed a 1,000-fold dosing error. Pediatrics residents need to receive additional education in performing the calculations needed to prescribe medications. In addition, residents should be required to demonstrate these necessary mathematical skills before they are allowed to prescribe medications.

Comparison of intermittent preventive treatment with chemoprophylaxis for the prevention of malaria during pregnancy in Mali.

PubMed

Kayentao, Kassoum; Kodio, Mamoudou; Newman, Robert D; Maiga, Hamma; Doumtabe, Didier; Ongoiba, Aissata; Coulibaly, Drissa; Keita, Abdoul Salam; Maiga, Bouboucar; Mungai, Mary; Parise, Monica E; Doumbo, Ogobara

2005-01-01

Malaria during pregnancy contributes to maternal anemia and low birth weight. In East Africa, several studies have demonstrated that intermittent preventive treatment (IPT) with sulfadoxine-pyrimethamine (SP) is more efficacious than weekly chloroquine (CQ) chemoprophylaxis in preventing these adverse consequences. To our knowledge, there are no published trials evaluating IPT in West Africa. We undertook a randomized controlled trial of weekly CQ chemoprophylaxis, 2-dose IPT with CQ, and 2-dose IPT with SP; 1163 women were enrolled. In multivariate analyses, when compared with weekly CQ, IPT/SP was associated with a reduction in third-trimester anemia (adjusted odds ratio [AOR], 0.49; P<.001), placental parasitemia (AOR, 0.69; P=.04), and low birth weight (<2500 g) (AOR, 0.69; P=.04). The prevalence of placental infection remained unexpectedly high, even in the IPT/SP group (24.5%), possibly because of the intensity of seasonal transmission. There were no significant differences in stillbirths, spontaneous abortions, or neonatal deaths among the 3 groups. In Mali, IPT with SP appears more efficacious than weekly chloroquine chemoprophylaxis in preventing malaria during pregnancy. These data support World Health Organization recommendations to administer at least 2 doses of IPT during pregnancy. In intensely seasonal transmission settings in Mali, >2 doses may be required to prevent placental reinfection prior to delivery.

[EEG-adjusted target-controlled infusion : Propofol target concentration with different doses of remifentanil].

PubMed

Büttner, N; Schultz, B; Grouven, U; Schultz, A

2010-02-01

The aim of this study was to examine to what extent the use of electroencephalography (EEG) monitoring leads to an adaptation of the target-controlled infusion (TCI) concentration of propofol during propofol anaesthesia with different doses of remifentanil. With ethics committee approval 60 patients (27-69 years old) with American Society of Anesthesiologists classification (ASA) I-III received anaesthestics with propofol (TCI, Diprifusor, AstraZeneca, Wedel, Deutschland) and 0.2, 0.4, or 0.6 microg/kg body weight remifentanil, respectively (groups 1-3). Anaesthesia was maintained at a level of deep hypnosis (EEG stages D(2)/E(0), EEG monitor: Narcotrend, version 2.0/5.0, manufacturer: MT MonitorTechnik, Bad Bramstedt, Germany). During the steady state the propofol concentration in groups 1-3 was 3.02+/-0.86, 1.93+/-0.53 and 1.60+/-0.55 microg/ml, respectively (p<0.001). Women had a higher propofol consumption than men (p<0.05). Dreams during anaesthesia were more often reported by women than by men (p<0.05). The need for postoperative analgesia decreased with an increasing intraoperative remifentanil dose (p<0.05). The study demonstrates that remifentanil has both analgetic and hypnotic effects. With increasing remifentanil dose the propofol requirement decreased and in this context EEG monitoring is useful to adapt the target concentrations of propofol to the patients' age and gender.

Aspirin is associated with reduced cartilage loss in knee osteoarthritis: Data from a cohort study.

PubMed

Wluka, Anita E; Ding, Changhai; Wang, Yuanyuan; Jones, Graeme; Urquhart, Donna M; Cicuttini, Flavia M

2015-07-01

Aspirin, widely used in the prevention of cardiovascular disease, in low dose, has anti-inflammatory and vasculoprotective effects: both of these processes contribute to the pathogenesis of osteoarthritis. We examined whether use of low dose aspirin affects change in knee cartilage volume in osteoarthritis. Participants from the Melbourne osteoarthritis cohort were classified as users and non-users of aspirin, according to baseline use (≤300 mg/day). Their knees were imaged twice over 2 years. Tibial cartilage volumes were measured and change calculated. Twenty one (18%) of 117 eligible participants were aspirin users. Annual change in medial tibial cartilage volume was -43 mm(3) (95% confidence intervals (CI) -93, 10) in aspirin users and -101 mm(3) (95% CI -125, -77) in non-users (p=0.043 for difference) after adjusting for age, gender, BMI and radiographic severity. Similar results were seen for annual percentage loss (1.9% vs 5.4%, p=0.034). No difference was observed for lateral tibial cartilage change and annual change (p=0.98, 0.87 respectively) Low dose aspirin use was associated with reduced medial tibial cartilage loss over 2 years in people with knee osteoarthritis. This data is hypothesis generating and clinical trials are required to confirm efficacy. If this hypothesis is confirmed, low dose aspirin may be used to reduce the progression of knee osteoarthritis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Clinical implementation of an exit detector-based dose reconstruction tool for helical tomotherapy delivery quality assurance.

PubMed

Deshpande, Shrikant; Xing, Aitang; Metcalfe, Peter; Holloway, Lois; Vial, Philip; Geurts, Mark

2017-10-01

The aim of this study was to validate the accuracy of an exit detector-based dose reconstruction tool for helical tomotherapy (HT) delivery quality assurance (DQA). Exit detector-based DQA tool was developed for patient-specific HT treatment verification. The tool performs a dose reconstruction on the planning image using the sinogram measured by the HT exit detector with no objects in the beam (i.e., static couch), and compares the reconstructed dose to the planned dose. Vendor supplied (three "TomoPhant") plans with a cylindrical solid water ("cheese") phantom were used for validation. Each "TomoPhant" plan was modified with intentional multileaf collimator leaf open time (MLC LOT) errors to assess the sensitivity and robustness of this tool. Four scenarios were tested; leaf 32 was "stuck open," leaf 42 was "stuck open," random leaf LOT was closed first by mean values of 2% and then 4%. A static couch DQA procedure was then run five times (once with the unmodified sinogram and four times with modified sinograms) for each of the three "TomoPhant" treatment plans. First, the original optimized delivery plan was compared with the original machine agnostic delivery plan, then the original optimized plans with a known modification applied (intentional MLC LOT error) were compared to the corresponding error plan exit detector measurements. An absolute dose comparison between calculated and ion chamber (A1SL, Standard Imaging, Inc., WI, USA) measured dose was performed for the unmodified "TomoPhant" plans. A 3D gamma evaluation (2%/2 mm global) was performed by comparing the planned dose ("original planned dose" for unmodified plans and "adjusted planned dose" for each intentional error) to exit detector-reconstructed dose for all three "Tomophant" plans. Finally, DQA for 119 clinical (treatment length <25 cm) and three cranio-spinal irradiation (CSI) plans were measured with both the ArcCHECK phantom (Sun Nuclear Corp., Melbourne, FL, USA) and the exit detector DQA tool to assess the time required for DQA and similarity between two methods. The measured ion chamber dose agreed to within 1.5% of the reconstructed dose computed by the exit detector DQA tool on a cheese phantom for all unmodified "Tomophant" plans. Excellent agreement in gamma pass rate (>95%) was observed between the planned and reconstructed dose for all "Tomophant" plans considered using the tool. The gamma pass rate from 119 clinical plan DQA measurements was 94.9% ± 1.5% and 91.9% ± 4.37% for the exit detector DQA tool and ArcCHECK phantom measurements (P = 0.81), respectively. For the clinical plans (treatment length <25 cm), the average time required to perform DQA was 24.7 ± 3.5 and 39.5 ± 4.5 min using the exit detector QA tool and ArcCHECK phantom, respectively, whereas the average time required for the 3 CSI treatments was 35 ± 3.5 and 90 ± 5.2 min, respectively. The exit detector tool has been demonstrated to be faster for performing the DQA with equivalent sensitivity for detecting MLC LOT errors relative to a conventional phantom-based QA method. In addition, comprehensive MLC performance evaluation and features of reconstructed dose provide additional insight into understanding DQA failures and the clinical relevance of DQA results. © 2017 American Association of Physicists in Medicine.

The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials.

PubMed

Mohler, Emile R; Ellenberg, Susan S; Lewis, Cora E; Wenger, Nanette K; Budoff, Matthew J; Lewis, Michael R; Barrett-Connor, Elizabeth; Swerdloff, Ronald S; Stephens-Shields, Alisa; Bhasin, Shalender; Cauley, Jane A; Crandall, Jill P; Cunningham, Glenn R; Ensrud, Kristine E; Gill, Thomas M; Matsumoto, Alvin M; Molitch, Mark E; Pahor, Marco; Preston, Peter E; Hou, Xiaoling; Cifelli, Denise; Snyder, Peter J

2018-02-01

Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Double-blind, placebo-controlled trial. Twelve academic medical centers in the United States. In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes. Copyright © 2017 Endocrine Society

Salivary cortisol day curves in assessing glucocorticoid replacement therapy in Addison's disease.

PubMed

Smans, Lisanne; Lentjes, Eef; Hermus, Ad; Zelissen, Pierre

2013-01-01

Patients with Addison's disease require lifelong treatment with glucocorticoids. At present, no glucocorticoid replacement therapy (GRT) can exactly mimic normal physiology. As a consequence, under- and especially overtreatment can occur. Suboptimal GRT may lead to various side effects. The aim of this study was to investigate the use of salivary cortisol day curves (SCDC) in the individual adjustment of GRT in order to approach normal cortisol levels as closely as possible, reduce over- and underreplacement and study the short-term effects on quality of life (QoL). Twenty patients with Addison's disease were included in this prospective study. A SCDC was obtained and compared to normal controls; general and disease specific QoL-questionnaires were completed. Based on SCDC assessment of over- and undertreatment (calculated as duration (h) × magnitude (nmol/L) at different time points, glucocorticoid dose and regime were adjusted. After 4 weeks SCDC and QoL assessment were repeated and the effect of adjusting GRT was analysed. At baseline, underreplacement was present in 3 and overreplacement in 18 patients; total calculated overreplacement was 32.8 h.nmol/L. Overreplacement decreased significantly to 13.3 h. nmol/L (p =0.005) after adjustment of GRT. Overreplacement was found particularly in the afternoon and evening. After reducing overreplacement in the evening, complaints about sleep disturbances significantly decreased. Individual adjustment of GRT based on SCDC to approach normal cortisol concentrations during the day can reduce overreplacement, especially in the evening. This can lead to a reduction of sleep disturbances and fatigue in patients with Addison's disease. A SCDC is a simple and patient-friendly tool for adjusting GRT and can be useful in the follow-up of patients with Addison's disease.

Image processing for IMRT QA dosimetry.

PubMed

Zaini, Mehran R; Forest, Gary J; Loshek, David D

2005-01-01

We have automated the determination of the placement location of the dosimetry ion chamber within intensity-modulated radiotherapy (IMRT) fields, as part of streamlining the entire IMRT quality assurance process. This paper describes the mathematical image-processing techniques to arrive at the appropriate measurement locations within the planar dose maps of the IMRT fields. A specific spot within the found region is identified based on its flatness, radiation magnitude, location, area, and the avoidance of the interleaf spaces. The techniques used include applying a Laplacian, dilation, erosion, region identification, and measurement point selection based on three parameters: the size of the erosion operator, the gradient, and the importance of the area of a region versus its magnitude. These three parameters are adjustable by the user. However, the first one requires tweaking in extremely rare occasions, the gradient requires rare adjustments, and the last parameter needs occasional fine-tuning. This algorithm has been tested in over 50 cases. In about 5% of cases, the algorithm does not find a measurement point due to the extremely steep and narrow regions within the fluence maps. In such cases, manual selection of a point is allowed by our code, which is also difficult to ascertain, since the fluence map does not yield itself to an appropriate measurement point selection.

Disability adjusted life year (DALY): a useful tool for quantitative assessment of environmental pollution.

PubMed

Gao, Tingting; Wang, Xiaochang C; Chen, Rong; Ngo, Huu Hao; Guo, Wenshan

2015-04-01

Disability adjusted life year (DALY) has been widely used since 1990s for evaluating global and/or regional burden of diseases. As many environmental pollutants are hazardous to human health, DALY is also recognized as an indicator to quantify the health impact of environmental pollution related to disease burden. Based on literature reviews, this article aims to give an overview of the applicable methodologies and research directions for using DALY as a tool for quantitative assessment of environmental pollution. With an introduction of the methodological framework of DALY, the requirements on data collection and manipulation for quantifying disease burdens are summarized. Regarding environmental pollutants hazardous to human beings, health effect/risk evaluation is indispensable for transforming pollution data into disease data through exposure and dose-response analyses which need careful selection of models and determination of parameters. Following the methodological discussions, real cases are analyzed with attention paid to chemical pollutants and pathogens usually encountered in environmental pollution. It can be seen from existing studies that DALY is advantageous over conventional environmental impact assessment for quantification and comparison of the risks resulted from environmental pollution. However, further studies are still required to standardize the methods of health effect evaluation regarding varied pollutants under varied circumstances before DALY calculation. Copyright © 2014 Elsevier B.V. All rights reserved.

Does unilateral laparoscopic diathermy adjusted to ovarian volume increase the chances of ovulation in women with polycystic ovary syndrome?

PubMed

Sunj, M; Canic, T; Baldani, D P; Tandara, M; Jeroncic, A; Palada, I

2013-09-01

Does unilateral volume-adjusted laparoscopic diathermy increase the chances of ovulation in women with polycystic ovary syndrome (PCOS)? Although unilateral laparoscopic ovarian drilling (ULOD) using adjusted thermal doses was more efficient than bilateral laparoscopic ovarian drilling (BLOD) using fixed doses, the chances of ovulation were improved in patients irrespective of the technique used. The adjustment of the thermal dose to ovarian volume in BLOD increases ovulation and pregnancy rates compared with fixed-dose treatment, but BLOD causes the formation of adhesions, particularly on the left ovary, and increases the risk of damage to ovarian tissue. In contrast, ULOD with a fixed thermal dose minimizes the risk of ovarian tissue damage, and can increase the activity in both right and left ovaries, although this varies in humans and in other species. This prospective, longitudinal, study, between September 2009 and January 2013, included 96 infertile women with PCOS who were unresponsive to clomiphene citrate treatment and had underwent either ULOD or BLOD. After surgery, the groups were followed up for 6 months to assess ovulatory response. Patients were assigned to two groups; one group underwent laparoscopic ovarian drilling of the right ovary alone, while both ovaries were treated in the second group. The ULOD group (n = 49) received thermal doses adjusted to the volume of the right ovary (60 J/cm³). The BLOD group (n = 47) received fixed doses of 600 J per ovary, regardless of its volume. The two treatment groups were matched by the number of participants, age and baseline parameters. The ovulation rate during the first menstrual cycle after LOD was significantly higher in the ULOD group than in the BLOD group [73 versus 49%; absolute risk reduction (ARR), -0.25; 95% confidence interval (CI), -0.44 to -0.03; P = 0.014]. Treatment with ULOD on the right ovary significantly increased the chances of ovulation in patients with a larger right ovary compared with those who had a smaller right ovary (100 versus 36%; ARR, -0.64; 95% CI, -0.84 to -0.37; P = 0.004). Interestingly, the chances of ovulation were also significantly higher in patients in the BLOD group who had a larger right ovary compared with those who had a smaller right ovary (88 versus 33%; ARR, -0.55; 95% CI, -0.73 to -0.28; P = 0.002). The pregnancy rate was also significantly higher in patients with a larger right ovary compared with those with a smaller right ovary, regardless of the treatment group. The 6-month follow-up was too short to demonstrate any long-term differences in the ovulation rates. Future research should therefore extend the follow-up beyond 6 months. Another limitation is that ULOD was used to treat only the right ovary. Future studies should investigate whether ULOD treatment of the larger ovary, whether left or right, would significantly increase the ovulation rate. This study represents an advance in the determination of the optimal laparoscopic treatment for women with PCOS, as it was shown that improved results can be achieved using less thermal energy in volume-adjusted ULOD.

A nested case-control study of leukemia mortality and ionizing radiation at the Portsmouth Naval Shipyard.

PubMed

Kubale, Travis L; Daniels, Robert D; Yiin, James H; Couch, James; Schubauer-Berigan, Mary K; Kinnes, Gregory M; Silver, Sharon R; Nowlin, Susan J; Chen, Pi-Hsueh

2005-12-01

A nested case-control study using conditional logistic regression was conducted to evaluate the exposure-response relationship between external ionizing radiation exposure and leukemia mortality among civilian workers at the Portsmouth Naval Shipyard (PNS), Kittery, Maine. The PNS civilian workers received occupational radiation exposure while performing construction, overhaul, repair and refueling activities on nuclear-powered submarines. The study age-matched 115 leukemia deaths with 460 controls selected from a cohort of 37,853 civilian workers employed at PNS between 1952 and 1992. In addition to radiation doses received in the workplace, a secondary analysis incorporating doses from work-related medical X rays and other occupational radiation exposures was conducted. A significant positive association was found between leukemia mortality and external radiation exposure, adjusting for gender, radiation worker status, and solvent exposure duration (OR = 1.08 at 10 mSv of exposure; 95% CI = 1.01, 1.16). Solvent exposure (including benzene and carbon tetrachloride) was also significantly associated with leukemia mortality adjusting for radiation dose, radiation worker status, and gender. Incorporating doses from work-related medical X rays did not change the estimated leukemia risk per unit of dose.

Impact of total radiotherapy dose on survival for head and neck Merkel cell carcinoma after resection.

PubMed

Patel, Sagar A; Qureshi, Muhammad M; Mak, Kimberley S; Sahni, Debjani; Giacalone, Nicholas J; Ezzat, Waleed; Jalisi, Scharukh; Truong, Minh Tam

2017-07-01

Head and neck Merkel cell carcinoma (MCC) is commonly treated with surgery and adjuvant radiotherapy (RT) for high-risk features. The optimal radiation dose is unknown. One thousand six hundred twenty-five eligible patients with head and neck MCC were identified in the National Cancer Data Base (NCDB). Radiation dose was divided into 3 groups: 30 to <50 Gray (Gy), 50-55 Gy, and >55-70 Gy. Cox regression was used to compare overall survival (OS) between groups, accounting for age, sex, stage, surgery type, margin status, comorbidities, and use of chemotherapy. With a median follow-up of 33.5 months, 3-year OS was 48.9%, 70.3%, and 58.7% for 30 to <50 Gy, 50-55 Gy, and >55-70 Gy, respectively (P < .001). Compared to 50-55 Gy, doses between 30 to <50 Gy (adjusted hazard ratio [HR] 1.53; 95% confidence interval [CI] 1.17-1.99; P = .002) and >55-70 Gy (adjusted HR 1.21; 95% CI 1.0-1.46; P = .06) were associated with worse survival. Adjuvant radiation doses within 50-55 Gy may be optimal for head and neck MCC. © 2017 Wiley Periodicals, Inc.

Seroprevalence of Measles Antibodies and Predictors for Seropositivity among Chinese Children.

PubMed

Wang, Xiaoqin; Ma, Mei; Hui, Zhaozhao; Terry, Paul D; Zhang, Yue; Su, Rui; Wang, Mingxu; Gu, Wei; Li, Ling

2017-06-06

Background : Supplementary measles immunization has been implemented since 2010 throughout China, yet few studies have reported its effect in the northwest regions. Methods: A cross-sectional study was conducted among children aged 2 to 4 years old ( n = 755) from February to September 2014 in 25 towns of Qian County, Shaanxi Province. Blood samples were analyzed for measles antibodies using enzyme-linked immunosorbent immunoglobulin G (IgG) assays. Socio-demographic factors were assessed by questionnaire. Data on vaccine dose were collected from town medical records. Univariate and logistic regression analyses were used to determine factors associated with measles antibody seropositivity. Results : Measles antibody seroprevalence was 91.13% (95% CI: 89.52-92.83) in our sample. Compared with children whose mother's highest education was primary school, seroprevalence was higher in children whose maternal education was middle school (adjusted OR: 1.4, 95% CI: 0.7-2.8), high school (adjusted OR: 2.4, 95% CI: 1.3-7.7), and college/university (adjusted OR: 2.9, 95% CI: 1.2-9.3). Vaccine dose was positively associated with seropositivity. Conclusions : Measles seroprevalence is high in China and is associated with the mother's education and vaccine dose.

Customizing our approach in deep vein thrombosis and pulmonary embolism treatment: overview of our clinical experience.

PubMed

Turpie, A G

1999-08-01

Until recently, the management of established deep vein thrombosis (DVT) and pulmonary embolism remained largely unchanged and unchallenged. Treatment comprised an initial intravenous bolus of unfractionated heparin (UFH), followed by dose-adjusted intravenous UFH for 5-7 days, and oral warfarin for three months. UFH is traditionally administered in hospital, and monitoring and dose adjustment remain essential features of both UFH and warfarin treatment, making therapy both costly and inconvenient. Recent clinical trials have shown that subcutaneous UFH, or low-molecular-weight heparins (LMWHs), administered subcutaneously at a weight-adjusted fixed dose, are at least as effective as standard UFH given intravenously in the treatment of DVT. The feasibility of initial treatment of DVT at home in selected patients, with associated cost-savings and improved convenience have also been demonstrated with LMWHs. Clinical trials are currently investigating the potential value of LMWHs in the treatment of pulmonary embolism and as an alternative to warfarin in secondary prevention of DVT. The role of newer anticoagulants, such as recombinant hirudin, in initial treatment of DVT, and of thrombolysis in the management of pulmonary embolism remain to be defined.

Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass.

PubMed

Barpe, Deise Raquel; Rosa, Daniela Dornelles; Froehlich, Pedro Eduardo

2010-11-20

Although being used for decades in the treatment of several types of cancer, either alone or in association, only a few data about the pharmacokinetics of doxorubicin (DOX) in humans are available. DOX is frequently used in association with other anticancer drugs in the management of breast cancer. Pharmacokinetic data available in the literature show that after i.v. administration DOX follows a two-compartment open model, with a fast distribution phase followed by a very slow elimination phase. The objective of this work is to perform a pilot study in order to verify if the usual dose adjustment based on body surface area (BSA) would be producing the same plasma concentration-time profiles in patients with normal (<25) and above normal (>25) body mass index (BMI). In order to assess the pharmacokinetics of DOX after a short-term i.v. infusion of 60mg/m(2) of BSA, an experimental design using only five plasma samples of each patient was applied. Samples were collected at 0.00, 0.66 (right after the end of infusion), 1.66, 8.66, and 24.66h. DOX pharmacokinetic profiles were evaluated after quantification of DOX using a new HPLC method developed and validated. Pharmacokinetic parameters (AUC(0-24.66) and C(max)) were analyzed by non-compartmental and compartmental approaches. Significant differences (α=0.05) between overweight and normal weight groups were found with respect to AUC and C(max). After adjustment of dose by weight and by BMI, the compartmental model was used to simulate plasma concentrations and new values for C(max) and AUC(0-24.66) were calculated. The new values obtained using both body weight (BW) and BMI were closer to the normal group than those obtained with BSA. According to the simulation, the differences of AUC and C(max) between the overweight group and the group of patients with normal weight were lower when the dose was adjusted by BW and BMI. These results suggest that more studies must be conducted, with more patients, in order to evaluate the best dose adjustment for DOX in women with breast cancer and overweight. Copyright © 2010. Published by Elsevier B.V.

Low-Dose Aspirin Use Does Not Increase Survival in 2 Independent Population-Based Cohorts of Patients With Esophageal or Gastric Cancer.

