Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

PubMed

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Biodistribution after Intravenous Dosing in Rats

PubMed Central

Beekman, Christopher R.; Matta, Murali K.; Thomas, Christopher D.; Mohammad, Adil; Stewart, Sharron; Xu, Lin; Chockalingam, Ashok; Shea, Katherine; Sun, Dajun; Jiang, Wenlei; Patel, Vikram; Rouse, Rodney

2017-01-01

Relative biodistribution of FDA-approved innovator and generic sodium ferric gluconate (SFG) drug products was investigated to identify differences in tissue distribution of iron after intravenous dosing to rats. Three equal cohorts of 42 male Sprague-Dawley rats were created with each cohort receiving one of three treatments: (1) the innovator SFG product dosed intravenously at a concentration of 40 mg/kg; (2) the generic SFG product dosed intravenously at a concentration of 40 mg/kg; (3) saline dosed intravenously at equivalent volume to SFG products. Sampling time points were 15 min, 1 h, 8 h, 1 week, two weeks, four weeks, and six weeks post-treatment. Six rats from each group were sacrificed at each time point. Serum, femoral bone marrow, lungs, brain, heart, kidneys, liver, and spleen were harvested and evaluated for total iron concentration by ICP-MS. The ICP-MS analytical method was validated with linearity, range, accuracy, and precision. Results were determined for mean iron concentrations (µg/g) and mean total iron (whole tissue) content (µg/tissue) for each tissue of all groups at each time point. A percent of total distribution to each tissue was calculated for both products. At any given time point, the overall percent iron concentration distribution did not vary between the two SFG drugs by more than 7% in any tissue. Overall, this study demonstrated similar tissue biodistribution for the two SFG products in the examined tissues. PMID:29283393

Multiple Intravenous Infusions Phase 1b

PubMed Central

Cassano-Piché, A; Fan, M; Sabovitch, S; Masino, C; Easty, AC

2012-01-01

Background Minimal research has been conducted into the potential patient safety issues related to administering multiple intravenous (IV) infusions to a single patient. Previous research has highlighted that there are a number of related safety risks. In Phase 1a of this study, an analysis of 2 national incident-reporting databases (Institute for Safe Medical Practices Canada and United States Food and Drug Administration MAUDE) found that a high percentage of incidents associated with the administration of multiple IV infusions resulted in patient harm. Objectives The primary objectives of Phase 1b of this study were to identify safety issues with the potential to cause patient harm stemming from the administration of multiple IV infusions; and to identify how nurses are being educated on key principles required to safely administer multiple IV infusions. Data Sources and Review Methods A field study was conducted at 12 hospital clinical units (sites) across Ontario, and telephone interviews were conducted with program coordinators or instructors from both the Ontario baccalaureate nursing degree programs and the Ontario postgraduate Critical Care Nursing Certificate programs. Data were analyzed using Rasmussen’s 1997 Risk Management Framework and a Health Care Failure Modes and Effects Analysis. Results Twenty-two primary patient safety issues were identified with the potential to directly cause patient harm. Seventeen of these (critical issues) were categorized into 6 themes. A cause-consequence tree was established to outline all possible contributing factors for each critical issue. Clinical recommendations were identified for immediate distribution to, and implementation by, Ontario hospitals. Future investigation efforts were planned for Phase 2 of the study. Limitations This exploratory field study identifies the potential for errors, but does not describe the direct observation of such errors, except in a few cases where errors were observed. Not all

Bioequivalence of HX575 (recombinant human epoetin alfa) and a comparator epoetin alfa after multiple intravenous administrations: an open-label randomised controlled trial.

PubMed

Sörgel, Fritz; Thyroff-Friesinger, Ursula; Vetter, Andrea; Vens-Cappell, Bernhard; Kinzig, Martina

2009-05-22

HX575 is a human recombinant epoetin alfa that was approved for use in Europe in 2007 under the European Medicines Agency biosimilar approval pathway. Therefore, in order to demonstrate the bioequivalence of HX575 to an existing epoetin alfa, the pharmacokinetic and pharmacodynamic response to steady state circulating concentrations of HX575 and a comparator epoetin alfa were compared following multiple intravenous administrations. An open, randomised, parallel group study was conducted in 80 healthy adult males. Subjects were randomised to multiple intravenous doses of 100 IU/kg body weight of HX575 or of the comparator epoetin alfa three-times-weekly for four weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratio of haematological characteristics were used as surrogate parameters for efficacy evaluation. The haematological profiles of both treatments were similar, as determined from their population mean curves and the AUECHb ratio and 90% confidence interval (99.9% [98.5-101.2%]), the primary pharmacodynamic endpoint of this study. The pharmacokinetic parameters after the treatments showed minor differences after single dosing, but not at steady state doses. After multiple doses, HX575 was bioequivalent to the comparator with respect to the rate and extent of exposure of exogenous epoetin (AUCtau ratio and 90% confidence interval: 89.2% [82.5-96.2%]). Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected. HX575 and the comparator epoetin alfa were bioequivalent at steady state circulating drug concentrations with respect to their pharmacokinetic profile and pharmacodynamic action. This supports the conclusion that HX575 and the comparator epoetin alfa, when administered intraveneously, will be

Pharmacokinetics and Safety of Intravenous Murepavadin Infusion in Healthy Adult Subjects Administered Single and Multiple Ascending Doses.

PubMed

Wach, Achim; Dembowsky, Klaus; Dale, Glenn E

2018-04-01

Murepavadin is the first in class of the outer membrane protein-targeting antibiotics (OMPTA) and a pathogen-specific peptidomimetic antibacterial with a novel, nonlytic mechanism of action targeting Pseudomonas aeruginosa Murepavadin is being developed for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP). The pharmacokinetics (PK) and safety of single and multiple doses of murepavadin were investigated in healthy male subjects. Part A of the study was a double-blind, randomized, placebo-controlled, single-ascending-dose investigation in 10 sequential cohorts where each cohort comprised 6 healthy male subjects; 4 subjects were randomized to murepavadin, and 2 subjects were randomized to placebo. Part B was a double-blind, randomized, placebo-controlled, multiple-ascending-dose investigation in 3 sequential cohorts. After a single dose of murepavadin, the geometric mean half-life (2.52 to 5.30 h), the total clearance (80.1 to 114 ml/h/kg), and the volume of distribution (415 to 724 ml/kg) were consistent across dose levels. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Murepavadin was well tolerated, adverse events were transient and generally mild, and no dose-limiting toxicity was identified. Copyright © 2018 American Society for Microbiology.

Intravenous Single Dose Toxicity of Sweet Bee Venom in Sprague-Dawley Rats

PubMed Central

Lee, Kwang-Ho; Yu, JunSang; Sun, Seungho; Kwon, KiRok

2015-01-01

Objectives: Anaphylactic shock can be fatal to people who become hypersensitive when bee venom pharmacopuncture (BVP) is used. Thus, sweet bee venom (SBV) was developed to reduce these allergic responses. SBV is almost pure melittin, and SBV has been reported to have fewer allergic responses than BVP. BVP has been administered only into acupoints or intramuscularly, but we thought that intravenous injection might be possible if SBV were shown to be a safe medium. The aim of this study is to evaluate the intravenous injection toxicity of SBV through a single-dose test in Sprague-Dawley (SD) rats. Methods: Male and female 6-week-old SD rats were injected intravenously with SBV (high dosage: 1.0 mL/animal; medium dosage: 0.5 mL/animal; low dosage: 0.1 mL/animal). Normal saline was injected into the control group in a similar method. We conducted clinical observations, body weight measurements, and hematology, biochemistry, and histological observations. Results: No death was observed in any of the experimental groups. Hyperemia was observed in the high and the medium dosage groups on the injection day, but from next day, no general symptoms were observed in any of the experimental groups. No significant changes due to intravenous SBV injection were observed in the weights, in the hematology, biochemistry, and histological observations, and in the local tolerance tests. Conclusion: The results of this study confirm that the lethal dose of SBV is over 1.0 mL/animal in SD rats and that the intravenous injection of SBV is safe in SD rats. PMID:26389001

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

PubMed

Landen, Jaren W; Cohen, Sharon; Billing, Clare B; Cronenberger, Carol; Styren, Scot; Burstein, Aaron H; Sattler, Catherine; Lee, Jae-Hong; Jack, Clifford R; Kantarci, Kejal; Schwartz, Pamela F; Duggan, William T; Zhao, Qinying; Sprenger, Ken; Bednar, Martin M; Binneman, Brendon

2017-09-01

Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD). In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose-dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1-x and Aβ 1-40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Multiple-dose ponezumab was generally safe, but not efficacious, in mild-to-moderate AD.

Acute symptomatic sinus bradycardia in a woman treated with pulse dose steroids for multiple sclerosis: a case report.

PubMed

Kundu, Amartya; Fitzgibbons, Timothy P

2015-09-24

Sinus bradycardia has been reported after administration of pulse dose steroids, although most cases have occurred in children and are asymptomatic. We report a case of acute symptomatic sinus bradycardia due to pulse dose steroids in a woman with multiple sclerosis. Interestingly, this patient also suffered from inappropriate sinus tachycardia due to autonomic involvement of multiple sclerosis. A 48-year-old Caucasian woman with multiple sclerosis and chronic palpitations due to inappropriate sinus tachycardia was prescribed a 5-day course of intravenous methylprednisolone for treatment of an acute flare. Immediately following the fourth dose of intravenous methylprednisolone, she developed dyspnea, chest heaviness, and lightheadedness. She was referred to the emergency department where an electrocardiogram showed marked sinus bradycardia (40 beats per minute). Initial laboratory test results, including a complete blood count, basic metabolic profile and cardiac biomarkers, were normal. She was admitted for observation on telemetry monitoring. Her heart rate gradually increased and her symptoms resolved. Her outpatient dose of atenolol, taken for symptomatic inappropriate sinus tachycardia, was resumed. Our patient's acute symptoms were attributed to symptomatic sinus bradycardia due to pulse dose steroid treatment. Although several theories have been suggested to explain this phenomenon, the exact mechanism still remains unknown. It does not warrant any specific treatment, as it is a self-limiting side effect that resolves after discontinuing steroid infusion. Young patients who are free of any active cardiac conditions can safely be administered pulse dose steroids without monitoring. However, older patients with active cardiac conditions should have heart rate and blood pressure monitoring during infusion. Our patient also suffered from inappropriate sinus tachycardia, a manifestation of autonomic involvement of multiple sclerosis that has not been previously

Topical and low-dose intravenous tranexamic acid in cyanotic cardiac surgery.

PubMed

Patel, Jigar; Prajapati, Mrugesh; Patel, Hardik; Gandhi, Hemang; Deodhar, Shilpa; Pandya, Himani

2017-02-01

Background Coagulopathy is a major problem in surgery for cyanotic congenital heart disease. Tranexamic acid has been used both topically and systemically and plays a vital role in pediatric cardiac surgery by reducing blood loss and blood product requirement. We aimed to determine the anti-fibrinolytic effectiveness of low-dose systemic or topical tranexamic acid or a combination of both. Methods Seventy-five patients were divided in 3 groups of 25. Group A patients were given tranexamic acid 20 mg kg -1 intravenously after sternotomy and 20 mg kg -1 after heparin reversal. Group B patients were given tranexamic acid 50 mg kg -1 in 20 mL of saline intrapericardially before sternal closure, with the drain clamped for 20 min. Group C patients were given tranexamic acid 20 mg kg -1 intravenously after sternotomy and 50 mg kg -1 intrapericardially before sternal closure. A number of clinical variables were recorded in the first 3 postoperative days. Ventilator time, intensive care unit stay, and outcome were also recorded. Results Chest tube drainage and blood product requirements were lowest in group C. Blood urea and serum creatinine levels were higher in groups A and C ( p < 0.05). Intensive care unit stay and ventilator time were similar in all 3 groups. No patient died and none had a seizure or other neurological event or thromboembolic complication postoperatively. Conclusion The combination of low-dose intravenous and topical tranexamic acid reduces postoperative blood loss and blood product requirement without incurring neurological, renal or thromboembolic complications. We recommend the routine use of topical and low-dose systemic tranexamic acid in cyanotic pediatric cardiac surgery.

Influence of the intravenous contrast media on treatment planning dose calculations of lower esophageal and rectal cancers.

PubMed

Nasrollah, Jabbari; Mikaeil, Molazadeh; Omid, Esnaashari; Mojtaba, Seyed Siahi; Ahad, Zeinali

2014-01-01

The impact of intravenous (IV) contrast media (CM) on radiation dose calculations must be taken into account in treatment planning. The aim of this study is to evaluate the effect of an intravenous contrast media on dose calculations in three-dimensional conformal radiation therapy (3D-CRT) for lower esophageal and rectal cancers. Seventeen patients with lower esophageal tumors and 12 patients with rectal cancers were analyzed. At the outset, all patients were planned for 3D-CRT based on the computed tomography (CT) scans with IV contrast media. Subsequently, all the plans were copied and replaced on the scans without intravenous CM. The radiation doses calculated from the two sets of CTs were compared. The dose differences between the planning image set using intravenous contrast and the image set without contrast showed an average increase in Monitor Units (MUs) in the lower esophageal region that was 1.28 and 0.75% for 6 and 15 MV photon beams, respectively. There was no statistical significant difference in the rectal region between the two sets of scans in the 3D-CRT plans. The results showed that the dose differences between the plans for the CT scans with and without CM were small and clinically tolerable. However, the differences in the lower esophageal region were significant in the statistical analysis.

Intravenous heparin dosing strategy in hospitalized patients with atrial dysrhythmias.

PubMed

Roswell, Robert O; Greet, Brian; Shah, Sunny; Bernard, Samuel; Milin, Alexandra; Lobach, Iryna; Guo, Yu; Radford, Martha J; Berger, Jeffrey S

2016-08-01

Patients with non-valvular atrial fibrillation (AF) have an elevated stroke risk that is 2-7 times greater than in those without AF. Intravenous unfractionated heparin (UFH) is commonly used for hospitalized patients with atrial fibrillation and atrial flutter (AFL) to prevent stroke. Dosing strategies exist for intravenous anticoagulation in patients with acute coronary syndromes and venous thromboembolic diseases, but there are no data to guide providers on a dosing strategy for intravenous anticoagulation in patients with AF/AFL. 996 hospitalized patients with AF/AFL on UFH were evaluated. Bolus dosing and initial infusion rates of UFH were recorded along with rates of stroke, thromboemobolic events, and bleeding events as defined by the International Society on Thrombosis and Haemostasis criteria. Among 226 patients included in the analysis, 76 bleeding events occurred. Using linear regression analysis, initial rates of heparin infusion ranging from 9.7 to 11.8 units/kilogram/hour (U/kg/h) resulted in activated partial thromboplastin times that were within therapeutic range. The median initial infusion rate in patients with bleeding was 13.3 U/kg/h, while in those without bleeding it was 11.4 U/kg/h; p = 0.012. An initial infusion rate >11.0 U/kg/h yielded an OR 1.95 (1.06-3.59); p = 0.03 for any bleeding event. Using IV heparin boluses neither increased the probability of attaining a therapeutic aPTT (56.1 vs 56.3 %; p = 0.99) nor did it significantly increase bleeding events in the study (35.7 vs 31.3 %; p = 0.48). The results suggest that higher initial rates of heparin are associated with increased bleeding risk. From this dataset, initial heparin infusion rates of 9.7-11.0 U/kg/h without a bolus can result in therapeutic levels of anticoagulation in hospitalized patients with AF/AFL without increasing the risk of bleeding.

The assesment of effectiveness of plasmonic resonance photothermal therapy in tumor-bearing rats after multiple intravenous administration of gold nanorods

NASA Astrophysics Data System (ADS)

Bucharskaya, Alla B.; Maslyakova, Galina N.; Navolokin, Nikita A.; Terentyuk, Georgy S.; Khlebtsov, Boris N.; Khlebtsov, Nikolai G.; Bashkatov, Alexey N.; Genina, Elina A.; Tuchin, V. V.

2017-03-01

To assess the effectiveness of plasmonic photothermal therapy (PPT) multiple intravenous strategy of gold nanorods (GNRs) administration was used before laser exposure. The model of alveolar liver cancer PC-1 was used in male outbred albino rats, which were intravenously administrated by single and multiple injections of GNRs and then were treated by PPT. The gold dosage was 400 μg (single injection group), 800 μg (double injection group), 1200 μg (triple injection group), and absorption maximum of gold nanorods suspension was at the wavelength of 808 nm. 24 hours after last injection the tumors were irradiated by the 808-nm diode laser during 15 min at power density 2.3 W/cm2. Temperature control of the tumor heating was provided by IR imager. 24 hours after the PPT the half of animals from each group was withdrawn from the experiments and the sampling tumor tissue for morphological study was performed. In survived animals the growth of tumors was evaluated during 21 days after the PPT. The antitumor effects of PPT after triple intravenous injection were comparable with those obtained at direct intratumoral administration of similar total dose of GNRs. The effectiveness of PPT depended on gold accumulation in tumor, probably, due to sufficient vascularization of tumor tissue.

Dose-ranging pharmacokinetics of colistin methanesulphonate (CMS) and colistin in rats following single intravenous CMS doses.

PubMed

Marchand, Sandrine; Lamarche, Isabelle; Gobin, Patrice; Couet, William

2010-08-01

The aim of this study was to evaluate the effect of colistin methanesulphonate (CMS) dose on CMS and colistin pharmacokinetics in rats. Three rats per group received an intravenous bolus of CMS at a dose of 5, 15, 30, 60 or 120 mg/kg. Arterial blood samples were drawn at 0, 5, 15, 30, 60, 90, 120, 150 and 180 min. CMS and colistin plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of CMS and colistin were calculated by non-compartmental analysis. Linear relationships were observed between CMS and colistin AUCs to infinity and CMS doses, as well as between CMS and colistin C(max) and CMS doses. CMS and colistin pharmacokinetics were linear for a range of colistin concentrations covering the range of values encountered and recommended in patients even during treatment with higher doses.

Short-term intravenous antimicrobial prophylaxis for elective rectal cancer surgery: results of a prospective randomized non-inferiority trial.

PubMed

Ishibashi, Keiichiro; Ishida, Hideyuki; Kuwabara, Kouki; Ohsawa, Tomonori; Okada, Norimichi; Yokoyama, Masaru; Kumamoto, Kensuke

2014-04-01

To investigate the non-inferiority of postoperative single-dose intravenous antimicrobial prophylaxis to multiple-dose intravenous antimicrobial prophylaxis in terms of the incidence of surgical site infections (SSIs) in patients undergoing elective rectal cancer surgery by a prospective randomized study. Patients undergoing elective surgery for rectal cancer were randomized to receive a single intravenous injection of flomoxef (group 1) or five additional doses (group 2) of flomoxef after the surgery. All the patients had received preoperative oral antibiotic prophylaxis (kanamycin and erythromycin) after mechanical cleansing within 24 h prior to surgery, and had received intravenous flomoxef during surgery. A total of 279 patients (including 139 patients in group 1 and 140 in group 2) were enrolled in the study. The incidence of SSIs was 13.7% in group 1 and 13.6% in group 2 (difference [95% confidence interval]: -0.2% [-0.9 to 0.7%]). The incidence of SSIs was not significantly different in patients undergoing elective rectal surgery who were treated using a single dose of postoperative antibiotics compared to those treated using multiple-dose antibiotics when preoperative mechanical and chemical bowel preparations were employed.