PubMed

Spence, Andrew D; Busby, John; Johnston, Brian T; Baron, John A; Hughes, Carmel M; Coleman, Helen G; Cardwell, Chris R

2018-03-01

Preclinical studies have shown aspirin to have anticancer properties and epidemiologic studies have associated aspirin use with longer survival times of patients with cancer. We studied 2 large cohorts to determine the association between aspirin use and cancer-specific mortality in patients with esophageal or gastric cancer. We performed a population-based study using cohorts of patients newly diagnosed with esophageal or gastric cancer, identified from cancer registries in England from 1998 through 2012 and the Scottish Cancer Registry from 2009 through 2012. Low-dose aspirin prescriptions were identified from linkages to the United Kingdom Clinical Research Practice Datalink in England and the Prescribing Information System in Scotland. Deaths were identified from linkage to national mortality records, with follow-up until September 2015 in England and January 2015 in Scotland. Time-dependent Cox regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer-specific mortality by low-dose aspirin use after adjusting for potential confounders. Meta-analysis was used to pool results across the 2 cohorts. The combined English and Scottish cohorts contained 4654 patients with esophageal cancer and 3833 patients with gastric cancer, including 3240 and 2392 cancer-specific deaths, respectively. The proportions surviving 1 year, based on cancer-specific mortality, were similar in aspirin users vs non-users after diagnosis with esophageal cancer (48% vs 50% in England and 49% vs 46% in Scotland, respectively) or gastric cancer (58% vs 57% in England and 59% vs 55% in Scotland, respectively). There was no association between postdiagnosis use of low-dose aspirin and cancer-specific mortality among patients with esophageal cancer (pooled adjusted HR, 0.98; 95% CI, 0.89-1.09) or gastric cancer (pooled adjusted HR, 0.96; 95% CI, 0.85-1.08). Long-term aspirin use was not associated with cancer-specific mortality after diagnosis of esophageal cancer (pooled adjusted HR, 1.03; 95% CI, 0.85-1.25) or gastric cancer (pooled adjusted HR, 1.06; 95% CI, 0.85-1.32). In analyses of 2 large independent cohorts in the United Kingdom, low-dose aspirin usage was not associated with increased survival of patients diagnosed with esophageal or gastric cancer. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effectiveness of a drug dosing service provided by community pharmacists in polymedicated elderly patients with renal impairment — a comparative study

PubMed Central

2013-01-01

Background Drug dosing errors are common in renal-impaired patients. Appropriate dosing adjustment and drug selection is important to ensure patients’ safety and to avoid adverse drug effects and poor outcomes. There are few studies on this issue in community pharmacies. The aims of this study were, firstly, to determine the prevalence of dosing inadequacy as a consequence of renal impairment in patients over 65 taking 3 or more drug products who were being attended in community pharmacies and, secondly, to evaluate the effectiveness of the community pharmacist’s intervention in improving dosing inadequacy in these patients when compared with usual care. Methods The study was carried out in 40 Spanish community pharmacies. The study had two phases: the first, with an observational, multicentre, cross sectional design, served to determine the dosing inadequacy, the drug-related problems per patient and to obtain the control group. The second phase, with a controlled study with historical control group, was the intervention phase. When dosing adjustments were needed, the pharmacists made recommendations to the physicians. A comparison was made between the control and the intervention group regarding the prevalence of drug dosing inadequacy and the mean number of drug-related problems per patient. Results The mean of the prevalence of drug dosing inadequacy was 17.5% [95% CI 14.6-21.5] in phase 1 and 15.5% [95% CI 14.5-16.6] in phase 2. The mean number of drug-related problems per patient was 0.7 [95% CI 0.5-0.8] in phase 1 and 0.50 [95% CI 0.4-0.6] in phase 2. The difference in the prevalence of dosing inadequacy between the control and intervention group before the pharmacists’ intervention was 0.73% [95% CI (−6.0) - 7.5] and after the pharmacists’ intervention it was 13.5% [95% CI 8.0 - 19.5] (p < 0.001) while the difference in the mean of drug-related problems per patient before the pharmacists’ intervention was 0.05 [95% CI( -0.2) - 0.3] and following the intervention it was 0.5 [95% CI 0.3 - 0.7] (p < 0.001). Conclusion A drug dosing adjustment service for elderly patients with renal impairment in community pharmacies can increase the proportion of adequate drug dosing, and improve the drug-related problems per patient. Collaborative practice with physicians can improve these results. PMID:23849005

Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident

PubMed Central

Ohira, Tetsuya; Takahashi, Hideto; Yasumura, Seiji; Ohtsuru, Akira; Midorikawa, Sanae; Suzuki, Satoru; Fukushima, Toshihiko; Shimura, Hiroki; Ishikawa, Tetsuo; Sakai, Akira; Yamashita, Shunichi; Tanigawa, Koichi; Ohto, Hitoshi; Abe, Masafumi; Suzuki, Shinichi

2016-01-01

Abstract The 2011 Great East Japan Earthquake led to a subsequent nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In its wake, we sought to examine the association between external radiation dose and thyroid cancer in Fukushima Prefecture. We applied a cross-sectional study design with 300,476 participants aged 18 years and younger who underwent thyroid examinations between October 2011 and June 2015. Areas within Fukushima Prefecture were divided into three groups based on individual external doses (≥1% of 5 mSv, <99% of 1 mSv/y, and the other). The odds ratios (ORs) and 95% confidence intervals of thyroid cancer for all areas, with the lowest dose area as reference, were calculated using logistic regression models adjusted for age and sex. Furthermore, the ORs of thyroid cancer for individual external doses of 1 mSv or more and 2 mSv or more, with the external dose less than 1 mSv as reference, were calculated. Prevalence of thyroid cancer for the location groups were 48/100,000 for the highest dose area, 36/100,000 for the middle dose area, and 41/100,000 for the lowest dose area. Compared with the lowest dose area, age-, and sex-adjusted ORs (95% confidence intervals) for the highest-dose and middle-dose areas were 1.49 (0.36–6.23) and 1.00 (0.67–1.50), respectively. The duration between accident and thyroid examination was not associated with thyroid cancer prevalence. There were no significant associations between individual external doses and prevalence of thyroid cancer. External radiation dose was not associated with thyroid cancer prevalence among Fukushima children within the first 4 years after the nuclear accident. PMID:27583855

Comparison of childhood thyroid cancer prevalence among 3 areas based on external radiation dose after the Fukushima Daiichi nuclear power plant accident: The Fukushima health management survey.

PubMed

Ohira, Tetsuya; Takahashi, Hideto; Yasumura, Seiji; Ohtsuru, Akira; Midorikawa, Sanae; Suzuki, Satoru; Fukushima, Toshihiko; Shimura, Hiroki; Ishikawa, Tetsuo; Sakai, Akira; Yamashita, Shunichi; Tanigawa, Koichi; Ohto, Hitoshi; Abe, Masafumi; Suzuki, Shinichi

2016-08-01

The 2011 Great East Japan Earthquake led to a subsequent nuclear accident at the Fukushima Daiichi Nuclear Power Plant. In its wake, we sought to examine the association between external radiation dose and thyroid cancer in Fukushima Prefecture. We applied a cross-sectional study design with 300,476 participants aged 18 years and younger who underwent thyroid examinations between October 2011 and June 2015. Areas within Fukushima Prefecture were divided into three groups based on individual external doses (≥1% of 5 mSv, <99% of 1 mSv/y, and the other). The odds ratios (ORs) and 95% confidence intervals of thyroid cancer for all areas, with the lowest dose area as reference, were calculated using logistic regression models adjusted for age and sex. Furthermore, the ORs of thyroid cancer for individual external doses of 1 mSv or more and 2 mSv or more, with the external dose less than 1 mSv as reference, were calculated. Prevalence of thyroid cancer for the location groups were 48/100,000 for the highest dose area, 36/100,000 for the middle dose area, and 41/100,000 for the lowest dose area. Compared with the lowest dose area, age-, and sex-adjusted ORs (95% confidence intervals) for the highest-dose and middle-dose areas were 1.49 (0.36-6.23) and 1.00 (0.67-1.50), respectively. The duration between accident and thyroid examination was not associated with thyroid cancer prevalence. There were no significant associations between individual external doses and prevalence of thyroid cancer. External radiation dose was not associated with thyroid cancer prevalence among Fukushima children within the first 4 years after the nuclear accident.

Development of a risk-adjustment model for antimicrobial utilization data in 21 public hospitals in Queensland, Australia (2006-11).

PubMed

Rajmokan, M; Morton, A; Marquess, J; Playford, E G; Jones, M

2013-10-01

Making valid comparisons of antimicrobial utilization between hospitals requires risk adjustment for each hospital's case mix. Data on individual patients may be unavailable or difficult to process. Therefore, risk adjustment for antimicrobial usage frequently needs to be based on a hospital's services. This study evaluated such a strategy for hospital antimicrobial utilization. Data were obtained on five broad subclasses of antibiotics [carbapenems, β-lactam/β-lactamase inhibitor combinations (BLBLIs), fluoroquinolones, glycopeptides and third-generation cephalosporins] from the Queensland pharmacy database (MedTrx) for 21 acute public hospitals (2006-11). Eleven clinical services and a variable for hospitals from the tropical region were employed for risk adjustment. Multivariable regression models were used to identify risk and protective services for these antibiotics. Funnel plots were used to display hospitals' antimicrobial utilization. Total inpatient antibiotic utilization for these antibiotics increased from 130.6 defined daily doses (DDDs)/1000 patient-days in 2006 to 155.8 DDDs/1000 patient-days in 2011 (P < 0.0001). Except for third-generation cephalosporins, the average utilization rate was higher for intensive care, renal/nephrology, cardiac, burns/plastic surgery, neurosurgery, transplant and acute spinal services than for the respective reference group (no service). In addition, oncology, high-activity infectious disease and coronary care services were associated with higher utilization of carbapenems, BLBLIs and glycopeptides. Our model predicted antimicrobial utilization rates by hospital services. The funnel plots displayed hospital utilization data after adjustment for variation among the hospitals. However, the methodology needs to be validated in other populations, ideally using a larger group of hospitals.

A mini-review of non-parenteral clonidine preparations for paediatric sedation.

PubMed

Hanning, Sara M; Orlu Gul, Mine; Toni, Irmgard; Neubert, Antje; Tuleu, Catherine

2017-04-01

To provide an overview of non-parenteral clonidine formulations and assess the feasibility of their use for paediatric sedation. A literature search was conducted using electronic databases and a combination of search terms. Forty articles met the inclusion criteria. Publications were grouped into different dosage forms and assessed for their potential application for sedation of children in intensive care. Several routes of clonidine administration have been investigated for numerous indications in children, including perioperative sedation and analgesia. These include oral liquids, tablets, oral transmucosal systems, nasal sprays and rectal suspensions. Conflicting studies on oral transmucosal clonidine formulations suggest that further research is required to fully establish efficacy. Nasal sprays and rectal suspensions have the advantages of rapid onset of action and potential for dose flexibility, but predictable absorption is difficult to obtain. Provided age-appropriate strengths are available, intravenous formulations remain the most predictable in terms of bioavailability and flexible in terms of dose adjustment. However, as with all routes, down-titration is difficult given the long half-life of clonidine. Oral transmucosal systems, nasal sprays and rectal suspensions have potential in a less acute setting, but significant clinical work is required to elucidate a full pharmacokinetic and pharmacodynamic profile. © 2016 Royal Pharmaceutical Society.

High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort

PubMed Central

Clarke, Alan T.; Johnson, Paul C. D.; Hall, Gillian C.; Ford, Ian; Mills, Peter R.

2016-01-01

Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID:26983033

Successful salvage treatment of native valve Enterococcus faecalis infective endocarditis with telavancin: two case reports.

PubMed

Thompson, Mickala M; Hassoun, Ali

2017-07-01

Infective endocarditis (IE) one-year mortality rates approach 40%. Here, we report two native valve Enterococcus faecalis IE cases in patients successfully treated with telavancin. An 88-year-old with mitral valve endocarditis and a penicillin allergy, initially treated with intravenous vancomycin, was switched to telavancin. A 69-year-old, who previously received amoxicillin and intravenous vancomycin for presumed enterococcal bacteraemia, was diagnosed with dual valve endocarditis for which he received telavancin. Both received six weeks of telavancin. Neither had telavancin-related adverse events, evidence of infection at six months, nor required telavancin dosing adjustments. Documented use of novel treatments for serious enterococcal infections is needed.

Is Exercise Really Medicine? An Evolutionary Perspective.

PubMed

Lieberman, Daniel E

2015-01-01

An evolutionary perspective helps evaluate the extent to which exercise is medicine and to explain the exercise paradox: why people tend to avoid exercise despite its benefits. Many lines of evidence indicate that humans evolved to be adapted for regular, moderate amounts of endurance physical activity into late age. However, because energy from food was limited, humans also were selected to avoid unnecessary exertion, and most anatomical and physiological systems evolved to require stimuli from physical activity to adjust capacity to demand. Consequently, selection never operated to cope with the long-term effects of chronic inactivity. However, because all adaptations involve trade-offs, there is no evolutionary-determined dose or type of physical activity that will optimize health. Furthermore, because humans evolved to be active for play or necessity, efforts to promote exercise will require altering environments in ways that nudge or even compel people to be active and to make exercise fun.

Sensitivity of predicted bioaerosol exposure from open windrow composting facilities to ADMS dispersion model parameters.

PubMed

Douglas, P; Tyrrel, S F; Kinnersley, R P; Whelan, M; Longhurst, P J; Walsh, K; Pollard, S J T; Drew, G H

2016-12-15

Bioaerosols are released in elevated quantities from composting facilities and are associated with negative health effects, although dose-response relationships are not well understood, and require improved exposure classification. Dispersion modelling has great potential to improve exposure classification, but has not yet been extensively used or validated in this context. We present a sensitivity analysis of the ADMS dispersion model specific to input parameter ranges relevant to bioaerosol emissions from open windrow composting. This analysis provides an aid for model calibration by prioritising parameter adjustment and targeting independent parameter estimation. Results showed that predicted exposure was most sensitive to the wet and dry deposition modules and the majority of parameters relating to emission source characteristics, including pollutant emission velocity, source geometry and source height. This research improves understanding of the accuracy of model input data required to provide more reliable exposure predictions. Copyright © 2016. Published by Elsevier Ltd.

Risk factors for symptomatic hypocalcaemia complicating treatment with zoledronic acid.

PubMed

Chennuru, S; Koduri, J; Baumann, M A

2008-08-01

The bisphosphonate zoledronic acid is commonly prescribed to prevent skeletal complications in patients with multiple myeloma or metastatic cancer. Although symptomatic hypocalcaemia is a potential risk of treatment, it has been thought to be uncommon. After seeing several episodes of symptomatic hypocalcaemia following zoledronic acid administration, we undertook a review to determine the incidence of this complication in our population and to attempt to identify risk factors. We reviewed the records of all patients receiving zoledronic acid in two teaching hospitals over a 2-year period. Findings collected included the indication for treatment, whether dosing was adjusted for creatinine clearance, coadministered medications, serum chemistries and clinical course. Of 120 patients who received a total of 546 zoledronic acid infusions, hypocalcaemia developed related to 55 infusions (10%) in 42 patients (35%). Symptomatic hypocalcaemia requiring i.v. supplementation occurred in 10 patients (8%), in spite of appropriate dose adjustment for creatinine clearance and despite prophylactic administration of oral calcium and vitamin D. More patients who became hypocalcaemic developed impairment of creatinine clearance during zoledronic acid treatment than in the group that remained normocalcaemic. Hypomagnesaemia was found in all patients who developed hypocalcaemia who had serum magnesium measured. Hypocalcaemia was common in our patient group following zoledronic acid treatment. Because of the prolonged elimination half-life of this agent (146 h), renal impairment occurring during a number of days after administration may increase risk. Hypomagnesaemia may further increase risk by blunting compensatory increase in parathyroid hormone secretion.

Documenting pharmacist interventions on an intranet.

PubMed

Simonian, Armen I

2003-01-15

The process of developing and implementing an intranet Web site for clinical intervention documentation is described. An inpatient pharmacy department initiated an organizationwide effort to improve documentation of interventions by pharmacists at its seven hospitals to achieve real-time capture of meaningful benchmarking data. Standardization of intervention types would allow the health system to contrast and compare medication use, process improvement, and patient care initiatives among its hospitals. After completing a needs assessment and reviewing current methodologies, a computerized tracking tool was developed in-house and integrated with the organization's intranet. Representatives from all hospitals agreed on content and functionality requirements for the Web site. The site was completed and activated in February 2002. Before this Web site was established, the most documented intervention types were Renal Adjustment and Clarify Dose, with a daily average of four and three, respectively. After site activation, daily averages for Renal Adjustment remained unchanged, but Clarify Dose is now documented nine times per day. Drug Information and i.v.-to-p.o. intervention types, which previously averaged less than one intervention per day, are now documented an average of four times daily. Approximately 91% of staff pharmacists are using this site. Future plans for this site include enhanced accessibility to the site with wireless personal digital assistants. The design and implementation of an intranet Web site to document pharmacists' interventions doubled the rate of intervention documentation and standardized the intervention types among hospitals in the health system.

Association of Proton Pump Inhibitors Usage with Risk of Pneumonia in Dementia Patients.

PubMed

Ho, Sai-Wai; Teng, Ying-Hock; Yang, Shun-Fa; Yeh, Han-Wei; Wang, Yu-Hsun; Chou, Ming-Chih; Yeh, Chao-Bin

2017-07-01

To determine the association between usages of proton pump inhibitors (PPIs) and subsequent risk of pneumonia in dementia patients. Retrospective cohort study. Taiwanese National Health Insurance Research Database. The study cohort consisted of 786 dementia patients with new PPI usage and 786 matched dementia patients without PPI usage. The study endpoint was defined as the occurrence of pneumonia. The Cox proportional hazard model was used to estimate the pneumonia risk. Defined daily dose methodology was applied to evaluate the cumulative and dose-response relationships of PPI. Incidence of pneumonia was higher among patients with PPI usage (adjusted hazard ratio (HR) = 1.89; 95% CI = 1.51-2.37). Cox model analysis also demonstrated that age (adjusted HR = 1.05; 95% CI = 1.03-1.06), male gender (adjusted HR = 1.57; 95% CI = 1.25-1.98), underlying cerebrovascular disease (adjusted HR = 1.30; 95% CI = 1.04-1.62), chronic pulmonary disease (adjusted HR = 1.39; 95% CI = 1.09-1.76), congestive heart failure (adjusted HR = 1.54; 95% CI = 1.11-2.13), diabetes mellitus (adjusted HR = 1.54; 95% CI = 1.22-1.95), and usage of antipsychotics (adjusted HR = 1.29; 95% CI = 1.03-1.61) were independent risk factors for pneumonia. However, usage of cholinesterase inhibitors and histamine receptor-2 antagonists were shown to decrease pneumonia risk. PPI usage in dementia patients is associated with an 89% increased risk of pneumonia. © 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.

Individualized adjustments to reference phantom internal organ dosimetry—scaling factors given knowledge of patient internal anatomy

NASA Astrophysics Data System (ADS)

Wayson, Michael B.; Bolch, Wesley E.

2018-04-01

Various computational tools are currently available that facilitate patient organ dosimetry in diagnostic nuclear medicine, yet they are typically restricted to reporting organ doses to ICRP-defined reference phantoms. The present study, while remaining computational phantom based, provides straightforward tools to adjust reference phantom organ dose for both internal photon and electron sources. A wide variety of monoenergetic specific absorbed fractions were computed using radiation transport simulations for tissue spheres of varying size and separation distance. Scaling methods were then constructed for both photon and electron self-dose and cross-dose, with data validation provided from patient-specific voxel phantom simulations, as well as via comparison to the scaling methodology given in MIRD Pamphlet No. 11. Photon and electron self-dose was found to be dependent on both radiation energy and sphere size. Photon cross-dose was found to be mostly independent of sphere size. Electron cross-dose was found to be dependent on sphere size when the spheres were in close proximity, owing to differences in electron range. The validation studies showed that this dataset was more effective than the MIRD 11 method at predicting patient-specific photon doses for at both high and low energies, but gave similar results at photon energies between 100 keV and 1 MeV. The MIRD 11 method for electron self-dose scaling was accurate for lower energies but began to break down at higher energies. The photon cross-dose scaling methodology developed in this study showed gains in accuracy of up to 9% for actual patient studies, and the electron cross-dose scaling methodology showed gains in accuracy up to 9% as well when only the bremsstrahlung component of the cross-dose was scaled. These dose scaling methods are readily available for incorporation into internal dosimetry software for diagnostic phantom-based organ dosimetry.

Individualized adjustments to reference phantom internal organ dosimetry-scaling factors given knowledge of patient internal anatomy.

PubMed

Wayson, Michael B; Bolch, Wesley E

2018-04-13

Various computational tools are currently available that facilitate patient organ dosimetry in diagnostic nuclear medicine, yet they are typically restricted to reporting organ doses to ICRP-defined reference phantoms. The present study, while remaining computational phantom based, provides straightforward tools to adjust reference phantom organ dose for both internal photon and electron sources. A wide variety of monoenergetic specific absorbed fractions were computed using radiation transport simulations for tissue spheres of varying size and separation distance. Scaling methods were then constructed for both photon and electron self-dose and cross-dose, with data validation provided from patient-specific voxel phantom simulations, as well as via comparison to the scaling methodology given in MIRD Pamphlet No. 11. Photon and electron self-dose was found to be dependent on both radiation energy and sphere size. Photon cross-dose was found to be mostly independent of sphere size. Electron cross-dose was found to be dependent on sphere size when the spheres were in close proximity, owing to differences in electron range. The validation studies showed that this dataset was more effective than the MIRD 11 method at predicting patient-specific photon doses for at both high and low energies, but gave similar results at photon energies between 100 keV and 1 MeV. The MIRD 11 method for electron self-dose scaling was accurate for lower energies but began to break down at higher energies. The photon cross-dose scaling methodology developed in this study showed gains in accuracy of up to 9% for actual patient studies, and the electron cross-dose scaling methodology showed gains in accuracy up to 9% as well when only the bremsstrahlung component of the cross-dose was scaled. These dose scaling methods are readily available for incorporation into internal dosimetry software for diagnostic phantom-based organ dosimetry.

45 CFR 153.740 - Failure to comply with HHS-operated risk adjustment and reinsurance data requirements.

Code of Federal Regulations, 2014 CFR

2014-10-01

... adjustment data submission and data storage requirements set forth in §§ 153.610 through 153.630, HHS may... adjustment and reinsurance data requirements. 153.740 Section 153.740 Public Welfare Department of Health and... CORRIDORS, AND RISK ADJUSTMENT UNDER THE AFFORDABLE CARE ACT Distributed Data Collection for HHS-Operated...

Principles and frequency of self-adjustment of insulin dose in people with diabetes mellitus type 1 and correlation with markers of metabolic control.

PubMed

Kramer, Guido; Kuniss, Nadine; Kloos, Christof; Lehmann, Thomas; Müller, Nicolle; Wolf, Gunter; Lorkowski, Stefan; Müller, Ulrich A

2016-06-01

Insulin dose self-adjustment (ISA) to different blood glucose levels, carbohydrate intake, exercise or illness is a core element of structured education programmes for people with diabetes mellitus type 1 (DM1). The aim of this study was to register the patients' current principles and frequency of ISA and to check the ability for correct adjustments. 117 people with DM1 (mean HbA1c 7.1%, diabetes duration 24y) were interviewed in a tertiary care centre. The number of ISA was drawn from the last 28days of the patients' diary. The ability to find the correct insulin dose was assessed using five different calculation examples. All patients had participated in a structured education programme. Mean frequency of ISA was 72.1±29.4 per 28days. ISA by adjustment rules was used in 48% (56/117) and by personal experience or feeling in 44% (52/117). Patients adjusting by feeling were older, did less ISA and had lower social status. There were no differences in HbA1c (feeling 7.2±0.8 vs. rules 7.0±0.9, p=0.403), non severe hypoglycaemia (feeling 1.7±1.8 vs. rules 1.9±1.9, p=0.132) and comprehensibility of ISA between both groups. Overall, the participants answered on average 2.8±2.3 of the five calculation examples correctly. Although all people were trained to use a factor for correction for ISA in case of high premeal blood glucose levels, only half of the patients adjusted their insulin dosage using the complex rules from the treatment and education programme. Patients, who performed their ISA based upon feeling, did not show worse metabolic control. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose-response model

EPA Science Inventory

A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (BPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the HPT axis. Model calibrations, carried out by adjusting key model p...

Evaluation of iodide deficiency in the lactating rat and pup using a biologically based dose response (BBDR) Model***

EPA Science Inventory

A biologically-based dose response (BBDR) model for the hypothalamic-pituitary thyroid (HPT) axis in the lactating rat and nursing pup was developed to describe the perturbations caused by iodide deficiency on the 1-IPT axis. Model calibrations, carried out by adjusting key model...

Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: Results of an indirect comparison meta-analysis of RCTs.

PubMed

Brigo, Francesco; Bragazzi, Nicola Luigi; Nardone, Raffaele; Trinka, Eugen

2016-11-01

Brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) have been recently marketed as adjunctive treatments for focal onset seizures. To date, no randomized controlled trial (RCT) has directly compared BRV with ESL, LCM, or PER. To compare BRV with the other add-on AEDs in patients with uncontrolled focal epilepsy, estimating their efficacy and tolerability through an adjusted, common-reference based indirect comparison meta-analysis. We systematically searched RCTs in which add-on treatment with ESL or LCM in patients with focal onset seizures have been compared with placebo. Efficacy and tolerability outcomes were considered. Random-effects Mantel-Haenszel meta-analyses were performed to obtain odds ratios (ORs) for the efficacy of BRV, LCM, ESL, or PER versus placebo. Adjusted indirect comparisons were then made between BRV and the other three AEDs using the obtained results, comparing the minimum and the highest effective recommended daily dose of each drug. Seventeen RCTs, with a total of 4971 patients were included. After adjusting for dose-effects, indirect comparisons showed no difference between BRV and LCM, ESL, or PER for responder rate and seizure freedom. Lower adverse events were observed with high dose BRV compared to high dose ESL or PER, but no difference was found in withdrawing because of adverse events. Indirect comparisons do not demonstrate a significant difference in efficacy between add-on BRV and LCM, ESL, or PER in focal epilepsy, and might suggest a better tolerability of BRV than ESL, and possibly also PER, at the highest effective recommended dose. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Gender-Specific Differences in Low-Dose Haloperidol Response for Prevention of Postoperative Nausea and Vomiting: A Register-Based Cohort Study.

PubMed

Brettner, Florian; Janitza, Silke; Prüll, Kathrin; Weninger, Ernst; Mansmann, Ulrich; Küchenhoff, Helmut; Jovanovic, Alexander; Pollwein, Bernhard; Chappell, Daniel; Zwissler, Bernhard; von Dossow, Vera

2016-01-01

Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU). Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital. Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: [0.56, 0.99], p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: [0.28, 0.73], p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: [0.71, 1.46], p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis. This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine.

Gender-Specific Differences in Low-Dose Haloperidol Response for Prevention of Postoperative Nausea and Vomiting: A Register-Based Cohort Study

PubMed Central

Prüll, Kathrin; Weninger, Ernst; Mansmann, Ulrich; Küchenhoff, Helmut; Jovanovic, Alexander; Pollwein, Bernhard; Chappell, Daniel; Zwissler, Bernhard; von Dossow, Vera

2016-01-01

Background Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU). Methods Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital. Results Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: [0.56, 0.99], p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: [0.28, 0.73], p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: [0.71, 1.46], p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis. Conclusion This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine. PMID:26751066

Six-month, open-label study of hydrocodone extended release formulated with abuse-deterrence technology: Safety, maintenance of analgesia, and abuse potential.