Intravenous paracetamol with a lower dose is also effective for the treatment of patent ductus arteriosus in pre-term infants.

PubMed

Tekgündüz, Kadir Şerafettin; Ceviz, Naci; Caner, İbrahim; Olgun, Haşim; Demirelli, Yaşar; Yolcu, Canan; Şahin, İrfan Oğuz; Kara, Mustafa

2015-08-01

Haemodynamically significant patent ductus arteriosus is a significant cause of morbidity and mortality in pre-term infants. This retrospective study was conducted to investigate the usefulness of lower-dose paracetamol for the treatment of patent ductus arteriosus in pre-term infants. A total of 13 pre-term infants who received intravenous paracetamol because of contrindications or side effects to oral ibuprofen were retrospectively enrolled. In the first patient, the dose regimen was 15 mg/kg/dose, every 6 hours. As the patient developed significant elevation in transaminase levels, the dose was decreased to 10 mg/kg/dose, every 8 hours in the following 12 patients. Echocardiographic examination was conducted daily. In case of closure, it was repeated after 2 days and when needed thereafter in terms of reopening. A total of 13 patients received intravenous paracetamol. Median gestational age was 29 weeks ranging from 24 to 31 weeks and birth weight was 950 g ranging from 470 to 1390 g. The median postnatal age at the first intravenous paracetamol dose was 3 days ranging from 2 to 9 days. In 10 of the 13 patients (76.9%), patent ductus arteriosus was closed at the median 2nd day of intravenous paracetamol ranging from 1 to 4 days. When the patient who developed hepatotoxicity was eliminated, the closure rate was found to be 83.3% (10/12). Intravenous paracetamol may be a useful treatment option for the treatment of patent ductus arteriosus in pre-term infants with contrindication to ibuprofen. In our experience, lower-dose paracetamol is effective in closing the patent ductus arteriosus in 83.3% of the cases.

Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

PubMed

Berger, J S; Gonzalez, A; Hopkins, A; Alshaeri, T; Jeon, D; Wang, S; Amdur, R L; Smiley, R

2016-12-01

The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300μg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15μg and a randomized dose of 50, 100, or 150μg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150μg groups than the 50μg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50μg produces analgesia similar to that produced by either 100μg or 150μg. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple oral dosing of ketoconazole influences pharmacokinetics of quinidine after intravenous and oral administration in beagle dogs.

PubMed

Kuroha, M; Shirai, Y; Shimoda, M

2004-10-01

In this study, we investigated the effect of multiple oral dosing of ketoconazole (KTZ) on pharmacokinetics of quinidine (QN), a CYP3A substrate with low hepatic clearance, after i.v. and oral administration in beagle dogs. Four dogs were given p.o. KTZ for 20 days (200 mg, b.i.d.). QN was administered either i.v. (1 mg/kg) or p.o. (100 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. Multiple oral dosing of KTZ decreased significantly alpha and beta, whereas increased t(1/2beta), V(1), and k(a). The KTZ treatment also decreased significantly both total body clearance (Cl(tot)) and oral clearance (Cl(oral)). No significant change in bioavailability was observed in the presence of KTZ. Co-administration of KTZ increased C(max) of QN to about 1.5-fold. Mean resident time after i.v. administration (MRT(i.v.)), and after oral administration (MRT(p.o.)) of QN were prolonged to about twofold, whereas mean absorption time (MAT) was decreased to 50%. Volume of distribution at steady state (V(d(ss))) of QN was unchanged in the presence of KTZ. These alterations may be because of a decrease in metabolism of QN by inhibition of KTZ on hepatic CYP3A activity. In conclusion, multiple oral dosing of KTZ affected largely pharmacokinetics of QN after i.v. and oral administration in beagle dogs. Therefore, KTZ at a clinical dosing regimen may markedly change the pharmacokinetics of drugs primarily metabolized by CYP3A with low hepatic clearance in dogs. In clinical use, much attention should be paid to concomitant administration of KTZ with the drug when given either p.o. or i.v.

Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients.

PubMed Central

Schaad, U B; Casey, P A; Cooper, D L

1983-01-01

Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after dosing were 89.4 micrograms of amoxicillin per ml and 19.5 micrograms of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms. Images PMID:6838187

Single-dose pharmacokinetics of intravenous clavulanic acid with amoxicillin in pediatric patients.

PubMed

Schaad, U B; Casey, P A; Cooper, D L

1983-02-01

Pharmacokinetics of a parenteral formulation comprised of 5 parts of amoxicillin and 1 part of clavulanic acid were determined in 12 pediatric patients, 2 to 14 years of age. A single dose amounting to 25 mg of amoxicillin and 5 mg of clavulanic acid per kg of body weight was infused intravenously over 2 min. Mean plasma concentrations 5 min after dosing were 89.4 micrograms of amoxicillin per ml and 19.5 micrograms of clavulanic acid per ml. Terminal phase plasma half-lives were 1.2 and 0.8 h, respectively. The data acquired in this study indicate that amoxicillin and clavulanic acid are pharmacokinetically compatible. Moreover, taken with assessment of microbiological activities by others, the present data suggest that intravenous administration of 25 mg of amoxicillin plus 5 mg of clavulanic acid per kg every 6 h is a reasonable starting regimen for assessing the activity of the combined drug formulation in noninvasive childhood diseases caused by Haemophilus influenzae, Staphylococcus aureus, Streptococci spp., Neisseria spp., Branhamella catarrhalis, and other susceptible organisms.

Safety and tolerability of adjunctive lacosamide intravenous loading dose in lacosamide-naive patients with partial-onset seizures.

PubMed

Fountain, Nathan B; Krauss, Gregory; Isojarvi, Jouko; Dilley, Deanne; Doty, Pamela; Rudd, G David

2013-01-01

To examine the safety and tolerability of rapidly initiating adjunctive lacosamide via a single intravenous loading dose followed by twice-daily oral lacosamide in lacosamide-naive adults with partial-onset seizures. This open-label, multicenter trial, enrolled patients with epilepsy who were taking 1-2 antiepileptic drugs (AEDs) in one of four sequential cohorts containing 25 subjects each. An intravenous lacosamide loading dose (200, 300, or 400 mg) was administered over 15 min followed 12 h later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. The first cohort was administered lacosamide 200 mg/day, followed by a cohort at 300 mg/day, and then a cohort at 400 mg/day. The results from each cohort were evaluated before enrolling the next highest dose level. The fourth cohort enrolled patients at the highest dose with clinically acceptable safety and tolerability results. Safety evaluations included treatment-emergent adverse events (TEAEs), patient withdrawals due to TEAEs, and changes in vital signs, 12-lead electrocardiography (ECG) studies, laboratory parameters, and clinical examinations. Postinfusion lacosamide plasma concentrations were also evaluated. A total of 100 patients were enrolled, 25 in each cohort. The loading dose for the repeat cohort was 300 mg; therefore, 25 patients were enrolled at 200 mg/day, 50 at 300 mg/day, and 25 at 400 mg/day. Most TEAEs occurred within the first 4 h following infusion; dose-related TEAEs (incidence ≥10%) during this timeframe included dizziness, somnolence, and nausea. Seven patients withdrew, all due to TEAEs: three (6%) from the combined 300 mg group and four (16%) from the 400 mg group; four of these patients discontinued within 4 h following infusion. The most common TEAEs leading to discontinuation (overall incidence >1%) were dizziness (6%), nausea (5%), and vomiting (3%). No clinically relevant pattern of changes from baseline ECG, clinical

Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial.

PubMed

Lee, Banghyun; Kim, Kidong; Suh, Dong Hoon; Shin, Hyun-Jung; No, Jae Hong; Lee, Jung Ryeol; Jee, Byung Chul; Hwang, Jung Won; Do, Sang Hwan; Kim, Yong Beom

2017-06-01

This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.

[Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (1)--Single oral and intravenous dose toxicity studies in rats].

PubMed

Yahara, I; Furukawa, H; Sato, K; Nishimura, K; Harihara, A; Yabuuchi, K; Miyauchi, H; Kii, Y; Muraoka, Y; Kitamura, T; Kato, I

2001-05-01

A single oral dose toxicity study of Cefmatilen hydrochloride hydrate (S-1090) and a single intravenous dose toxicity study of its sodium salt (S-1090-Na) were conducted in rats. One dose level of 2000 mg potency/kg was set in both studies. Single oral dose toxicity study of S-1090 No deaths occurred. Diarrhea occurred on the dosing day and slightly soft feces lasted until 6 days after administration. These changes were considered to result from changes of intestinal flora induced by the antibiotic activity of S-1090. Reddish-brown feces (due to chelated products of S-1090 or its decomposition products with Fe3+ in the diet) were also observed until the next day after administration. Body weights increased favorably, and no S-1090-related pathological changes were observed. The oral lethal dose of S-1090 was estimated to be more than 2000 mg potency/kg. Single intravenous dose toxicity study of S-1090-Na No deaths occurred. The rats showed characteristic clinical signs such as hypoactivity, abnormal gait and hypopnea immediately after dosing, and some rats showed prone position or paleness of eyeballs and ear auricles in due course. These signs disappeared by 4 hr after administration. Slightly soft feces and reddish-brown feces were observed much the same as in the orally-treated rats. Body weights increased favorably. In the pathological examinations, slight cecal enlargement and increased basophilia, dilatation and calcification of the renal tubules in the kidney were observed. The intravenous lethal dose of S-1090-Na was estimated to be more than 2000 mg potency/kg.

Placebo-controlled pilot trial testing dose titration and intravenous, intramuscular and subcutaneous routes for ketamine in depression.

PubMed

Loo, C K; Gálvez, V; O'Keefe, E; Mitchell, P B; Hadzi-Pavlovic, D; Leyden, J; Harper, S; Somogyi, A A; Lai, R; Weickert, C S; Glue, P

2016-07-01

This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Action of ethanol low doses on heart rate variability following intravenous administration in rabbits.

PubMed

Khvedelidze, M; Chitanava, E; Nadareishvili, D; Jiqia, G; Gvasalia, M

2007-05-01

Effects of low ethanol doses on the vagosympathetic mechanisms of heart rate regulation were studied in rabbits. Analysis of heart rate variability showed that single intravenous administration of 0.5 mg/kg ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics in contrast to vagotonics. This was associated with activation of the whole complex of regulatory mechanisms. In vagotonics, perturbations in power spectrum indicated on rapidly shunting of regulatory activity from lower to high levels of regulatory mechanisms to realize a "first class" undifferentiated response on stress induction. Sympathicotonics were unready to ethanol intravenous administration that resulted in reduction of all spectral component. Intravenous administration of ethanol caused a higher probability of heart electrophysiological instability in sympathicotonics then in vagotonics. It is important to consider these differences for therapeutic application of ethanol to some acute poisoning (methyl alcohol, ethylene glycol).

Defining unnecessary disinfection procedures for single-dose and multiple-dose vials.

PubMed

Buckley, T; Dudley, S M; Donowitz, L G

1994-11-01

Recommendations in the literature conflict on the necessity of disinfecting single-use vials prior to aspiration of fluid. Interventions to disinfect the stopper surface on multiple-dose vials vary considerably. To determine the necessity of alcohol disinfection of the stopper on single-dose vials and to compare povidone-iodine and alcohol versus alcohol-only disinfection of the stopper prior to each needle penetration on multiple-dose vials. The rubber stopper surfaces of 100 single-dose vials were cultured for the presence of bacteria. To determine the efficacy of two procedures for disinfection of multiple-dose vials, 87 stopper surfaces routinely disinfected with both povidone-iodine and alcohol were cultured for bacteria. After a change in practice, 100 multiple-dose vials routinely disinfected with alcohol only were cultured for the presence of bacteria. Of the cultures done on single-dose vial stoppers, 99% were sterile. A comparison of the two disinfection techniques for multiple-dose vials revealed that 83 (95%) of the 87 vials prepped with both povidone-iodine and alcohol were sterile, compared with all stoppers disinfected with alcohol only. This study shows the lack of necessity of any disinfection procedure on the rubber stopper of single-dose vials and the efficacy of alcohol only for disinfecting the stopper of multiple-dose vials.

Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases.

PubMed

Sherer, Yaniv; Kuechler, Sabine; Jose Scali, Juan; Rovensky, Josef; Levy, Yair; Zandman-Goddard, Gisele; Shoenfeld, Yehuda

2008-01-01

Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol. To investigate whether lower doses of IVIg are beneficial for SLE patients. We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight). The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy. Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.

The incidence of phlebitis with intravenous amiodarone at guideline dose recommendations.

PubMed

Slim, Ahmad M; Roth, Jason E; Duffy, Benjamin; Boyd, Sheri Y N; Rubal, Bernard J

2007-12-01

Postoperative atrial fibrillation following cardiothoracic surgery is common and frequently managed with intravenous (IV) amiodarone. Phlebitis is the most common complication with peripheral infusion of this agent. Current practice guidelines for peripheral IV administration of <2 mg/mL amiodarone were established to reduce the risk of phlebitis. The present study examines the incidence of phlebitis in a postoperative patient population given current dose recommendations. A total of 273 patient charts were reviewed. The incidence of phlebitis in patients given IV amiodarone (n = 36) was 13.9% (95% confidence interval, 2.6-25.2%; p = 0.001). Logistic regression analysis with backward elimination of other therapeutic risk factors suggests that the odds ratio for phlebitis using current dose regimens without IV filters is 19-fold greater than baseline risk in this population. Phlebitis remains a significant complication associated with peripheral infusion of amiodarone within recommended dosing limits.

Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish Ictalurus punctatus

USDA-ARS?s Scientific Manuscript database

Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10mg/kg) of intravenous i.v.) or oral administration in freshwater at a mean water temperature of 25.4°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography...

High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy.

PubMed

Depositario-Cabacar, Dewi T; Peters, Jurriaan M; Pong, Amanda W; Roth, Julie; Rotenberg, Alexander; Riviello, James J; Takeoka, Masanori

2010-07-01

We review our experience with high-dose intravenous levetiracetam (IV-LEV) for acute seizure exacerbations in nine children with medically intractable epilepsy. All children had acute repetitive seizures-while on chronic antiepileptic drugs-that either led to hospitalization (eight) or occurred during hospitalization (one), and received doses of IV-LEV of 150 mg/kg/day or greater, with a mean dose of 228 +/- 48 mg/kg/day. Eight of nine children had resolution of the acute repetitive seizures. Seizure frequency was reduced to less than baseline in seven children (seizure-free in two, >/=80% reduction in four, and 50% reduction in one). Except for one child with increased seizures, IV-LEV was well tolerated in all children without complications.

Standard and double-dose intravenous proton pump inhibitor injections for prevention of bleeding after endoscopic resection.

PubMed

Jung, Sung Woo; Kim, Seung Young; Choe, Jung Wan; Hyun, Jong Jin; Jung, Young Kul; Koo, Ja Seol; Yim, Hyung Joon; Lee, Sang Woo

2017-04-01

Endoscopic resection is commonly used to remove gastric neoplasms. However, effective dosing or scheduling of proton pump inhibitors for the prevention of delayed bleeding after endoscopic resection remains unclear. One hundred sixty-six patients with gastric adenoma or early gastric cancer were enrolled. After an endoscopic procedure, each subject was randomly assigned to 40 mg every 24 h (standard dose group) or 40 mg every 12 h (double-dose group) of intravenous pantoprazole for 48 h. Second-look endoscopy was performed on day 2 after endoscopic resection to compare signs of rebleeding and ulcer status between the two groups. Eighty-one patients of the standard dose group and 81 of the double-dose group were analyzed. There were no significant differences in the incidence of delayed bleeding events (1.3% vs 6.2%, P = 0.21) and bleeding ulcer at the second-look endoscopy (6.2% vs 3.9%, P = 0.69) between standard and double-dose groups. There were no other significant variables associated with delayed bleeding or bleeding ulcer on second-look endoscopy. Intravenous pantoprazole 40 mg every 24 h or 12 h for 2 days after endoscopic resection was equally effective for the prevention of delayed bleeding. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Continuous Intravenous Sub-Dissociative Dose Ketamine Infusion for Managing Pain in the Emergency Department

PubMed Central

Drapkin, Jefferson; Likourezos, Antonios; Beals, Tyler; Monfort, Ralph; Fromm, Christian; Marshall, John

2018-01-01

Introduction Our objective was to describe dosing, duration, and pre- and post-infusion analgesic administration of continuous intravenous sub-dissociative dose ketamine (SDK) infusion for managing a variety of painful conditions in the emergency department (ED). Methods We conducted a retrospective chart review of patients aged 18 and older presenting to the ED with acute and chronic painful conditions who received continuous SDK infusion in the ED for a period over six years (2010–2016). Primary data analyses included dosing and duration of infusion, rates of pre- and post-infusion analgesic administration, and final diagnoses. Secondary data included pre- and post-infusion pain scores and rates of side effects. Results A total of 104 patients were enrolled in the study. Average dosing of SDK infusion was 11.26 mg/hr, and the mean duration of infusion was 135.87 minutes. There was a 38% increase in patients not requiring post-infusion analgesia. The average decrease in pain score was 5.04. There were 12 reported adverse effects, with nausea being the most prevalent. Conclusion Continuous intravenous SDK infusion has a role in controlling pain of various etiologies in the ED with a potential to reduce the need for co-analgesics or rescue analgesic administration. There is a need for more robust, prospective, randomized trials that will further evaluate the analgesic efficacy and safety of this modality across a wide range of pain syndromes and different age groups in the ED. PMID:29760856

Human kinetics of orally and intravenously administered low-dose 1,2-(13)C-dichloroacetate.

PubMed

Jia, Minghong; Coats, Bonnie; Chadha, Monisha; Frentzen, Barbara; Perez-Rodriguez, Javier; Chadik, Paul A; Yost, Richard A; Henderson, George N; Stacpoole, Peter W

2006-12-01

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 microg/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.

Effects of intravenous Escherichia coli dose on the pathophysiological response of colostrum-fed Jersey calves

USDA-ARS?s Scientific Manuscript database

Objectives of the present study were to characterize the dose dependency of an intravenous Escherichia coli (E. coli) challenge in colostrum-fed Jersey calves and to identify biochemical markers indicative of septicemia. Eighteen 3-wk old colostrum-fed Jersey calves were completely randomized to 1 o...

Disposition of styrene-acrylonitrile (SAN) trimer in female rats: single dose intravenous and gavage studies.