PubMed

Hale, Martin E; Ma, Yuju; Malamut, Richard

2016-01-01

To evaluate long-term safety, maintenance of analgesia, and aberrant drug-related behaviors of hydrocodone extended release (ER) formulated with CIMA® Abuse-Deterrence Technology. Phase 3, multicenter, open-label extension. Fifty-six US centers. Adults with chronic low back pain completing a 12-week placebocontrolled study of abuse-deterrent hydrocodone ER were eligible. One hundred eighty-two patients enrolled and received ≥1 dose of study drug, 170 entered openlabel treatment, and 136 completed the study. Patients receiving hydrocodone ER in the 12-week, placebo-controlled study continued their previous dose unless adjustment was needed; those previously receiving placebo (n=78) underwent dose titration/adjustment to an analgesic dose (15-90 mg every 12 hours). Patients received 22 weeks of open-label treatment. adverse events (AEs). Maintenance of analgesia: worst pain intensity (WPI) and average pain intensity (API) at each study visit. Aberrant drug behavior: study drug loss and diversion. AEs were reported for 65/182 (36 percent) patients during dose titration/ adjustment and 88/170 (52 percent) during open-label treatment. No treatmentrelated serious AEs were reported. There were no clinically meaningful trends in other safety assessments, including physical examinations and pure tone audiometry. One patient receiving hydrocodone ER 30 mg twice daily experienced a severe AE of neurosensory deafness that was considered treatment related. Mean WPI and API remained steady throughout open-label treatment. Six (3 percent) patients reported medication loss, and 5 (3 percent) reported diversion. Abuse-deterrent hydrocodone ER was generally well tolerated in patients with chronic low back pain, maintained efficacy, and was associated with low rates of loss and diversion.

Clinical and Pharmacogenetic Predictors of Circulating Atorvastatin and Rosuvastatin Concentration in Routine Clinical Care

PubMed Central

DeGorter, Marianne K.; Tirona, Rommel G.; Schwarz, Ute I.; Choi, Yun-Hee; Dresser, George K.; Suskin, Neville; Myers, Kathryn; Zou, GuangYong; Iwuchukwu, Otito; Wei, Wei-Qi; Wilke, Russell A.; Hegele, Robert A.; Kim, Richard B.

2014-01-01

Background A barrier to statin therapy is myopathy associated with elevated systemic drug exposure. Our objective was to examine the association between clinical and pharmacogenetic variables and statin concentrations in patients. Methods and Results In total, 299 patients taking atorvastatin or rosuvastatin were prospectively recruited at an outpatient referral center. The contribution of clinical variables and transporter gene polymorphisms to statin concentration was assessed using multiple linear regression. We observed 45-fold variation in statin concentration among patients taking the same dose. After adjustment for gender, age, body mass index, ethnicity, dose, and time from last dose, SLCO1B1 c.521T>C (p < 0.001) and ABCG2 c.421C>A (p < 0.01) were important to rosuvastatin concentration (adjusted R2 = 0.56 for the final model). Atorvastatin concentration was associated with SLCO1B1 c.388A>G (p < 0.01) and c.521T>C (p < 0.05), and 4β-hydroxycholesterol, a CYP3A activity marker (adjusted R2 = 0.47). A second cohort of 579 patients from primary and specialty care databases were retrospectively genotyped. In this cohort, genotypes associated with statin concentration were not differently distributed among dosing groups, implying providers had not yet optimized each patient's risk-benefit ratio. Nearly 50% of patients in routine practice taking the highest doses were predicted to have statin concentrations greater than the 90th percentile. Conclusions Interindividual variability in statin exposure in patients is associated with uptake and efflux transporter polymorphisms. An algorithm incorporating genomic and clinical variables to avoid high atorvastatin and rosuvastatin levels is described; further study will determine if this approach reduces incidence of statin-myopathy. PMID:23876492

Baseline AMH Level Associated With Ovulation Following Ovulation Induction in Women With Polycystic Ovary Syndrome.

PubMed

Mumford, Sunni L; Legro, Richard S; Diamond, Michael P; Coutifaris, Christos; Steiner, Anne Z; Schlaff, William D; Alvero, Ruben; Christman, Gregory M; Casson, Peter R; Huang, Hao; Santoro, Nanette; Eisenberg, Esther; Zhang, Heping; Cedars, Marcelle I

2016-09-01

Anti-Müllerian hormone (AMH) reduces aromatase activity and sensitivity of follicles to FSH stimulation. Therefore, elevated serum AMH may indicate a higher threshold for response to ovulation induction in women with polycystic ovary syndrome (PCOS). This study sought to determine the association between AMH levels and ovulatory response to treatment among the women enrolled into the Pregnancy in PCOS II (PPCOS II) trial. This was a secondary analysis of data from a randomized clinical trial in academic health centers throughout the United States Participants: A total of 748 women age 18-40 years, with PCOS and measured AMH levels at baseline, were included in this study. Couples were followed for up to five treatment cycles to determine ovulation (midluteal serum progesterone > 5 ng/mL) and the dose required to achieve ovulation. A lower mean AMH and AMH per follicle was observed among women who ovulated compared with women who never achieved ovulation during the study (geometric mean AMH, 5.54 vs 7.35 ng/mL; P = .0001; geometric mean AMH per follicle, 0.14 vs 0.18; P = .01) after adjustment for age, body mass index, T, and insulin level. As AMH levels increased, the dose of ovulation induction medication needed to achieve ovulation also increased. No associations were observed between antral follicle count and ovulation. These results suggest that high serum AMH is associated with a reduced response to ovulation induction among women with PCOS. Women with higher AMH levels may require higher doses of medication to achieve ovulation.

A Patient-level Analysis of Efficacy and Hypoglycaemia Outcomes Across Treat-to-target Trials with Insulin Glargine Added to Oral Antidiabetes Agents in People with Type 2 Diabetes

PubMed Central

DeVries, J Hans; Meneghini, Luigi; Barnett, Anthony H; Reid, Timothy; Dain, Marie-Paule; Vlajnic, Aleksandra; Traylor, Louise; Bergenstal, Richard M

2014-01-01

Abstract Background: A better understanding of hypoglycaemia risk when insulin is used in combination with one or more oral antidiabetes agents may assist in the treatment decision-making process for the clinician and address concerns regarding hypoglycaemia when initiating or intensifying insulin therapy. The objective of this study was to analyse efficacy and hypoglycaemia outcomes in people with type 2 diabetes receiving insulin glargine (IG) with metformin (MET), sulphonylurea (SU) or MET+SU. Methods: Patient-level data were pooled from 15 randomised, treat-to-target trials (fasting plasma glucose [FPG] targets <5.6 mmol/l) with a duration >24 weeks. Efficacy outcomes included glycated haemoglobin (HbA1c), FPG and HbA1c target achievement. Overall hypoglycaemia events were assessed by a confirmed PG value of <3.9, <3.1 and <2.8 mmol/l or assistance required; daytime, nocturnal (00:01-05:59 AM); and severe (assistance required or with confirmed PG <2.0 mmol/l). Results: Overall, 2,837 IG patients were analysed, with either MET (634), SU (906) or MET+SU (1,297) as background oral antidiabetes agents. Endpoint HbA1c in IG+MET and IG+MET+SU-treated patients was significantly lower than in IG+SU-treated patients (adjusted difference -0.32 %; p=0.0001 and -0.33 %; p=0.0002, respectively). Fewer patients achieved endpoint HbA1c <7.0 % with IG+SU (32 %) versus IG+MET (57 %) or IG+MET+SU (49 %). IG+SU and IG+MET+SU led to significant increases in overall, daytime and nocturnal hypoglycaemia versus IG+MET; severe hypoglycaemia was rare. Weight gain was lowest in IG+MET patients (adjusted difference -1.51 kg versus IG+SU; p<0.0001; -0.78 kg versus IG+MET+SU; p=0.0037) despite higher insulin doses (0.51 U/kg versus 0.43 and 0.42 U/kg, respectively). Conclusions: Better glycaemic goal achievement and reduced risk of hypoglycaemia and weight gain were observed with IG+MET versus IG+SU and IG+MET+SU, albeit with an increased insulin dose requirement. PMID:29872460

Development and testing in healthy adults of oral hydrocortisone granules with taste masking for the treatment of neonates and infants with adrenal insufficiency.

PubMed

Whitaker, Martin J; Spielmann, Sarah; Digweed, Dena; Huatan, Hiep; Eckland, David; Johnson, Trevor N; Tucker, Geoffrey; Krude, Heiko; Blankenstein, Oliver; Ross, Richard J

2015-04-01

Treatment of neonates and infants with adrenal insufficiency is unsatisfactory because unlicensed hydrocortisone formulations are used. The objectives were to survey current hydrocortisone prescribing practice and develop a novel hydrocortisone formulation, Infacort. The use of hydrocortisone by European pediatric endocrinologists was surveyed. Based on this, an oral hydrocortisone granule formulation, Infacort, with taste masking was developed and evaluated in vitro and then in vivo in a phase I pharmacokinetic study. The survey showed that pediatricians use a variety of unlicensed compounded adult medications at doses of between 0.5 and 5 mg. Infacort was formulated with a taste-masking layer stable for at least 5 minutes in aqueous media and was produced in unit doses of 0.5, 1, 2, and 5 mg. Infacort 10 mg is the bioequivalent of a 10-mg hydrocortisone tablet (mean area under the curve from zero to infinity [AUC(0-inf)] ratio, 101%; 90% confidence interval, 96-107%). Mean cortisol maximum concentration (C(max)) and AUC(0-inf) values after administration of Infacort were linear with dose and dose proportional when adjusted for saturable plasma protein binding. Subjects rated Infacort as "not good or bad" for smell (86%), feel in the mouth (71%), and taste (79%). No serious adverse events were reported. This phase 1 study demonstrates that Infacort is safe, well tolerated, of neutral taste, bioequivalent to hydrocortisone licensed for adults, and shows dose proportionality with respect to cortisol exposure. Infacort is expected to facilitate optimization of hydrocortisone dosing in neonates and children with adrenal insufficiency; however, clinical studies will be required to demonstrate efficacy in this patient age group.

Carbohydrate-to-insulin ratio is estimated from 300-400 divided by total daily insulin dose in type 1 diabetes patients who use the insulin pump.

PubMed

Kuroda, Akio; Yasuda, Tetsuyuki; Takahara, Mitsuyoshi; Sakamoto, Fumie; Kasami, Ryuichi; Miyashita, Kazuyuki; Yoshida, Sumiko; Kondo, Eri; Aihara, Ken-ichi; Endo, Itsuro; Matsuoka, Taka-aki; Kaneto, Hideaki; Matsumoto, Toshio; Shimomura, Iichiro; Matsuhisa, Munehide

2012-11-01

To optimize insulin dose using insulin pump, basal and bolus insulin doses are widely calculated from total daily insulin dose (TDD). It is recommended that total daily basal insulin dose (TBD) is 50% of TDD and that the carbohydrate-to-insulin ratio (CIR) equals 500 divided by TDD. We recently reported that basal insulin requirement is approximately 30% of TDD. We therefore investigated CIR after adjustment of the proper basal insulin rate. Forty-five Japanese patients with type 1 diabetes were investigated during several weeks of hospitalization. The patients were served standard diabetes meals (25-30 kcal/kg of ideal body weight). Each meal omission was done to confirm basal insulin rate. Target blood glucose level was set at 100 and 150 mg/dL before and 2 h after each meal, respectively. After the basal insulin rate was fixed and target blood glucose levels were achieved, TBD, CIR, TDD, and their products were determined. Mean (±SD) blood glucose levels before and 2 h after meals were 121±47 and 150±61 mg/dL, respectively. TDD was 31.5±9.0 U, and TBD was 27.0±6.5% of TDD. CIR×TDD of breakfast was significantly lower than those of lunch and supper (288±73 vs. 408±92 and 387±83, respectively; P<0.01). CIR has diurnal variance and is estimated from the formula CIR=300/TDD at breakfast or CIR=400/TDD at lunch and supper in type 1 diabetes patients. These results indicate that the insulin dose has been underestimated by using previously established calculations.

Quantitative dose-response assessment of inhalation exposures to toxic air pollutants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jarabek, A.M.; Foureman, G.L.; Gift, J.S.

1997-12-31

Implementation of the 1990 Clean Air Act Amendments, including evaluation of residual risks. requires accurate human health risk estimates of both acute and chronic inhalation exposures to toxic air pollutants. The U.S. Environmental Protection Agency`s National Center for Environmental Assessment, Research Triangle Park, NC, has a research program that addresses several key issues for development of improved quantitative approaches for dose-response assessment. This paper describes three projects underway in the program. Project A describes a Bayesian approach that was developed to base dose-response estimates on combined data sets and that expresses these estimates as probability density functions. A categorical regressionmore » model has been developed that allows for the combination of all available acute data, with toxicity expressed as severity categories (e.g., mild, moderate, severe), and with both duration and concentration as governing factors. Project C encompasses two refinements to uncertainty factors (UFs) often applied to extrapolate dose-response estimates from laboratory animal data to human equivalent concentrations. Traditional UFs have been based on analyses of oral administration and may not be appropriate for extrapolation of inhalation exposures. Refinement of the UF applied to account for the use of subchronic rather than chronic data was based on an analysis of data from inhalation exposures (Project C-1). Mathematical modeling using the BMD approach was used to calculate the dose-response estimates for comparison between the subchronic and chronic data so that the estimates were not subject to dose-spacing or sample size variability. The second UF that was refined for extrapolation of inhalation data was the adjustment for the use of a LOAEL rather than a NOAEL (Project C-2).« less

Awareness and knowledge among internal medicine house-staff for dose adjustment of commonly used medications in patients with CKD.

PubMed

Surana, Sikander; Kumar, Neeru; Vasudeva, Amita; Shaikh, Gulvahid; Jhaveri, Kenar D; Shah, Hitesh; Malieckal, Deepa; Fogel, Joshua; Sidhu, Gurwinder; Rubinstein, Sofia

2017-01-17

Drug dosing errors result in adverse patient outcomes and are more common in patients with chronic kidney disease (CKD). As internists treat the majority of patients with CKD, we study if Internal Medicine house-staff have awareness and knowledge about the correct dosage of commonly used medications for those with CKD. A cross-sectional survey was performed and included 341 participants. The outcomes were the awareness of whether a medication needs dose adjustment in patients with CKD and whether there was knowledge for the level of glomerular filtration rate (GFR) a medication needs to be adjusted. The overall pattern for all post-graduate year (PGY) groups in all medication classes was a lack of awareness and knowledge. For awareness, there were statistically significant increased mean differences for PGY2 and PGY3 as compared to PGY1 for allergy, endocrine, gastrointestinal, and rheumatologic medication classes but not for analgesic, cardiovascular, and neuropsychotropic medication classes. For knowledge, there were statistically significant increased mean differences for PGY2 and PGY3 as compared to PGY1 for allergy, cardiovascular, endocrine, and gastrointestinal, medication classes but not for analgesic, neuropsychotropic, and rheumatologic medication classes. Internal Medicine house-staff across all levels of training demonstrated poor awareness and knowledge for many medication classes in CKD patients. Internal Medicine house-staff should receive more nephrology exposure and formal didactic educational training during residency to better manage complex treatment regimens and prevent medication dosing errors.

Association of Low-Dose Aspirin and Survival of Women With Endometrial Cancer.

PubMed

Matsuo, Koji; Cahoon, Sigita S; Yoshihara, Kosuke; Shida, Masako; Kakuda, Mamoru; Adachi, Sosuke; Moeini, Aida; Machida, Hiroko; Garcia-Sayre, Jocelyn; Ueda, Yutaka; Enomoto, Takayuki; Mikami, Mikio; Roman, Lynda D; Sood, Anil K

2016-07-01

To examine the survival outcomes in women with endometrial cancer who were taking low-dose aspirin (81-100 mg/d). A multicenter retrospective study was conducted examining patients with stage I-IV endometrial cancer who underwent hysterectomy-based surgical staging between January 2000 and December 2013 (N=1,687). Patient demographics, medical comorbidities, medication types, tumor characteristics, and treatment patterns were correlated to survival outcomes. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio for disease-free and disease-specific overall survival. One hundred fifty-eight patients (9.4%, 95% confidence interval [CI] 8.8-11.9) were taking low-dose aspirin. Median follow-up time for the study cohort was 31.5 months. One hundred twenty-seven patients (7.5%) died of endometrial cancer. Low-dose aspirin use was significantly correlated with concurrent obesity, hypertension, diabetes mellitus, and hypercholesterolemia (all P<.001). Low-dose aspirin users were more likely to take other antihypertensive, antiglycemic, and anticholesterol agents (all P<.05). Low-dose aspirin use was not associated with histologic subtype, tumor grade, nodal metastasis, or cancer stage (all P>.05). On multivariable analysis, low-dose aspirin use remained an independent prognostic factor associated with an improved 5-year disease-free survival rate (90.6% compared with 80.9%, adjusted hazard ratio 0.46, 95% CI 0.25-0.86, P=.014) and disease-specific overall survival rate (96.4% compared with 87.3%, adjusted hazard ratio 0.23, 95% CI 0.08-0.64, P=.005). The increased survival effect noted with low-dose aspirin use was greatest in patients whose age was younger than 60 years (5-year disease-free survival rates, 93.9% compared with 84.0%, P=.013), body mass index was 30 or greater (92.2% compared with 81.4%, P=.027), who had type I cancer (96.5% compared with 88.6%, P=.029), and who received postoperative whole pelvic radiotherapy (88.2% compared with 61.5%, P=.014). These four factors remained significant for disease-specific overall survival (all P<.05). Our results suggest that low-dose aspirin use is associated with improved survival outcomes in women with endometrial cancer, especially in those who are young, obese, with low-grade disease, and who receive postoperative radiotherapy.

Comparison of pencil beam–based homogeneous vs inhomogeneous target dose planning for stereotactic body radiotherapy of peripheral lung tumors through Monte Carlo–based recalculation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohtakara, Kazuhiro, E-mail: ohtakara@murakami.asahi-u.ac.jp; Hoshi, Hiroaki

2015-10-01

This study was conducted to ascertain whether homogeneous target dose planning is suitable for stereotactic body radiotherapy (SBRT) of peripheral lung cancer under appropriate breath-holding. For 20 peripheral lung tumors, paired dynamic conformal arc plans were generated by only adjusting the leaf margin to the planning target volume (PTV) edge for fulfilling the conditions such that the prescription isodose surface (IDS) encompassing exactly 95% of the PTV (PTV D{sub 95}) corresponds to 95% and 80% IDS, normalized to 100% at the PTV isocenter under a pencil beam (PB) algorithm with radiologic path length correction. These plans were recalculated using themore » x-ray voxel Monte Carlo (XVMC) algorithm under otherwise identical conditions, and then compared. Lesions abutting the parietal pleura or not were defined as edge or island tumors, respectively, and the influences of the target volume and its location relative to the chest wall on the target dose were examined. The median (range) leaf margin required for the 95% and 80% plans was 3.9 mm (1.3 to 5.0) and −1.2 mm (−1.8 to 0.1), respectively. Notably, the latter was significantly correlated negatively with PTV. In the 80% plans, the PTV D{sub 95} was slightly higher under XVMC, whereas the PTV D{sub 98} was significantly lower, irrespective of the dose calculation algorithm used. Other PTV and all gross tumor volume doses were significantly higher, while the lung doses outside the PTV were slightly lower. The target doses increased as a function of PTV and were significantly lower for island tumors than for edge tumors. In conclusion, inhomogeneous target dose planning using smaller leaf margin for a larger tumor volume was deemed suitable in ensuring more sufficient target dose while slightly reducing lung dose. In addition, more inhomogeneous target dose planning using <80% IDS (e.g., 70%) for PTV covering would be preferable for island tumors.« less

A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova(®) compared to Lovaza(®) in a pharmacokinetic single-dose evaluation) study.

PubMed

Davidson, Michael H; Johnson, Judith; Rooney, Michael W; Kyle, Michael L; Kling, Douglas F

2012-01-01

Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova(®), Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet. To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza(®), GlaxoSmithKline, Research Triangle Park, NC). This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC(0-t)) during a 24-hour interval for EPA and DHA (baseline-adjusted). The baseline-adjusted AUC(0-t) for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol·h/mL, respectively; P < .0001). During the high-fat period, AUC(0-t) for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC(0-t) that was ≥50% of the respective high-fat AUC(0-t) in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE. During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet. Copyright © 2012 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Comparative Efficacy of Daratumumab Monotherapy and Pomalidomide Plus Low-Dose Dexamethasone in the Treatment of Multiple Myeloma: A Matching Adjusted Indirect Comparison.

PubMed

Van Sanden, Suzy; Ito, Tetsuro; Diels, Joris; Vogel, Martin; Belch, Andrew; Oriol, Albert

2018-03-01

Daratumumab (a human CD38-directed monoclonal antibody) and pomalidomide (an immunomodulatory drug) plus dexamethasone are both relatively new treatment options for patients with heavily pretreated multiple myeloma. A matching adjusted indirect comparison (MAIC) was used to compare absolute treatment effects of daratumumab versus pomalidomide + low-dose dexamethasone (LoDex; 40 mg) on overall survival (OS), while adjusting for differences between the trial populations. The MAIC method reduces the risk of bias associated with naïve indirect comparisons. Data from 148 patients receiving daratumumab (16 mg/kg), pooled from the GEN501 and SIRIUS studies, were compared separately with data from patients receiving pomalidomide + LoDex in the MM-003 and STRATUS studies. The MAIC-adjusted hazard ratio (HR) for OS of daratumumab versus pomalidomide + LoDex was 0.56 (95% confidence interval [CI], 0.38-0.83; p  = .0041) for MM-003 and 0.51 (95% CI, 0.37-0.69; p  < .0001) for STRATUS. The treatment benefit was even more pronounced when the daratumumab population was restricted to pomalidomide-naïve patients (MM-003: HR, 0.33; 95% CI, 0.17-0.66; p  = .0017; STRATUS: HR, 0.41; 95% CI, 0.21-0.79; p  = .0082). An additional analysis indicated a consistent trend of the OS benefit across subgroups based on M-protein level reduction (≥50%, ≥25%, and <25%). The MAIC results suggest that daratumumab improves OS compared with pomalidomide + LoDex in patients with heavily pretreated multiple myeloma. This matching adjusted indirect comparison of clinical trial data from four studies analyzes the survival outcomes of patients with heavily pretreated, relapsed/refractory multiple myeloma who received either daratumumab monotherapy or pomalidomide plus low-dose dexamethasone. Using this method, daratumumab conferred a significant overall survival benefit compared with pomalidomide plus low-dose dexamethasone. In the absence of head-to-head trials, these indirect comparisons provide useful insights to clinicians and reimbursement authorities around the relative efficacy of treatments. © AlphaMed Press 2017.

Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia.

PubMed

Crowe, Elizabeth; Pandeya, Nirmala; Brotherton, Julia M L; Dobson, Annette J; Kisely, Stephen; Lambert, Stephen B; Whiteman, David C

2014-03-04

To measure the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical abnormalities four years after implementation of a nationally funded vaccination programme in Queensland, Australia. Case-control analysis of linked administrative health datasets. Queensland, Australia. Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011. High grade cases were women with histologically confirmed high grade cervical abnormalities (n = 1062) and "other cases" were women with any other abnormality at cytology or histology (n = 10,887). Controls were women with normal cytology (n = 96,404). Exposure odds ratio (ratio of odds of antecedent vaccination (one, two, or three vaccine doses compared with no doses) among cases compared with controls), vaccine effectiveness ((1-adjusted odds ratio) × 100), and number needed to vaccinate to prevent one cervical abnormality at first screening round. We stratified by four age groups adjusted for follow-up time, year of birth, and measures of socioeconomic status and remoteness. The primary analysis concerned women whose first ever smear test defined their status as a case or a control. The adjusted odds ratio for exposure to three doses of HPV vaccine compared with no vaccine was 0.54 (95% confidence interval 0.43 to 0.67) for high grade cases and 0.66 (0.62 to 0.70) for other cases compared with controls with normal cytology, equating to vaccine effectiveness of 46% and 34%, respectively. The adjusted numbers needed to vaccinate were 125 (95% confidence interval 97 to 174) and 22 (19 to 25), respectively. The adjusted exposure odds ratios for two vaccine doses were 0.79 (95% confidence interval 0.64 to 0.98) for high grade cases and 0.79 (0.74 to 0.85) for other cases, equating to vaccine effectiveness of 21%. The quadrivalent HPV vaccine conferred statistically significant protection against cervical abnormalities in young women who had not started screening before the implementation of the vaccination programme in Queensland, Australia.

Meeting The Joint Commission's Dose Incident Identification and External Benchmarking Requirements Using the ACR's Dose Index Registry.

PubMed

Bohl, Michael A; Goswami, Roopa; Strassner, Brett; Stanger, Paula

2016-08-01

The purpose of this investigation was to evaluate the potential of using the ACR's Dose Index Registry(®) to meet The Joint Commission's requirements to identify incidents in which the radiation dose index from diagnostic CT examinations exceeded the protocol's expected dose index range. In total, 10,970 records in the Dose Index Registry were statistically analyzed to establish both an upper and lower expected dose index for each protocol. All 2015 studies to date were then retrospectively reviewed to identify examinations whose total examination dose index exceeded the protocol's defined upper threshold. Each dose incident was then logged and reviewed per the new Joint Commission requirements. Facilities may leverage their participation in the ACR's Dose Index Registry to fully meet The Joint Commission's dose incident identification review and external benchmarking requirements. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Modification of Enrofloxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance▿

PubMed Central

Randall, Luke P.; Cooles, Sue W.; Coldham, Nick C.; Stapleton, Ken S.; Piddock, Laura J. V.; Woodward, Martin J.