PubMed

Gargas, Michael L; Collins, Brad; Fennell, Timothy R; Gaudette, Norman F; Sweeney, Lisa M

2008-04-21

Styrene-acrylonitrile trimer (SAN Trimer), a mixture of six isomers (four isomers of 4-cyano-1,2,3,4-tetrahydro-alpha-methyl-1-naphthaleneacetonitrile [THAN] and two isomers of 4-cyano-1,2,3,4-tetrahydro-1-naphthaleneproprionitrile [THNP]), is a by-product of a specific production process of styrene-acrylonitrile polymer. Disposition studies in female rats were conducted to evaluate the pharmacokinetic behavior of [3H]SAN Trimer following a single intravenous administration (26 mg/kg) to nonpregnant rats; a single gavage administration (nominal doses of 25 mg/kg, 75 mg/kg, or 200 mg/kg in corn oil) to nonpregnant rats; and a single gavage administration (nominal dose of 200 mg/kg in corn oil) to pregnant and lactating rats. SAN Trimer was rapidly eliminated from blood (T1/2 approximately 1h) following a single intravenous dose and following single oral doses (T1/2 approximately 3-4h). SAN Trimer was also rapidly excreted in the urine and feces following single oral doses, while total radioactivity was cleared more slowly. In pregnant rats, the concentrations of both radioactivity and SAN Trimer 2h after dosing were highest in the blood, followed by the placenta, with the lowest levels in the fetus. In lactating rats, the concentrations of both radioactivity and SAN Trimer were higher in milk than in maternal blood. Total radioactivity and SAN Trimer blood concentrations in nonpregnant, pregnant, and lactating rats were both higher in lactating rats compared to nonpregnant and pregnant rats.

Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

PubMed Central

Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

2015-01-01

Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

PubMed Central

Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

2015-01-01

We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Evaluation of an every-other-day palonosetron schedule to control emesis in multiple-day high-dose chemotherapy.

PubMed

Mirabile, Aurora; Celio, Luigi; Magni, Michele; Bonizzoni, Erminio; Gianni, Alessandro Massimo; Di Nicola, Massimo

2014-12-01

Efficacy of intermittent palonosetron dosing in patients undergoing multiple-day, high-dose chemotherapy (HDC) was investigated. Fifty-eight patients received palonosetron (0.25 mg intravenous [iv.]) every other day plus daily dexamethasone (8 mg iv. twice daily) dosing. The primary end point was complete control (CC; no emesis, no rescue anti-emetics, and no more than mild nausea) in the overall acute-period (until 24 h after chemotherapy completion). Acute-period CC occurred in 81% and 50% of patients receiving palonosetron and ondansetron (historical control cohort), respectively. Palonosetron (odds ratio [OR]: 4.37; p = 0.001) and a longer duration of HDC regimen (OR: 3.47; p = 0.011) independently predicted a better anti-emetic outcome. Palonosetron every other day plus daily dexamethasone is an effective anti-emetic coverage in patients undergoing HDC.

Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.

PubMed

Holm, C; Thomsen, L L; Norgaard, A; Langhoff-Roos, J

2017-04-01

To evaluate the clinical efficacy of a single-dose intravenous infusion of iron isomaltoside compared with current treatment practice with oral iron measured by physical fatigue in women after postpartum haemorrhage. Single-centre, open-label, randomized controlled trial. Participants received intravenous iron (n = 97) or oral iron (n = 99), and completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and haematological and iron parameters were measured. Primary outcome was the aggregated change in physical fatigue score from baseline to 12 weeks postpartum. The difference in physical fatigue score was -0·97 (95% CI: -1·65; -0·28, P = 0·006) in favour of intravenous iron, but did not meet the predefined difference of 1·8. Across visits, we found statistically significant differences in fatigue and depression scores, as well as in haematological and iron parameters, all in favour of intravenous iron. There were no serious adverse reactions. A single dose of intravenous iron was associated with a statistically significant reduction in aggregated physical fatigue within 12 weeks after postpartum haemorrhage compared to standard medical care with oral iron below the prespecified criteria of clinical superiority. As patient-reported outcomes improved significantly and intravenous iron resulted in a fast hematopoietic response without serious adverse reactions, intravenous iron may be a useful alternative after postpartum haemorrhage if oral iron is not absorbed or tolerated. © 2017 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.

Intravenous Iron Therapy in Patients with Iron Deficiency Anemia: Dosing Considerations

PubMed Central

Myers, Jennifer; Goodnough, Lawrence Tim

2015-01-01

Objective. To provide clinicians with evidence-based guidance for iron therapy dosing in patients with iron deficiency anemia (IDA), we conducted a study examining the benefits of a higher cumulative dose of intravenous (IV) iron than what is typically administered. Methods. We first individually analyzed 5 clinical studies, averaging the total iron deficit across all patients utilizing a modified Ganzoni formula; we then similarly analyzed 2 larger clinical studies. For the second of the larger studies (Study 7), we also compared the efficacy and retreatment requirements of a cumulative dose of 1500 mg ferric carboxymaltose (FCM) to 1000 mg iron sucrose (IS). Results. The average iron deficit was calculated to be 1531 mg for patients in Studies 1–5 and 1392 mg for patients in Studies 6-7. The percentage of patients who were retreated with IV iron between Days 56 and 90 was significantly (p < 0.001) lower (5.6%) in the 1500 mg group, compared to the 1000 mg group (11.1%). Conclusions. Our data suggests that a total cumulative dose of 1000 mg of IV iron may be insufficient for iron repletion in a majority of patients with IDA and a dose of 1500 mg is closer to the actual iron deficit in these patients. PMID:26257955

Pharmacokinetics of Oral and Intravenous Paracetamol (Acetaminophen) When Co-Administered with Intravenous Morphine in Healthy Adult Subjects.

PubMed

Raffa, Robert B; Pawasauskas, Jayne; Pergolizzi, Joseph V; Lu, Luke; Chen, Yin; Wu, Sutan; Jarrett, Brant; Fain, Randi; Hill, Lawrence; Devarakonda, Krishna

2018-03-01

Several features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine. In this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations. Twenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max ) and area under the plasma concentration-time curve over the dosing interval (AUC 0-6 ) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC 0-6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max ) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine. Morphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain. CLINICALTRIALS. NCT02848729.

Dose-Dependent Effect of Intravenous Administration of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Neonatal Stroke Mice

PubMed Central

Tanaka, Emi; Ogawa, Yuko; Mukai, Takeo; Sato, Yoshiaki; Hamazaki, Takashi; Nagamura-Inoue, Tokiko; Harada-Shiba, Mariko; Shintaku, Haruo; Tsuji, Masahiro

2018-01-01

Neonatal brain injury induced by stroke causes significant disability, including cerebral palsy, and there is no effective therapy for stroke. Recently, mesenchymal stem cells (MSCs) have emerged as a promising tool for stem cell-based therapies. In this study, we examined the safety and efficacy of intravenously administered human umbilical cord-derived MSCs (UC-MSCs) in neonatal stroke mice. Pups underwent permanent middle cerebral artery occlusion at postnatal day 12 (P12), and low-dose (1 × 104) or high-dose (1 × 105) UC-MSCs were administered intravenously 48 h after the insult (P14). To evaluate the effect of the UC-MSC treatment, neurological behavior and cerebral blood flow were measured, and neuroanatomical analysis was performed at P28. To investigate the mechanisms of intravenously injected UC-MSCs, systemic blood flowmetry, in vivo imaging and human brain-derived neurotrophic factor (BDNF) measurements were performed. Functional disability was significantly improved in the high-dose UC-MSC group when compared with the vehicle group, but cerebral blood flow and cerebral hemispheric volume were not restored by UC-MSC therapy. The level of exogenous human BDNF was elevated only in the cerebrospinal fluid of one pup 24 h after UC-MSC injection, and in vivo imaging revealed that most UC-MSCs were trapped in the lungs and disappeared in a week without migration toward the brain or other organs. We found that systemic blood flow was stable over the 10 min after cell administration and that there were no differences in mortality among the groups. Immunohistopathological assessment showed that the percent area of Iba1-positive staining in the peri-infarct cortex was significantly reduced with the high-dose UC-MSC treatment compared with the vehicle treatment. These results suggest that intravenous administration of UC-MSCs is safe for a mouse model of neonatal stroke and improves dysfunction after middle cerebral artery occlusion by modulating

Pharmacokinetics of Intravenous Finafloxacin in Healthy Volunteers

PubMed Central

Chiesa, Joseph; Lückermann, Mark; Fischer, Carsten; Dalhoff, Axel; Fuhr, Uwe

2017-01-01

ABSTRACT Finafloxacin is a novel fluoroquinolone exhibiting enhanced activity under acidic conditions and a broad-spectrum antibacterial profile. The present study assessed the pharmacokinetic properties and the safety and tolerability of finafloxacin following intravenous infusions. In this mixed-parallel-group, crossover study, healthy male and female volunteers received single ascending doses (18 volunteers, 200 to 1,000 mg) or multiple ascending doses (40 volunteers, 600 to 1,000 mg) of finafloxacin or placebo. Plasma and urine samples were collected by a dense sampling scheme to determine the pharmacokinetics of finafloxacin using a noncompartmental approach. Standard safety and tolerability data were documented. Finafloxacin had a volume of distribution of 90 to 127 liters (range) at steady state and 446 to 550 liters at pseudoequilibrium, indicating the elimination of a large fraction before pseudoequilibrium was reached. Areas under the concentration-time curves and maximum plasma concentrations (geometric means) increased slightly more than proportionally (6.73 to 45.9 μg · h/ml and 2.56 to 20.2 μg/ml, respectively), the terminal elimination half-life increased (10.6 to 17.1 h), and the urinary recovery decreased (44.2% to 31.7%) with increasing finafloxacin doses (single doses of 200 to 1,000 mg). The pharmacokinetic profiles suggested multiphasic elimination by both glomerular filtration and saturable tubular secretion. The values of the parameters were similar for single and multiple administrations. The coefficient of variation for the between-subject variability of exposure ranged from 10% (≤600 mg) to 38% (>600 mg). Adverse events were mild and nonspecific, with no dependence of adverse events on dose or treatment (including placebo) being detected. Despite a relatively high interindividual variability at higher doses, the level of exposure following intravenous administration of finafloxacin appears to be predictable. Individual elimination

Immediate hypersensitivity to iodinated contrast media: diagnostic accuracy of skin tests and intravenous provocation test with low dose.

PubMed

Sesé, L; Gaouar, H; Autegarden, J-E; Alari, A; Amsler, E; Vial-Dupuy, A; Pecquet, C; Francès, C; Soria, A

2016-03-01

The diagnosis of HSR to iodinated contrast media (ICM) is challenging based on clinical history and skin tests. This study evaluates the negative predictive value (NPV) of skin tests and intravenous provocation test (IPT) with low-dose ICM in patients with suspected immediate hypersensitivity reaction (HSR) to ICM. Thirty-seven patients with suspected immediate hypersensitivity reaction to ICM were included retrospectively. Skin tests and a single-blind placebo-controlled intravenous provocation test (IPT) with low-dose iodinated contrast media (ICM) were performed. Skin tests with ICM were positive in five cases (one skin prick test and five intradermal test). Thirty-six patients were challenged successfully by IPT, and only one patient had a positive challenge result, with a grade I reaction by the Ring and Messmer classification. Ten of 23 patients followed up by telephone were re-exposed to a negative tested ICM during radiologic examination; two experienced a grade I immediate reaction. For immediate hypersensitivity reaction to ICM, the NPV for skin tests and IPT with low dose was 80% (95% CI 44-97%). © 2016 John Wiley & Sons Ltd.

Pharmacokinetics, Safety, and Tolerability of a Single 500-mg or 1000-mg Intravenous Dose of Dalbavancin in Healthy Japanese Subjects.

PubMed

Scoble, Patrick J; Owens, Robert C; Puttagunta, Sailaja; Yen, Mark; Dunne, Michael W

2015-12-01

Dalbavancin is a novel, once-weekly glycopeptide antibiotic approved for treatment of acute bacterial skin infections. Given the importance of understanding any pharmacokinetic variability across different patient populations, a double-blind, placebo-controlled study was conducted to evaluate the pharmacokinetics, safety, and tolerability of a single 500-mg and a single 1000-mg intravenous dose of dalbavancin in healthy Japanese subjects. Ten subjects received intravenous dalbavancin 1000 mg, five subjects received intravenous dalbavancin 500 mg, and three subjects received intravenous placebo. After a single infusion of dalbavancin, the maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC) increased in a proportional manner from 500 mg to 1000 mg (C max: 157 μg/ml and 299 μg/ml; AUClast: 10,850 μg·h/ml and 22,679 μg·h/ml, on the 500-mg and 1000-mg regimens, respectively) with low inter-subject variability. The mean terminal phase half-life (t 1/2) was 204 and 193 h after the 500-mg and 1000-mg dose, respectively. Clearance and volume of distribution were similar for the two dose concentrations. Treatment-emergent adverse events reported were considered to be of mild intensity. There were no relevant changes in laboratory values or vital signs over time in subjects in either treatment group. Overall, dalbavancin 500 mg and dalbavancin 1000 mg, administered as a single 30-min infusion, was well tolerated in this population and resulted in plasma exposures similar to those in non-Asians.

Effect of high-dose intravenous vitamin C on inflammation in cancer patients.

PubMed

Mikirova, Nina; Casciari, Joseph; Rogers, Andrea; Taylor, Paul

2012-09-11

An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that

Effect of high-dose intravenous vitamin C on inflammation in cancer patients

PubMed Central

2012-01-01

Background An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer. Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels. Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients. Methods 45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods. CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests. Results According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment. There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein. Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments. Conclusions The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels. In

Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial.

PubMed

Motov, Sergey; Yasavolian, Matthew; Likourezos, Antonios; Pushkar, Illya; Hossain, Rukhsana; Drapkin, Jefferson; Cohen, Victor; Filk, Nicholas; Smith, Andrew; Huang, Felix; Rockoff, Bradley; Homel, Peter; Fromm, Christian

2017-08-01

Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per

Review of high-dose intravenous vitamin C as an anticancer agent.

PubMed

Wilson, Michelle K; Baguley, Bruce C; Wall, Clare; Jameson, Michael B; Findlay, Michael P

2014-03-01

In the 1970s, Pauling and Cameron reported increased survival of patients with advanced cancer treated with high-dose intravenous (IV) vitamin C (L-ascorbate, ascorbic acid). These studies were criticized for their retrospective nature and lack of standardization of key prognostic factors including performance status. Subsequently, several well-designed randomized controlled trials failed to demonstrate a significant survival benefit, although these trials used high-dose oral vitamin C. Marked differences are now recognized in the pharmacokinetics of vitamin C with oral and IV administration, opening the issue of therapeutic efficacy to question. In vitro evidence suggests that vitamin C functions at low concentrations as an antioxidant but may have pro-oxidant activity at high concentrations. The mechanism of its pro-oxidant action is not fully understood, and both intra- and extracellular mechanisms that generate hydrogen peroxide have been proposed. It remains to be proven whether vitamin C-induced reactive oxygen species occur in vivo and, if so, whether this will translate to a clinical benefit. Current clinical evidence for a therapeutic effect of high-dose IV vitamin C is ambiguous, being based on case series. The interpretation and validation of these studies is hindered by limited correlation of plasma vitamin C concentrations with response. The methodology exists to determine if there is a role for high-dose IV vitamin C in the treatment of cancer, but the limited understanding of its pharmacodynamic properties makes this challenging. Currently, the use of high-dose IV vitamin C cannot be recommended outside of a clinical trial. © 2014 Wiley Publishing Asia Pty Ltd.

Three-dimensional visualization of endolymphatic hydrops after intravenous administration of single-dose gadodiamide.

PubMed

Naganawa, Shinji; Yamazaki, Masahiro; Kawai, Hisashi; Bokura, Kiminori; Sone, Michihiko; Nakashima, Tsutomu

2013-01-01

Endolymphatic hydrops can be visualized with high contrast-to-noise ratio even after intravenous injection of single-dose gadolinium-based contrast material (IV-SD-GBCM) using HYDROPS-Mi2 images. We applied 3-dimensional rendering software to process HYDROPS-Mi2 images of 15 ears with and without suspected Ménière's disease and separately visualized the volumes of endo- and perilymph in patients with Ménière's disease even after IV-SD-GBCM. Such dimensional visualization will aid understanding of the pathophysiology of Ménière's disease.

Comparative trial of two intravenous doses of granisetron (1 versus 3 mg) in the prevention of chemotherapy-induced acute emesis: a double-blind, randomized, non-inferiority trial.

PubMed

Tsuji, Daiki; Kim, Yong-Il; Taku, Keisei; Nakagaki, Shigeru; Ikematsu, Yoshito; Tsubota, Hiromi; Maeda, Masato; Hashimoto, Naoya; Kimura, Masayuki; Daimon, Takashi

2012-05-01

A single 3 mg or 40 μg/kg intravenous dose of granisetron combined with dexamethasone is routinely used in several countries, although the antiemetic guidelines have recommended granisetron at the dose of 1 mg or 10 μg/kg. A randomized, multicenter trial was conducted to determine the optimal intravenous granisetron dose, 1 or 3 mg, in cancer patients receiving emetogenic chemotherapy. We enrolled 365 patients and randomly assigned them to receive intravenous granisetron 3 mg (3-mg group) or 1 mg (1-mg group), combined with dexamethasone at an adequate dose fixed as per the emetic risk category. The primary end point was the proportion of patients with a complete response during the first 24 h after chemotherapy. The study demonstrated that 1 mg of granisetron was not inferior in effect to 3 mg. For the primary end point, 359 patients were evaluable according to the modified intention-to-treat (ITT) analysis. Complete protection was achieved in the modified ITT population, 90.6% and 88.8% for the 3- and 1-mg groups, respectively (p < 0.01 for non-inferiority). This study showed that 1 mg granisetron is not inferior to 3 mg when both doses are combined with dexamethasone. Therefore, 1-mg dose of intravenous granisetron should be the recommended prophylactic regimen for the prevention of acute emesis.

Intravenous Clomipramine for Treatment-Resistant Obsessive-Compulsive Disorder

PubMed Central

Khani, Munir

2016-01-01

Background: This open trial was conducted to evaluate the effectiveness of intravenous clomipramine (CMI) in refractory obsessive-compulsive disorder (OCD). Methods: Thirty OCD poor responders to previous multiple trials of anti-obsessive medications were selected and admitted to the hospital. Severity of the illness and response to treatment were primarily assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). CMI was gradually administered intravenously for one week. All patients were thereafter switched to oral CMI with a maximum dose of 225mg/day. Results: The Y-BOCS total score mean at admission was in the severe range (24–31), and dropped on discharge and follow-ups to the moderate range (16–23). At discharge, 23 patients (76.7%) had a decrease in Y-BOCS ≥25% and were considered responders, while only 18 (60%) were still responders at 24 weeks. No relevant persistent side effects were reported. Conclusion: Intravenous clomipramine could be of benefit for severe OCD cases that have not adequately responded to several therapies, including oral clomipramine. PMID:26221004

Intravenous Clomipramine for Treatment-Resistant Obsessive-Compulsive Disorder.

PubMed

Karameh, Wael Karameh; Khani, Munir

2015-07-28

This open trial was conducted to evaluate the effectiveness of intravenous clomipramine (CMI) in refractory obsessive-compulsive disorder (OCD). Thirty OCD poor responders to previous multiple trials of anti-obsessive medications were selected and admitted to the hospital. Severity of the illness and response to treatment were primarily assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). CMI was gradually administered intravenously for one week. All patients were thereafter switched to oral CMI with a maximum dose of 225 mg/day. The Y-BOCS total score mean at admission was in the severe range (24-31), and dropped on discharge and follow-ups to the moderate range (16-23). At discharge, 23 patients (76.7%) had a decrease in Y-BOCS ≥ 25% and were considered responders, while only 18 (60%) were still responders at 24 weeks. No relevant persistent side effects were reported. Intravenous clomipramine could be of benefit for severe OCD cases that have not adequately responded to several therapies, including oral clomipramine. © The Author 2015. Published by Oxford University Press on behalf of CINP.