2006-01-01

We hypothesized that higher doses of fluoroquinolones for a shorter duration could maintain efficacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enrofloxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 μg/ml enrofloxacin correlated with increased activity. In vivo, the efficacy of the 1-day treatment was significantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efficacy similar to that of the 5-day treatment in all but one repeat treatment group and significantly (P < 0.01) reduced the Salmonella counts. Dosing at 2.5× the recommended dose and pulsed dosing both increased the peak antibiotic concentrations in cecal contents, liver, lung, and sera as determined by high-pressure liquid chromatography. There was limited evidence that shorter treatment regimens (in particular the 1-day regimen) selected for fewer strains with reduced susceptibility. In conclusion, the 2-day treatment would overall require a shorter withholding time than the 5-day treatment and, in view of the increased peak antibiotic concentrations, may give rise to improved efficacy, in particular for treating respiratory and systemic infections. However, it would be necessary to validate the 2-day regimen in a field situation and in particular against respiratory and systemic infections to validate or refute this hypothesis. PMID:17030564

Novel oxytocin receptor variants in laboring women requiring high doses of oxytocin.

PubMed

Reinl, Erin L; Goodwin, Zane A; Raghuraman, Nandini; Lee, Grace Y; Jo, Erin Y; Gezahegn, Beakal M; Pillai, Meghan K; Cahill, Alison G; de Guzman Strong, Cristina; England, Sarah K

2017-08-01

Although oxytocin commonly is used to augment or induce labor, it is difficult to predict its effectiveness because oxytocin dose requirements vary significantly among women. One possibility is that women requiring high or low doses of oxytocin have variations in the oxytocin receptor gene. To identify oxytocin receptor gene variants in laboring women with low and high oxytocin dosage requirements. Term, nulliparous women requiring oxytocin doses of ≤4 mU/min (low-dose-requiring, n = 83) or ≥20 mU/min (high-dose-requiring, n = 104) for labor augmentation or induction provided consent to a postpartum blood draw as a source of genomic DNA. Targeted-amplicon sequencing (coverage >30×) with MiSeq (Illumina) was performed to discover variants in the coding exons of the oxytocin receptor gene. Baseline relevant clinical history, outcomes, demographics, and oxytocin receptor gene sequence variants and their allele frequencies were compared between low-dose-requiring and high-dose-requiring women. The Scale-Invariant Feature Transform algorithm was used to predict the effect of variants on oxytocin receptor function. The Fisher exact or χ 2 tests were used for categorical variables, and Student t tests or Wilcoxon rank sum tests were used for continuous variables. A P value < .05 was considered statistically significant. The high-dose-requiring women had greater rates of obesity and diabetes and were more likely to have undergone labor induction and required prostaglandins. High-dose-requiring women were more likely to undergo cesarean delivery for first-stage arrest and less likely to undergo cesarean delivery for nonreassuring fetal status. Targeted sequencing of the oxytocin receptor gene in the total cohort (n = 187) revealed 30 distinct coding variants: 17 nonsynonymous, 11 synonymous, and 2 small structural variants. One novel variant (A243T) was found in both the low- and high-dose-requiring groups. Three novel variants (Y106H, A240_A249del, and P197delfs*206) resulting in an amino acid substitution, loss of 9 amino acids, and a frameshift stop mutation, respectively, were identified only in low-dose-requiring women. Nine nonsynonymous variants were unique to the high-dose-requiring group. These included 3 known variants (R151C, G221S, and W228C) and 6 novel variants (M133V, R150L, H173R, A248V, G253R, and I266V). Of these, R150L, R151C, and H173R were predicted by Scale-Invariant Feature Transform algorithm to damage oxytocin receptor function. There was no statistically significant association between the numbers of synonymous and nonsynonymous substitutions in the patient groups. Obesity, diabetes, and labor induction were associated with the requirement for high doses of oxytocin. We did not identify significant differences in the prevalence of oxytocin receptor variants between low-dose-requiring and high-dose-requiring women, but novel oxytocin receptor variants were enriched in the high-dose-requiring women. We also found 3 oxytocin receptor variants (2 novel, 1 known) that were predicted to damage oxytocin receptor function and would likely increase an individual's risk for requiring a high oxytocin dose. Further investigation of oxytocin receptor variants and their effects on protein function will inform precision medicine in pregnant women. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Development and Validation of a Questionnaire to Assess Carbohydrate and Insulin-Dosing Knowledge in Youth With Type 1 Diabetes

PubMed Central

Koontz, Michaela B.; Cuttler, Leona; Palmert, Mark R.; O'Riordan, MaryAnn; Borawski, Elaine A.; McConnell, Judy; Kern, Elizabeth O.

2010-01-01

OBJECTIVE The American Diabetes Association advocates insulin regimens for youth with type 1 diabetes that involve adjusting insulin dose based on carbohydrate intake and blood glucose level. Implementing these regimens requires knowledge about carbohydrate content of foods and subsequent calculations of insulin dose, skills that may be difficult to gauge in practice. Therefore, we sought to develop and validate a questionnaire, the PedCarbQuiz (PCQ), to assess carbohydrate and insulin-dosing knowledge in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS After development by an expert panel, the PCQ was administered to 75 youth with type 1 diabetes or their parents. Reliability was assessed by Cronbach α and split-half testing. To assess validity, scores were correlated with A1C, expert assessments, parent educational level, and complexity of insulin regimen. RESULTS PCQ mean score was 87 ± 9.7% (range 42–98%). Cronbach α was 0.88, and correlation of split halves was 0.59 (P < 0.0001). Higher PCQ scores correlated significantly with lower A1C (r = −0.29, P = 0.01) and expert assessments (r = 0.56, P < 0.001). Scores were significantly higher in parents with college degrees than in those without (P = 0.01) and in participants with more complex insulin regimens (P = 0.003). CONCLUSIONS The PCQ is a novel, easily administered instrument to assess knowledge about carbohydrates and insulin dosing calculations. Initial analyses support the reliability and validity of the PCQ. PMID:20007940

The use of nomograms in LDR-HDR prostate brachytherapy.

PubMed

Pujades, Ma Carmen; Camacho, Cristina; Perez-Calatayud, Jose; Richart, José; Gimeno, Jose; Lliso, Françoise; Carmona, Vicente; Ballester, Facundo; Crispín, Vicente; Rodríguez, Silvia; Tormo, Alejandro

2011-09-01

The common use of nomograms in Low Dose Rate (LDR) permanent prostate brachytherapy (BT) allows to estimate the number of seeds required for an implant. Independent dosimetry verification is recommended for each clinical dosimetry in BT. Also, nomograms can be useful for dose calculation quality assurance and they could be adapted to High Dose Rate (HDR). This work sets nomograms for LDR and HDR prostate-BT implants, which are applied to three different institutions that use different implant techniques. Patients treated throughout 2010 till April 2011 were considered for this study. This example was chosen to be the representative of the latest implant techniques and to ensure consistency in the planning. A sufficient number of cases for both BT modalities, prescription dose and different work methodology (depending on the institution) were taken into account. The specific nomograms were built using the correlation between the prostate volume and some characteristic parameters of each BT modality, such as the source Air Kerma Strength, number of implanted seeds in LDR or total radiation time in HDR. For each institution and BT modality, nomograms normalized to the prescribed dose were obtained and fitted to a linear function. The parameters of the adjustment show a good agreement between data and the fitting. It should be noted that for each institution these linear function parameters are different, indicating that each centre should construct its own nomograms. Nomograms for LDR and HDR prostate brachytherapy are simple quality assurance tools, specific for each institution. Nevertheless, their use should be complementary to the necessary independent verification.

The use of nomograms in LDR-HDR prostate brachytherapy

PubMed Central

Camacho, Cristina; Perez-Calatayud, Jose; Richart, José; Gimeno, Jose; Lliso, Françoise; Carmona, Vicente; Ballester, Facundo; Crispín, Vicente; Rodríguez, Silvia; Tormo, Alejandro

2011-01-01

Purpose The common use of nomograms in Low Dose Rate (LDR) permanent prostate brachytherapy (BT) allows to estimate the number of seeds required for an implant. Independent dosimetry verification is recommended for each clinical dosimetry in BT. Also, nomograms can be useful for dose calculation quality assurance and they could be adapted to High Dose Rate (HDR). This work sets nomograms for LDR and HDR prostate-BT implants, which are applied to three different institutions that use different implant techniques. Material and methods Patients treated throughout 2010 till April 2011 were considered for this study. This example was chosen to be the representative of the latest implant techniques and to ensure consistency in the planning. A sufficient number of cases for both BT modalities, prescription dose and different work methodology (depending on the institution) were taken into account. The specific nomograms were built using the correlation between the prostate volume and some characteristic parameters of each BT modality, such as the source Air Kerma Strength, number of implanted seeds in LDR or total radiation time in HDR. Results For each institution and BT modality, nomograms normalized to the prescribed dose were obtained and fitted to a linear function. The parameters of the adjustment show a good agreement between data and the fitting. It should be noted that for each institution these linear function parameters are different, indicating that each centre should construct its own nomograms. Conclusions Nomograms for LDR and HDR prostate brachytherapy are simple quality assurance tools, specific for each institution. Nevertheless, their use should be complementary to the necessary independent verification. PMID:23346120

Single-Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment.

PubMed

Dudkowski, Caroline; Karim, Aziz; Zhao, Zhen; Alonso, Alberto B; Garg, Dyal; Preston, Richard A

2018-01-01

Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M-II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single-center, open-label, phase 1 parallel-group study that examined the single-dose (day 1) and multiple-dose (days 4-8) - 40 mg - pharmacokinetics of AZL and M-II in 16 subjects with mild and moderate hepatic impairment by Child-Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M-II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M-II. Single and multiple doses of AZL-M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with mild and moderate hepatic impairment. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial.

PubMed

Denham, James W; Steigler, Allison; Joseph, David; Lamb, David S; Spry, Nigel A; Duchesne, Gillian; Atkinson, Chris; Matthews, John; Turner, Sandra; Kenny, Lizbeth; Tai, Keen-Hun; Gogna, Nirdosh Kumar; Gill, Suki; Tan, Hendrick; Kearvell, Rachel; Murray, Judy; Ebert, Martin; Haworth, Annette; Kennedy, Angel; Delahunt, Brett; Oldmeadow, Christopher; Holliday, Elizabeth G; Attia, John

2015-06-01

The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS±18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p<0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.

PubMed

Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob

2015-05-01

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

45 CFR 153.630 - Data validation requirements when HHS operates risk adjustment.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 1 2013-10-01 2013-10-01 false Data validation requirements when HHS operates... Program § 153.630 Data validation requirements when HHS operates risk adjustment. (a) General requirement... performed on its risk adjustment data as described in this section. (b) Initial validation audit. (1) An...

45 CFR 153.630 - Data validation requirements when HHS operates risk adjustment.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 1 2014-10-01 2014-10-01 false Data validation requirements when HHS operates... Program § 153.630 Data validation requirements when HHS operates risk adjustment. (a) General requirement... performed on its risk adjustment data as described in this section. (b) Initial validation audit. (1) An...

Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

PubMed Central

le Roux, Stanzi M; Cotton, Mark F; Golub, Jonathan E; le Roux, David M; Workman, Lesley; Zar, Heather J

2009-01-01

Background Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children. Methods We investigated adherence to study medication in a two centre, randomized trial comparing daily to three times a week dosing of isoniazid. The study was conducted at two tertiary paediatric care centres in Cape Town, South Africa. Over a 5 year period, we followed 324 HIV-infected children aged ≥ 8 weeks. Adherence information based on pill counts was available for 276 children. Percentage adherence was calculated by counting the number of pills returned. Adherence ≥ 90% was considered to be optimal. Analysis was done using summary and repeated measures, comparing adherence to the two dosing schedules. Mean percentage adherence (per child during follow-up time) was used to compare the mean of each group as well as the proportion of children achieving an adherence of ≥ 90% in each group. For repeated measures, percentage adherence (per child per visit) was dichotomized at 90%. A logistic regression model with generalized estimating equations, to account for within-individual correlation, was used to evaluate the impact of the dosing schedule. Adjustments were made for potential confounders and we assessed potential baseline and time-varying adherence determinants. Results The overall adherence to isoniazid was excellent, with a mean adherence of 94.7% (95% confidence interval [CI] 93.5-95.9); similar mean adherence was achieved by the group taking daily medication (93.8%; 95% CI 92.1-95.6) and by the three times a week group (95.5%; 95% CI 93.8-97.2). Two-hundred and seventeen (78.6%) children achieved a mean adherence of ≥ 90%. Adherence was similar for daily and three times a week dosing schedules in univariate (odds ratio [OR] 0.88; 95% CI 0.66-1.17; P = 0.38) and multivariate (adjusted OR 0.85; 95% CI 0.64-1.11; P = 0.23) models. Children from overcrowded homes were less adherent (adjusted OR 0.71; 95% CI 0.54-0.95; P = 0.02). Age at study visit was predictive of adherence, with better adherence achieved in children older than 4 years (adjusted OR 1.96; 95% CI 1.16-3.32; P = 0.01). Conclusion Adherence to isoniazid was excellent regardless of the dosing schedule used. Intermittent dosing of isoniazid prophylaxis can be considered as an alternative to daily dosing, without compromising adherence or efficacy. Trial registration Clinical Trials NCT00330304 PMID:19886982

Dialysis Dose Scaled to Body Surface Area and Size-Adjusted, Sex-Specific Patient Mortality

PubMed Central

Kapke, Alissa; Port, Friedrich K.; Wolfe, Robert A.; Saran, Rajiv; Pearson, Jeffrey; Hirth, Richard A.; Messana, Joseph M.; Daugirdas, John T.

2012-01-01

Summary Background and objectives When hemodialysis dose is scaled to body water (V), women typically receive a greater dose than men, but their survival is not better given a similar dose. This study sought to determine whether rescaling dose to body surface area (SA) might reveal different associations among dose, sex, and mortality. Design, setting, participants, & measurements Single-pool Kt/V (spKt/V), equilibrated Kt/V, and standard Kt/V (stdKt/V) were computed using urea kinetic modeling on a prevalent cohort of 7229 patients undergoing thrice-weekly hemodialysis. Data were obtained from the Centers for Medicare & Medicaid Services 2008 ESRD Clinical Performance Measures Project. SA-normalized stdKt/V (SAN-stdKt/V) was calculated as stdKt/V × ratio of anthropometric volume to SA/17.5. Patients were grouped into sex-specific dose quintiles (reference: quintile 1 for men). Adjusted hazard ratios (HRs) for 1-year mortality were calculated using Cox regression. Results spKt/V was higher in women (1.7±0.3) than in men (1.5±0.2; P<0.001), but SAN-stdKt/V was lower (women: 2.3±0.2; men: 2.5±0.3; P<0.001). For both sexes, mortality decreased as spKt/V increased, until spKt/V was 1.6–1.7 (quintile 4 for men: HR, 0.62; quintile 3 for women: HR, 0.64); no benefit was observed with higher spKt/V. HR for mortality decreased further at higher SAN-stdKt/V in both sexes (quintile 5 for men: HR, 0.69; quintile 5 for women: HR, 0.60). Conclusions SA-based dialysis dose results in dose-mortality relationships substantially different from those with volume-based dosing. SAN-stdKt/V analyses suggest women may be relatively underdosed when treated by V-based dosing. SAN-stdKt/V as a measure for dialysis dose may warrant further study. PMID:22977208

Pharmacokinetics of oral hydrocortisone - Results and implications from a randomized controlled trial.

PubMed

Werumeus Buning, Jorien; Touw, Daan J; Brummelman, Pauline; Dullaart, Robin P F; van den Berg, Gerrit; van der Klauw, Melanie M; Kamp, Jasper; Wolffenbuttel, Bruce H R; van Beek, André P

2017-06-01

This study aimed at comparing pharmacokinetics of two different doses of hydrocortisone (HC) in patients with secondary adrenal insufficiency (SAI). Forty-six patients with SAI participated in this randomized double-blind crossover study. Patients received two different doses of HC (0.2-0.3mg HC/kg body weight/day and 0.4-0.6mg HC/kg body weight/day). One- and two-compartment population models for plasma free cortisol, plasma total cortisol and salivary cortisol were parameterized. The individual pharmacokinetic parameters clearance (CL), volume of distribution (V d ), elimination half-life (t 1/2 ), maximum concentration (C max ), and area under the curve (AUC) were calculated. The one-compartment models gave a better description of the data compared to the two-compartment models. Weight-adjusted dosing reduced variability in cortisol exposure with comparable AUCs between weight groups. However, there was large inter-individual variation in CL and V d of plasma free cortisol, plasma total cortisol and salivary cortisol. As a consequence, AUC 24h varied more than 10 fold. Cortisol exposure was increased with the higher dose, but this was dose proportional only for free cortisol concentrations and not for total cortisol. Cortisol concentrations after a doubling of the dose were only dose proportional for free cortisol. HC pharmacokinetics can differ up to 10-fold inter-individually and individual adjustment of treatment doses may be necessary. Doubling of the HC dose in fast metabolizers (patients that showed relative low AUC and thus high clearance compared to other patients), does not result in significantly enhanced exposure during large parts of the day and these patients may need other management strategies. Copyright © 2017 Elsevier Inc. All rights reserved.

Liquid medication dosing errors in children: role of provider counseling strategies.

PubMed

Yin, H Shonna; Dreyer, Benard P; Moreira, Hannah A; van Schaick, Linda; Rodriguez, Luis; Boettger, Susanne; Mendelsohn, Alan L

2014-01-01

To examine the degree to which recommended provider counseling strategies, including advanced communication techniques and dosing instrument provision, are associated with reductions in parent liquid medication dosing errors. Cross-sectional analysis of baseline data on provider communication and dosing instrument provision from a study of a health literacy intervention to reduce medication errors. Parents whose children (<9 years) were seen in 2 urban public hospital pediatric emergency departments (EDs) and were prescribed daily dose liquid medications self-reported whether they received counseling about their child's medication, including advanced strategies (teachback, drawings/pictures, demonstration, showback) and receipt of a dosing instrument. The primary dependent variable was observed dosing error (>20% deviation from prescribed). Multivariate logistic regression analyses were performed, controlling for parent age, language, country, ethnicity, socioeconomic status, education, health literacy (Short Test of Functional Health Literacy in Adults); child age, chronic disease status; and site. Of 287 parents, 41.1% made dosing errors. Advanced counseling and instrument provision in the ED were reported by 33.1% and 19.2%, respectively; 15.0% reported both. Advanced counseling and instrument provision in the ED were associated with decreased errors (30.5 vs. 46.4%, P = .01; 21.8 vs. 45.7%, P = .001). In adjusted analyses, ED advanced counseling in combination with instrument provision was associated with a decreased odds of error compared to receiving neither (adjusted odds ratio 0.3; 95% confidence interval 0.1-0.7); advanced counseling alone and instrument alone were not significantly associated with odds of error. Provider use of advanced counseling strategies and dosing instrument provision may be especially effective in reducing errors when used together. Copyright © 2014 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Race influences warfarin dose changes associated with genetic factors

PubMed Central

Brown, Todd M.; Yan, Qi; Thigpen, Jonathan L.; Shendre, Aditi; Liu, Nianjun; Hill, Charles E.; Arnett, Donna K.; Beasley, T. Mark

2015-01-01

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. PMID:26024874

Race influences warfarin dose changes associated with genetic factors.

PubMed

Limdi, Nita A; Brown, Todd M; Yan, Qi; Thigpen, Jonathan L; Shendre, Aditi; Liu, Nianjun; Hill, Charles E; Arnett, Donna K; Beasley, T Mark

2015-07-23

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race. © 2015 by The American Society of Hematology.

Frequency and severity of potential drug interactions in a cohort of HIV-infected patients Identified through a Multidisciplinary team.

PubMed

Molas, E; Luque, S; Retamero, A; Echeverría-Esnal, D; Guelar, A; Montero, M; Guerri, R; Sorli, L; Lerma, E; Villar, J; Knobel, H

2018-02-01

Interactions between antiretroviral treatment (ART) and comedications are a concern in HIV-infected patients. This study aimed to determine the frequency and severity of potential drug-drug interactions (PDDIs) with ART in our setting. Observational study by a multidisciplinary team in 1259 consecutive HIV patients (March 2015-September 2016). Data on demographics, toxic habits, comorbidities, and current ART were collected. A structured questionnaire recorded concomitant medications (including occasional and over-the-counter drugs). PDDIs were classified into four categories: (1) no interactions, (2) mild (clinically non-significant), (3) moderate (requiring close monitoring or drug modification/dose adjustment), and (4) severe (contraindicated). chi-square test, logistic regression analysis. In total, 881 (70%) patients took comedication, and 563 (44.7%) had ≥ PDDI. Forty-one comedicated patients (4.6%) had severe and 522 (59.2%) moderate PDDIs. Moderate PDDIs mainly involved cardiovascular (53.8%) and central nervous system (40.2%) drugs. Independent risk factors for PDDIs were ART containing a boosted protease inhibitor (odds ratio [OR]=9.11, 95% confidence interval [CI] 5.15-16.11; p = 0.0001) and/or non-nucleoside reverse transcriptase (NNRTI) (OR = 4.34, 95%CI 2.49-7.55; p = 0.0001), HCV co-infection (OR = 3.26, 95%CI 2.15-4.93; p = 0.0001), and use of two or more comedications (OR = 3.36, 95%CI 2.27-4.97; p = 0.0001). Adherence and effectiveness of ART were similar in patients with and without PDDIs. The team made 133 recommendations related to comedications (drug change or dose adjustment) or ART (drug switch or change in administration schedule). Systematic evaluation detected a significant percentage of PDDIs requiring an intervention in HIV patients on ART. Monitoring and advice about drug-drug interactions should be part of routine practice.

A comparison of the extended-release and standard-release formulations of tacrolimus in de novo kidney transplant recipients: a 12-month outcome study.

PubMed

Fanous, Helen; Zheng, Rebecca; Campbell, Carolyn; Huang, Michael; Nash, Michelle M; Rapi, Lindita; Zaltzman, Jeffrey S; Prasad, G V Ramesh

2013-02-01

BACKGROUND: Limited comparative data are available on the outcomes between extended-release and standard-release tacrolimus when used de novo in kidney transplant recipients (KTRs). METHODS: We identified KTRs transplanted at our institution during 2009-10 routinely prescribed extended-release tacrolimus and compared them with those transplanted during 2008-09 prescribed standard-release tacrolimus. Graft function (eGFR by MDRD-7 equation) at 12 months post-transplant (primary outcome); new-onset diabetes and other cardiovascular risk factors, BK viremia incidence, acute rejection, and graft survival to 12 months (secondary outcomes) were compared by intent-to-treat analysis. Time-to-steady-state concentration and number of dose adjustments required to attain steady state were recorded. RESULTS: There were no important demographic differences between the extended-release (N = 106) and standard-release (N = 95) cohorts. The estimated glomerular filtration rate (eGFR) at 12 months was similar (58.8 ± 17 versus 59.2 ± 18 mL/min/1.73 m(2), P = 0.307). There was no difference in new-onset diabetes (17 versus 20%, P = 0.581), BK viremia (10 versus 7%, P = 0.450), acute rejection (7 versus 16%, P = 0.067) or graft survival (97 versus 95%, P = 0.301). Time-to-steady state was similar (9.2 ± 1.1 versus 8.1 ± 4.7 days, P = 0.490) although extended-release patients required fewer adjustments to attain steady state (1.2 ± 1.7 [0-8] versus 1.7 ± 1.5 [0-7], P = 0.030) but a similar dose (7.2 ± 2.4 [2-17] versus 7 ± 2.7 [2-16] mg/day, P = 0.697). CONCLUSION: De novo KTRs prescribed extended-release or standard-release tacrolimus demonstrate similar 12-month outcomes.

Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension.

PubMed

Fadl Elmula, Fadl Elmula M; Hoffmann, Pavel; Larstorp, Anne C; Fossum, Eigil; Brekke, Magne; Kjeldsen, Sverre E; Gjønnæss, Eyvind; Hjørnholm, Ulla; Kjaer, Vibeke N; Rostrup, Morten; Os, Ingrid; Stenehjem, Aud; Høieggen, Aud

2014-05-01

We aimed to investigate for the first time the blood pressure (BP)-lowering effect of renal sympathetic denervation (RDN) versus clinically adjusted drug treatment in true treatment-resistant hypertension (TRH) after excluding patients with confounding poor drug adherence. Patients with apparent TRH (n=65) were referred for RDN, and those with secondary and spurious hypertension (n=26) were excluded. TRH was defined as office systolic BP (SBP) >140 mm Hg, despite maximally tolerated doses of ≥3 antihypertensive drugs including a diuretic. In addition, ambulatory daytime SBP >135 mm Hg after witnessed intake of antihypertensive drugs was required, after which 20 patients had normalized BP and were excluded. Patients with true TRH were randomized and underwent RDN (n=9) performed with Symplicity Catheter System versus clinically adjusted drug treatment (n=10). The study was stopped early for ethical reasons because RDN had uncertain BP-lowering effect. Office SBP and diastolic BP in the drug-adjusted group changed from 160±14/88±13 mm Hg (±SD) at baseline to 132±10/77±8 mm Hg at 6 months (P<0.0005 and P=0.02, SBP and diastolic BP, respectively) and in the RDN group from 156±13/91±15 to 148±7/89±8 mm Hg (P=0.42 and P=0.48, SBP and diastolic BP, respectively). SBP and diastolic BP were significantly lower in the drug-adjusted group at 6 months (P=0.002 and P=0.004, respectively), and absolute changes in SBP were larger in the drug-adjusted group (P=0.008). Ambulatory BPs changed in parallel to office BPs. Our data suggest that adjusted drug treatment has superior BP lowering effects compared with RDN in patients with true TRH. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01673516.

Isoniazid, Pyrazinamide and Rifampicin Content Variation in Split Fixed-Dose Combination Tablets

PubMed Central

Pouplin, Thomas; Phuong, Pham Nguyen; Toi, Pham Van; Nguyen Pouplin, Julie; Farrar, Jeremy

2014-01-01

Setting In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. Objective To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Design Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. Results All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. Conclusion In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis. PMID:25004128

Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets.

PubMed

Pouplin, Thomas; Phuong, Pham Nguyen; Toi, Pham Van; Nguyen Pouplin, Julie; Farrar, Jeremy

2014-01-01

In most developing countries, paediatric tuberculosis is treated with split tablets leading to potential inaccuracy in the dose delivery and drug exposure. There is no data on the quality of first-line drugs content in split fixed-dose combination tablets. To determine Isoniazid, Pyrazinamide and Rifampicin content uniformity in split FDC tablets used in the treatment of childhood tuberculosis. Drug contents of 15 whole tablets, 30 half tablets and 36 third tablets were analysed by high performance liquid chromatography. The content uniformity was assessed by comparing drug content measured in split portions with their expected amounts and the quality of split portions was assessed applying qualitative specifications for whole tablets. All whole tablets measurements fell into the USP proxy for the three drugs. But a significant number of half and third portions was found outside the tolerated variation range and the split formulation failed the requirements for content uniformity. To correct for the inaccuracy of splitting the tablets into equal portions, a weight-adjustment strategy was used but this did not improve the findings. In split tablets the content of the three drugs is non-uniform and exceeded the USP recommendations. There is an absolute need to make child-friendly formulations available for the treatment of childhood tuberculosis.

Patterns of beta-blocker intensification in ambulatory heart failure patients and short-term association with hospitalization

PubMed Central

2012-01-01

Background In response to the short-term negative inotropic and chronotropic effects of β-blockers, heart failure (HF) guidelines recommend initiating β-blockers at low dose with gradual uptitration as tolerated to doses used in clinical trials. However, patterns and safety of β-blocker intensification in routine practice are poorly described. Methods We described β-blocker intensification among Kaiser Colorado enrollees with a primary discharge diagnosis of HF between 2001–2009. We then assessed β-blocker intensification in the 30 days prior to first hospital readmission for cases compared to the same time period following index hospitalization for non-rehospitalized matched controls. In separate analysis of the subgroup initiated on β-blocker after index hospital discharge, we compared adjusted rates of 30-day hospitalization following initiation of high versus low dose β-blocker. Results Among 3,227 patients, median age was 76 years and 37% had ejection fraction ≤40% (LVSD). During a median follow up of 669 days, 14% were never on β-blocker, 21% were initiated on β-blocker, 43% were discharged on β-blocker but never uptitrated, and 22% had discharge β-blocker uptitrated; 63% were readmitted and 49% died. β-blocker intensification occurred in the 30 days preceding readmission for 39 of 1,674 (2.3%) readmitted cases compared to 27 (1.6%) of matched controls (adjusted OR 1.36, 95% CI 0.81-2.27). Among patients initiated on therapy, readmission over the subsequent 30 days occurred in 6 of 155 (3.9%) prescribed high dose and 9 of 513 (1.8%) prescribed low dose β-blocker (adjusted OR 3.10, 95% CI 1.02-9.40). For the subgroup with LVSD, findings were not significantly different. Conclusion While β-blockers were intensified in nearly half of patients following hospital discharge and high starting dose was associated with increased readmission risk, the prevailing finding was that readmission events were rarely preceded by β-blocker intensification. These data suggest that β-blocker intensification is not a major precipitant of hospitalization, provided recommended dosing is followed. PMID:22709128

Usefulness of Time-Point Serum Cortisol and ACTH Measurements for the Adjustment of Glucocorticoid Replacement in Adrenal Insufficiency.

PubMed

Rousseau, Elise; Joubert, Michael; Trzepla, Géraldine; Parienti, Jean Jacques; Freret, Thomas; Vanthygem, Marie Christine; Desailloud, Rachel; Lefebvre, Hervé; Coquerel, Antoine; Reznik, Yves

2015-01-01

Adjustment of daily hydrocortisone dose on clinical criteria lacks sensitivity for fine tuning. Long term hydrocortisone (HC) over-replacement may lead to increased morbidity and mortality in patients with adrenal insufficiency (AI). Biochemical criteria may help detecting over- or under-replacement but have been poorly evaluated. Multicenter, institutional, pharmacokinetic study on ACTH and cortisol plasma profiles during HC replacement in 27 AI patients compared to 29 matched controls. All AI patients were administered HC thrice daily at doses of 6, 10 and 14 mg/m2/d. Blood samples were drawn hourly from 0800h to 1900h. The main outcome measures were: i) plasma peak cortisol and cortisol area under the curve (AUC) in AI patients compared to controls, ii) correlations between cortisol AUC vs single-point cortisol or ACTH decrease from baseline (ΔACTH) and iii) the predictive value of the two latters for obtaining AI patients' cortisol AUC in the control range. Cortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC. The comparison of AI patients' cortisol AUC to controls showed that 81.5% AI patients receiving 6mg/m2/d were adequately replaced, whereas most patients receiving higher doses were over-replaced. The correlation coefficient between 1000h/1400h cortisol concentrations and 0800-1900h cortisol AUC were 0.93/0.88 respectively, whereas the 0800-1200h ΔACTH fairly correlated with 0800-1900h cortisol AUC (R = 0.57). ROC curve analysis indicated that the 1000h and 1400h cortisol concentrations best predicted over-replacement. Patients receiving a 6mg/m2 hydrocortisone daily dose exhibited the most physiological daytime cortisol profile. Single point plasma cortisol correlated with daytime cortisol AUC in AI patients. Although hydrocortisone dose should be currently determined on clinical grounds, our data suggest that single point plasma cortisol may be an adjunct for further hydrocortisone dose adjustment in AI patients.

Usefulness of Time-Point Serum Cortisol and ACTH Measurements for the Adjustment of Glucocorticoid Replacement in Adrenal Insufficiency

PubMed Central

Trzepla, Géraldine; Parienti, Jean Jacques; Freret, Thomas; Vanthygem, Marie Christine; Desailloud, Rachel; Lefebvre, Hervé; Coquerel, Antoine; Reznik, Yves

2015-01-01

Background Adjustment of daily hydrocortisone dose on clinical criteria lacks sensitivity for fine tuning. Long term hydrocortisone (HC) over-replacement may lead to increased morbidity and mortality in patients with adrenal insufficiency (AI). Biochemical criteria may help detecting over- or under-replacement but have been poorly evaluated. Methods Multicenter, institutional, pharmacokinetic study on ACTH and cortisol plasma profiles during HC replacement in 27 AI patients compared to 29 matched controls. All AI patients were administered HC thrice daily at doses of 6, 10 and 14 mg/m2/d. Blood samples were drawn hourly from 0800h to 1900h. The main outcome measures were: i) plasma peak cortisol and cortisol area under the curve (AUC) in AI patients compared to controls, ii) correlations between cortisol AUC vs single-point cortisol or ACTH decrease from baseline (ΔACTH) and iii) the predictive value of the two latters for obtaining AI patients’ cortisol AUC in the control range. Results Cortisol peaks were observed 1h after each HC intake and a dose response was demonstrated for cortisol peak and cortisol AUC. The comparison of AI patients’ cortisol AUC to controls showed that 81.5% AI patients receiving 6mg/m2/d were adequately replaced, whereas most patients receiving higher doses were over-replaced. The correlation coefficient between 1000h/1400h cortisol concentrations and 0800-1900h cortisol AUC were 0.93/0.88 respectively, whereas the 0800-1200h ΔACTH fairly correlated with 0800-1900h cortisol AUC (R = 0.57). ROC curve analysis indicated that the 1000h and 1400h cortisol concentrations best predicted over-replacement. Conclusions Patients receiving a 6mg/m2 hydrocortisone daily dose exhibited the most physiological daytime cortisol profile. Single point plasma cortisol correlated with daytime cortisol AUC in AI patients. Although hydrocortisone dose should be currently determined on clinical grounds, our data suggest that single point plasma cortisol may be an adjunct for further hydrocortisone dose adjustment in AI patients. PMID:26317782

Outcomes using exhaled nitric oxide measurements as an adjunct to primary care asthma management.

PubMed

Hewitt, Richard S; Modrich, Catherine M; Cowan, Jan O; Herbison, G Peter; Taylor, D Robin

2009-12-01

Exhaled nitric oxide (FENO) measurements may help to highlight when inhaled corticosteroid (ICS) therapy should or should not be adjusted in asthma. This is often difficult to judge. Our aim was to evaluate a decision-support algorithm incorporating FENO measurements in a nurse-led asthma clinic. Asthma management was guided by an algorithm based on high (>45ppb), intermediate (30-45ppb), or low (<30ppb) FENO levels and asthma control status. This provided for one of eight possible treatment options, including diagnosis review and ICS dose adjustment. Well controlled asthma increased from 41% at visit 1 to 68% at visit 5 (p=0.001). The mean fluticasone dose decreased from 312 mcg/day at visit 2 to 211mcg/day at visit 5 (p=0.022). There was a high level of protocol deviations (25%), often related to concerns about reducing the ICS dose. The % fall in FENO associated with a change in asthma status from poor control to good control was 35%. An FENO-based algorithm provided for a reduction in ICS doses without compromising asthma control. However, the results may have been influenced by the education and support which patients received. Reluctance to reduce ICS dose was an issue which may have influenced the overall results. Australian Clinical Trials Registry # 012605000354684.

38 CFR 18.444 - Academic adjustments.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2013-07-01 2013-07-01 false Academic adjustments. 18....444 Academic adjustments. (a) Academic requirements. A recipient shall make necessary modifications to its academic requirements to ensure that these requirements do not discriminate or have the effect of...

38 CFR 18.444 - Academic adjustments.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2014-07-01 2014-07-01 false Academic adjustments. 18....444 Academic adjustments. (a) Academic requirements. A recipient shall make necessary modifications to its academic requirements to ensure that these requirements do not discriminate or have the effect of...

38 CFR 18.444 - Academic adjustments.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2012-07-01 2012-07-01 false Academic adjustments. 18....444 Academic adjustments. (a) Academic requirements. A recipient shall make necessary modifications to its academic requirements to ensure that these requirements do not discriminate or have the effect of...

38 CFR 18.444 - Academic adjustments.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 2 2011-07-01 2011-07-01 false Academic adjustments. 18....444 Academic adjustments. (a) Academic requirements. A recipient shall make necessary modifications to its academic requirements to ensure that these requirements do not discriminate or have the effect of...

Intracerebroventricular opiate infusion for refractory head and facial pain

PubMed Central

Lee, Darrin J; Gurkoff, Gene G; Goodarzi, Amir; Muizelaar, J Paul; Boggan, James E; Shahlaie, Kiarash

2014-01-01

AIM: To study the risks and benefits of intracerebroventricular (ICV) opiate pumps for the management of benign head and face pain. METHODS: SSix patients with refractory trigeminal neuralgia and/or cluster headaches were evaluated for implantation of an ICV opiate infusion pump using either ICV injections through an Ommaya reservoir or external ventricular drain. Four patients received morphine ICV pumps and two patientS received a hydromorphone pump. Of the Four patients with morphine ICV pumps, one patient had the medication changed to hydromorphone. Preoperative and post-operative visual analog scores (VAS) were obtained. Patients were evaluated post-operatively for a minimum of 3 mo and the pump dosage was adjusted at each outpatient clinic visit according to the patient’s pain level. RESULTS: All 6 patients had an intracerebroventricular opiate injection trial period, using either an Ommaya reservoir or an external ventricular drain. There was an average VAS improvement of 75.8%. During the trial period, no complications were observed. Pump implantation was performed an average of 3.7 wk (range 1-7) after the trial injections. After implantation, an average of 20.7 ± 8.3 dose adjustments were made over 3-56 mo after surgery to achieve maximal pain relief. At the most recent follow-up (26.2 mo, range 3-56), VAS scores significantly improved from an average of 7.8 ± 0.5 (range 6-10) to 2.8 ± 0.7 (range 0-5) at the final dose (mean improvement 5.0 ± 1.0, P < 0.001). All patients required a stepwise increase in opiate infusion rates to achieve maximal benefit. The most common complications were nausea and drowsiness, both of which resolved with pump adjustments. On average, infusion pumps were replaced every 4-5 years. CONCLUSION: These results suggest that ICV delivery of opiates may potentially be a viable treatment option for patients with intractable pain from trigeminal neuralgia or cluster headache. PMID:25133146

Accounting for neutron exposure in the Japanese atomic bomb survivors.

PubMed

Cullings, Harry M; Pierce, Donald A; Kellerer, Albrecht M

2014-12-01

The Japanese atomic bomb survivors that were directly exposed to both γ rays and neutrons have been followed by the Radiation Effects Research Foundation (RERF). The estimation of the γ-ray risks requires some adjustment for the greater biological effect of the neutrons per unit dose. Because the small neutron doses and the predominant γ-ray doses are highly correlated, the neutron relative biological effectiveness (RBE) cannot be reliably estimated from the survivors' data and information from radiobiology must be invoked. As data became available on neutron doses, RERF has used a constant neutron RBE value of 10, even though radiobiological studies indicate that the RBE values appear to have considerably larger values at low doses. The approximation RBE = 10 assumes that if the RBE is variable it takes roughly this value in the range of total dose most relevant for linear risk estimation, namely about 1 Gy. We consider some possible RBE functions to explain the correct use and the impact of a dose-dependent RBE. However, we do not advocate any particular choice or even that a variable RBE be employed. Rather we show that the assumed neutron RBE, within a wide range of choices, is far less important to the outcome of risk assessment of the RERF data than generally believed. Some of these misperceptions have been related to the consideration of variable RBE functions, and without due attention to the fact that in the case of the A-bomb survivors' data, the mixed field of neutrons and γ rays must be considered. Therefore, the RBE value of neutrons is much lower than the RBE in pure neutron fields that are used in radiobiological experiments. Thus, applying the pure neutron field RBE to the mixed-field A-bomb radiation can lead to an overestimation of the actual neutron RBE for moderate total dose levels of 1 Gy by a factor of more than four. While in a pure neutron exposure the RBE depends on the neutron dose, in the mixed field it depends on both components of exposure, and in particular, we show that in the RERF setting the RBE depends mainly on the accompanying γ-ray dose.

Factors Related to Blood Hydroxychloroquine Concentration in Patients With Systemic Lupus Erythematosus.

PubMed

Yeon Lee, Ji; Lee, Jennifer; Ki Kwok, Seung; Hyeon Ju, Ji; Su Park, Kyung; Park, Sung-Hwan

2017-04-01

To identify factors associated with blood concentrations of hydroxychloroquine (HCQ) and its major metabolite, N-desethylhydroxychloroquine (DHCQ), in patients with systemic lupus erythematosus (SLE; lupus) receiving long-term oral HCQ treatment. SLE patients who had been taking HCQ for more than 3 months were recruited. Various clinical characteristics, laboratory values, and SLE Disease Activity Index (SLEDAI) scores were examined. The concentrations of HCQ and DHCQ ([HCQ] and [DHCQ]) were measured by liquid chromatography mass spectrometry, and the relationship between [HCQ], [DHCQ], and [HCQ]:[DHCQ] ratio to various factors was investigated. In total, 189 SLE patients receiving long-term HCQ treatment were included in the analysis. The median (interquartile range [IQR]) [HCQ] was 515 (IQR 353-720) ng/ml, the median [DHCQ] was 417 (IQR 266-591) ng/ml, and the median [HCQ]:[DHCQ] ratio was 1.3 (range 1.0-1.7). [HCQ] was closely associated with [DHCQ] (r = 0.81, P < 0.0001). The weight-adjusted oral HCQ dose was strongly associated with both [HCQ] (P < 0.001) and [DHCQ] (P < 0.001). Time since last dose was associated with [HCQ] (P < 0.001). No statistically significant association was found between renal function or smoking and [HCQ] or [DHCQ]. Use of additional immunosuppressants increased both [HCQ] and [DHCQ] after adjusting for possible confounders (P = 0.04 and P = 0.03, respectively). The lower SLEDAI score was significantly related to higher [HCQ], after adjusting for age, sex, weight-adjusted HCQ dose, time since last dose, number of other immunosuppressants, and smoking status (P = 0.007). Various factors affected blood levels of [HCQ], [DHCQ], or the [HCQ]:[DHCQ] ratio of SLE patients receiving long-term oral HCQ treatment. Notably, higher [HCQ] was associated with a lower SLEDAI score in our typical outpatient clinic population with lupus. © 2016, American College of Rheumatology.

Variation in intravenous iron use internationally and over time: the Dialysis Outcomes and Practice Patterns Study (DOPPS).

PubMed

Bailie, George R; Larkina, Maria; Goodkin, David A; Li, Yun; Pisoni, Ronald L; Bieber, Brian; Mason, Nancy; Tong, Lin; Locatelli, Francesco; Marshall, Mark R; Inaba, Masaki; Robinson, Bruce M

2013-10-01

To examine patterns of intravenous (IV) iron use across 12 countries from 1999 to 2011. Trends in iron use are described among 32 192 hemodialysis (HD) patients in the Dialysis Outcomes and Practice Patterns Study. Adjusted associations of IV iron dose with serum ferritin and transferrin saturation (TSAT) values were also studied. IV iron was administered to 50% of patients over 4 months in 1999, increasing to 71% during 2009-11, with increasing use in most countries. Among patients receiving IV iron, the mean monthly dose increased from 232 ± 167 to 281 ± 211 mg. Most countries used 3 to 4 doses/month, but Canada used about 2 doses/month, Italy increased from 3 to almost 6 doses/month and Germany used 5 to 6 doses/month. The USA and most European countries predominantly used iron sucrose and sodium ferric gluconate. A significant use of iron dextran was limited to Canada and France; iron polymaltose was used in Australia and New Zealand; and Japan used ferric oxide saccharate, chondroitin polysulfate iron complex and cideferron. Ferritin values rose in most countries: 22% of patients had ≥ 800 ng/mL in the recent years of study. TSAT levels increased to a lesser degree over time. Japan had much lower IV iron dosing and ferritin levels, but similar TSAT levels. In adjusted analyses, serum ferritin and TSAT levels increased signifcantly by 14 ng/mL and 0.16%, respectively, for every 100 mg/month higher mean monthly iron dose. IV iron prescription patterns varied between countries and changed over time from 1999 to 2011. IV iron use and dose increased in most countries, with notable increases in ferritin but not TSAT levels. With rising cumulative IV iron doses, studies of the effects of changing IV iron dosing and other anemia management practices on clinical outcomes should be a high priority.

Individual exposures to drinking water trihalomethanes, low birth weight and small for gestational age risk: a prospective Kaunas cohort study.

PubMed

Grazuleviciene, Regina; Nieuwenhuijsen, Mark J; Vencloviene, Jone; Kostopoulou-Karadanelli, Maria; Krasner, Stuart W; Danileviciute, Asta; Balcius, Gediminas; Kapustinskiene, Violeta

2011-04-19

Evidence for an association between exposure during pregnancy to trihalomethanes (THMs) in drinking water and impaired fetal growth is still inconsistent and inconclusive, in particular, for various exposure routes. We examined the relationship of individual exposures to THMs in drinking water on low birth weight (LBW), small for gestational age (SGA), and birth weight (BW) in singleton births. We conducted a cohort study of 4,161 pregnant women in Kaunas (Lithuania), using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, to estimate an internal dose of THM. We used regression analysis to evaluate the relationship between internal THM dose and birth outcomes, adjusting for family status, education, smoking, alcohol consumption, body mass index, blood pressure, ethnic group, previous preterm, infant gender, and birth year. The estimated internal dose of THMs ranged from 0.0025 to 2.40 mg/d. We found dose-response relationships for the entire pregnancy and trimester-specific THM and chloroform internal dose and risk for LBW and a reduction in BW. The adjusted odds ratio for third tertile vs. first tertile chloroform internal dose of entire pregnancy was 2.17, 95% CI 1.19-3.98 for LBW; the OR per every 0.1 μg/d increase in chloroform internal dose was 1.10, 95% CI 1.01-1.19. Chloroform internal dose was associated with a slightly increased risk of SGA (OR 1.19, 95% CI 0.87-1.63 and OR 1.22, 95% CI 0.89-1.68, respectively, for second and third tertile of third trimester); the risk increased by 4% per every 0.1 μg/d increase in chloroform internal dose (OR 1.04, 95% CI 1.00-1.09). THM internal dose in pregnancy varies substantially across individuals, and depends on both water THM levels and water use habits. Increased internal dose may affect fetal growth.

Reducing Xerostomia After Chemo-IMRT for Head and Neck Cancer: Beyond Sparing the Parotid Glands

PubMed Central

Little, Michael; Schipper, Matthew; Feng, Felix Y.; Vineberg, Karen; Cornwall, Craig; Murdoch-Kinch, Carol-Anne; Eisbruch, Avraham

2011-01-01

Purpose To assess whether in addition to sparing parotid glands (PGs), xerostomia after chemo-IMRT of head and neck cancer is affected by reducing doses to other salivary glands. Methods Prospective study: 78 patients with stages III/IV oropharynx/nasopharynx cancers received chemo-IMRT aiming to spare the parts outside the targets of bilateral PGs, oral cavity (OC) containing the minor salivary glands, and contralateral submandibular gland (SMG) (when contralateral level I was not a target). Pretherapy and periodically through 24 months, validated patient-reported xerostomia questionnaires (XQ) scores and observer-graded xerostomia were recorded, and stimulated and unstimulated saliva measured selectively from each of the PGs and SMGs. Mean OC doses served as surrogates of minor salivary glands dysfunction. Regression models assessed XQ and observer-graded xerostomia predictors. Results Statistically significant predictors of the XQ score in univariate analysis included OC, PG, and SMG mean doses, as well as baseline XQ score, time since RT, and both stimulated and unstimulated PG saliva flow rates. Similar factors were statistically significant predictors of observer-graded xerostomia. OC, PG and SMG mean doses were moderately inter-correlated (r=0.47–0.55). In multivariate analyses, after adjusting for PG and SMG doses, OC mean dose (p < 0.0001), time from RT (p < 0.0001), and stimulated PG saliva (p < 0.0025) were significant predictors for XQ scores, and OC mean dose and time for observer-graded xerostomia. While scatter plots showed no thresholds, OC mean doses <40 Gy and contralateral SMG mean <50 Gy were each associated with low patient-reported and observer-rated xerostomia at almost all post-therapy time points. Conclusion PG, SMG and OC mean doses were significant predictors of both patient-reported and observer-rated xerostomia after chemo-IMRT, with OC doses remaining significant after adjusting for PG and SMG doses. These results support efforts to spare all salivary glands by IMRT, beyond the PGs alone. PMID:22056067

Individual exposures to drinking water trihalomethanes, low birth weight and small for gestational age risk: a prospective Kaunas cohort study

PubMed Central

2011-01-01

Background Evidence for an association between exposure during pregnancy to trihalomethanes (THMs) in drinking water and impaired fetal growth is still inconsistent and inconclusive, in particular, for various exposure routes. We examined the relationship of individual exposures to THMs in drinking water on low birth weight (LBW), small for gestational age (SGA), and birth weight (BW) in singleton births. Methods We conducted a cohort study of 4,161 pregnant women in Kaunas (Lithuania), using individual information on drinking water, ingestion, showering and bathing, and uptake factors of THMs in blood, to estimate an internal dose of THM. We used regression analysis to evaluate the relationship between internal THM dose and birth outcomes, adjusting for family status, education, smoking, alcohol consumption, body mass index, blood pressure, ethnic group, previous preterm, infant gender, and birth year. Results The estimated internal dose of THMs ranged from 0.0025 to 2.40 mg/d. We found dose-response relationships for the entire pregnancy and trimester-specific THM and chloroform internal dose and risk for LBW and a reduction in BW. The adjusted odds ratio for third tertile vs. first tertile chloroform internal dose of entire pregnancy was 2.17, 95% CI 1.19-3.98 for LBW; the OR per every 0.1 μg/d increase in chloroform internal dose was 1.10, 95% CI 1.01-1.19. Chloroform internal dose was associated with a slightly increased risk of SGA (OR 1.19, 95% CI 0.87-1.63 and OR 1.22, 95% CI 0.89-1.68, respectively, for second and third tertile of third trimester); the risk increased by 4% per every 0.1 μg/d increase in chloroform internal dose (OR 1.04, 95% CI 1.00-1.09). Conclusions THM internal dose in pregnancy varies substantially across individuals, and depends on both water THM levels and water use habits. Increased internal dose may affect fetal growth. PMID:21501533

10 CFR 835.702 - Individual monitoring records.

Code of Federal Regulations, 2010 CFR

2010-01-01

... emergency exposures. (b) Recording of the non-uniform equivalent dose to the skin is not required if the... internal dose (committed effective dose or committed equivalent dose) is not required for any monitoring...: (i) The effective dose from external sources of radiation (equivalent dose to the whole body may be...