[Efficacy of intravenous phenobarbital treatment for status epilepticus].

PubMed

Muramoto, Emiko; Mizobuchi, Masahiro; Sumi, Yoshihiro; Sako, Kazuya; Nihira, Atsuko; Takeuchi, Akiko; Nakamura, Hirohiko

2013-08-01

Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. The initial doses of IV-PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV-PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose.

Vedolizumab Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability Following Administration of a Single, Ascending, Intravenous Dose to Healthy Volunteers.

PubMed

Rosario, Maria; Wyant, Timothy; Leach, Timothy; Sankoh, Serap; Scholz, Catherine; Parikh, Asit; Fox, Irving; Feagan, Brian G

2016-11-01

Vedolizumab, a humanized monoclonal antibody against the α 4 β 7 integrin, is indicated for treatment of moderately to severely active ulcerative colitis or Crohn's disease. In this placebo-controlled, double-blind, randomized, single ascending-dose study, the pharmacokinetics, pharmacodynamics, safety, and tolerability of vedolizumab were evaluated in healthy volunteers. Forty-nine participants (in five cohorts) were randomly assigned in a 4:1 ratio to receive a single intravenous infusion of either vedolizumab (0.2, 0.5, 2.0, 6.0, or 10.0 mg/kg) or placebo. Blood samples were collected for measurement of vedolizumab serum concentrations and α 4 β 7 saturation on peripheral blood lymphocytes by vedolizumab. Pharmacokinetic parameters were computed using a non-compartmental approach. Adverse events were monitored. Vedolizumab maximum observed serum concentration (C max ) demonstrated dose proportionality over the dose range tested. Greater than dose-proportional increases in area under the serum concentration-time curve from time 0 to infinity (AUC 0-inf ) and shorter terminal elimination half-life (t 1/2 ) were observed from 0.2 to 2.0 mg/kg, suggestive of nonlinear pharmacokinetics at lower doses. At doses higher than 2.0 mg/kg, these parameters increased dose proportionally. Saturation of α 4 β 7 was at or near maximal levels (>90 %) at all doses and time points when vedolizumab was measurable in serum. A total of 21 of 39 (54 %) vedolizumab-treated participants were anti-drug antibody (ADA) positive, and 11 (28 %) were persistently ADA positive. Overall, no adverse event signals, including serious infections or malignancies, were apparent. Vedolizumab exhibited target-mediated disposition, characterized by a rapid, saturable, nonlinear elimination process at low concentrations and a slower linear elimination process at higher concentrations. Nearly complete α 4 β 7 saturation was observed at all doses. A single intravenous infusion of vedolizumab

Pharmacokinetics of escin Ia in rats after intravenous administration.

PubMed

Wu, Xiu-Jun; Cui, Xiang-Yong; Tian, Lian-tian; Gao, Feng; Guan, Xin; Gu, Jing-Kai

2014-10-28

Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg

Does intravenous induction dosing among patients undergoing gastrointestinal surgical procedures follow current recommendations: a study of contemporary practice.

PubMed

Akhtar, Shamsuddin; Liu, Jia; Heng, Joseph; Dai, Feng; Schonberger, Robert B; Burg, Matthew M

2016-09-01

It is recommended to correct intravenous induction doses by up to 50% for patients older than 65 years. The objectives were to determine (a) the degree to which anesthesia providers correct induction doses for age and (b) additionally adjust for American Society of Anesthesiologists physical status (ASA-PS) class (severity of illness) and (c) whether postinduction hypotension is more common among patients aged >65. Retrospective chart review. Academic medical center. A total of 1869 adult patients receiving general anesthesia for GI surgical procedures from February 2013 to January 2014. Patients were divided into 3 age groups (age <65, 65-79, ≥80 years) and then further stratified into ASA-PS class (I/II vs III/IV). Multiple pairwise comparisons were conducted using Welch t tests for continuous variables to determine whether dosing was different for the older groups vs the younger group; separate analyses were performed within and across ASA-PS class. This approach was also used to determine differences in mean arterial pressure change in the older groups vs the younger group, whereas the rates of hypotension among different age groups were compared by Cochran-Armitage trend test. No significant decrease in dosing between age groups was observed for fentanyl and midazolam. For propofol, there was a significantly lower dosing for older patients: 17% for patients aged 65-79 and 29% for those aged >80, which was still in less than the recommendations. An inverse relationship was observed between propofol dosing and ASA-PS class, but no consistent relationship was noted for fentanyl and midazolam. There were a significantly larger drop in mean arterial pressure and a greater likelihood of hypotension following induction in patients aged 65-79 years and >80 years as compared with those aged <65 years. This study shows that the administered dose of anesthetic induction agents is significantly higher than that recommended for patients older than 65 years. This failure

Survey of pain specialists regarding conversion of high-dose intravenous to neuraxial opioids

PubMed Central

Gorlin, Andrew W; Rosenfeld, David M; Maloney, Jillian; Wie, Christopher S; McGarvey, Johnathan; Trentman, Terrence L

2016-01-01

The conversion of high-dose intravenous (IV) opioids to an equianalgesic epidural (EP) or intrathecal (IT) dose is a common clinical dilemma for which there is little evidence to guide practice. Expert opinion varies, though a 100 IV:10:EP:1 IT conversion ratio is commonly cited in the literature, especially for morphine. In this study, the authors surveyed 724 pain specialists to elucidate the ratios that respondents apply to convert high-dose IV morphine, hydromorphone, and fentanyl to both EP and IT routes. Eighty-three respondents completed the survey. Conversion ratios were calculated and entered into graphical scatter plots. The data suggest that there is wide variation in how pain specialists convert high-dose IV opioids to EP and IT routes. The 100 IV:10 EP:1 IT ratio was the most common answer of survey respondent, especially for morphine, though also for hydromorphone and fentanyl. Furthermore, more respondents applied a more aggressive conversion strategy for hydromorphone and fentanyl, likely reflecting less spinal selectivity of those opioids compared with morphine. The authors conclude that there is little consensus on this issue and suggest that in the absence of better data, a conservative approach to opioid conversion between IV and neuraxial routes is warranted. PMID:27703394

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

PubMed

Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

2015-02-01

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats.

PubMed

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-12-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats.

Four-Week Repeated Intravenous Dose Toxicity and Toxicokinetic Study of TS-DP2, a Novel Human Granulocyte Colony Stimulating Factor in Rats

PubMed Central

Lee, JooBuom; Lee, Kyungsun; Choe, Keunbum; Jung, Hyunseob; Cho, Hyunseok; Choi, Kiseok; Kim, Taegon; Kim, Seojin; Lee, Hyeong-Seok; Cha, Mi-Jin; Song, Si-Whan; Lee, Chul Kyu; Chun, Gie-Taek

2015-01-01

TS-DP2 is a recombinant human granulocyte colony stimulating factor (rhG-CSF) manufactured by TS Corporation. We conducted a four-week study of TS-DP2 (test article) in repeated intravenous doses in male and female Sprague-Dawley (SD) rats. Lenograstim was used as a reference article and was administered intravenously at a dose of 1000 μg/kg/day. Rats received TS-DP2 intravenously at doses of 250, 500, and 1000 μg/kg/day once daily for 4 weeks, and evaluated following a 2-week recovery period. Edema in the hind limbs and loss of mean body weight and body weight gain were observed in both the highest dose group of TS-DP2 and the lenograstim group in male rats. Fibro-osseous lesions were observed in the lenograstim group in both sexes, and at all groups of TS-DP2 in males, and at doses of TS-DP2 500 μg/kg/day and higher in females. The lesion was considered a toxicological change. Therefore, bone is the primary toxicological target of TS-DP2. The lowest observed adverse effect level (LOAEL) in males was 250 μg/kg/day, and no observed adverse effect level (NOAEL) in females was 250 μg/kg/day in this study. In the toxicokinetic study, the serum concentrations of G-CSF were maintained until 8 hr after administration. The systemic exposures (AUC0-24h and C0) were not markedly different between male and female rats, between the administration periods, or between TS-DP2 and lenograstim. In conclusion, TS-DP2 shows toxicological similarity to lenograstim over 4-weeks of repeated doses in rats. PMID:26877840

The economics of a pharmacy-based central intravenous additive service for paediatric patients.

PubMed

Armour, D J; Cairns, C J; Costello, I; Riley, S J; Davies, E G

1996-10-01

This study was designed to compare the costs of a pharmacy-based Central Intravenous Additive Service (CIVAS) with those of traditional ward-based preparation of intravenous doses for a paediatric population. Labour costs were derived from timings of preparation of individual doses in both the pharmacy and ward by an independent observer. The use of disposables and diluents was recorded and their acquisition costs apportioned to the cost of each dose prepared. Data were collected from 20 CIVAS sessions (501 doses) and 26 ward-based sessions (30 doses). In addition, the costs avoided by the use of part vials in CIVAS was calculated. This was derived from a total of 50 CIVAS sessions. Labour, disposable and diluent costs were significantly lower for CIVAS compared with ward-based preparation (p < 0.001). The ratio of costs per dose [in 1994 pounds sterling] between ward and pharmacy was 2.35:1 (2.51 pounds:1.07 pounds). Sensitivity analysis of the best and worst staff mixes in both locations ranged from 2.3:1 to 4.0:1, always in favour of CIVAS. There were considerable costs avoided in CIVAS from the multiple use of vials; the estimated annual sum derived from the study was 44,000 pounds. In addition, CIVAS was less vulnerable to unanticipated interruptions in work flow than ward-based preparation. CIVAS for children was more economical than traditional ward-based preparation, because of a cost-minimisation effect. Sensitivity analysis showed that these advantages were maintained over a full range of skill mixes. Additionally, significant savings accrued from the multiple use of vials in CIVAS.

Propofol intravenous conscious sedation for anxious children in a specialist paediatric dentistry unit.

PubMed

Hosey, M T; Makin, A; Jones, R M; Gilchrist, F; Carruthers, M

2004-01-01

To report on both the use and dosage of propofol, as a new intravenous (IV) conscious sedative agent, for anxious children referred to a specialist paediatric dentistry service. Paediatric Dentistry Unit, Glasgow Dental Hospital and School. Thirty-four children, 25 females and 9 males, mean age 12 years 10 months, with a mean weight of 54.6 kg (range 30-110 kg). Report from 34 patients receiving intravenous sedation for the first time in respect of weight dose and amount of treatment completed. Thirty-two children successfully accepted operative dental care on their first visit, they received a mean total dose of 146.25 mg of propofol (range 10 mg to 356 mg); in relation to body weight, the mean was 2.5 mg/kg (range 0.2-5.4 mg/kg). The treatment that they received included fissure sealants, amalgam and adhesive restorations, root canal therapy and single and multiple extractions. Their sedation and recovery were uneventful. Sub-anaesthetic doses of propofol used for IV conscious sedation infusion facilitated operative dental treatment in anxious children.

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation

PubMed Central

Lee, Seung-Shin; Jung, Sung-Hoon; Ahn, Seo-Yeon; Kim, Jae-Yong; Jang, Hee-Chang; Kang, Seung-Ji; Jang, Mi-Ok; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

2015-01-01

Background/Aims BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Methods Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Results Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Conclusions Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC. PMID:25750563

Treatment of BK virus-associated hemorrhagic cystitis with low-dose intravenous cidofovir in patients undergoing allogeneic hematopoietic cell transplantation.

PubMed

Lee, Seung-Shin; Ahn, Jae-Sook; Jung, Sung-Hoon; Ahn, Seo-Yeon; Kim, Jae-Yong; Jang, Hee-Chang; Kang, Seung-Ji; Jang, Mi-Ok; Yang, Deok-Hwan; Kim, Yeo-Kyeoung; Lee, Je-Jung; Kim, Hyeoung-Joon

2015-03-01

BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC) in recipients of hematopoietic stem cell transplantation (HSCT). Cidofovir has been used at higher doses (3 to 5 mg/kg/wk) with probenecid prophylaxis; however, cidofovir may result in nephrotoxicity or cytopenia at high doses. Allogeneic HSCT recipients with BKV-associated HC are treated with 1 mg/kg intravenous cidofovir weekly at our institution. A microbiological response was defined as at least a one log reduction in urinary BKV viral load, and a clinical response was defined as improvement in symptoms and stability or reduction in cystitis grade. Eight patients received a median of 4 weekly (range, 2 to 11) doses of cidofovir. HC occurred a median 69 days (range, 16 to 311) after allogeneic HSCT. A clinical response was detected in 7/8 patients (86%), and 4/5 (80%) had a measurable microbiological response. One patient died of uncontrolled graft-versus-host disease; therefore, we could not measure the clinical response to HC treatment. One microbiological non-responder had a stable BKV viral load with clinical improvement. Only three patients showed transient grade 2 serum creatinine toxicities, which resolved after completion of concomitant calcineurin inhibitor treatment. Weekly intravenous low-dose cidofovir without probenecid appears to be a safe and effective treatment option for patients with BKV-associated HC.

Azithromycin to prevent bronchopulmonary dysplasia in ureaplasma-infected preterm infants: pharmacokinetics, safety, microbial response, and clinical outcomes with a 20-milligram-per-kilogram single intravenous dose.

PubMed

Viscardi, Rose M; Othman, Ahmed A; Hassan, Hazem E; Eddington, Natalie D; Abebe, Elias; Terrin, Michael L; Kaufman, David A; Waites, Ken B

2013-05-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)(0.75) [WT(kg)(0.75) indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)(0.75); central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥ 96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial

Azithromycin To Prevent Bronchopulmonary Dysplasia in Ureaplasma-Infected Preterm Infants: Pharmacokinetics, Safety, Microbial Response, and Clinical Outcomes with a 20-Milligram-per-Kilogram Single Intravenous Dose

PubMed Central

Othman, Ahmed A.; Hassan, Hazem E.; Eddington, Natalie D.; Abebe, Elias; Terrin, Michael L.; Kaufman, David A.; Waites, Ken B.

2013-01-01

Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Previously, we demonstrated that a single intravenous (i.v.) dose of azithromycin (10 mg/kg of body weight) is safe but inadequate to eradicate Ureaplasma spp. in preterm infants. We performed a nonrandomized, single-arm open-label study of the pharmacokinetics (PK) and safety of intravenous 20-mg/kg single-dose azithromycin in 13 mechanically ventilated neonates with a gestational age between 24 weeks 0 days and 28 weeks 6 days. Pharmacokinetic data from 25 neonates (12 dosed with 10 mg/kg i.v. and 13 dosed with 20 mg/kg i.v.) were analyzed using a population modeling approach. Using a two-compartment model with allometric scaling of parameters on body weight (WT), the population PK parameter estimates were as follows: clearance, 0.21 liter/h × WT(kg)0.75 [WT(kg)0.75 indicates that clearance was allometrically scaled on body weight (in kilograms) with a fixed exponent of 0.75]; intercompartmental clearance, 2.1 liters/h × WT(kg)0.75; central volume of distribution (V), 1.97 liters × WT (kg); and peripheral V, 17.9 liters × WT (kg). There was no evidence of departure from dose proportionality in azithromycin exposure over the tested dose range. The calculated area under the concentration-time curve over 24 h in the steady state divided by the MIC90 (AUC24/MIC90) for the single dose of azithromycin (20 mg/kg) was 7.5 h. Simulations suggest that 20 mg/kg for 3 days will maintain azithromycin concentrations of >MIC50 of 1 μg/ml for this group of Ureaplasma isolates for ≥96 h after the first dose. Azithromycin was well tolerated with no drug-related adverse events. One of seven (14%) Ureaplasma-positive subjects and three of six (50%) Ureaplasma-negative subjects developed physiologic BPD. Ureaplasma was eradicated in all treated Ureaplasma-positive subjects. Simulations suggest that a multiple-dose regimen may be efficacious for microbial clearance

Safety and Pharmacokinetics of Multiple Dose myo-Inositol in Preterm Infants

PubMed Central

Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Nolen, Tracy L.; Watterberg, Kristi L.; Oh, William; Goedecke, Michael; Ehrenkranz, Richard A.; Fennell, Timothy; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; Lacy, Conra Backstrom; Walsh, Michele C.; Carlo, Waldemar A.; Sánchez, Pablo J.; Bell, Edward F.; Shankaran, Seetha; Carlton, David P.; Chess, Patricia R.; Higgins, Rosemary D.

2016-01-01

BACKGROUND Preterm infants with RDS given inositol had reduced BPD, death and severe ROP. We assessed the safety and pharmacokinetics(PK) of daily inositol to select a dose providing serum levels previously associated with benefit, and to learn if accumulation occurred when administered throughout the normal period of retinal vascularization. METHODS Infants ≤29wks GA (n=122, 14 centers) were randomized and treated with placebo or inositol at 10, 40 or 80mg/kg/day. Intravenous administration converted to enteral when feedings were established, and continued to the first of 10 weeks, 34weeks PMA or discharge. Serum collection employed a sparse sampling population PK design. Inositol urine losses and feeding intakes were measured. Safety was prospectively monitored. RESULTS At 80mg/kg/day mean serum levels reached 140mg/L, similar to Hallman’s findings. Levels declined after 2 weeks, converging in all groups by 6 wks. Analyses showed a mean volume of distribution 0.657 L/kg, clearance 0.058 L/kg/hr, and half-life 7.90 hr. Adverse events and co-morbidities were fewer in the inositol groups, but not significantly so. CONCLUSIONS Multiple dose inositol at 80mg/kg/day was not associated with increased adverse events, achieves previously effective serum levels, and is appropriate for investigation in a Phase 3 trial. PMID:27074126

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

PubMed

Pappas, Dimitrios A; John, Ani; Curtis, Jeffrey R; Reed, George W; Karki, Chitra; Magner, Robert; Kremer, Joel M; Shewade, Ashwini; Greenberg, Jeffrey D

2016-06-01

In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. ClinicalTrials.gov identifier, NCT01625650.

Attenuation of Multiple Organ Damage by Continuous Low-Dose Solvent-Free Infusions of Resveratrol after Severe Hemorrhagic Shock in Rats

PubMed Central

Kirsch, Michael; Petrat, Frank

2017-01-01

Therapeutic effects of continuous intravenous infusions of solvent-free low doses of resveratrol on organ injury and systemic consequences resulting from severe hemorrhagic shock in rats were studied. Hemorrhagic shock was induced by withdrawing arterial blood until a mean arterial blood pressure (MAP) of 25–30 mmHg was reached. Following a shock phase of 60 min, rats were resuscitated with the withdrawn blood plus lactated Ringer’s. Resveratrol (20 or 60 μg/kg × h) was continuously infused intravenously starting with the resuscitation phase (30 min) and continued until the end of the experiment (total treatment time 180 min). Animals of the shock control group received 0.9% NaCl solution. After the observation phase (150 min), rats were sacrificed. Resveratrol significantly stabilized the MAP and peripheral oxygen saturation after hemorrhagic shock, decreased the macroscopic injury of the small intestine, significantly attenuated the shock-induced increase in tissue myeloperoxidase activity in the small intestine, liver, kidney and lung, and diminished tissue hemorrhages (particularly in the small intestine and liver) as well as the rate of hemolysis. Already very low doses of resveratrol, continuously infused during resuscitation after severe hemorrhagic shock, can significantly improve impaired systemic parameters and attenuate multiple organ damage in rats. PMID:28817064

Intravenous ketamine in a dissociating dose as a temporizing measure to avoid mechanical ventilation in adult patient with severe asthma exacerbation.