10 CFR 835.702 - Individual monitoring records.

Code of Federal Regulations, 2011 CFR

2011-01-01

... emergency exposures. (b) Recording of the non-uniform equivalent dose to the skin is not required if the... internal dose (committed effective dose or committed equivalent dose) is not required for any monitoring...: (i) The effective dose from external sources of radiation (equivalent dose to the whole body may be...

10 CFR 835.702 - Individual monitoring records.

Code of Federal Regulations, 2014 CFR

2014-01-01

... emergency exposures. (b) Recording of the non-uniform equivalent dose to the skin is not required if the... internal dose (committed effective dose or committed equivalent dose) is not required for any monitoring...: (i) The effective dose from external sources of radiation (equivalent dose to the whole body may be...

10 CFR 835.702 - Individual monitoring records.

Code of Federal Regulations, 2013 CFR

2013-01-01

... emergency exposures. (b) Recording of the non-uniform equivalent dose to the skin is not required if the... internal dose (committed effective dose or committed equivalent dose) is not required for any monitoring...: (i) The effective dose from external sources of radiation (equivalent dose to the whole body may be...

10 CFR 835.702 - Individual monitoring records.

Code of Federal Regulations, 2012 CFR

2012-01-01

... emergency exposures. (b) Recording of the non-uniform equivalent dose to the skin is not required if the... internal dose (committed effective dose or committed equivalent dose) is not required for any monitoring...: (i) The effective dose from external sources of radiation (equivalent dose to the whole body may be...

47 CFR 80.169 - Operators required to adjust transmitters or radar.

Code of Federal Regulations, 2011 CFR

2011-10-01

... radar. 80.169 Section 80.169 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Requirements § 80.169 Operators required to adjust transmitters or radar. (a) All adjustments of radio... transmitting Morse code. (c) Only persons holding an operator certificate containing a ship radar endorsement...

47 CFR 80.169 - Operators required to adjust transmitters or radar.

Code of Federal Regulations, 2010 CFR

2010-10-01

... radar. 80.169 Section 80.169 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Requirements § 80.169 Operators required to adjust transmitters or radar. (a) All adjustments of radio... transmitting Morse code. (c) Only persons holding an operator certificate containing a ship radar endorsement...

47 CFR 80.169 - Operators required to adjust transmitters or radar.

Code of Federal Regulations, 2012 CFR

2012-10-01

... radar. 80.169 Section 80.169 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Requirements § 80.169 Operators required to adjust transmitters or radar. (a) All adjustments of radio... transmitting Morse code. (c) Only persons holding an operator certificate containing a ship radar endorsement...

SU-C-BRE-02: BED Vs. Local Control: Radiobiological Effect of Tumor Volume in Monte Carlo (MC) Lung SBRT Planning

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pokhrel, D; Badkul, R; Jiang, H

2014-06-15

Purpose: SBRT with hypofractionated dose schemata has emerged a compelling treatment modality for medically inoperable early stage lung cancer patients. It requires more accurate dose calculation and treatment delivery technique. This report presents the relationship between tumor control probability(TCP) and size-adjusted biological effective dose(sBED) of tumor volume for MC lung SBRT patients. Methods: Fifteen patients who were treated with MC-based lung SBRT to 50Gy in 5 fractions to PTVV100%=95% were studied. ITVs were delineated on MIP images of 4DCT-scans. PTVs diameter(ITV+5mm margins) ranged from 2.7–4.9cm (mean 3.7cm). Plans were generated using non-coplanar conformal arcs/beams using iPlan XVMC algorithm (BrainLABiPlan ver.4.1.2)more » for Novalis-TX with HD-MLCs and 6MVSRS(1000MU/min) mode, following RTOG-0813 dosimetric guidelines. To understand the known uncertainties of conventional heterogeneities-corrected/uncorrected pencil beam (PBhete/ PB-homo) algorithms, dose distributions were re-calculated with PBhete/ PB-homo using same beam configurations, MLCs and monitor units. Biologically effective dose(BED10) was computed using LQ-model with α/β=10Gy for meanPTV and meanITV. BED10-c*L, gave size-adjusted BED(sBED), where c=10Gy/cm and L=PTV diameter in centimeter. The TCP model was adopted from Ohri et al.(IJROBP, 2012): TCP = exp[sBEDTCD50]/ k /(1.0 + exp[sBED-TCD50]/k), where k=31Gy corresponding to TCD50=0Gy; and more realistic MC-based TCP was computed for PTV(V99%). Results: Mean PTV PB-hete TCP value was 6% higher, but, mean PTV PB-homo TCP value was 4% lower compared to mean PTV MC TCP. Mean ITV PB-hete/PB-homo TCP values were comparable (within ±3.0%) to mean ITV MC TCP. The mean PTV(V99%)had BED10=90.9±3.7%(median=92.2%),sBED=54.1±8.2%(median=53.5%) corresponding to mean MC TCP value of 84.8±3.3%(median=84.9%) at 2- year local control. Conclusion: The TCP model which incorporates BED10 and tumor diameter indicates that radiobiological effect of target volume and dose calculation algorithm significantly affects TCP for lung SBRT patients. Dose calculation using MC-based algorithm is more realistic with tissue heterogeneities and is routinely performed in our clinic. Patients will be followed up to determine whether TCP prediction correlate clinical outcomes.« less

Population pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes.

PubMed

Riggs, Matthew M; Staab, Alexander; Seman, Leo; MacGregor, Thomas R; Bergsma, Timothy T; Gastonguay, Marc R; Macha, Sreeraj

2013-10-01

Data from five randomized, placebo-controlled, multiple oral dose studies of empagliflozin in patients with type 2 diabetes mellitus (T2DM; N = 974; 1-100 mg q.d.; ≤12 weeks) were used to develop a population pharmacokinetic (PK) model for empagliflozin. The model consisted of two-compartmental disposition, lagged first-order absorption and first-order elimination, and incorporated appropriate covariates. Population estimates (interindividual variance, CV%) of oral apparent clearance, central and peripheral volumes of distribution, and inter-compartmental clearance were 9.87 L/h (26.9%), 3.02 L, 60.4 L (30.8%), and 5.16 L/h, respectively. An imposed allometric weight effect was the most influential PK covariate effect, with a maximum effect on exposure of ±30%, using 2.5th and 97.5th percentiles of observed weights, relative to the median observed weight. Sex and race did not lend additional description to PK variability beyond allometric weight effects, other than ∼25% greater oral absorption rate constant for Asian patients. Age, total protein, and smoking/alcohol history did not affect PK parameters. Predictive check plots were consistent with observed data, implying an adequate description of empagliflozin PKs following multiple dosing in patients with T2DM. The lack of marked covariate effects, including weight, suggests that no exposure-based dose adjustments were required within the study population and dose range. © The Author(s) 2013 John Wiley & Sons, Ltd.

Use of Sugammadex in Patients With Obesity: A Pooled Analysis.

PubMed

Monk, Terri G; Rietbergen, Henk; Woo, Tiffany; Fennema, Hein

A growing proportion of patients undergoing surgical procedures are obese, providing anesthesiologists with numerous challenges for patient management. The current pooled analysis evaluated recovery times following sugammadex reversal of neuromuscular blockade by body mass index (BMI) in general, and in particular, in patients with BMIs ≥30 kg/m (defined as obese) and <30 kg/m (defined as non-obese). Data were pooled from 27 trials evaluating recommended sugammadex doses for reversal of moderate [reappearance of the second twitch of the train-of-four (TOF); sugammadex 2 mg/kg] or deep (1-2 post-tetanic counts or 15 minutes after rocuronium; sugammadex 4 mg/kg) rocuronium- or vecuronium-induced neuromuscular blockade. All doses of sugammadex were administered based on actual body weight. The recovery time from sugammadex administration to a TOF ratio ≥0.9 was the primary efficacy variable in all individual studies and in the pooled analysis. This analysis comprised a total of 1418 adult patients treated with sugammadex; 267 (18.8%) of these patients had a BMI ≥30 kg/m. The average time to recovery of the TOF ratio to 0.9 was 1.9 minutes for rocuronium-induced blockade and 3.0 minutes for vecuronium-induced blockade. No clinically relevant correlation was observed between BMI and recovery time. The recommended sugammadex doses based on actual body weight provide rapid recovery from neuromuscular blockade in both obese and non-obese patients; no dose adjustments are required in the obese patient.

Single‐Center Evaluation of the Pharmacokinetics and Safety of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Mild to Moderate Hepatic Impairment

PubMed Central

Karim, Aziz; Zhao, Zhen; Alonso, Alberto B.; Garg, Dyal; Preston, Richard A.

2017-01-01

Abstract Azilsartan medoxomil (AZL‐M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose‐dependent manner. It is a prodrug that is not detected in blood after its oral administration because of its rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite, M‐II, and minor metabolites. The objective of this study was to determine the effect of mild to moderate hepatic impairment on the pharmacokinetics of AZL and its major metabolite. This was a single‐center, open‐label, phase 1 parallel‐group study that examined the single‐dose (day 1) and multiple‐dose (days 4–8) — 40 mg — pharmacokinetics of AZL and M‐II in 16 subjects with mild and moderate hepatic impairment by Child‐Pugh classification (n = 8 per group) and subjects (n = 16) matched based on age, sex, race, weight, and smoking status. Mild or moderate hepatic impairment did not cause clinically meaningful increases in exposure to AZL and M‐II. Mild or moderate hepatic impairment had no clinically meaningful effect on the plasma protein binding of AZL and M‐II. Single and multiple doses of AZL‐M 40 mg were well tolerated in all subject groups. Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL‐M is required for subjects with mild and moderate hepatic impairment. PMID:28750149

Bioequivalence of a single 400-mg dose of imatinib 100-mg oral tablets and a 400-mg tablet in healthy adult Korean volunteers.

PubMed

Lee, Hae Won; Seong, Sook Jin; Park, Sung Min; Lee, Joomi; Gwon, Mi-Ri; Kim, Hyun-Ju; Lim, Sung Mook; Lim, Mi-Sun; Kim, Woomi; Yang, Dong Heon; Yoon, Young-Ran

2015-06-01

Imatinib mesylate (IM) is a selective tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. A new once-daily 400-mg film-coated tablet of imatinib has been developed by a pharmaceutical company in Korea. The present study was designed to assess and compare the PK parameters, bioavailability, and bioequivalence of the new imatinib 400-mg formulation (test) versus the conventional 100-mg formulation (reference) administered as a single 400-mg dose in healthy adult male volunteers. This randomized, open-label, single-dose, two-way crossover study was conducted in healthy Korean male volunteers. Eligible subjects were randomly assigned in a 1 : 1 ratio to receive 400 mg of the test (one 400-mg tablet) or reference (four 100-mg tablets) formulation, followed by a 2-week washout period and administration of the alternate formulation. Serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, and 72 hours after administration. Plasma imatinib concentrations were determined using liquid chromatography coupled with tandem mass spectrometry. The formulations were to be considered bioequivalent if the 90% confidence intervals (CIs) of the adjusted geometric mean ratios for Cmax, AUC(0-t), and AUC(0-∞)ž were within the predetermined range of 0.80 - 1.25. In total, 35 subjects completed the study. No serious adverse event was reported during the study. The 90% CIs of the adjusted geometric mean ratios of the test formulation to the reference formulation for C(max), AUC(0-t) and AUC(0-∞)ž of imatinib were all within the bioequivalence criteria range of 0.8 - 1.25. The test formulation of imatinib met the Korean regulatory requirements for bioequivalence. Both imatinib formulations were well-tolerated in all subjects.

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4-week, randomized, placebo-controlled trial (EASE-1).

PubMed

Pieber, T R; Famulla, S; Eilbracht, J; Cescutti, J; Soleymanlou, N; Johansen, O E; Woerle, H J; Broedl, U C; Kaspers, S

2015-10-01

To investigate the pharmacodynamics, efficacy and safety of empagliflozin as adjunct to insulin in patients with type 1 diabetes. A total of 75 patients with glycated haemoglobin (HbA1c) concentrations of ≥7.5 to ≤10.5% (≥58 to ≤91 mmol/mol) were randomized to receive once-daily empagliflozin 2.5 mg, empagliflozin 10 mg, empagliflozin 25 mg, or placebo as adjunct to insulin for 28 days. Insulin dose was to be kept as stable as possible for 7 days then adjusted, at the investigator's discretion, to achieve optimum glycaemic control. The primary exploratory endpoint was change from baseline in 24-h urinary glucose excretion (UGE) on day 7. Empagliflozin significantly increased 24-h UGE versus placebo on days 7 and 28. On day 28, adjusted mean differences with empagliflozin versus placebo in changes from baseline in: HbA1c were -0.35 to -0.49% (-3.8 to -5.4 mmol/mol; all p < 0.05 vs. placebo); total daily insulin dose -0.07 to -0.09 U/kg (all p<0.05 vs placebo); and weight were -1.5 to -1.9 kg (all p < 0.001 vs. placebo). In the placebo, empagliflozin 2.5, 10 and 25 mg groups, respectively, adverse events were reported in 94.7, 89.5, 78.9 and 100.0% of patients, and the rate of symptomatic hypoglycaemic episodes with glucose ≤3.0 mmol/l not requiring assistance was 1.0, 0.4, 0.5 and 0.8 episodes per 30 days. In patients with type 1 diabetes, empagliflozin for 28 days as adjunct to insulin increased UGE, improved HbA1c and reduced weight with lower insulin doses compared with placebo and without increasing hypoglycaemia. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemotherapy-related neuropathic symptoms and functional impairment in adult survivors of extracranial solid tumors of childhood: results from the St. Jude Lifetime Cohort Study.

PubMed

Ness, Kirsten K; Jones, Kendra E; Smith, Webb A; Spunt, Sheri L; Wilson, Carmen L; Armstrong, Gregory T; Srivastava, Deo Kumar; Robison, Leslie L; Hudson, Melissa M; Gurney, James G

2013-08-01

To ascertain prevalence of peripheral sensory and motor neuropathy, and to evaluate impairments in relation to function. St. Jude Lifetime Cohort Study, a clinical follow-up study designed to evaluate adverse late effects in adult survivors of childhood cancer. A children's research hospital. Eligibility required treatment for an extracranial solid malignancy between 1962 and 2002, age ≥ 18 years, ≥ 10 years postdiagnosis, and no history of cranial radiation. Survivors (N=531) were included in the evaluation with a median age of 32 years and a median time from diagnosis of 25 years. Not applicable. Primary exposure measures were cumulative doses of vinca-alkaloid and platinum-based chemotherapies. Survivors with scores ≥ 1 on the sensory subscale of the Modified Total Neuropathy Score were classified with prevalent sensory impairment. Those with sex-specific z scores of ≤-1.3 for dorsiflexion strength were classified with prevalent motor impairment. Participants completed the 6-minute walk test (endurance), the Timed Up & Go test (mobility), and the Sensory Organization Test (balance). The prevalence of sensory and motor impairment was 20% and 17.5%, respectively. Vinca-alkaloid exposure was associated with an increased risk of motor impairment (adjusted odds ratio [OR]=1.66; 95% confidence interval [CI], 1.04-2.64) without evidence for a dose response. Platinum exposure was associated with increased risk of sensory impairment (adjusted OR=1.62; 95% CI, .97-2.72) without evidence of a dose response. Sensory impairment was associated with poor endurance (OR=1.99; 95% CI, .99-4.0) and mobility (OR=1.65; 95% CI, .96-2.83). Vincristine and cisplatin exposure may increase risk for long-term motor and sensory impairment, respectively. Survivors with sensory impairment are at increased risk for functional performance limitations. Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

SU-E-T-287: Patterns of Patient Specific Dosimetry in Total Body Irradiation.

PubMed

Akino, Y; McMullen, K; Das, I

2012-06-01

Total body irradiation (TBI) is commonly used for conditioning prior to transplant in hematologic and immunologic diseases. Due to variability in body thickness, achieving dose uniformity across body within ±10% of the prescribed dose is challenging. The dose uniformity is further complicated by, techniques and beam energy used, lung shielding and selection of detector. The translational table technique for TBI could compensate for estimated delivered dose to whole body by adjusting couch speed during treatment. However, it is difficult to accurately estimate the dose by calculation and hence in vivo dosimetry (IVD) is routinely performed for TBI. The patterns of patient specific dosimetry, IVD are presented in this study. Under IRB exempt status, 161 patients who received TBI treatment between 2006 and 2011 were retrospectively analyzed using the treatment records from Cobalt-60 teletherapy unit and translational treatment couch. During treatment, IVD detectors (TLD, diode, or MOSFET) were placed on patient surface; both entrance and exit dose were recorded at the patient's head, neck, mediastinum, umbilicus, and knee. When large differences between prescribed and measured dose were observed, the dose delivery was corrected for subsequent fractions by adjustment in couch speed and/or bolus placement. Across the entire cohort, the mean (range) percent variance between calculated and measured dose were -2.3% (-66.2 - 35.3), 1.1% (-62.2 - 40.3), -1.9% (-66.4 - 46.6), -1.1% (-35.2 - 42.9), and 3.4% (-47.9 - 108.5) for head, neck, mediastinum, umbilicus, and knee, respectively. When the dose differences for multiple fractions were averaged, the compliance (±10%) between prescription and measured dose was improved as at umbilicus from 83.9% to 98.5%. Actual dose measurement analysis of TBI patients reveals a potentially wide variance from calculated dose. Dose uniformity can be significantly improved with immediate feedback after the first fraction prior to subsequent treatments. This work was supported by the JSPS Core-to-Core Program No. 23003. © 2012 American Association of Physicists in Medicine.

Tobacco smoking is associated with psychotic experiences in the general population of South London.

PubMed

Bhavsar, V; Jauhar, S; Murray, R M; Hotopf, M; Hatch, S L; McNeill, A; Boydell, J; MacCabe, J H

2018-01-01

The association between cigarette smoking and psychosis remains unexplained, but could relate to causal effects in both directions, confounding by socioeconomic factors, such as ethnicity, or use of other substances, including cannabis. Few studies have evaluated the association between cigarettes and psychotic experiences (PEs) in diverse, inner-city populations, or relationships with number of cigarettes consumed. We assessed associations and dose-response relationships between cigarette smoking and PEs in a cross-sectional survey of household residents (n = 1680) in South East London, using logistic regression to adjust for cannabis use, other illicit substances, and socioeconomic factors, including ethnicity. We found association between any PEs and daily cigarette smoking, which remained following adjustment for age, gender, ethnicity, cannabis and use of illicit stimulant drugs (fully adjusted odds ratio 1.47, 95% confidence interval 1.01-2.15). Fully adjusted estimates for the association, and with number of PEs, increased with number of cigarettes smoked daily, implying a dose-response effect (p = 0.001 and <0.001, respectively). Odds of reporting any PEs in ex-smokers were similar to never-smokers. In this diverse epidemiological sample, association between smoking and PEs was not explained by confounders such as cannabis or illicit drugs. Daily cigarette consumption showed a dose-response relationship with the odds of reporting PEs, and of reporting a greater number of PEs. There was no difference in odds of reporting PEs between ex-smokers and never-smokers, raising the possibility that the increase in PEs associated with smoking may be reversible.

Effects of Regional Differences in Asia on Efficacy and Safety of Edoxaban Compared With Warfarin--Insights From the ENGAGE AF-TIMI 48 Trial.

PubMed

Shimada, Yuichi J; Yamashita, Takeshi; Koretsune, Yukihiro; Kimura, Tetsuya; Abe, Kenji; Sasaki, Shunichi; Mercuri, Michele; Ruff, Christian T; Giugliano, Robert P

2015-01-01

In 21,105 patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial, edoxaban was non-inferior to warfarin in preventing thromboembolic events while reducing bleeding. We compared results in Japan with the rest of East Asia (EA), including China, Korea, and Taiwan. We compared baseline characteristics, time-in-therapeutic range (TTR) for warfarin, and outcomes (efficacy: stroke or systemic embolic events [SEE], safety: major bleeding). Interaction P values were used to assess for effect modification of treatment (higher-dose edoxaban [HDE, 60 mg/30 mg] vs. warfarin; lower-dose edoxaban [LDE, 30 mg/15 mg] vs. warfarin) by region with adjustments for baseline characteristics. Fewer patients in Japan (n=1,010) were female, taking aspirin or amiodarone, naïve to warfarin (P<0.001 for each), had a history of stroke or transient ischemic attack (P=0.02), and more patients needed dose reduction (P<0.001) compared with EA (n=933). The mean TTR was higher in Japan (70% vs. 56%, P<0.001). Evidence for statistical interactions was observed for HDE vs. warfarin by region for stroke/SEE (adjusted P-int=0.052) and major bleeding (adjusted P-int=0.048) with greater relative efficacy and safety with HDE in EA compared with Japan. No interactions were observed for LDE vs. warfarin after adjustment. HDE had a greater relative efficacy and safety in EA compared with Japan that was only partially explained by differences in baseline characteristics and TTR.

A poly(glycerol sebacate)-coated mesoporous bioactive glass scaffold with adjustable mechanical strength, degradation rate, controlled-release and cell behavior for bone tissue engineering.

PubMed

Lin, Dan; Yang, Kai; Tang, Wei; Liu, Yutong; Yuan, Yuan; Liu, Changsheng

2015-07-01

Various requirements in the field of tissue engineering have motivated the development of three-dimensional scaffold with adjustable physicochemical properties and biological functions. A series of multiparameter-adjustable mesoporous bioactive glass (MBG) scaffolds with uncrosslinked poly(glycerol sebacate) (PGS) coating was prepared in this article. MBG scaffold was prepared by a modified F127/PU co-templating process and then PGS was coated by a simple adsorption and lyophilization process. Through controlling macropore parameters and PGS coating amount, the mechanical strength, degradation rate, controlled-release and cell behavior of the composite scaffold could be modulated in a wide range. PGS coating successfully endowed MBG scaffold with improved toughness and adjustable mechanical strength covering the bearing range of trabecular bone (2-12MPa). Multilevel degradation rate of the scaffold and controlled-release rate of protein from mesopore could be achieved, with little impact on the protein activity owing to an "ultralow-solvent" coating and "nano-cavity entrapment" immobilization method. In vitro studies indicated that PGS coating promoted cell attachment and proliferation in a dose-dependent manner, without affecting the osteogenic induction capacity of MBG substrate. These results first provide strong evidence that uncrosslinked PGS might also yield extraordinary achievements in traditional MBG scaffold. With the multiparameter adjustability, the composite MBG/PGS scaffolds would have a hopeful prospect in bone tissue engineering. The design considerations and coating method of this study can also be extended to other ceramic-based artificial scaffolds and are expected to provide new thoughts on development of future tissue engineering materials. Copyright © 2015 Elsevier B.V. All rights reserved.

Insulin therapy for type 2 diabetes - are we there yet? The d-Nav® story.

PubMed

Hodish, I

2018-01-01

Insulin replacement therapy is mostly used by patients with type 2 diabetes who become insulin deficient and have failed other therapeutic options. They comprise about a quarter of those with diabetes, endures the majority of the complications and consumes the majority of the resources. Adequate insulin replacement therapy can prevent complications and reduce expenses, as long as therapy goals are achieved and maintained. Sadly, these therapy goals are seldom achieved and outcomes have not improved for decades despite advances in pharmacotherapy and technology. There is a growing recognition that the low success rate of insulin therapy results from intra-individual and inter-individual variations in insulin requirements. Total insulin requirements per day vary considerably between patients and constantly change without achieving a steady state. Thus, the key element in effective insulin therapy is unremitting and frequent dosage adjustments that can overcome those dynamics. In practice, insulin adjustments are done sporadically during outpatient clinic. Due to time constraints, providers are not able to deliver appropriate insulin dosage optimization. The d-Nav® Insulin Guidance Service has been developed to provide appropriate insulinization in insulin users without increasing the burden on healthcare systems. It relies on dedicated clinicians and a spectrum of technological solutions. Patients are provided with a handheld device called d-Nav® which advises them what dose of insulin to administer during each injection and automatically adjust insulin dosage when needed. The d-Nav care specialists periodically follow-up with users through telephone calls and in-person consultations to bestow user confidence, correct usage errors, triage, and identify uncharacteristic clinical courses. The following review provide details about the service and its clinical outcomes.

47 CFR 80.169 - Operators required to adjust transmitters or radar.

Code of Federal Regulations, 2013 CFR

2013-10-01

... radar. 80.169 Section 80.169 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Requirements § 80.169 Operators required to adjust transmitters or radar. (a) All adjustments of radio... certificate containing a ship radar endorsement must perform such functions on radar equipment. [51 FR 31213...

47 CFR 80.169 - Operators required to adjust transmitters or radar.

Code of Federal Regulations, 2014 CFR

2014-10-01

... radar. 80.169 Section 80.169 Telecommunication FEDERAL COMMUNICATIONS COMMISSION (CONTINUED) SAFETY AND... Requirements § 80.169 Operators required to adjust transmitters or radar. (a) All adjustments of radio... certificate containing a ship radar endorsement must perform such functions on radar equipment. [51 FR 31213...

45 CFR 84.44 - Academic adjustments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 45 Public Welfare 1 2013-10-01 2013-10-01 false Academic adjustments. 84.44 Section 84.44 Public... Academic adjustments. (a) Academic requirements. A recipient to which this subpart applies shall make such modifications to its academic requirements as are necessary to ensure that such requirements do not discriminate...

45 CFR 84.44 - Academic adjustments.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 1 2014-10-01 2014-10-01 false Academic adjustments. 84.44 Section 84.44 Public... Academic adjustments. (a) Academic requirements. A recipient to which this subpart applies shall make such modifications to its academic requirements as are necessary to ensure that such requirements do not discriminate...