PubMed

Shlamovitz, Gil Z; Hawthorne, Tracy

2011-11-01

Patients experiencing severe asthma exacerbations occasionally deteriorate to respiratory failure requiring endotracheal intubation and mechanical ventilation. Mechanical ventilation in this setting exposes the patients to substantial iatrogenic risk and should be avoided if at all possible. To describe the use of intravenous ketamine in acute asthma exacerbation. We present a case of severe asthma exacerbation in an adult female patient who failed to improve with standard therapies, but promptly improved with the administration of intravenous ketamine (0.75 mg/kg i.v. bolus followed by continuous drip of 0.15 mg/kg/h). This case suggests that intravenous ketamine given in a dissociative dose may be an effective temporizing measure to avoid mechanical ventilation in adult patients with severe asthma exacerbations. Copyright © 2011 Elsevier Inc. All rights reserved.

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

Single-Dose and Multiple-Dose Pharmacokinetics of Nicotine 6 mg Gum.

PubMed

Hansson, Anna; Rasmussen, Thomas; Kraiczi, Holger

2017-04-01

Under-dosing is a recognized problem with current nicotine replacement therapy (NRT). Therefore, a new 6mg nicotine gum has been developed. To compare the nicotine uptake from the 6mg gum versus currently available NRT products, two pharmacokinetic studies were performed. In one randomized crossover study, 44 healthy adult smokers received single doses of 6, 4, and 2mg nicotine gum, and 4mg nicotine lozenge on separate occasions. In a separate randomized crossover multiple-dose study over 11 hours, 50 healthy adult smokers received one 6mg gum every hour and 90 minutes, respectively, one 4mg gum every hour, and one 4mg lozenge every hour. In both studies, blood samples were collected over 12 hours to determine single-dose and multiple-dose pharmacokinetic variables. In the single-dose study, the amount of nicotine released from the 2, 4, and 6mg gums (1.44, 3.36, and 4.94mg) as well as the resulting maximum concentration and area under the curve (5.9, 10.1, and 13.8ng/mL, and 17.1, 30.7, 46.2ng/mL × h, respectively) increased with dose. The maximum concentration and area under the curve of the 6mg gum were 44% and 30% greater, respectively, than those for 4mg lozenge. Upon hourly administration, the steady-state average plasma nicotine concentration with 6mg gum (37.4ng/mL) was significantly higher than those for 4mg lozenge (28.3ng/mL) and 4mg gum (27.1ng/mL). Nicotine delivery via the 6mg gum results in higher plasma nicotine concentrations after a single dose and at steady state than with currently available oral NRT. Under-dosing is a recognized problem with current NRT. Therefore, a new 6mg nicotine gum has been developed. Our studies show that upon single-dose and multiple-dose administration, the 6mg gum releases and delivers more nicotine to the systemic circulation than 2mg gum, 4mg gum, and 4mg lozenge. Thus, each 6mg nicotine gum provides a higher degree of nicotine substitution and/or lasts for a longer period of time than currently available nicotine

High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

PubMed

Chen, Chia-Chi; Wu, Chien-Chih

2016-01-01

Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.

[Single intravenous tranexamic acid dose to reduce blood loss in primary total knee replacement].

PubMed

Sanz-Reig, J; Parra Ruiz, B; Ferrández Martínez, J; Martínez López, J F

2016-01-01

To evaluate the effectiveness and safety of a single intravenous dose of tranexamic acid in order to reduce blood loss in total knee replacement. Prospective observational study of the administration of tranexamic acid in patients undergoing primary total knee arthroplasty from November 2013 to February 2015, in which an autologous blood recovery system was used. The study included 98 patients, distributed into two groups of 49 patients according to whether or not they received intravenous tranexamic acid. The primary endpoint was the number of patients requiring autologous transfusion from the recovery system autologous blood recovery system. No drop-outs were recorded during follow-up. There were no significant differences between groups as regards the preoperative and hospital variables. The mean preoperative haemoglobin and haematocrit at 24 and 48 hours postoperatively were similar in both groups. The average volume of bleeding in the autologous blood recovery system and estimated average blood loss was lower in patients who had been administered tranexamic acid, with significant differences. No patients in the group that was administered tranexamic acid required blood autotransfusion. The transfusion rate was zero in the two groups. No adverse events related to the administration of tranexamic acid were recorded. Intravenous administration of tranexamic acid, according to the described protocol, has presented a non-autotransfusion or allo-transfusion rate of 100%, with no increased incidence of thrombotic events. Thus, its use in this group of patients is recommended. The indication should be individualized, its use justified in the patient medical records, and informed consent is mandatory. Copyright © 2015 SECOT. Published by Elsevier Espana. All rights reserved.

Electroporation-delivered transdermal neostigmine in rats: equivalent action to intravenous administration

PubMed Central

Berkó, Szilvia; Szűcs, Kálmán F; Balázs, Boglárka; Csányi, Erzsébet; Varju, Gábor; Sztojkov-Ivanov, Anita; Budai-Szűcs, Mária; Bóta, Judit; Gáspár, Róbert

2016-01-01

Purpose Transdermal electroporation has become one of the most promising noninvasive methods for drug administration, with greatly increased transport of macromolecules through the skin. The cecal-contracting effects of repeated transdermal electroporation delivery and intravenous administration of neostigmine were compared in anesthetized rats. Methods The cecal contractions were detected with implantable strain gauge sensors, and the plasma levels of neostigmine were followed by high-performance liquid chromatography. Results Both intravenously and EP-administered neostigmine (0.2–66.7 μg/kg) increased the cecal contractions in a dose-dependent manner. For both the low doses and the highest dose, the neostigmine plasma concentrations were the same after the two modes of administration, while an insignificantly higher level was observed at a dose of 20 μg/kg after intravenous administration as compared with the electroporation route. The contractile responses did not differ significantly after the two administration routes. Conclusion The results suggest that electroporation-delivered neostigmine elicits action equivalent to that observed after intravenous administration as concerning both time and intensity. Electroporation permits the delivery of even lower doses of water-soluble compounds through the skin, which is very promising for clinical practice. PMID:27274203

Treatment with acetaminophen/paracetamol or ibuprofen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.

PubMed

Wark, J D; Bensen, W; Recknor, C; Ryabitseva, O; Chiodo, J; Mesenbrink, P; de Villiers, T J

2012-02-01

Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms. Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen. In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion. The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen. Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels

PubMed Central

Hyun, Seung Won; Wong, Weng Kee

2016-01-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs. PMID:26565557

Multiple-Objective Optimal Designs for Studying the Dose Response Function and Interesting Dose Levels.

PubMed

Hyun, Seung Won; Wong, Weng Kee

2015-11-01

We construct an optimal design to simultaneously estimate three common interesting features in a dose-finding trial with possibly different emphasis on each feature. These features are (1) the shape of the dose-response curve, (2) the median effective dose and (3) the minimum effective dose level. A main difficulty of this task is that an optimal design for a single objective may not perform well for other objectives. There are optimal designs for dual objectives in the literature but we were unable to find optimal designs for 3 or more objectives to date with a concrete application. A reason for this is that the approach for finding a dual-objective optimal design does not work well for a 3 or more multiple-objective design problem. We propose a method for finding multiple-objective optimal designs that estimate the three features with user-specified higher efficiencies for the more important objectives. We use the flexible 4-parameter logistic model to illustrate the methodology but our approach is applicable to find multiple-objective optimal designs for other types of objectives and models. We also investigate robustness properties of multiple-objective optimal designs to mis-specification in the nominal parameter values and to a variation in the optimality criterion. We also provide computer code for generating tailor made multiple-objective optimal designs.

Comparison of two doses of intravenous temsirolimus in patients with relapsed/refractory mantle cell lymphoma.

PubMed

Jurczak, Wojciech; Ramanathan, Sundra; Giri, Pratyush; Romano, Alessandra; Mocikova, Heidi; Clancy, Jill; Lechuga, Mariajose; Casey, Michelle; Boni, Joseph; Giza, Agnieszka; Hess, Georg

2018-03-01

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versus 4.5 months (hazard ratio [HR] 0.731; 80% confidence interval [CI], 0.520-1.027), and median OS 18.7 versus 11.0 months (HR 0.681; 80% CI, 0.472-0.982) with 175/75 mg versus 75 mg. There were fewer patients with serious AEs, dose reduction, or death with 175/75 mg (57.4%, 48.9%, and 48.9%) versus 75 mg (73.8%, 64.3%, and 65.1%). Temsirolimus 175/75 mg remains the preferred dosing regimen for relapsed/refractory MCL.

A pilot study assessing pharmacokinetics and tolerability of oral and intravenous baclofen in healthy adult volunteers.

PubMed

Agarwal, Suresh K; Kriel, Robert L; Cloyd, James C; Coles, Lisa D; Scherkenbach, Lisa A; Tobin, Michael H; Krach, Linda E

2015-01-01

Our objective was to characterize baclofen pharmacokinetics and safety given orally and intravenously. Twelve healthy subjects were enrolled in a randomized, open-label, crossover study and received single doses of baclofen: 3 or 5 mg given intravenously and 5 or 10 mg taken orally with a 48-hour washout. Blood samples for baclofen analysis were collected pre-dose and at regular intervals up to 24 hours post-dose. Clinical response was assessed by sedation scores, ataxia, and nystagmus. Mean absolute bioavailability of oral baclofen was 74%. Dose-adjusted areas under the curve between the oral and intravenous arms were statistically different (P = .0024), whereas area under the curve variability was similar (coefficient of variation: 18%-24%). Adverse effects were mild in severity and not related to either dose or route of administration. Three- and 5-mg intravenous doses of baclofen were well tolerated. Seventy-four percent oral bioavailability indicates that smaller doses of intravenous baclofen are needed to attain comparable total drug exposures. © The Author(s) 2014.

Intermittent Drug Dosing Intervals Guided by the Operational Multiple Dosing Half Lives for Predictable Plasma Accumulation and Fluctuation

PubMed Central

Grover, Anita; Benet, Leslie Z.

2013-01-01

Intermittent drug dosing intervals are usually initially guided by the terminal pharmacokinetic half life and are dependent on drug formulation. For chronic multiple dosing and for extended release dosage forms, the terminal half life often does not predict the plasma drug accumulation or fluctuation observed. We define and advance applications for the operational multiple dosing half lives for drug accumulation and fluctuation after multiple oral dosing at steady-state. Using Monte Carlo simulation, our results predict a way to maximize the operational multiple dosing half lives relative to the terminal half life by using a first-order absorption rate constant close to the terminal elimination rate constant in the design of extended release dosage forms. In this way, drugs that may be eliminated early in the development pipeline due to a relatively short half life can be formulated to be dosed at intervals three times the terminal half life, maximizing compliance, while maintaining tight plasma concentration accumulation and fluctuation ranges. We also present situations in which the operational multiple dosing half lives will be especially relevant in the determination of dosing intervals, including for drugs that follow a direct PKPD model and have a narrow therapeutic index, as the rate of concentration decrease after chronic multiple dosing (that is not the terminal half life) can be determined via simulation. These principles are illustrated with case studies on valproic acid, diazepam, and anti-hypertensives. PMID:21499748

Low dose intravenous immunoglobulins and steroids in toxic epidermal necrolysis: a prospective comparative open-labelled study of 36 cases.

PubMed

Jagadeesan, Soumya; Sobhanakumari, K; Sadanandan, Sadeep Melethil; Ravindran, Sheeba; Divakaran, Manjula Velikkakathu; Skaria, Lissy; Kurien, George

2013-01-01

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with high mortality. Though different modalities of treatment are advocated, there is no consensus regarding specific therapy. Corticosteroids have shown conflicting results and for high dose intravenous immunoglobulins (IVIG), cost is a limiting factor. To find out the effectiveness of combination therapy with low-dose IVIG and steroids versus steroids alone in our TEN patients. After obtaining Ethical Committee approval, 36 consecutive TEN patients (2008-2012) were alternately allocated to 2 groups - Group A was given combination of low-dose IVIG (0.2-0.5 g/kg) and rapidly tapering course of steroids (intravenous dexamethasone 0.1- 0.3 mg/kg/day tapered in 1-2 weeks) while Group B was given same dose of steroids alone. Outcome parameters assessed were time taken for arrest of disease progression, time taken for re-epithelization, duration of hospital stay and mortality rates. Both groups had 18 patients. Baseline characteristics like age, sex ratio, SCORTEN, body surface area involvement and treatment interval were comparable. Time for arrest of disease progression and for re-epithelization was significantly lowered in Group A (P = 0.0001, P = 0.0009 respectively). Though duration of hospital stay and deaths were less in Group A, difference was not statistically significant. SCORTEN based standardized mortality ratio (SMR) analysis revealed that combination therapy reduced the probability of dying by 82% (SMR = 0.18 ± 0.36) and steroids by 37% (SMR = 0.63 ± 0.71). Difference in SMR was statistically significant (P = 0.00001). No significant side effects due to either modality were found in any of the patients. Combination therapy with low-dose IVIG and steroids is more effective in terms of reduced mortality and faster disease resolution when compared to steroids alone in TEN.

Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination

PubMed Central

Schneider, M; Paulin, A; Dron, F; Woehrlé, F

2014-01-01

The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl®). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4–16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. PMID:24666477

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration.

PubMed

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

Multiple Intravenous Infusions Phase 2a: Ontario Survey

PubMed Central

Fan, Mark; Koczmara, Christine; Masino, Caterina; Cassano-Piché, Andrea; Trbovich, Patricia; Easty, Anthony

2014-01-01

Background Research conducted in earlier phases of this study prospectively identified a number of concerns related to the safe administration of multiple intravenous (IV) infusions in Ontario hospitals. Objective To investigate the potential prevalence of practices or policies that may contribute to the patient safety risks identified in Phase 1b of this study. Data Sources and Review Methods Sixty-four survey responses were analyzed from clinical units where multiple IV infusions may occur (e.g., adult intensive care units). Survey questions were organized according to the topics identified in Phase 1b as potential contributors to patient harm (e.g., labelling practices, patient transfer practices, secondary infusion policies). Results Survey results indicated suboptimal practices and policies in some clinical units, and variability in a number of infusion practices. Key areas of concern included the following: use of primary IV tubing without back check valves when administering secondary infusions administration of secondary infusions with/as high-alert continuous IV medications potential confusion about how IV tubing should be labelled to reflect replacement date and time interruptions to IV therapy due to IV pump and/or tubing changes when patients are transferred between clinical units coadministration of continuous or intermittent infusions on central venous pressure monitoring ports variability in respondents’ awareness of the infusion pump's bolus capabilities Limitations Due to the limited sample size, survey responses may not be representative of infusion practices across Ontario. Answers to some questions indicated that the intent of the questions might have been misunderstood. Due to a design error, 1 question about bolus administration methods was not shown to as many respondents as appropriate. Conclusions The Ontario survey revealed variability in IV infusion practice across the province and potential opportunities to improve safety. PMID

Schedule Dependence in Cancer Therapy: Intravenous Vitamin C and the Systemic Saturation Hypothesis

PubMed Central

Miranda Massari, Jorge R.; Duconge, Jorge; Riordan, Neil H.; Ichim, Thomas

2013-01-01

Despite the significant number of in vitro and in vivo studies to assess vitamin C effects on cancer following the application of large doses and its extensive use by alternative medicine practitioners in the USA; the precise schedule for successful cancer therapy is still unknown. Based on interpretation of the available data, we postulate that the relationship between Vitamin C doses and plasma concentration x time, the capability of tissue stores upon distribution, and the saturable mechanism of urinary excretion are all important determinants to understand the physiology of high intravenous vitamin C dose administration and its effect on cancer. Practitioners should pay more attention to the cumulative vitamin C effect instead of the vitamin C concentrations to account for observed discrepancy in antitumor response. We suggest that multiple, intermittent, short-term intravenous infusions of vitamin C over a longer time period will correlate with greater antitumor effects than do single continuous IV doses of the same total exposure. This approach would be expected to minimize saturation of renal reabsorption, providing a continuous “dynamic flow” of vitamin C in the body for optimal systemic exposure and clinical outcomes. This prevents the “systemic saturation” phenomena, which may recycle vitamin C and render it less effective as an anticancer agent. Nonetheless, more pharmacokinetic and pharmacodynamic studies are needed to fully understand this schedule-dependence phenomenon. PMID:24860238

Backscattering measuring system for optimization of intravenous laser irradiation dose

NASA Astrophysics Data System (ADS)

Rusina, Tatyana V.; Popov, V. D.; Melnik, Ivan S.; Dets, Sergiy M.

1996-11-01

Intravenous laser blood irradiation as an effective method of biostimulation and physiotherapy becomes a more popular procedure. Optimal irradiation conditions for each patient are needed to be established individually. A fiber optics feedback system combined with conventional intravenous laser irradiation system was developed to control of irradiation process. The system consists of He-Ne laser, fiber optics probe and signal analyzer. Intravenous blood irradiation was performed in 7 healthy volunteers and 19 patients with different diseases. Measurements in vivo were related to in vitro blood irradiation which was performed in the same conditions with force-circulated venous blood. Comparison of temporal variations of backscattered light during all irradiation procedures has shown a strong discrepancy on optical properties of blood in patients with various health disorders since second procedure. The best cure effect was achieved when intensity of backscattered light was constant during at least five minutes. As a result, the optical irradiation does was considered to be equal 20 minutes' exposure of 3 mW He-Ne laser light at the end of fourth procedure.

Intravenous Iron Supplementation Practices and Short-Term Risk of Cardiovascular Events in Hemodialysis Patients

PubMed Central

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

2013-01-01

Background & Objectives Intravenous iron supplementation is widespread in the hemodialysis population, but there is uncertainty about the safest dosing strategy. We compared the safety of different intravenous iron dosing practices on the risk of adverse cardiovascular outcomes in a large population of hemodialysis patients. Design settings, participants, & measurements A retrospective cohort was created from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the United States Renal Data System. Dosing comparisons were (1) bolus (consecutive doses ≥ 100 mg exceeding 600 mg during one month) versus maintenance (all other iron doses during the month); and (2) high (> 200 mg over 1 month) versus low dose (≤ 200 mg over 1 month). We established a 6-month baseline period (to identify potential confounders and effect modifiers), a one-month iron exposure period, and a three-month follow-up period. Outcomes were myocardial infarction, stroke, and death from cardiovascular disease. Results 117,050 patients contributed 776,203 unique iron exposure/follow-up periods. After adjustment, we found no significant associations of bolus dose versus maintenance, hazards ratio for composite outcome, 1.03 (95% C.I. 0.99, 1.07), or high dose versus low dose intravenous iron, hazards ratio for composite outcome, 0.99 (95% C.I. 0.96, 1.03). There were no consistent associations of either high or bolus dose versus low or maintenance respectively among pre-specified subgroups. Conclusions Strategies favoring large doses of intravenous iron were not associated with increased short-term cardiovascular morbidity and mortality. Investigation of the long-term safety of the various intravenous iron supplementation strategies may still be warranted. PMID:24223866

Optimization of initial propofol bolus dose for EEG Narcotrend Index-guided transition from sevoflurane induction to intravenous anesthesia in children.

PubMed

Dennhardt, Nils; Boethig, Dietmar; Beck, Christiane; Heiderich, Sebastian; Boehne, Martin; Leffler, Andreas; Schultz, Barbara; Sümpelmann, Robert

2017-04-01

Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia (TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram (EEG) during the transition phase. The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg -1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg -1 ·h -1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 μg·kg -1 ·min -1 . Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [IQR 0.9-2.5] mg·kg -1 and median NI thereafter was 33 [IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg -1 . Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg -1 after

Pharmacokinetics of marbofloxacin in pigs after intravenous and intramuscular administration of a single dose of 8 mg/kg: dose proportionality, influence of the age of the animals and urinary elimination.

PubMed

Schneider, M; Paulin, A; Dron, F; Woehrlé, F

2014-12-01

The pharmacokinetics of marbofloxacin in pigs were evaluated as a function of dose and animal age following intravenous and intramuscular administration of a 16% solution (Forcyl(®) ). The absolute bioavailability of marbofloxacin as well as the dose proportionality was evaluated in 27-week-old fattening pigs. Blood PK and urinary excretion of marbofloxacin were evaluated after a single intramuscular dose of 8 mg/kg in 16-week-old male pigs. An additional group of 12-week-old weaned piglets was used for the evaluation of age-related kinetics. The plasma and urine concentration of marbofloxacin was determined using a HPLC method. Pharmacokinetic parameters were calculated using noncompartmental methods. After intravenous administration in 27-week-old fattening pigs, the total body clearance was 0.065 L/h·kg. After intramuscular administration to the same animals, the mean observed Cmax was 6.30 μg/mL, and the AUCINF was 115 μg·h/mL. The absolute bioavailability was 91.5%, and dose proportionality was shown within the dose range of 4-16 mg/kg. The renal clearance was about half of the value of the total clearance. The total systemic clearance values significantly decreased as a function of age, being 0.092 L/h·kg and 0.079 L/h·kg in pigs aged 12 and 16 weeks, respectively. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

PubMed Central

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

Serum toxicokinetics after intravenous and oral dosing of larkspur toxins in goats

USDA-ARS?s Scientific Manuscript database

Poisoning of cattle by larkspur plants (Delphinium spp.) is a concern for cattle ranchers in western North America. Previous research studies have evaluated the toxicokinetic profile of multiple larkspur toxins in several livestock species. However, those studies were all performed by orally dosing ...

Preincisional administration of intravenous or subcutaneous infiltration of low-dose ketamine suppresses postoperative pain after appendectomy

PubMed Central

Honarmand, Azim; Safavi, Mohammadreza; Karaky, Hasan

2012-01-01

Background Ketamine, an N-methyl-D-aspartate receptor antagonist, can suppress hyperalgesia and allodynia. The purpose of the present study was to evaluate the clinical efficacy of preincisional intravenous or subcutaneous infiltration of ketamine for postoperative pain relief after appendectomy. Methods Ninety patients, aged 18–60 years, scheduled for appendectomy was enrolled in this study. Patients were divided into three groups of 30 each and received subcutaneous infiltration of ketamine 0.5 mg/kg (KS), intravenous ketamine 0.5 mg/kg (KI), or subcutaneous infiltration of normal saline 3 mL (C) before surgery. Visual analog scale (VAS) values and analgesic consumption were evaluated for 24 hours after surgery. Results VAS scores were significantly lower at the time of arrival in the recovery room, and at 10, 20, and 30 minutes thereafter in group KI and group KS compared with group C (P < 0.05). VAS scores were not significantly different between group KI and group KS at these intervals. Postoperative VAS scores were significantly lower at 6, 12, 18, and 24 hours in group KI compared with group C (P < 0.05). In group KS, the postoperative VAS score was significantly lower at 6 hours (P < 0.05). VAS scores were significantly lower at 12, 18, and 24 hours after surgery in group KI compared with group KS (P < 0.05). Conclusion A 0.5 mg/kg dose of ketamine given at approximately 15 minutes before surgery by the intravenous route provided analgesia for 24 hours after surgery in patients undergoing appendectomy. PMID:22328829

Comparison of intravenous pantoprazole with intravenous ranitidine in peptic ulcer bleeding.

PubMed

Demetrashvili, Z M; Lashkhi, I M; Ekaladze, E N; Kamkamidze, G K

2013-10-01

Following successful endoscopic therapy in patients with peptic ulcer bleeding, rebleeding occurs in 4% to 30% of cases. Rebleeding remains the most important determinant of poor prognosis. The aim of our study is to compare the efficacy of intravenous pantoprazole and ranitidine for prevention of rebleeding of peptic ulcers following initial endoscopic hemostasis. In our study patients who had gastric or duodenal ulcers with bleeding received combined endoscopy therapy with injection of epinephrine and thermocoagulation. Patients with initial hemostasis were randomly assigned to two groups. One group (45 patients) was treated with intravenous pantoprazole, with an initial dose of 40 mg and subsequently with 40 mg every twelve hours during the first three days, followed by 40 mg a day orally. The other group (44 patients) was treated with intravenous ranitidine, with an initial dose of 50 mg and subsequently every eight hours during the first three days, followed by 150 mg ranitidine every 12 h. In all case of rebleeding repeated endoscopy was performed. One patient (2,2%) had rebleeding in pantoprazole group. Bleeding could not be blocked by repeated endoscopic intervention, thus the patient underwent emergency surgery. 6 patients (13,6%) from ranitidine group had recurrence of bleeding. Repeated endoscopy was performed in all these patients: bleeding was stopped in 3 cases endoscopically, other 3 patients were surgically treated urgently as endoscopic hemostasis was not successful. None of the patients died of uncontrolled rebleeding. The frequency of rebleeding was significantly low in the group of pantoprazole compared to ranitidine group (2,2% vs 13,6% P=0,046). There were no statistically significant differences between the groups with regard to need for emergency surgery (2,2% vs 6,8%), the length of hospital stay (6,7±3,3 vs 7,4±4,3 d) and mortality (0%vs 0%). After endoscopic treatment of bleeding peptic ulcers, intravenous pantoprazole is more effective

Results of intravenous steroid injection on reduction of postoperative edema in rhinoplasty.

PubMed

Alajmi, Monther Ali; Al-Abdulhadi, Khalid A; Al-Noumas, Hamoud Saud; Kavitha, Gopalan

2009-12-01

To determine the efficacy of intravenous dexamethasone in reducing postrhinoplasty edema. A prospective, randomized clinical trial with placebo control. Department of Otorhinolaryngology, Al-Sabah and Zain Hospital, Kuwait. Eighty-four patients (male = 28; female = 56) aged between 20 and 40 years, undergoing open rhinoplasty with hump removal and bilateral lateral osteotomies were enrolled in this study. Patients were randomized to receive two doses of 10 mg of dexamethasone intravenously or placebo, first dose during surgery and second dose 12 hours after surgery. Patients were evaluated postoperatively at 24 hours, days 2, 5, 7 and 10 for periorbital edema. 10 mg of dexamethasone given intravenously during rhinoplasty and a second dose 12 hours after surgery, reduced postoperative periorbital edema significantly. This study showed a statistically significant benefit of dexamethasone over placebo in reducing periorbital edema after rhinoplasty. No complications were attributed to the administration of dexamethasone.

Cost effectiveness of high-dose intravenous esomeprazole for peptic ulcer bleeding.

PubMed

Barkun, Alan N; Adam, Viviane; Sung, Joseph J Y; Kuipers, Ernst J; Mössner, Joachim; Jensen, Dennis; Stuart, Robert; Lau, James Y; Nauclér, Emma; Kilhamn, Jan; Granstedt, Helena; Liljas, Bengt; Lind, Tore

2010-01-01

Peptic ulcer bleeding (PUB) is a serious and sometimes fatal condition. The outcome of PUB strongly depends on the risk of rebleeding. A recent multinational placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT00251979) showed that high-dose intravenous (IV) esomeprazole, when administered after successful endoscopic haemostasis in patients with PUB, is effective in preventing rebleeding. From a policy perspective it is important to assess the cost efficacy of this benefit so as to enable clinicians and payers to make an informed decision regarding the management of PUB. Using a decision-tree model, we compared the cost efficacy of high-dose IV esomeprazole versus an approach of no-IV proton pump inhibitor for prevention of rebleeding in patients with PUB. The model adopted a 30-day time horizon and the perspective of third-party payers in the USA and Europe. The main efficacy variable was the number of averted rebleedings. Healthcare resource utilization costs (physician fees, hospitalizations, surgeries, pharmacotherapies) relevant for the management of PUB were also determined. Data for unit costs (prices) were primarily taken from official governmental sources, and data for other model assumptions were retrieved from the original clinical trial and the literature. After successful endoscopic haemostasis, patients received either high-dose IV esomeprazole (80 mg infusion over 30 min, then 8 mg/hour for 71.5 hours) or no-IV esomeprazole treatment, with both groups receiving oral esomeprazole 40 mg once daily from days 4 to 30. Rebleed rates at 30 days were 7.7% and 13.6%, respectively, for the high-dose IV esomeprazole and no-IV esomeprazole treatment groups (equating to a number needed to treat of 17 in order to prevent one additional patient from rebleeding). In the US setting, the average cost per patient for the high-dose IV esomeprazole strategy was $US14 290 compared with $US14 239 for the no-IV esomeprazole strategy (year 2007 values). For

[Late sequelae of central nervous system prophylaxis in children with acute lymphoblastic leukemia: high doses of intravenous methotrexate versus radiotherapy of the central nervous system--review of literature].

PubMed

Zając-Spychała, Olga; Wachowiak, Jacek

2012-01-01

Acute lymphoblastic leukemia is the most common malignancy in children. All current therapy regimens used in the treatment of childhood acute lymphoblastic leukemia include prophylaxis of the central nervous system. Initially it was thought that the best way of central nervous system prophylaxis is radiotherapy. But despite its effectiveness this method, may cause late sequelae and complications. In the programme currently used in Poland to treat acute lymphoblastic leukemia, prophylactic radiotherapy has been reduced by 50% (12 Gy) and is used only in patients stratified into the high risk group and in patients diagnosed as T-cell ALL (T-ALL). Complementary to radiotherapy, intrathecal methotrexate is given alone or in combination with cytarabine and hydrocortisone is given, as well as systemic chemotherapy with intravenous methotrexate is administered in high or medium doses (depending on risk groups and leukemia immunophenotype). Recent studies have shown that high dose irradiation of the central nervous system impairs cognitive development causing memory loss, visuomotor coordination impairment, attention disorders and reduction in the intelligence quotient. It has been proved that the degree of cognitive impairment depends on the radiation dose directed to the medial temporal lobe structures, particularly in the hippocampus and the surrounding cortex. Also, methotrexate used intravenously in high doses, interferes with the metabolism of folic acid which is necessary for normal development and the optimal functioning of neurons in the central nervous system. It has been proved that patients who have been treated with high doses of methotrexate are characterized by reduced memory skills and a lower intelligence quotient. The literature data concerning long term neuroanatomical abnormalities and neuropsychological deficits are ambiguous, and there is still no data concerning current methods of central nervous system prophylaxis with low doses of irradiation in

Aminothiol Receptors for Decorporation of Intravenously Administered 60Co in the Rat

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

Levitskaia, Tatiana G.; Morris, James E.; Creim, Jeffrey A.

2010-01-01

The reported investigation provides a comparison of the oral decorporation efficacy of L-glutathione (GSH), L-cysteine (Cys), and a liposomal GSH formulation (ReadiSorb) toward systemic cobalt-60 (60Co) to that observed following intravenous administration of GSH and Cys in F344 rats. L-histidine (His) was tested intravenously to compare in vivo efficacy of the aminothiol GSH and Cys chelators with that of aminoimidazole (His) chelator. 60Co was administered to animals by intravenous injection, followed by intravenous or oral gavage doses of a chelator repeated at 24 hour intervals for a total of 5 doses. The results suggest that GSH and Cys are potentmore » decorporation agents for 60Co in the rat model, although the efficacy of treatment depends largely on systemic availability of a chelator. The intravenous GSH or Cys were most effective in reducing tissue 60Co levels and in increasing excretion of radioactivity compared to control animals. Liposomal encapsulation was found to markedly enhance the oral bioavailability of GSH compared to non-formulated GSH. Oral administration of ReadiSorb reduced 60Co levels in nearly all tissues by 12-43% compared to that observed for non-formulated GSH. Efficacy of oral Cys was only slightly reduced in comparison with intravenous Cys. Further studies to optimize the dosing regimen in order to maximize decorporation efficiency are warranted.« less

Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs.

PubMed

Kuroha, Masanori; Azumano, Akinori; Kuze, Yoji; Shimoda, Minoru; Kokue, Eiichi

2002-01-01

To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CL(tot)) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CL(tot) appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K(i) values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 microM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CL(tot) values estimated from in vitro K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CL(tot) of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K(i) values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

PubMed

El-Kersh, Karim; Ruf, Kathryn M; Smith, J Shaun

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice

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

Kang, Shin-Ae; Tsolmon, Bilegtsaikhan; Mann, Aman P.

2015-08-15

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100 μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500 μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels ofmore » plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. - Highlights: • Intravenous administration of ESTA was well tolerated. • ESTA up to 500 μg does not cause hematologic, organs, and immunologic responses. • ESTA-mediated hepatic abnormality was considered minor.« less

Multiple anatomy optimization of accumulated dose

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

Watkins, W. Tyler, E-mail: watkinswt@virginia.edu; Siebers, Jeffrey V.; Moore, Joseph A.

Purpose: To investigate the potential advantages of multiple anatomy optimization (MAO) for lung cancer radiation therapy compared to the internal target volume (ITV) approach. Methods: MAO aims to optimize a single fluence to be delivered under free-breathing conditions such that the accumulated dose meets the plan objectives, where accumulated dose is defined as the sum of deformably mapped doses computed on each phase of a single four dimensional computed tomography (4DCT) dataset. Phantom and patient simulation studies were carried out to investigate potential advantages of MAO compared to ITV planning. Through simulated delivery of the ITV- and MAO-plans, target dosemore » variations were also investigated. Results: By optimizing the accumulated dose, MAO shows the potential to ensure dose to the moving target meets plan objectives while simultaneously reducing dose to organs at risk (OARs) compared with ITV planning. While consistently superior to the ITV approach, MAO resulted in equivalent OAR dosimetry at planning objective dose levels to within 2% volume in 14/30 plans and to within 3% volume in 19/30 plans for each lung V20, esophagus V25, and heart V30. Despite large variations in per-fraction respiratory phase weights in simulated deliveries at high dose rates (e.g., treating 4/10 phases during single fraction beams) the cumulative clinical target volume (CTV) dose after 30 fractions and per-fraction dose were constant independent of planning technique. In one case considered, however, per-phase CTV dose varied from 74% to 117% of prescription implying the level of ITV-dose heterogeneity may not be appropriate with conventional, free-breathing delivery. Conclusions: MAO incorporates 4DCT information in an optimized dose distribution and can achieve a superior plan in terms of accumulated dose to the moving target and OAR sparing compared to ITV-plans. An appropriate level of dose heterogeneity in MAO plans must be further investigated.« less

Safety of intravenous lacosamide in critically ill children.

PubMed

Welsh, Sarah S; Lin, Nan; Topjian, Alexis A; Abend, Nicholas S

2017-11-01

Acute seizures are common in critically ill children. These patients would benefit from intravenous anti-seizure medications with few adverse effects. We reviewed the usage and effects of intravenous lacosamide in critically ill children with seizures or status epilepticus. This retrospective series included consecutive patients who received at least one dose of intravenous lacosamide from April 2011 to February 2016 in the pediatric intensive care unit of a quaternary care children's hospital, including patients with new lacosamide initiation and continuation of outpatient oral lacosamide. Dosing and prescribing practices were reviewed. Adverse effects were defined by predefined criteria, and most were evaluated during the full admission. We identified 51 intensive care unit admissions (47 unique patients) with intravenous lacosamide administration. Lacosamide was utilized as a third or fourth-line anti-seizure medication for acute seizures or status epilepticus in the lacosamide-naïve cohort. One patient experienced bradycardia and one patient experienced a rash that were considered potentially related to lacosamide. No other adverse effects were identified, including no evidence of PR interval prolongation. Lacosamide was well tolerated in critically ill children. Further study is warranted to evaluate the effectiveness of earlier lacosamide use for pediatric status epilepticus and acute seizures. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

[Intravenous clomipramine for depressive disorders].

PubMed

Landowski, Jerzy; Lamparska, Ewa; Wichowicz, Hubert; Gizińska, Dorota; Godlewska, Beata; Wiglusz, Mariusz

2002-01-01

51 patients with depressive episode (40--recurrent depressive disorder, 11--bipolar affective disorder) were treated by the clomipramine intravenous infusions. The number of infusions varied from 5 to 21 (mostly 10-16). The median of maximal dose was 150 mg. There were significant clinical improvement measured by CGI. The therapy was well tolerated.

Pharmacokinetics of sulfamethoxazole and trimethoprim in Pacific white shrimp, Litopenaeus vannamei, after oral administration of single-dose and multiple-dose.

PubMed

Ma, Rongrong; Wang, Yuan; Zou, Xiong; Hu, Kun; Sun, Beibei; Fang, Wenhong; Fu, Guihong; Yang, Xianle

2017-06-01

The tissue distribution and depletion of sulfamethoxazole (SMZ) and trimethoprim (TMP) were studied in Pacific white shrimp, Litopenaeus vannamei, after single-dose and multiple-dose oral administration of SMZ-TMP (5:1) via medicated feed. In single-dose oral administration, shrimps were fed once at a dose of 100 mg/kg (drug weight/body weight). In multiple-dose oral administration, shrimps were fed three times a day for three consecutive days at a dose of 100mg/kg. The results showed the kinetic characteristic of SMZ was different from TMP in Pacific white shrimp. In the single-dose administration, the SMZ was widely distributed in the tissues, while TMP was highly concentrated in the hepatopancreas. The t 1/2z values of SMZ were larger and persist longer than TMP in Pacific white shrimp. In the multiple-dose administration, SMZ accumulated well in the tissues, and reached steady state level after successive administrations, while TMP did not. TMP concentration even appeared the downward trend with the increase of drug times. Compared with the single dose, the t 1/2z values of SMZ in hepatopancreas (8.22-11.33h) and muscle (6.53-10.92h) of Pacific white shrimps rose, but the haemolymph dropped (13.76-11.03) in the multiple-dose oral administration. Meanwhile, the corresponding values of TMP also rose in hepatopancreas (4.53-9.65h) and muscle (2.12-2.71h), and declined in haemolymph (7.38-5.25h) following single-dose and multiple-dose oral administration in Pacific white shrimps. In addition, it is worth mentioning that the ratios of SMZ and TMP were unusually larger than the general aim ratio. Copyright © 2017 Elsevier B.V. All rights reserved.