45 CFR 84.44 - Academic adjustments.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 1 2012-10-01 2012-10-01 false Academic adjustments. 84.44 Section 84.44 Public... Academic adjustments. (a) Academic requirements. A recipient to which this subpart applies shall make such modifications to its academic requirements as are necessary to ensure that such requirements do not discriminate...

Economic Impact of Dengue Illness and the Cost-Effectiveness of Future Vaccination Programs in Singapore

PubMed Central

Carrasco, Luis R.; Lee, Linda K.; Lee, Vernon J.; Ooi, Eng Eong; Shepard, Donald S.; Thein, Tun L.; Gan, Victor; Cook, Alex R.; Lye, David; Ng, Lee Ching; Leo, Yee Sin

2011-01-01

Background Dengue illness causes 50–100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings. Methods and Findings We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US$ ranged between $0.85 billion and $1.15 billion, of which control costs constitute 42%–59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9–14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from $50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to $300 for vaccination requiring 2 doses and conferring lifetime immunity. The thresholds for these vaccine programs to not be cost-effective for Singapore were $100 and $500 per dose respectively. Conclusions Dengue illness presents a serious economic and disease burden in Singapore. Dengue vaccines are expected to be cost-effective if reasonably low prices are adopted and will help to reduce the economic and disease burden of dengue in Singapore substantially. PMID:22206028

Recombinant factor VIII Fc fusion protein for the prevention and treatment of bleeding in children with severe hemophilia A.

PubMed

Young, G; Mahlangu, J; Kulkarni, R; Nolan, B; Liesner, R; Pasi, J; Barnes, C; Neelakantan, S; Gambino, G; Cristiano, L M; Pierce, G F; Allen, G

2015-06-01

Prophylactic factor replacement, which prevents hemarthroses and thereby reduces the musculoskeletal disease burden in children with hemophilia A, requires frequent intravenous infusions (three to four times weekly). Kids A-LONG was a phase 3 open-label study evaluating the safety, efficacy and pharmacokinetics of a longer-acting factor, recombinant factor VIII Fc fusion protein (rFVIIIFc), in previously treated children with severe hemophilia A (endogenous FVIII level of < 1 IU dL(-1) [< 1%]). The study enrolled 71 subjects. The starting rFVIIIFc regimen was twice-weekly prophylaxis (Day 1, 25 IU kg(-1) ; Day 4, 50 IU kg(-1) ); dose (≤ 80 IU kg(-1) ) and dosing interval (≥ 2 days) were adjusted as needed. A subset of subjects had sequential pharmacokinetic evaluations of FVIII and rFVIIIFc. The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included pharmacokinetics, annualized bleeding rate (ABR), and number of infusions required to control a bleed. No subject developed an inhibitor to rFVIIIFc. Adverse events were typical of a pediatric hemophilic population. The rFVIIIFc half-life was prolonged relative to that of FVIII, consistent with observations in adults and adolescents. The median ABR was 1.96 overall, and 0.00 for spontaneous bleeds; 46.4% of subjects reported no bleeding episodes on study. Ninety-three per cent of bleeding episodes were controlled with one to two infusions. The median average weekly rFVIIIFc prophylactic dose was 88.11 IU kg(-1) . At study end, 62 of 69 subjects (90%) were infusing twice weekly. Among subjects who had been previously receiving FVIII prophylaxis, 74% reduced their dosing frequency with rFVIIIFc. Twice-weekly infusions with rFVIIIFc were well tolerated and yielded low bleeding rates in children with severe hemophilia A. © 2015 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Association of benzodiazepine and Z-drug use with the risk of hospitalisation for fall-related injuries among older people: a nationwide nested case-control study in Taiwan.

PubMed

Yu, Nan-Wen; Chen, Pei-Jung; Tsai, Hui-Ju; Huang, Chih-Wan; Chiu, Yu-Wen; Tsay, Wen-Ing; Hsu, Jui; Chang, Chia-Ming

2017-07-11

Non-benzodiazepine hypnotics (Z-drugs) are advocated to be safer than benzodiazepines (BZDs). This study comprehensively investigated the association of BZD and Z-drug usage with the risk of hospitalisation for fall-related injuries in older people. This study used the Taiwan National Health Insurance Database with a nested matched case-control design. We identified 2238 elderly patients who had been hospitalised for fall-related injuries between 2003 and 2012. They were individually matched (1:4) with a comparison group by age, sex, and index year. Conditional logistic regression was used to determine independent effects of drug characteristics (type of exposure, dosage, half-life, and polypharmacy) on older people. Older people hospitalisation for fall-related injuries were significantly associated with current use of BZDs (adjusted odds ratio [AOR] = 1.32, 95% confidential interval [CI] = 1.17-1.50) and Z-drugs (AOR = 1.24, 95%CI = 1.05-1.48). At all dose levels of BZDs, high dose levels of Z-drugs, long-acting BZD, and short-acting BZD use were all significantly increased the risk of fall-related injuries requiring hospitalisation. Polypharmacy, the use of two or more kinds of BZDs, one kind of BZD plus Z-drugs and two or more kinds of BZDs plus Z-drugs, also significantly increased the risk (AOR = 1.61, 95% CI = 1.38-1.89; AOR = 1.65, 95% CI = 1.08-2.50, and AOR = 1.58, 95% CI = 1.21-2.07). Different dose levels and half-lives of BZDs, a high dose of Z-drugs, and polypharmacy with BZDs and Z-drugs were associated with an increased risk of fall-related injury requiring hospitalisation in older people. Physicians should balance the risks and benefits when prescribing these drug regimens to older people considering the risk of falls.

Neurological Change after Gamma Knife Radiosurgery for Brain Metastases Involving the Motor Cortex

PubMed Central

Park, Chang-Yong; Choi, Hyun-Yong; Lee, Sang-Ryul; Roh, Tae Hoon; Seo, Mi-Ra

2016-01-01

Background Although Gamma Knife radiosurgery (GKRS) can provide beneficial therapeutic effects for patients with brain metastases, lesions involving the eloquent areas carry a higher risk of neurologic deterioration after treatment, compared to those located in the non-eloquent areas. We aimed to investigate neurological change of the patients with brain metastases involving the motor cortex (MC) and the relevant factors related to neurological deterioration after GKRS. Methods We retrospectively reviewed clinical, radiological and dosimetry data of 51 patients who underwent GKRS for 60 brain metastases involving the MC. Prior to GKRS, motor deficits existed in 26 patients (50.9%). The mean target volume was 3.2 cc (range 0.001–14.1) at the time of GKRS, and the mean prescription dose was 18.6 Gy (range 12–24 Gy). Results The actuarial median survival time from GKRS was 19.2±5.0 months. The calculated local tumor control rates at 6 and 12 months after GKRS were 89.7% and 77.4%, respectively. During the median clinical follow-up duration of 12.3±2.6 months (range 1–54 months), 18 patients (35.3%) experienced new or worsened neurologic deficits with a median onset time of 2.5±0.5 months (range 0.3–9.7 months) after GKRS. Among various factors, prescription dose (>20 Gy) was a significant factor for the new or worsened neurologic deficits in univariate (p=0.027) and multivariate (p=0.034) analysis. The managements of 18 patients were steroid medication (n=10), boost radiation therapy (n=5), and surgery (n=3), and neurological improvement was achieved in 9 (50.0%). Conclusion In our series, prescription dose (>20 Gy) was significantly related to neurological deterioration after GKRS for brain metastases involving the MC. Therefore, we suggest that careful dose adjustment would be required for lesions involving the MC to avoid neurological deterioration requiring additional treatment in the patients with limited life expectancy. PMID:27867921

Effectiveness of pentavalent rotavirus vaccine in a large urban population in the United States.

PubMed

Boom, Julie A; Tate, Jacqueline E; Sahni, Leila C; Rench, Marcia A; Hull, Jennifer J; Gentsch, Jon R; Patel, Manish M; Baker, Carol J; Parashar, Umesh D

2010-02-01

The goal was to assess the effectiveness of complete (3-dose) or partial (1- or 2-dose) immunization with pentavalent rotavirus vaccine (RV5) against rotavirus acute gastroenteritis (AGE) in US clinical practice. A case-control evaluation was conducted in February through June 2008 at an emergency department in Houston, Texas. Case patients with rotavirus AGE (N = 90) were identified through testing for rotavirus in fecal specimens obtained from 205 children 15 days through 23 months of age presenting with AGE. Control groups included rotavirus-negative AGE patients (N = 115), concurrently enrolled patients with acute respiratory infection (ARI) (N = 228), and up to 10 age- and zip code-matched children sampled from the Houston-Harris County Immunization Registry (HHCIR) for each case patient >8 months of age. Immunization data were obtained from parent records, health care providers, and/or the HHCIR. Vaccine effectiveness was calculated as 1 minus odds of RV5 vaccination for case patients versus control patients, after adjustment for age at presentation and birth date. The vaccine effectiveness of a complete RV5 series was 89% (95% confidence interval [CI]: 70%-96%) and 85% (95% CI: 55%-95%) with rotavirus-negative AGE and ARI control patients, respectively. Immunization data were available for 44% of case patients (n = 40) from the HHCIR; the estimated 3-dose vaccine effectiveness with these HHCIR control patients was 82% (95% CI: 19%-96%). A complete RV5 series conferred 100% protection (95% CI: 71%-100%) against severe rotavirus disease requiring hospitalization and 96% protection (95% CI: 72%-99%) against disease requiring intravenous hydration. Vaccine effectiveness of 1 and 2 doses against hospitalization and emergency department visits was 69% (95% CI: 13%-89%) and 81% (95% CI: 13%-96%), respectively, using rotavirus-negative AGE and ARI control groups combined. In this setting, a complete series of RV5 was highly effective against severe rotavirus AGE. Partial immunization also conferred substantial protection.

Serum and tissue concentrations of gallium after oral administration of gallium nitrate and gallium maltolate to neonatal calves.

PubMed

Monk, Caroline S; Sweeney, Raymond W; Bernstein, Lawrence R; Fecteau, Marie-Eve

2016-02-01

To determine serum and tissue concentrations of gallium (Ga) after oral administration of gallium nitrate (GaN) and gallium maltolate (GaM) to neonatal calves. 8 healthy neonatal calves. Calves were assigned to 1 of 2 groups (4 calves/group). Gallium (50 mg/kg) was administered as GaN or GaM (equivalent to 13.15 mg of Ga/kg for GaN and 7.85 mg of Ga/kg for GaM) by oral gavage once daily for 5 days. Blood samples were collected 0, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after Ga administration on day 1; 4 and 24 hours after Ga administration on days 2, 3, and 4; and 4, 12, and 24 hours after Ga administration on day 5. On day 6, calves were euthanized and tissue samples were obtained. Serum and tissue Ga concentrations were measured by use of mass spectrometry. Data were adjusted for total Ga dose, and comparisons were made between the 2 groups. Calves receiving GaM had a significantly higher dose-adjusted area under the curve and dose-adjusted maximum serum Ga concentration than did calves receiving GaN. Despite receiving less Ga per dose, calves receiving GaM had tissue Ga concentrations similar to those for calves receiving GaN. In this study, calves receiving GaM had significantly higher Ga absorption than did calves receiving GaN. These findings suggested that GaM might be useful as a prophylactic agent against Mycobacterium avium subsp paratuberculosis infection in neonatal calves.

Influence of Gestational Age and Body Weight on the Pharmacokinetics of Labetalol in Pregnancy

PubMed Central

Fischer, James H.; Sarto, Gloria E.; Hardman, Jennifer; Endres, Loraine; Jenkins, Thomas M.; Kilpatrick, Sarah J.; Jeong, Hyunyoung; Geller, Stacie; Deyo, Kelly; Fischer, Patricia A.; Rodvold, Keith A.

2015-01-01

Background and Objectives Labetalol is frequently prescribed for treatment of hypertension during pregnancy. However, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension. Methods Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. Final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing. Results Lean body weight (LBW) and gestational age, i.e., weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy. Conclusions Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women. PMID:24297680

Responses to fertility treatment among patients with cancer: a retrospective cohort study.

PubMed

Dolinko, A V; Farland, L V; Missmer, S A; Srouji, S S; Racowsky, C; Ginsburg, E S

2018-01-01

Cancer treatments have significant negative impacts on female fertility, but the impact of cancer itself on fertility remains to be clarified. While some studies have shown that compared with healthy women, those with cancer require higher doses of gonadotropins resulting in decreased oocyte yields, others have shown comparable oocyte yields between the two groups. The purpose of this study is to evaluate whether there is an association between any cancer and/or type of cancer, and response to ovarian stimulation for egg and embryo banking. In this retrospective cohort study, ovarian stimulation cycles performed from June 2007 through October 2014 at a single academic medical center were reviewed to identify those undertaken for women with cancer undergoing fertility preservation ( n  = 147) or women with no cancer undergoing their first cycle due to male factor infertility ( n  = 664). Of the 147 women undergoing fertility preservation, 105 had local cancer (Stage I-III solid malignancies) and 42 had systemic cancer (hematologic or Stage IV solid malignancies). Response to ovarian stimulation was compared among these two groups and women with no cancer. Adjusting for age and BMI, women with systemic cancer had lower baseline antral follicle counts (AFC) than women with no cancer or local cancer. Women with systemic cancer required higher doses of FSH than women with no cancer or local cancer, and they had higher oocyte to AFC ratios than women with no cancer or local cancer, but greater odds of cycle cancellation as compared to women with no cancer or local cancer. No significant differences were observed among the three groups for duration of stimulation, number of oocytes and mature oocytes retrieved, or number of embryos created. Women with cancer achieve similar oocyte and embryo yields as women with no cancer, although those with systemic cancer require higher FSH doses and are at greater risk of cycle cancellation.

Solid Cancer Incidence in the Techa River Incidence Cohort: 1956-2007.

PubMed

Davis, F G; Yu, K L; Preston, D; Epifanova, S; Degteva, M; Akleyev, A V

2015-07-01

Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all-solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites.

Renal Insufficiency in Concert with Renin-angiotensin-aldosterone Inhibition Is a Major Risk Factor for Hyperkalemia Associated with Low-dose Trimethoprim-sulfamethoxazole in Adults.

PubMed

Higashioka, Kazuhiko; Niiro, Hiroaki; Yoshida, Kenji; Oryoji, Kensuke; Kamada, Kazuo; Mizuki, Shinichi; Yokota, Eisuke

2016-01-01

Low-dose trimethoprim-sulfamethoxazole (TMP-SMX) is commonly used to prevent pneumocystis pneumonia in daily practice. Previous reports have shown a relationship between high- or standard-dose of TMP-SMX and hyperkalemia, however it remains unclear whether this is true for low-dose TMP-SMX. In this study we sought to determine the risk factors for hyperkalemia associated with low-dose TMP-SMX. In this retrospective cohort study, 186 consecutive adult patients who received TMP-SMX as prophylaxis for pneumocystis pneumonia from January 2014 to January 2015 were evaluated. Data on the patients' age, gender, baseline estimated glomerular filtration rate (eGFR), baseline serum potassium, maximum serum potassium, duration reaching the maximal serum potassium level, dosage, and concomitant use of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB), β-blockers, non-steroidal anti-inflammatory drugs and potassium-sparing diuretics were retrospectively collected. Hyperkalemia was defined as a serum potassium level ≥5 mEq/L. Univariate and multivariate analyses were performed. The median age of the patients was 66 years and 51.1% were men. Hyperkalemia associated with low-dose TMP-SMX was observed in 32 patients (17.2%). The median duration to reach the maximal serum potassium level was 12 days. The multivariate logistic regression analysis identified renal insufficiency to be a major risk factor for hyperkalemia associated with low-dose TMP-SMX (eGFR <60 mL/min/1.73 m(2), adjusted OR 4.62). Moreover, in the subpopulation of patients with renal insufficiency, ACEi/ARB use was considered to be a major risk factor for hyperkalemia (adjusted OR 3.96). Renal insufficiency in concert with ACEi/ARB use is a major risk factor for hyperkalemia induced by low-dose TMP-SMX.

Tunable, Quantitative Fenton-RAFT Polymerization via Metered Reagent Addition.

PubMed

Nothling, Mitchell D; McKenzie, Thomas G; Reyhani, Amin; Qiao, Greg G

2018-05-10

A continuous supply of radical species is a key requirement for activating chain growth and accessing quantitative monomer conversions in reversible addition-fragmentation chain transfer (RAFT) polymerization. In Fenton-RAFT, activation is provided by hydroxyl radicals, whose indiscriminate reactivity and short-lived nature poses a challenge to accessing extended polymerization times and quantitative monomer conversions. Here, an alternative Fenton-RAFT procedure is presented, whereby radical generation can be finely controlled via metered dosing of a component of the Fenton redox reaction (H 2 O 2 ) using an external pumping system. By limiting the instantaneous flux of radicals and ensuring sustained radical generation over tunable time periods, metered reagent addition reduces unwanted radical "wasting" reactions and provides access to consistent quantitative monomer conversions with high chain-end fidelity. Fine tuning of radical concentration during polymerization is achieved simply via adjustment of reagent dose rate, offering significant potential for automation. This modular strategy holds promise for extending traditional RAFT initiation toward more tightly regulated radical concentration profiles and affords excellent prospects for the automation of Fenton-RAFT polymerization. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A new apparatus for on-site calibration of gamma dose rate monitors

NASA Astrophysics Data System (ADS)

Zhang, Yu; Chen, Bo; Zhao, Chao; Zhuo, Weihai

2018-01-01

In order to carry out on-site calibrations of environmental gamma dose rate monitors, a new irradiation apparatus was developed in this study. The apparatus mainly consists of a piece of 137Cs source, a set of beam attenuators, and 3 built-in laser rangefinders, and it can be remotely controlled by using a laptop through WiFi network. With an activity of 4.6 × 108 Bq of 137Cs source, the reference air kerma rate could be adjusted from 0.26 μGy h-1 to 140 μGy h-1 by changing the calibration distance from 0.5 m to 5 m and using different beam attenuators (or none), and both the reproducibility and the homogeneity of reference radiation were better than 97%. The overall uncertainty of the calibration was estimated to be 6.5% (k = 2). Both the laboratory and field experiments confirmed that the calibration method met the requirements of ISO 4037-1. As the advantages of portability and simplicity, it is considered that the new irradiation apparatus is applicable to stationary gamma radiation monitors for on-site calibration.

Therapeutic drug monitoring in pregnancy.

PubMed

Matsui, Doreen M

2012-10-01

Therapeutic drug monitoring (TDM) is commonly recommended to optimize drug dosing regimens of various medications. It has been proposed to guide therapy in pregnant women, in whom physiological changes may lead to altered pharmacokinetics resulting in difficulty in predicting the appropriate drug dosage. Ideally, TDM may play a role in enhancing the effectiveness of treatment while minimizing toxicity of both the mother and fetus. Monitoring of drug levels may also be helpful in assessing adherence to prescribed therapy in selected cases. Limitations exist as therapeutic ranges have only been defined for a limited number of drugs and are based on data obtained in nonpregnant patients. TDM has been suggested for anticonvulsants, antidepressants, and antiretroviral drugs, based on pharmacokinetic studies that have shown reduced drug concentrations. However, there is only relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Further studies are required to determine whether implementation of TDM during pregnancy improves outcome and is associated with any benefit beyond that achieved by clinical judgment alone. The cost effectiveness of TDM programs during pregnancy also remains to be examined.

Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy.

PubMed

Newkirk, Kim M; Atkins, Rosalie M; Dickson, Patti I; Rohrbach, Barton W; McEntee, Michael F

2011-07-11

Mucopolysaccharidosis I (MPS I) is an inherited metabolic disorder resulting from deficiency of α-L-iduronidase and lysosomal accumulation of glycosaminoglycans (GAG) in multiple tissues. Accumulation of GAG in corneal stromal cells causes corneal opacity and reduced vision. The purpose of this study was to determine the extent of ocular GAG accumulation and investigate the effectiveness of intravenous enzyme replacement therapy (ERT) on corneal GAG accumulation in dogs. Ocular tissues were obtained from 58 dogs with mucopolysaccharidosis I and four unaffected controls. Affected dogs received either low-dose ERT, high-dose ERT, or no treatment; some low-dose dogs also received intrathecal treatments. Histologic severity of corneal stromal GAG accumulation was scored. Accumulation of GAG was found in corneal stromal cells and scleral fibroblasts but not in corneal epithelium, endothelium, ciliary epithelium, choroid, retina, retinal pigment epithelium, or optic nerve. Corneal GAG accumulation increased in severity with increasing age. Although low-dose ERT did not significantly reduce corneal stromal GAG accumulation in comparison with untreated animals, high-dose ERT did result in significantly less GAG accumulation compared with the untreated dogs (adjusted P = 0.0143) or the low-dose ERT group (adjusted P = 0.0031). Intrathecal treatments did not significantly affect GAG accumulation. Dogs that began ERT shortly after birth also had significantly less (P < 0.0001) GAG accumulation in the corneal stroma than dogs with a later onset of treatment. These data suggest that high-dose, intravenous ERT is effective at preventing and/or clearing corneal stromal GAG accumulation, particularly if initiated early after birth.

Can body composition be used to optimize the dose of platinum chemotherapy in lung cancer? A feasibility study.

PubMed

Crosby, Vincent; D'Souza, Catherine; Bristow, Carina; Proffitt, Amy; Hussain, Asmah; Potter, Vanessa; Hennig, Ivo; O'Connor, Richard; Baracos, Vickie; Wilcock, Andrew

2017-04-01

Current methods of dosing platinum-based chemotherapy are suboptimal. Potentially, taking lean body mass into account may help. To inform the design of a future study, we first examined the feasibility and acceptability of such an approach using dual-energy X-ray absorptiometry (DEXA) and explored aspects suggestive of over- and under-dosing. Patients with lung cancer offered platinum-based chemotherapy over 1 year were identified and, if eligible, invited to take part in a prospective feasibility study. Questionnaires examined acceptability of the DEXA scan and of a future study that randomized between traditional dosing and one adjusted according to body composition. Dose-limiting toxicity (DLT) and a lack of neutropenia explored potential over- and under-dosing, respectively. Of the 173 patients offered chemotherapy, 123 (71%) were ineligible, mostly because of failing entry criteria (84, 49%). Of the 50 approached, 18 (36%) participated, most receiving carboplatin, with 17 providing data. All found a DEXA scan acceptable; other assessments were fully completed, except nadir and pre-chemotherapy blood counts. Most (94%) were prepared to take part in a future study, although the additional hospital visits for a nadir blood count were unpopular with some. Five (29%) patients experienced six episodes of DLT which resulted in discontinuation (3), dose reduction (2) or change to a less toxic regimen (1). Nine (60%) patients experienced either no (2) or inconsistent (7) neutropenia. A randomized trial appears acceptable and feasible in patients receiving carboplatin. Adjustment of our entry criteria and avoiding a hospital visit for a nadir blood count should aid recruitment.

A review of protocols for 308 nm excimer laser phototherapy in psoriasis.

PubMed

Mudigonda, Tejaswi; Dabade, Tushar S; Feldman, Steven R

2012-01-01

308 nm excimer laser phototherapy is efficacious in the treatment of localized psoriasis. Different approaches regarding dose fluency, number of treatments, and maintenance have been utilized, and there is yet to be a consensus on standard protocol. To characterize treatment parameters for 308 nm excimer laser phototherapy. We performed a PubMed search for studies describing excimer laser treatment protocol with particular attention to dosage determination, dose adjustment, dose fluency, number of treatments, and maintenance. Seven prospective studies were found describing the excimer efficacy for psoriasis. All studies determined the initial treatment dose using either the minimal erythema dose (MED) or induration. Fluency ranged from 0.5 MED (low) to 16 MED (high); one study demonstrated that medium to high fluencies yielded better improvement in fewer number of treatments. Fluency adjustments during the course of treatment were important to minimize phototherapy-associated side effects. The use of higher fluencies was reported to result in higher occurrences of blistering. One study implemented a maintenance tapering of dose-frequency phase to better manage psoriasis flare-ups. The 308 nm excimer laser is an effective therapy for psoriasis regardless of the method used to determine initial dosage, dose fluency, or number of treatments. As its usage as a targeted monotherapy increases, future trials should consider evaluating and modifying these parameters to determine the most optimal management of localized psoriasis. Based on our reviewed studies, there is no consensus for a single excimer laser therapy protocol and as a result, patient preferences should continue to be an important consideration for phototherapy regimen planning.

Randomized pharmacokinetic cross-over study comparing two curcumin preparations in plasma and rectal tissue of healthy human volunteers

PubMed Central

Asher, Gary N.; Xie, Ying; Moaddel, Ruin; Sanghvi, Mitesh; Dossou, Katina S.S.; Kashuba, Angela D. M.; Sandler, Robert S.; Hawke, Roy L.

2016-01-01

Curcumin is poorly absorbed driving interest in new preparations. However, little is known about pharmacokinetics and tissue bioavailability between formulations. In this randomized, crossover study we evaluated the relationship between steady-state plasma and rectal tissue curcuminoid concentrations using standard and phosphatidylcholine curcumin extracts. There was no difference in the geometric mean plasma AUCs when adjusted for the 10-fold difference in curcumin dose between the two formulations. Phosphatidylcholine curcumin extract yielded only 20–30% plasma demethoxycurcumin and bisdemethoxycurcumin conjugates compared to standard extract, yet yielded 20-fold greater hexahydrocurcumin. When adjusting for curcumin dose, tissue curcumin concentrations were 5-fold greater for the phosphatidylcholine extract. Improvements in curcuminoid absorption due to phosphatidylcholine are not uniform across the curcuminoids. Furthermore, curcuminoid exposures in the intestinal mucosa are most likely due to luminal exposure rather than plasma disposition. Finally, once-daily dosing is sufficient to maintain detectable curcuminoids at steady-state in both plasma and rectal tissues. PMID:27503249

Genetic Polymorphism of Inosine Triphosphate Pyrophosphatase Is a Determinant of Mercaptopurine Metabolism and Toxicity During Treatment for Acute Lymphoblastic Leukemia

PubMed Central

Stocco, G; Cheok, MH; Crews, KR; Dervieux, T; French, D; Pei, D; Yang, W; Cheng, C; Pui, C-H; Relling, MV; Evans, WE

2009-01-01

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype. PMID:18685564

Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia.

PubMed

Stocco, G; Cheok, M H; Crews, K R; Dervieux, T; French, D; Pei, D; Yang, W; Cheng, C; Pui, C-H; Relling, M V; Evans, W E

2009-02-01

The influence of genetic polymorphism in inosine triphosphate pyrophosphatase (ITPA) on thiopurine-induced adverse events has not been investigated in the context of combination chemotherapy for acute lymphoblastic leukemia (ALL). This study investigated the effects of a common ITPA variant allele (rs41320251) on mercaptopurine metabolism and toxicity during treatment of children with ALL. Significantly higher concentrations of methyl mercaptopurine nucleotides were found in patients with the nonfunctional ITPA allele. Moreover, there was a significantly higher probability of severe febrile neutropenia in patients with a variant ITPA allele among patients whose dose of mercaptopurine had been adjusted for TPMT genotype. In a cohort of patients whose mercaptopurine dose was not adjusted for TPMT phenotype, the TPMT genotype had a greater effect than the ITPA genotype. In conclusion, genetic polymorphism of ITPA is a significant determinant of mercaptopurine metabolism and of severe febrile neutropenia, after combination chemotherapy for ALL in which mercaptopurine doses are individualized on the basis of TPMT genotype.

45 CFR 153.365 - General oversight requirements for State-operated risk adjustment programs.

Code of Federal Regulations, 2014 CFR

2014-10-01

... risk adjustment programs. 153.365 Section 153.365 Public Welfare Department of Health and Human Services REQUIREMENTS RELATING TO HEALTH CARE ACCESS STANDARDS RELATED TO REINSURANCE, RISK CORRIDORS, AND RISK ADJUSTMENT UNDER THE AFFORDABLE CARE ACT State Standards Related to the Risk Adjustment Program...

Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole

PubMed Central

Agudelo, M.

2012-01-01

Animal models of infection have been used to demonstrate the therapeutic failure of “bioequivalent” generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR2] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 ± 5.17 h) or to kill the first (90.8 ± 9.78 h) and second (155.5 ± 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials. PMID:22330928

Dosimetry around metallic ports in tissue expanders in patients receiving postmastectomy radiation therapy: an ex vivo evaluation.

PubMed

Moni, Janaki; Graves-Ditman, Maria; Cederna, Paul; Griffith, Kent; Krueger, Editha A; Fraass, Benedick A; Pierce, Lori J

2004-01-01

Postmastectomy breast reconstruction can be accomplished utilizing tissue expanders and implants. However, in patients who require postoperative radiotherapy, the complication rate with tissue expander/implant reconstruction can exceed 50%. One potential cause of this high complication rate may be the metallic port in the tissue expander producing altered dosimetry in the region of the metallic device. The purpose of this study was to quantify the radiation dose distribution in the vicinity of the metallic port and determine its potential contribution to this extremely high complication rate. The absolute dosimetric effect of the tissue expander's metallic port was quantified using film and thermoluminescent dosimetry (TLD) studies with a single beam incident on a metallic port extracted from an expander. TLD measurements were performed at 11 reproducible positions on an intact expander irradiated with tangential fields. A computed tomography (CT)-based treatment plan without inhomogeneity corrections was used to derive expected doses for all TLD positions. Multiple irradiation experiments were performed for all TLD data. Confidence intervals for the dose at TLD sites with the metallic port in place were compared to the expected dose at the site without the metallic port. Film studies did not reveal a significant component of scatter around the metallic port. TLD studies of the extracted metallic port revealed highest doses within the casing of the metallic port and no consistent increased dose at the surface of the expander. No excess dose due to the metallic port in the expander was noted with the phantom TLD data. Based upon these results, it does not appear that the metallic port in tissue expanders significantly contributes to the high complication rate experienced in patients undergoing tissue expander breast reconstruction and receiving radiation therapy. Strategies designed to reduce the breast reconstruction complication rate in this clinical setting will need to focus on factors other than adjusting the dosimetry around the tissue expander metallic port.

Dosage Considerations for Transcranial Direct Current Stimulation in Children: A Computational Modeling Study

PubMed Central

Kessler, Sudha Kilaru; Minhas, Preet; Woods, Adam J.; Rosen, Alyssa; Gorman, Casey; Bikson, Marom

2013-01-01

Transcranial direct current stimulation (tDCS) is being widely investigated in adults as a therapeutic modality for brain disorders involving abnormal cortical excitability or disordered network activity. Interest is also growing in studying tDCS in children. Limited empirical studies in children suggest that tDCS is well tolerated and may have a similar safety profile as in adults. However, in electrotherapy as in pharmacotherapy, dose selection in children requires special attention, and simple extrapolation from adult studies may be inadequate. Critical aspects of dose adjustment include 1) differences in neurophysiology and disease, and 2) variation in brain electric fields for a specified dose due to gross anatomical differences between children and adults. In this study, we used high-resolution MRI derived finite element modeling simulations of two healthy children, ages 8 years and 12 years, and three healthy adults with varying head size to compare differences in electric field intensity and distribution. Multiple conventional and high-definition tDCS montages were tested. Our results suggest that on average, children will be exposed to higher peak electrical fields for a given applied current intensity than adults, but there is likely to be overlap between adults with smaller head size and children. In addition, exposure is montage specific. Variations in peak electrical fields were seen between the two pediatric models, despite comparable head size, suggesting that the relationship between neuroanatomic factors and bioavailable current dose is not trivial. In conclusion, caution is advised in using higher tDCS doses in children until 1) further modeling studies in a larger group shed light on the range of exposure possible by applied dose and age and 2) further studies correlate bioavailable dose estimates from modeling studies with empirically tested physiologic effects, such as modulation of motor evoked potentials after stimulation. PMID:24086698

Augmentation index (AI) in a dose-response relationship with smoking habits in males: The Tanushimaru study.

PubMed

Tsuru, Tomoko; Adachi, Hisashi; Enomoto, Mika; Fukami, Ako; Kumagai, Eita; Nakamura, Sachiko; Nohara, Yume; Kono, Shoko; Nakao, Erika; Sakaue, Akiko; Morikawa, Nagisa; Fukumoto, Yoshihiro

2016-12-01

We investigated the relationship between augmentation index (AI) and smoking habits in community-dwelling Japanese.This cross-sectional study enrolled 1926 subjects (769 males and 1157 females) aged 40 to 95 years who underwent a health check-up in a Japanese cohort of the Seven Countries Study, in Tanushimaru, a typical farming town in Kyushu Island in 2009. The subjects' medical history, alcohol intake, smoking habit, and current medications for hypertension, dyslipidemia, and diabetes were ascertained by questionnaire. Radial arterial pressure wave analysis was used to obtain AI. We analyzed the data stratified by gender.Age-adjusted means of AI in males showed a clear dose-response relationship in 4 categories of smoking habits (P = 0.010). There was no significant relationship between AI and smoking habits in females (P = 0.127). The significant dose-response relationship (P = 0.036) in males between AI and 4 categories of smoking habits still remained even after adjustment for age, body mass index, systolic blood pressure, estimated glomerular filtration rate, glucose, hypertensive medication, and alcohol intake.The present study demonstrated that AI values were significantly associated with smoking habits in a dose-dependent manner in Japanese males.

Delivery quality assurance with ArcCHECK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Neilson, Christopher; Klein, Michael; Barnett, Rob

2013-04-01

Radiation therapy requires delivery quality assurance (DQA) to ensure that treatment is accurate and closely follows the plan. We report our experience with the ArcCHECK phantom and investigate its potential optimization for the DQA process. One-hundred seventy DQA plans from 84 patients were studied. Plans were classified into 2 groups: those with the target situated on the diodes of the ArcCHECK (D plans) and those with the target situated at the center (C plans). Gamma pass rates for 8 target sites were examined. The parameters used to analyze the data included 3%/3 mm with the Van Dyk percent difference criteriamore » (VD) on, 3%/3 mm with the VD off, 2%/2 mm with the VD on, and x/3 mm with the VD on and the percentage dosimetric agreement “x” for diode plans adjusted. D plans typically displayed maximum planned dose (MPD) on the cylindrical surface containing ArcCHECK diodes than center plans, resulting in inflated gamma pass rates. When this was taken into account by adjusting the percentage dosimetric agreement, C plans outperformed D plans by an average of 3.5%. ArcCHECK can streamline the DQA process, consuming less time and resources than radiographic films. It is unnecessary to generate 2 DQA plans for each patient; a single center plan will suffice. Six of 8 target sites consistently displayed pass rates well within our acceptance criteria; the lesser performance of head and neck and spinal sites can be attributed to marginally lower doses and increased high gradient of plans.« less

Optimal methotrexate dose is associated with better clinical outcomes than non-optimal dose in daily practice: results from the ESPOIR early arthritis cohort.

PubMed

Gaujoux-Viala, Cécile; Rincheval, Nathalie; Dougados, Maxime; Combe, Bernard; Fautrel, Bruno

2017-12-01

Although methotrexate (MTX) is the consensual first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), substantial heterogeneity remains with its prescription and dosage, which are often not optimal. To evaluate the symptomatic and structural impact of optimal MTX dose in patients with early RA in daily clinical practice over 2 years. Patients included in the early arthritis ESPOIR cohort who fulfilled the ACR-EULAR (American College of Rheumatology/European League against Rheumatism) criteria for RA and received MTX as a first DMARD were assessed. Optimal MTX dose was defined as ≥10 mg/week during the first 3 months, with escalation to ≥20 mg/week or 0.3 mg/kg/week at 6 months without Disease Activity Score in 28 joints remission. Symptomatic and structural efficacy with and without optimal MTX dose was assessed by generalised logistic regression with adjustment for appropriate variables. Within the first year of follow-up, 314 patients (53%) with RA received MTX as a first DMARD (mean dose 12.2±3.8 mg/week). Only 26.4% (n=76) had optimal MTX dose. After adjustment, optimal versus non-optimal MTX dose was more efficient in achieving ACR-EULAR remission at 1 year (OR 4.28 (95% CI 1.86 to 9.86)) and normal functioning (Health Assessment Questionnaire ≤0.5; OR at 1 year 4.36 (95% CI 2.03 to 9.39)), with no effect on radiological progression. Results were similar during the second year. Optimal MTX dose is more efficacious than non-optimal dose for remission and function in early arthritis in daily practice, with no impact on radiological progression over 2 years. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

Statistic and dosimetric criteria to assess the shift of the prescribed dose for lung radiotherapy plans when integrating point kernel models in medical physics: are we ready?

PubMed

Chaikh, Abdulhamid; Balosso, Jacques

2016-12-01

To apply the statistical bootstrap analysis and dosimetric criteria's to assess the change of prescribed dose (PD) for lung cancer to maintain the same clinical results when using new generations of dose calculation algorithms. Nine lung cancer cases were studied. For each patient, three treatment plans were generated using exactly the same beams arrangements. In plan 1, the dose was calculated using pencil beam convolution (PBC) algorithm turning on heterogeneity correction with modified batho (PBC-MB). In plan 2, the dose was calculated using anisotropic analytical algorithm (AAA) and the same PD, as plan 1. In plan 3, the dose was calculated using AAA with monitor units (MUs) obtained from PBC-MB, as input. The dosimetric criteria's include MUs, delivered dose at isocentre (Diso) and calculated dose to 95% of the target volume (D95). The bootstrap method was used to assess the significance of the dose differences and to accurately estimate the 95% confidence interval (95% CI). Wilcoxon and Spearman's rank tests were used to calculate P values and the correlation coefficient (ρ). Statistically significant for dose difference was found using point kernel model. A good correlation was observed between both algorithms types, with ρ>0.9. Using AAA instead of PBC-MB, an adjustment of the PD in the isocentre is suggested. For a given set of patients, we assessed the need to readjust the PD for lung cancer using dosimetric indices and bootstrap statistical method. Thus, if the goal is to keep on with the same clinical results, the PD for lung tumors has to be adjusted with AAA. According to our simulation we suggest to readjust the PD by 5% and an optimization for beam arrangements to better protect the organs at risks (OARs).

Radiation exposure assessment for portsmouth naval shipyard health studies.

PubMed

Daniels, R D; Taulbee, T D; Chen, P

2004-01-01

Occupational radiation exposures of 13,475 civilian nuclear shipyard workers were investigated as part of a retrospective mortality study. Estimates of annual, cumulative and collective doses were tabulated for future dose-response analysis. Record sets were assembled and amended through range checks, examination of distributions and inspection. Methods were developed to adjust for administrative overestimates and dose from previous employment. Uncertainties from doses below the recording threshold were estimated. Low-dose protracted radiation exposures from submarine overhaul and repair predominated. Cumulative doses are best approximated by a hybrid log-normal distribution with arithmetic mean and median values of 20.59 and 3.24 mSv, respectively. The distribution is highly skewed with more than half the workers having cumulative doses <10 mSv and >95% having doses <100 mSv. The maximum cumulative dose is estimated at 649.39 mSv from 15 person-years of exposure. The collective dose was 277.42 person-Sv with 96.8% attributed to employment at Portsmouth Naval Shipyard.

75 FR 7035 - Notice of Determinations Regarding Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-16

... adjustment assistance, each of the group eligibility requirements of Section 222(a) of the Act must be met. I... issued regarding eligibility to apply for worker adjustment assistance, each of the group eligibility... eligibility to apply for worker adjustment assistance, each of the group eligibility requirements of Section...

78 FR 21152 - Notice of Determinations Regarding Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2013-04-09

... adjustment assistance, each of the group eligibility requirements of Section 222(a) of the Act must be met. I... issued regarding eligibility to apply for worker adjustment assistance, each of the group eligibility... eligibility to apply for worker adjustment assistance, each of the group eligibility requirements of Section...

Dual control of pituitary thyroid stimulating hormone secretion by thyroxine and triiodothyronine in athyreotic patients

PubMed Central

Hoermann, Rudolf; Midgley, John E. M.; Dietrich, Johannes W.; Larisch, Rolf

2017-01-01

Background: Patient responses to levothyroxine (LT4) monotherapy vary considerably. We sought to differentiate contributions of FT4 and FT3 in controlling pituitary thyroid stimulating hormone (TSH) secretion. Methods: We retrospectively assessed the relationships between TSH and thyroid hormones in 319 patients with thyroid carcinoma through 2914 visits on various LT4 doses during follow-up for 5.5 years (median, IQR 4.2, 6.9). We also associated patient complaints with the relationships. Results: Under varying dose requirements (median 1.84 µg/kg, IQR 1.62, 2.11), patients reached TSH targets below 0.4, 0.1 or 0.01 mIU/l at 73%, 54% and 27% of visits. While intercept, slope and fit of linearity of the relationships between lnTSH and FT4/FT3 varied between individuals, gender, age, LT4 dose and deiodinase activity influenced the relationships in the cohort (all p < 0.001). Deiodinase activity impaired by LT4 dose significantly affected the lnTSH–FT4 relationship. Dose increase and reduced conversion efficiency displaced FT3–TSH equilibria. In LT4-treated patients, FT4 and FT3 contributed on average 52% versus 38%, and by interaction 10% towards TSH suppression. Symptomatic presentations (11%) accompanied reduced FT3 concentrations (–0.23 pmol/l, p = 0.001) adjusted for gender, age and BMI, their relationships being shifted towards higher TSH values at comparable FT3/FT4 levels. Conclusions: Variation in deiodinase activity and resulting FT3 levels shape the TSH–FT4 relationship in LT4-treated athyreotic patients, suggesting cascade control of pituitary TSH production by the two hormones. Consequently, measurement of FT3 and calculation of conversion efficiency may identify patients with impaired biochemistry and a resulting lack of symptomatic control. PMID:28794850

Alterations in cyclosporin A pharmacokinetics and metabolism during treatment with St John's wort in renal transplant patients

PubMed Central

Bauer, Steffen; Störmer, Elke; Johne, Andreas; Krüger, Hagen; Budde, Klemens; Neumayer, Hans-Hellmut; Roots, Ivar; Mai, Ingrid

2003-01-01

Aim This study investigated the effects of St John's wort extract (SJW) on the pharmacokinetics and metabolism of the immunosuppressant cyclosporin A (CSA). Methods In an open-label study, 11 renal transplant patients received 600 mg SJW extract daily for 14 days in addition to their regular regimen of CSA. Blood concentrations of CSA and its metabolites AM1, AM1C, AM9, AM19, and AM4N were measured by HPLC. Results After 2 weeks of SJW coadministration, dose-corrected AUC0–12, Cmax and Ctrough values for CSA decreased significantly by 46%[geometric mean ratio baseline/SJW (95% CI): 1.83 (1.63–2.05)], 42%[1.72 (1.42–2.08)], and 41%[1.70 (1.17–2.47)], respectively. CSA doses were increased from a median of 2.7 mg day−1 kg−1 at baseline to 4.2 mg day−1 kg−1 at day 15, with the first dose adjustment required only 3 days after initiation of SJW treatment. Additionally, the metabolite pattern of CSA was substantially altered during SJW treatment. Whereas dose-corrected AUC values for AM1, AM1c and AM4N significantly decreased by 59%, 61%, and 23% compared with baseline, AUC values for AM9 and AM19 were unchanged. Following the increase in CSA dose, observed AUC and Cmax values for AM9, AM19, and AM4N increased by 20–51% and 43–90%, respectively. Conclusion Administration of SJW extract to patients receiving CSA treatment resulted in a rapid and significant reduction of plasma CSA concentrations. Additionally, the substantial alterations in CSA metabolite kinetics observed may affect the toxicity profile of the drug. PMID:12580993

Evaluation of a 12-week targeted vitamin D supplementation regimen in patients with active inflammatory bowel disease.

PubMed

Garg, Mayur; Rosella, Ourania; Rosella, Gennaro; Wu, Yunqiu; Lubel, John S; Gibson, Peter R

2017-06-15

Vitamin D at serum 25(OH)D concentrations above 100 nmol/L is associated with disease remission in patients with IBD, suggesting targeted dosing might be anti-inflammatory. This study aimed to assess the effectiveness, safety and predictors of a 12-week regimen of vitamin D supplementation to achieve such a target in patients with active disease. In a pilot study, patients with active colitis and a serum 25(OH)D concentration <75 nmol/L were prescribed oral liquid vitamin D supplementation over 12 weeks using a specific protocol with dose adjusted 4-weekly to aim for a target level of 100-125 nmol/L. Five patients each with Crohn's colitis or ulcerative colitis (UC) had mean 25(OH)D concentration 52 (range 27-73 nmol/L). Five reached the targeted level and four 89-95 nmol/L. One withdrew after 4 weeks (88 nmol/L). Target dose was met only in those with BMI <30 kg/m 2 and total dose inversely correlated with initial serum 25(OH)D. One patient had developed a high level at 8 weeks (146 nmol/L) and another new hypercalciuria. There were no serious adverse events attributable to the therapy. Clinical disease activity consistently declined, but faecal calprotectin and circulating markers of inflammation did not. A specified oral vitamin D regimen successfully and safely achieved target or near-target levels, improved symptom-based activity scores, but did not alter objective measures of intestinal or systemic inflammation. A modified version of this dose-escalating regimen would be suitable for a randomised placebo-controlled trial, but does require regular safety monitoring. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Perioperative use of iloprost in cardiac surgery patients diagnosed with heparin-induced thrombocytopenia-reactive antibodies or with true HIT (HIT-reactive antibodies plus thrombocytopenia): An 11-year experience.

PubMed

Palatianos, George; Michalis, Alkiviadis; Alivizatos, Petros; Lacoumenda, Stavroula; Geroulanos, Stefanos; Karabinis, Andreas; Iliopoulou, Eugenia; Soufla, Giannoula; Kanthou, Chryso; Khoury, Mazen; Sfyrakis, Petros; Stavridis, George; Astras, George; Vassili, Maria; Antzaka, Christina; Marathias, Katerina; Kriaras, Ioannis; Tasouli, Androniki; Papadopoulos, Kyrillos; Katafygioti, Marina; Matoula, Nikoletta; Angelidis, Antonios; Melissari, Euthemia

2015-07-01

Thrombocytopenia and thromboembolism(s) may develop in heparin immune-mediated thrombocytopenia (HIT) patients after reexposure to heparin. At the Onassis Cardiac Surgery Center, 530 out of 17,000 patients requiring heart surgery over an 11-year period underwent preoperative HIT assessment by ELISA and a three-point heparin-induced platelet aggregation assay (HIPAG). The screening identified 110 patients with HIT-reactive antibodies, out of which 46 were also thrombocytopenic (true HIT). Cardiac surgery was performed in HIT-positive patients under heparin anticoagulation and iloprost infusion. A control group of 118 HIT-negative patients received heparin but no iloprost during surgery. For the first 20 patients, the dose of iloprost diminishing the HIPAG test to ≤5% was determined prior to surgery by in vitro titration using the patients' own plasma and donor platelets. In parallel, the iloprost "target dose" was also established for each patient intraoperatively, but before heparin administration. Iloprost was infused initially at 3 ng/kg/mL and further adjusted intraoperatively, until ex vivo aggregation reached ≤5%. As a close correlation was observed between the "target dose" identified before surgery and that established intraoperatively, the remaining 90 patients were administered iloprost starting at the presurgery identified "target dose." This process significantly reduced the number of intraoperative HIPAG reassessments needed to determine the iloprost target dose, and reduced surgical time, while maintaining similar primary clinical outcomes to controls. Therefore, infusion of iloprost throughout surgery, under continuous titration, allows cardiac surgery to be undertaken safely using heparin, while avoiding life-threatening iloprost-induced hypotension in patients diagnosed with HIT-reactive antibodies or true HIT. © 2015 Wiley Periodicals, Inc.

Comparison of estimated glomerular filtration rate equations for dosing new oral anticoagulants in patients with atrial fibrillation.

PubMed

Manzano-Fernández, Sergio; Andreu-Cayuelas, José M; Marín, Francisco; Orenes-Piñero, Esteban; Gallego, Pilar; Valdés, Mariano; Vicente, Vicente; Lip, Gregory Y H; Roldán, Vanessa

2015-06-01

New oral anticoagulants require dosing adjustment according to renal function. We aimed to determine discordance in hypothetical recommended dosing of these drugs using different estimated glomerular filtration rate equations in patients with atrial fibrillation. Cross-sectional analysis of 910 patients with atrial fibrillation and an indication for oral anticoagulation. The glomerular filtration rate was estimated using the Cockcroft-Gault, Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations. For dabigatran, rivaroxaban, and apixaban we identified dose discordance when there was disagreement in the recommended dose based on different equations. Among the overall population, relative to Cockcroft-Gault, discordance in dabigatran dosage was 11.4% for Modification of Diet in Renal Disease and 10% for Chronic Kidney Disease Epidemiology Collaboration, discordance in rivaroxaban dosage was 10% for Modification of Diet in Renal Disease and 8.5% for the Chronic Kidney Disease Epidemiology Collaboration. The lowest discordance was observed for apixaban: 1.4% for Modification of Diet in Renal Disease and 1.5% for the Chronic Kidney Disease Epidemiology Collaboration. In patients with Cockcroft-Gault<60mL/min or elderly patients, discordances in dabigatran and rivaroxaban dosages were higher, ranging from 13.2% to 30.4%. Discordance in apixaban dosage remained<5% in these patients. Discordance in new oral anticoagulation dosages using different equations is frequent, especially among elderly patients with renal impairment. This discordance was higher in dabigatran and rivaroxaban dosages than in apixaban dosages. Further studies are needed to clarify the clinical importance of these discordances and the optimal anticoagulant dosages depending on the use of different equations to estimate renal function. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors.

PubMed

Yu, Mingming; Gao, Zhiwei; Dai, Xiaojian; Gong, Hui; Zhang, Lianshan; Chen, Xiaoyan; Zhong, Da-Fang; Sy, Sherwin K B

2017-01-01

Apatinib is an oral tyrosine kinase inhibitor approved in China for the treatment of patients with advanced metastatic gastric cancer. The approved dosing schedule is 850 mg once daily. The objective of this study was to develop a population pharmacokinetic (popPK) model of apatinib and determine factors that affect its pharmacokinetics. A popPK model for apatinib was developed using data from 106 individuals, including healthy volunteers and patients with malignant solid tumors. The potential influence of demographic, patient, and laboratory characteristics on oral apatinib pharmacokinetics were investigated in a covariate analysis. The extent of the impact of significant covariates on the exposure of apatinib was evaluated using simulations. The final popPK model was a two-compartment model with mixed first- and zero-order absorption and first-order elimination. The population estimates of apparent clearance (CL/F) and apparent volume at steady-state were 57.8 L/h and 112.5 L, respectively. The non-linear dose proportionality in apatinib relative bioavailability was characterized by a sigmoidal maximum effect (E max ) equation wherein the midpoint dose for the decrease in bioavailability was 766 mg. Patients with advanced gastric cancer exhibited lower bioavailability. Cancer patients in general had lower CL/F than healthy volunteers. Simulation results indicated that apatinib exposure in various population groups were impacted by disease and laboratory characteristics. The increase in apatinib exposure was less than proportional to dose. The pharmacokinetics of apatinib in gastric cancer patients were significantly different from those in patients with other cancer types. Dosing of apatinib in various cancer subpopulations may require adjustments to optimize efficacy and benefits to patients.