Statistical strategies for averaging EC50 from multiple dose-response experiments.

PubMed

Jiang, Xiaoqi; Kopp-Schneider, Annette

2015-11-01

In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

Pharmacokinetic Study of Intravenous Acetaminophen Administered to Critically Ill Multiple-Trauma Patients at the Usual Dosage and a New Proposal for Administration.

PubMed

Fuster-Lluch, Oscar; Zapater-Hernández, Pedro; Gerónimo-Pardo, Manuel

2017-10-01

The pharmacokinetic profile of intravenous acetaminophen administered to critically ill multiple-trauma patients was studied after 4 consecutive doses of 1 g every 6 hours. Eleven blood samples were taken (predose and 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 minutes postdose), and urine was collected (during 6-hour intervals between doses) to determine serum and urine acetaminophen concentrations. These were used to calculate the following pharmacokinetic parameters: maximum and minimum concentrations, terminal half-life, area under serum concentration-time curve from 0 to 6 hours, mean residence time, volume of distribution, and serum and renal clearance of acetaminophen. Daily doses of acetaminophen required to obtain steady-state minimum (bolus dosing) and average plasma concentrations (continuous infusion) of 10 μg/mL were calculated (10 μg/mL is the presumed lower limit of the analgesic range). Data are expressed as median [interquartile range]. Twenty-two patients were studied, mostly young (age 44 [34-64] years) males (68%), not obese (weight 78 [70-84] kg). Acetaminophen concentrations and pharmacokinetic parameters were these: maximum concentration 33.6 [25.7-38.7] μg/mL and minimum concentration 0.5 [0.2-2.3] μg/mL, all values below 10 μg/mL and 8 below the detection limit; half-life 1.2 [1.0-1.9] hours; area under the curve for 6 hours 34.7 [29.7-52.7] μg·h/mL; mean residence time 1.8 [1.3-2.6] hours; steady-state volume of distribution 50.8 [42.5-66.5] L; and serum and renal clearance 28.8 [18.9-33.7] L/h and 15 [11-19] mL/min, respectively. Theoretically, daily doses for a steady-state minimum concentration of 10 μg/mL would be 12.2 [7.8-16.4] g/day (166 [112-202] mg/[kg·day]); for an average steady-state concentration of 10 μg/mL, they would be 6.9 [4.5-8.1] g/day (91 [59-111] mg/[kg·day]). In conclusion, administration of acetaminophen at the recommended dosage of 1 g per 6 hours to critically ill multiple-trauma patients yields

Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers.

PubMed

Bai, Stephen A; Xiang, Qinfang; Finn, Andrew

2016-02-01

Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine. Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded. In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to

Efficacy of high-dose intravenous immunoglobulins in two patients with idiopathic recurrent pericarditis refractory to previous immunosuppressive treatment.

PubMed

Tona, Francesco; Bellotto, Fabio; Laveder, Francesco; Meneghin, Alessia; Sinagra, Gianfranco; Marcolongo, Renzo

2003-01-01

Although idiopathic acute pericarditis is usually a self-limiting disease, in many patients it may recur over a period of months or years. Even if some evidence seems to suggest the possible role of a deranged immune reactivity in the pathogenesis of idiopathic recurrent pericarditis, the etiology of the disease is still unknown. Furthermore, while some trial data confirm the usefulness of colchicine, its medical treatment is not yet clearly established. We here report the clinical history of 2 patients with idiopathic recurrent pericarditis resistant to prednisone, colchicine and other immunosuppressive drugs, who have been successfully treated with high-dose intravenous immunoglobulins.

Safety of intravenous metoprolol use in unmonitored wards: a single-centre observational study.

PubMed

Kelly, D; Hawdon, G; Reeves, J; Morris, A; Cunningham, M; Barrett, J

2015-09-01

This study aims to examine and quantify the risks associated with the use of intravenous metoprolol on unmonitored wards. This study was a retrospective single-centre observational study from 1 January 2009 to 31 December 2013. The study hospital was a 415-bed, private hospital in Melbourne, Victoria. The study population was all patients who received intravenous metoprolol on an unmonitored ward. The primary outcome measure was the rate of serious adverse events (SAE), defined as a complication of intravenous metoprolol resulting in transfer to a critical-care environment, a medical emergency team call or death. Six hundred and nine patients received a total of 8260 doses of intravenous metoprolol. Seven cases were identified with a SAE deemed possibly related to beta-blocker use and there was one death. All SAE were hypotension, giving an overall rate of hypotension of 7/609 or 1.1% (95% confidence interval (CI), 0.5 to 2.4%) with a rate per dose delivered of 0.8/1000 doses (95% CI 0.3 to 1.7). The death occurred in a 94-year-old woman with abdominal sepsis. After case file review, consensus opinion deemed this to be unrelated to intravenous metoprolol. The use of intravenous metoprolol on unmonitored wards appears to be safe. The complication rate was low, suggesting that this may be a sensible approach to the management of in-hospital populations at risk of beta-blocker withdrawal. © 2015 Royal Australasian College of Physicians.

Disposition in male volunteers of a subanaesthetic intravenous dose of an oil in water emulsion of 14C-propofol.

PubMed

Simons, P J; Cockshott, I D; Douglas, E J; Gordon, E A; Hopkins, K; Rowland, M

1988-04-01

1. An intravenous dose of 14C-propofol (0.47 mg/kg) administered to six male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and less than 2% in faeces. 2. The dose was cleared by metabolism with less than 0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulphate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. 3. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 microgram/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 h post dose. 4. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 1/min.

Brain temperature effects of intravenous heroin: State dependency, environmental modulation, and the effects of dose.

PubMed

Bola, R Aaron; Kiyatkin, Eugene A

2017-11-01

Here we examined how intravenous heroin at a dose that maintains self-administration (0.1 mg/kg) affects brain temperature homeostasis in freely moving rats under conditions that seek to mimic some aspects of human drug use. When administered under standard laboratory conditions (quiet rest at 22 °C ambient temperature), heroin induced moderate temperature increases (1.0-1.5 °C) in the nucleus accumbens (NAc), a critical structure of the brain motivation-reinforcement circuit. By simultaneously recording temperatures in the temporal muscle and skin, we demonstrate that the hyperthermic effects of heroin results primarily from inhibition of heat loss due to strong and prolonged skin vasoconstriction. Heroin-induced brain temperature increases were enhanced during behavioral activation (i.e., social interaction) and in a moderately warm environment (29 °C). By calculating the "net" effects of the drug in these two conditions, we found that this enhancement results from the summation of the hyperthermic effects of heroin with similar effects induced by either social interaction or a warmer environment. When the dose of heroin was increased (to 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/kg), brain temperature showed a biphasic down-up response. The initial temperature decrease was dose-dependent and resulted from a transient inhibition of intra-brain heat production coupled with increased heat loss via skin surfaces-the effects typically induced by general anesthetics. These initial inhibitory effects induced by large-dose heroin injections could be related to profound CNS depression-the most serious health complications typical of heroin overdose in humans. Published by Elsevier Ltd.

Pharmacokinetics of intraperitoneal and intravenous fosfomycin in automated peritoneal dialysis patients without peritonitis.

PubMed

Tobudic, Selma; Matzneller, Peter; Stoiser, Brigitte; Wenisch, Judith Maria; Zeitlinger, Markus; Vychytil, Andreas; Jaeger, Walter; Boehmdorfer, Michaela; Reznicek, Gottfried; Burgmann, Heinz

2012-07-01

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose.

Intravenous glucose preparation as the source of an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae infections in the neonatal unit of a regional hospital in KwaZulu-Natal.

PubMed

Moodley, Prashini; Coovadia, Yacoob M; Sturm, A Willem

2005-11-01

In the last week of May 2005, staff at Mahatma Gandhi Memorial Hospital in KwaZulu-Natal realised that many babies in the high-care nursery ward had bloodstream infections involving Klebsiella pneumoniae bacteria. Attempts to identify a common source of infection failed. The ward was therefore closed and new babies needing high care were admitted to another empty ward. Despite this, babies still became infected. This resulted in a request for assistance from the Department of Medical Microbiology of the Nelson R Mandela School of Medicine. A search for common factors through case history studies of the 26 infected babies showed that blood cultures of the babies remained positive despite the administration of appropriate antibiotics. Different options that could explain this were investigated. The organism was found in intravenous glucose preparations used for multiple dosing. Unopened vials of the same medication were sterile. The nursery was found to lack proper hand-wash facilities and to be overcrowded and understaffed. Reinforcement of hand hygiene and a ban on the multiple dosing of medicines stopped the outbreak. In conclusion, this outbreak resulted from a combination of factors among which lack of hand hygiene and multiple dosing of an intravenous glucose preparation were most significant.

Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy.

PubMed

Auyeung, S Freda; Long, Qi; Royster, Erica Bruce; Murthy, Smitha; McNutt, Marcia D; Lawson, David; Miller, Andrew; Manatunga, Amita; Musselman, Dominique L

2009-10-01

Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon-alpha effects on dopamine. Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon-alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. This sequential, multiple assignment, randomized trial proposes a framework for developing

Pharmacokinetics of Intraperitoneal and Intravenous Fosfomycin in Automated Peritoneal Dialysis Patients without Peritonitis

PubMed Central

Tobudic, Selma; Matzneller, Peter; Stoiser, Brigitte; Wenisch, Judith Maria; Vychytil, Andreas; Jaeger, Walter; Boehmdorfer, Michaela; Reznicek, Gottfried; Burgmann, Heinz

2012-01-01

Blood and dialysate concentrations of fosfomycin were determined after intravenous and intraperitoneal application of 4 mg/liter in patients undergoing automated peritoneal dialysis. Maximum serum concentrations after intravenous (287.75 ± 86.34 mg/liter) and intraperitoneal (205.78 ± 66.78 mg/liter) administration were comparable. Ratios of intraperitoneal to systemic exposure were 1.12 (intraperitoneal administration) and 0.22 (intravenous administration), indicating good systemic exposure after intraperitoneal application but limited penetration of fosfomycin into the peritoneal fluid after the intravenous dose. PMID:22564843

Neurotoxicity of misonidazole in rats following intravenous administration.

PubMed

Graziano, M J; Henck, J W; Meierhenry, E F; Gough, A W

1996-06-01

Misonidazole is a hypoxic cell radiosensitizer that induces a peripheral neuropathy in humans after exceeding a schedule-dependent cumulative threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have been administered intravenously. Since route of exposure can potentially influence the toxicity of xenobiotics, the objective of this study was to assess the neurotoxicity of misonidazole in rats following intravenous dosing using a battery of routine clinical, neurofunctional, biochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg-1 once per day, 5 days per week, for 2 weeks. Animals were evaluated for neurofunctional and pathological changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg-1, and body weight gain of the 300 and 400 mg kg-1 groups was significantly decreased relative to the vehicle controls by 24% and 49%, respectively. Corresponding reductions in food consumption were 8% and 23%, respectively. Although most 400 mg kg-1 animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sniffing and hyperactivity. All of these animals recovered and appeared normal from Day 17 through study termination. There were no treatment-related effects on motor activity, acoustic startle response, rotorod performance, forelimb group strength, toe and tail pinch reflexes, tibial nerve beta-glucuronidase activity or tail nerve conduction velocity. Although hindlimb grip strength of the 400 mg

Pharmacokinetics and clinical application of intravenous valproate in Thai epileptic children.

PubMed

Visudtibhan, Anannit; Bhudhisawadi, Kasama; Vaewpanich, Jarin; Chulavatnatol, Suvatna; Kaojareon, Sming

2011-03-01

Roles of intravenous administration of valproate in status epilepticus and serial seizures are documented in adults and children. Pharmacokinetic parameters are necessary to predict the optimum therapeutic level after administration. A cross-sectional study to determine the pharmacokinetic parameters and safety of intravenous valproate for future application was conducted in Thai children from January to December 2008. There were eleven children, age-range 1-15 years (mean age 9.5 years) enrolled. Valproate of 15-20 mg/kg was administrated intravenously at the rate of 3 mg/kg/min, followed by 6 mg/kg every 6 h. Valproate level was determined prior to the initial dose and at ½, 1, 2, 4, 5, and 6 h postdose. Complete blood count, serum ammonia, and liver function tests were collected prior to the initial dose and at 6 h. Median loading dose was 19 mg/kg (range 15-20.5 mg/kg). Median maximum concentration at 30 min after infusion was 98.8 mcg/mL (range 67-161 mcg/mL). Median volume of distribution was 0.20 L/kg (range 0.15-0.53 L/kg). Median half-life was 9.5 h (range 4.4-24.2 h). Median clearance was 0.02 L/h/kg (range 0.01-0.05 L/h/kg). Six hours after initial dose, eight children did not have recurrent seizure. One child had brief seizure at 20 min after initial dose. Seizure recurred in two children at 4th and 5th hour. Asymptomatic transient elevation of serum ammonia was observed in two children. Volume of distribution of 0.20 L/kg could be applied for initial intravenous administration with a favorable efficacy. Copyright © 2010 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Pharmacokinetics and pharmacodynamics of multiple doses of BG00010, a neurotrophic factor with anti-hyperalgesic effects, in patients with sciatica.

PubMed

Okkerse, Pieter; Hay, Justin L; Versage, Eve; Tang, Yongqiang; Galluppi, Gerald; Ravina, Bernard; Verma, Ajay; Williams, Leslie; Aycardi, Ernesto; Groeneveld, Geert Jan

2016-07-01

BG00010 is a protein in the glial cell line-derived neurotrophic factor (GDNF) family. It is a selective ligand for the GDNF family receptor alpha-3 (GFRα3) co-receptor that normalizes cellular changes resulting from damage or disease, and potentially alleviates neuropathic pain. The main objectives of this study were to evaluate the pharmacokinetic and safety profiles and to determine the effects on pain of ascending doses of intravenous injections of BG00010 in patients with sciatica. This was a randomized, blinded, placebo-controlled multiple-dose study in subjects with sciatica. In Part I (16 patients), four IV dose levels were examined (50, 150, 400, 800 μg kg(-1) ) and in Part II (12 patients), three dose levels were examined (400, 600 and 1200 μg kg(-1) ). Safety and efficacy assessments were used as endpoints. The BG00010 concentration-time data indicated relatively low inter-patient variability and there was a dose-dependent (not dose-proportional) increase in serum exposure from 150 to 1200 μg kg(-1) . The effective half-life was between 40 and 60 h. The most frequently occurring adverse events (AEs) reported by patients receiving BG00010 were headache (67-83%), feeling hot (50-100%), and pruritus (42-67%). Most AEs were mild; no serious AEs or AEs leading to discontinuation occurred. Higher dose regimens of BG00010 resulted in greater pain reduction than placebo or lower dose regimens, although a clear dose-response relationship was not seen. The pharmacokinetic profile of BG00010 was characterized by low intra-patient variability. These data from a small sample suggest that BG00010 may have a benefit for patients with sciatica. © 2016 The British Pharmacological Society.

Effectiveness of intravenous levetiracetam as an adjunctive treatment in pediatric refractory status epilepticus.

PubMed

Kim, Jon Soo; Lee, Jeong Ho; Ryu, Hye Won; Lim, Byung Chan; Hwang, Hee; Chae, Jong-Hee; Choi, Jieun; Kim, Ki Joong; Hwang, Yong Seung; Kim, Hunmin

2014-08-01

Intravenous levetiracetam (LEV) has been shown to be effective and safe in treating adults with refractory status epilepticus (SE). We sought to investigate the efficacy and safety of intravenous LEV for pediatric patients with refractory SE. We performed a retrospective medical-record review of pediatric patients who were treated with intravenous LEV for refractory SE. Clinical information regarding age, sex, seizure type, and underlying neurological status was collected. We evaluated other anticonvulsants that were used prior to administration of intravenous LEV and assessed loading dose, response to treatment, and any adverse events from intravenous LEV administration. Fourteen patients (8 boys and 6 girls) received intravenous LEV for the treatment of refractory SE. The mean age of the patients was 4.4 ± 5.5 years (range, 4 days to 14.6 years). Ten of the patients were neurologically healthy prior to the refractory SE, and the other 4 had been previously diagnosed with epilepsy. The mean loading dose of intravenous LEV was 26 ± 4.6 mg/kg (range, 20-30 mg/kg). Seizure termination occurred in 6 (43%) of the 14 patients. In particular, 4 (57%) of the 7 patients younger than 2 years showed seizure termination. No immediate adverse events occurred during or after infusions. The current study demonstrated that the adjunctive use of intravenous LEV was effective and well tolerated in pediatric patients with refractory SE, even in patients younger than 2 years. Intravenous LEV should be considered as an effective and safe treatment option for refractory SE in pediatric patients.

Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia.

PubMed

van der Westhuizen, J; Kuo, P Y; Reed, P W; Holder, K

2011-03-01

Gastric absorption of oral paracetamol (acetaminophen) may be unreliable perioperatively in the starved and stressed patient. We compared plasma concentrations of parenteral paracetamol given preoperatively and oral paracetamol when given as premedication. Patients scheduled for elective ear; nose and throat surgery or orthopaedic surgery were randomised to receive either oral or intravenous paracetamol as preoperative medication. The oral dose was given 30 minutes before induction of anaesthesia and the intravenous dose given pre-induction. All patients were given a standardised anaesthetic by the same specialist anaesthetist who took blood for paracetamol concentrations 30 minutes after the first dose and then at 30 minute intervals for 240 minutes. Therapeutic concentrations of paracetamol were reached in 96% of patients who had received the drug parenterally, and 67% of patients who had received it orally. Maximum median plasma concentrations were 19 mg.l(-1) (interquartile range 15 to 23 mg.l(-1)) and 13 mg.l(-1) (interquartile range 0 to 18 mg.l(-1)) for the intravenous and oral group respectively. The difference between intravenous and oral groups was less marked after 150 minutes but the intravenous preparation gave higher plasma concentrations throughout the study period. It can be concluded that paracetamol gives more reliable therapeutic plasma concentrations when given intravenously.

Serum toxicokinetics after intravenous and oral dosing of larkspur toxins in goats.

PubMed

Welch, K D; Gardner, D R; Stonecipher, C A; Green, B T; Pfister, J A

2017-07-01

Poisoning of cattle by larkspur plants (Delphinium spp.) is a concern for cattle ranchers in western North America. Previous research studies have evaluated the toxicokinetic profile of multiple larkspur toxins in several livestock species. However, those studies were all performed by orally dosing plant material. Consequently some toxicokinetic parameters could not be definitively determined. In this study, we compared the serum toxicokinetic profile of the larkspur alkaloids methyllycaconitine (MLA) and deltaline in goats dosed both IV and via oral gavage. The results from this study indicate that the toxic alkaloids in larkspurs undergo flip-flop kinetics, meaning the rate of absorption of the alkaloids is slower than the rate of elimination. The implications of flip-flop kinetics in treating animals poisoned by larkspur is discussed. Published by Elsevier Ltd.

Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis.

PubMed

Subramanian, Raju; Zhu, Xiaochun; Hock, M Benjamin; Sloey, Bethlyn J; Wu, Benjamin; Wilson, Sarah F; Egbuna, Ogo; Slatter, J Greg; Xiao, Jim; Skiles, Gary L

2017-02-01

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [ 14 C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [ 14 C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

Safety, pharmacokinetics, and immunological activities of multiple intravenous or subcutaneous doses of an anti-HIV monoclonal antibody, VRC01, administered to HIV-uninfected adults: Results of a phase 1 randomized trial.

PubMed

Mayer, Kenneth H; Seaton, Kelly E; Huang, Yunda; Grunenberg, Nicole; Isaacs, Abby; Allen, Mary; Ledgerwood, Julie E; Frank, Ian; Sobieszczyk, Magdalena E; Baden, Lindsey R; Rodriguez, Benigno; Van Tieu, Hong; Tomaras, Georgia D; Deal, Aaron; Goodman, Derrick; Bailer, Robert T; Ferrari, Guido; Jensen, Ryan; Hural, John; Graham, Barney S; Mascola, John R; Corey, Lawrence; Montefiori, David C

2017-11-01

VRC01 is an HIV-1 CD4 binding site broadly neutralizing antibody (bnAb) that is active against a broad range of HIV-1 primary isolates in vitro and protects against simian-human immunodeficiency virus (SHIV) when delivered parenterally to nonhuman primates. It has been shown to be safe and well tolerated after short-term administration in humans; however, its clinical and functional activity after longer-term administration has not been previously assessed. HIV Vaccine Trials Network (HVTN) 104 was designed to evaluate the safety and tolerability of multiple doses of VRC01 administered either subcutaneously or by intravenous (IV) infusion and to assess the pharmacokinetics and in vitro immunologic activity of the different dosing regimens. Additionally, this study aimed to assess the effect that the human body has on the functional activities of VRC01 as measured by several in vitro assays. Eighty-eight healthy, HIV-uninfected, low-risk participants were enrolled in 6 United States clinical research sites affiliated with the HVTN between September 9, 2014, and July 15, 2015. The median age of enrollees was 27 years (range, 18-50); 52% were White (non-Hispanic), 25% identified as Black (non-Hispanic), 11% were Hispanic, and 11% were non-Hispanic people of diverse origins. Participants were randomized to receive the following: a 40 mg/kg IV VRC01 loading dose followed by five 20 mg/kg IV VRC01 doses every 4 weeks (treatment group 1 [T1], n = 20); eleven 5 mg/kg subcutaneous (SC) VRC01 (treatment group 3 [T3], n = 20); placebo (placebo group 3 [P3], n = 4) doses every 2 weeks; or three 40 mg/kg IV VRC01 doses every 8 weeks (treatment group 2 [T2], n = 20). Treatment groups T4 and T5 (n = 12 each) received three 10 or 30 mg/kg IV VRC01 doses every 8 weeks, respectively. Participants were followed for 32 weeks after their first VRC01 administration and received a total of 249 IV infusions and 208 SC injections, with no serious adverse events, dose-limiting toxicities

Effects of Intrarenal and Intravenous Infusion of the Phosphodiesterase 3 Inhibitor Milrinone on Renin Secretion

NASA Technical Reports Server (NTRS)

Kumagai, Kazuhiro; Reid, Ian A.

1994-01-01

We have reported that administration of the phosphodiesterase III inhibitor milrinone increases renin secretion in conscious rabbits. The aim of the present study was to determine if the increase in renin secretion results from a direct renal action of milrinone, or from an indirect extrarenal effect of the drug. This was accomplished by comparing the effects of intrarenal and intravenous infusion of graded doses of milrinone on plasma renin activity in unilaterally nephrectomized conscious rabbits. Milrinone was infused into the renal artery in doses of 0.01, 0.1 and 1.0 micro-g/kg/min, and intravenously in the same rabbits in doses of 0.01, 0.1, 1.0 and 10 micro-g/kg/min. Each dose was infused for 15 min. No intrarenal dose of milrinone altered plasma renin activity or arterial pressure, although at the highest dose, there was a small increase in heart rate. Intravenous infusion of milrinone at 1.0 micro-g/kg/min increased plasma renin activity to 176 +/- 55% of the control value (P less than 0.05). Heart rate increased but arterial pressure did not change. Intravenous infusion of milrinone at 1O micro-g/kg/min increased plasma renin activity to 386 +/- 193% of control in association with a decrease in arterial pressure and an increase in heart rate. These results confirm that milrinone increases renin secretion, and indicate that the stimulation is due to an extrarenal effect of the drug.

Intravenous iron vs blood for acute post-partum anaemia (IIBAPPA): a prospective randomised trial.

PubMed

Chua, Seng; Gupta, Sarika; Curnow, Jennifer; Gidaszewski, Beata; Khajehei, Marjan; Diplock, Hayley

2017-12-19

Acute post-partum anaemia can be associated with significant morbidity including a predisposition for postnatal depression. Lack of clear practice guidelines means a number of women are treated with multiple blood transfusions. Intravenous iron has the potential to limit the need for multiple blood transfusions but its role in the post-partum setting is unclear. IIBAPPA is a multi-centre randomised non-inferiority trial. Women with a primary post-partum haemorrhage (PPH) >1000 mL and resultant haemoglobin (Hb) 5.5-8.0 g/dL after resuscitation with ongoing symptomatic anaemia who are otherwise stable (no active bleeding) are eligible to participate. Patients with sepsis or conditions necessitating rapid Hb restoration are excluded. Eligible participants are randomised to receive a blood transfusion or a single dose of intravenous iron polymaltose calculated using the Ganzoni formula. Primary outcome measures include Hb, Ferritin and C-Reactive Protein levels on Day 7. Secondary outcomes evaluate (i) Hb, Ferritin and CRP levels on Day 14, 28, (ii) anaemia symptoms on Day 0, 7, 14 and 28 using structured health related quality of life questionnaires, (iii) treatment safety by assessing adverse reactions and infection endpoints and (iv) the quantitative impact of anaemia on breast feeding quality using a hospital designed questionnaire. If equivalence in Hb and ferritin levels, symptom scores and safety endpoints is demonstrated, intravenous iron may become the preferred treatment for women with acute post-partum anaemia to minimise transfusion reactions and costs. Australian and New Zealand Clinical Trials Registry: ACTRN12615001370594 on 16th December, 2015 (prospective approval).

INTRAVENOUS VALPROATE: A NEW PERSPECTIVE IN THE TREATMENT OF MANIC SYMPTOMS

PubMed Central

Duggal, Harpreet S.; Jagadheesan, K.; Gupta, Subhash; Basu, Soumya; Akhtar, Sayeed; Nizamie, Haque S.

2002-01-01

Over the last few years, the use of valproate in psychiatry has increased considerably. With the advent of oral loading dose strategy, its role in rapid treatment of acute mania has been demonstrated. The intravenous formulation of valproate, while retaining the rapidity of action of oral loading, also avoids some of the adverse effects of the oral preparation. Moreover, reports are pouring in that intravenous valproate loading may be more efficacious than oral valproate loading in the treatment of acute mania. We report two patients whose manic symptoms showed a dramatic response to intravenous valproate without adverse effects. The pharmacology of intravenous valproate and its clinical relevance to psychiatry are discussed. PMID:21206565

Intravenous augmentative citalopram versus clomipramine in partial/nonresponder depressed patients: a short-term, low dose, randomized, placebo-controlled study.

PubMed

Altamura, Alfredo Carlo; Dell'Osso, Bernardo; Buoli, Massimiliano; Zanoni, Silvia; Mundo, Emanuela

2008-08-01

The aim of the present study was to evaluate the efficacy of short-term low-dose intravenous augmentative citalopram (10 mg/d) versus clomipramine (25 mg/d) versus placebo in a sample of patients with MDE and partial or no response to selective serotonin reuptake inhibitors (SSRIs). Fifty-four patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, MDE and partial or no response to SSRIs per os (21-item Hamilton Depression Rating Scale [HAM-D21] score reduction, <50% or < or =25%, respectively, compared with pretreatment scores) were selected and randomized to citalopram (n = 18), clomipramine (n = 18), or placebo (n = 18) intravenous augmentation. The augmentation regimen lasted 5 days during which patients were maintained on their previous treatment with oral SSRIs. Analyses of variance with repeated measures on HAM-D(21), collected daily in blind-raters design, were performed to detect any change of depressive symptoms between the 3 groups. In addition, the number of responders and remitters was computed in the 3 groups of treatment. At end point, a significant treatment effect (F= 4.57; P = 0.015) and time-by-treatment effect (F = 11.22; P < 0.0001) were found on HAM-D21 total scores in favor of citalopram and clomipramine versus placebo, with a superiority of citalopram over clomipramine on overall symptoms (P = 0.05) as well as on anxiety-somatization symptoms (P = 0.027). The number of responders was significantly superior in the active treatment groups versus the placebo group ([chi](2)(2) = 16.36; P < 0.0001). The same result was found, considering the number of remitters ([chi](2)(2) = 13.50; P < 0.0001). Present findings suggest that both clomipramine and citalopram intravenous augmentation at low doses and for a short period are well tolerated and superior to placebo in major depressives with partial or no response to oral SSRIs with a possible superiority of citalopram over clomipramine with regard to

Pathology, Organ Distribution, and Immune Response after Single and Repeated Intravenous Injection of Rats with Clinical-Grade Parvovirus H1

PubMed Central

Geletneky, Karsten; Leoni, Anne-Laure; Pohlmeyer-Esch, Gabriele; Loebhard, Stephanie; Baetz, Andrea; Leuchs, Barbara; Roscher, Mandy; Hoefer, Constance; Jochims, Karin; Dahm, Michael; Huber, Bernard; Rommelaere, Jean; Krebs, Ottheinz; Hajda, Jacek

2015-01-01

Parvovirus H1 (H1PV) is an autonomous parvovirus that is transmitted in rodent populations. Its natural host is rats. H1PV infection is nonpathogenic except in rat and hamster fetuses and newborns. H1PV infection of human cancer cells caused strong oncolytic effects in preclinical models. For a clinical trial of H1PV in patients with brain tumors, clinical-grade H1PV was produced according to Good Manufacturing Practices. This report focuses on results obtained after a single high-dose intravenous injection of highly purified H1PV in 30 rats and multiple (n = 17) intravenous injections at 3 dose levels in 223 rats. In both studies, no virus-related mortality or macroscopic organ changes related to H1PV occurred. Histopathology after multiple virus injections revealed minimal diffuse bile duct hyperplasia in livers of animals of the highest dose group and germinal center development in spleens of animals from the high-dose group. Liver changes were reversible within a 2-wk recovery period after the last injection. Hematology, blood chemistry, and coagulation analyses did not reveal significant toxicologic changes due to H1PV. Virus injection stimulated the production of IgG antibodies but did not alter mononuclear cell function or induce cytokine release. PCR analysis showed dose-dependent levels of viral genomes in all organs tested. The virus was excreted primarily through feces. These data provide important information regarding H1PV infection in its natural host. Due to the confirmation of the favorable safety profile of H1PV in a permissive animal model, a phase I/IIa clinical trial of H1PV in brain tumor patients could be initiated. PMID:25730754

Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis.

PubMed

Moretti, Michele; Buiatti, Alessandra; Merlo, Marco; Massa, Laura; Fabris, Enrico; Pinamonti, Bruno; Sinagra, Gianfranco

2013-11-01

The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases. Copyright © 2013 Elsevier Inc. All rights reserved.

Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study.

PubMed

Lublin, Fred D; Bowen, James D; Huddlestone, John; Kremenchutzky, Marcelo; Carpenter, Adam; Corboy, John R; Freedman, Mark S; Krupp, Lauren; Paulo, Corri; Hariri, Robert J; Fischkoff, Steven A

2014-11-01

Infusion of PDA-001, a preparation of mesenchymal-like cells derived from full-term human placenta, is a new approach in the treatment of patients with multiple sclerosis. This safety study aimed to rule out the possibility of paradoxical exacerbation of disease activity by PDA-001 in patients with multiple sclerosis. This was a phase 1b, multicenter, randomized, double-blind, placebo-controlled, 2-dose ranging study including patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis. The study was conducted at 6 sites in the United States and 2 sites in Canada. Patients were randomized 3:1 to receive 2 low-dose infusions of PDA-001 (150×10(6) cells) or placebo, given 1 week apart. After completing this cohort, subsequent patients received high-dose PDA-001 (600×10(6) cells) or placebo. Monthly brain magnetic resonance imaging scans were performed. The primary end point was ruling out the possibility of paradoxical worsening of MS disease activity. This was monitored using Cutter׳s rule (≥5 new gadolinium lesions on 2 consecutive scans) by brain magnetic resonance imaging on a monthly basis for six months and also the frequency of multiple sclerosis relapse. Ten patients with relapsing-remitting multiple sclerosis and 6 with secondary progressive multiple sclerosis were randomly assigned to treatment: 6 to low-dose PDA-001, 6 to high-dose PDA-001, and 4 to placebo. No patient met Cutter׳s rule. One patient receiving high-dose PDA-001 had an increase in T2 and gadolinium lesions and in Expanded Disability Status Scale score during a multiple sclerosis flare 5 months after receiving PDA-001. No other patient had an increase in Expanded Disability Status Scale score>0.5, and most had stable or decreasing Expanded Disability Status Scale scores. With high-dose PDA-001, 1 patient experienced a grade 1 anaphylactoid reaction and 1 had grade 2 superficial thrombophlebitis. Other adverse events were mild to moderate and included

SOLITAIRE-IV: A Randomized, Double-Blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous-to-Oral Solithromycin to Intravenous-to-Oral Moxifloxacin for Treatment of Community-Acquired Bacterial Pneumonia.

PubMed

File, Thomas M; Rewerska, Barbara; Vucinic-Mihailovic, Violeta; Gonong, Joven Roque V; Das, Anita F; Keedy, Kara; Taylor, David; Sheets, Amanda; Fernandes, Prabhavathi; Oldach, David; Jamieson, Brian D

2016-10-15

Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. NCT01968733. © The Author 2016. Published by Oxford University Press for the Infectious

Intravenous ferric carboxymaltose for the treatment of iron deficiency anemia

PubMed Central

Friedrisch, João Ricardo; Cançado, Rodolfo Delfini

2015-01-01

Nutritional iron deficiency anemia is the most common deficiency disorder, affecting more than two billion people worldwide. Oral iron supplementation is usually the first choice for the treatment of iron deficiency anemia, but in many conditions, oral iron is less than ideal mainly because of gastrointestinal adverse events and the long course needed to treat the disease and replenish body iron stores. Intravenous iron compounds consist of an iron oxyhydroxide core, which is surrounded by a carbohydrate shell made of polymers such as dextran, sucrose or gluconate. The first iron product for intravenous use was the high molecular weight iron dextran. However, dextran-containing intravenous iron preparations are associated with an elevated risk of anaphylactic reactions, which made physicians reluctant to use intravenous iron for the treatment of iron deficiency anemia over many years. Intravenous ferric carboxymaltose is a stable complex with the advantage of being non-dextran-containing and a very low immunogenic potential and therefore not predisposed to anaphylactic reactions. Its properties permit the administration of large doses (15 mg/kg; maximum of 1000 mg/infusion) in a single and rapid session (15-minute infusion) without the requirement of a test dose. The purpose of this review is to discuss some pertinent issues in relation to the history, pharmacology, administration, efficacy, and safety profile of ferric carboxymaltose in the treatment of patients with iron deficiency anemia. PMID:26670403

Isavuconazole absorption following oral administration in healthy subjects is comparable to intravenous dosing, and is not affected by food, or drugs that alter stomach pH.

PubMed

Schmitt-Hoffmann, Anne; Desai, Amit; Kowalski, Donna; Pearlman, Helene; Yamazaki, Takao; Townsend, Robert

2016-08-01

Two openlabel, single-dose, randomized crossover studies and one open-label, multiple-dose, parallel group study in healthy volunteers were conducted with the prodrug, isavuconazonium sulfate, to determine absolute bioavailability of the active triazole, isavuconazole (EudraCT 2007-004949-15; n = 14), and the effect of food (EudraCT 2007- 004940-63; n = 26), and pH (NCT02128893; n = 24) on the absorption of isavuconazole. Isavuconazonium sulfate 744 mg designed to deliver 400 mg of the active triazole isavuconazole was administered in the absolute bioavailability (oral or intravenous (IV) (2-hour infusion)) and food-effect studies (oral). In the pH-effect study, isavuconazonium sulfate 372 mg designed to deliver 200 mg of isavuconazole was administered orally three times daily (t.i.d.) for 2 days, followed by a single daily oral dose for 3 days, in the presence of steady state esomeprazole dosed orally at 40 mg/day. Isavuconazole was well tolerated in each study. Bioavailability: Geometric least squares mean ratios (GLSMR; oral/IV) for isavuconazole AUC∞, and Cmax were 98% (90% confidence interval (CI): 94, 101) and 78% (90% CI: 72, 85), respectively. Food-effect: GLSMR (fed/fasted) for AUC∞ and Cmax of isavuconazole in plasma were 110% (90% CI: 102, 118) and 92% (90% CI: 86, 98), respectively. Median tmax was 5 hours with food and 3 hours under fasted conditions. pH-effect: GLSMR for isavuconazole AUCtau and Cmax were 108% (90% CI: 89, 130) and 105% (90% CI: 89, 124), respectively. Orally administered isavuconazonium sulfate effectively delivers isavuconazole, as evidenced by the fact that oral isavuconazole is bioequivalent to the IV formulation. Dose adjustments are not required when switching between oral and IV formulations, regardless of food or drugs that increase gastric pH.

High dose intravenous immunoglobulin in atopic dermatitis and hyper-IgE syndrome.

PubMed

Wakim, M; Alazard, M; Yajima, A; Speights, D; Saxon, A; Stiehm, E R

1998-08-01

High dose intravenous immunoglobulin (IVIG) has immunoregulatory and anti-inflammatory properties that might benefit illnesses with exaggerated IgE responses including atopic dermatitis and hyper-IgE immunodeficiency syndrome. To determine if high-dose IVIG would be of benefit to patients with severe atopic dermatitis and/or hyper-IgE syndrome using serial clinical, pulmonary, and laboratory studies for evaluation. This was an open label study in which we gave patients with hyper-IgE syndrome (n = 1) or severe atopic dermatitis (n = 9) IVIG as a 10% solution (Venoglobulin I-Alpha Therapeutic Corporation, Los Angeles, CA) at a dose of 2 g/kg every 30 days for seven infusions. Therapy was completed in nine of the ten patients. Skin disease improved slightly in six patients, remained unchanged in two patients, and worsened slightly in one patient. The average daily prednisone dosage was 6.8 mg/day prior to treatment and 5.1 mg/day during IVIG therapy (P = .1250). The three patients with abnormal pulmonary function showed very mild improvement of pulmonary function during treatment, but returned to baseline during follow-up. Flow cytometric studies showed no consistent pattern of change. IgA and IgM levels were unchanged. The mean serum IgE levels went from 3221+/-2454 IU/mL (SD) before IVIG to 2944+/-2491 IU/mL (P = .4609) during IVIG and then to 2321+/-2229 IU/mL (P = .1484) during the 6-month follow-up period. In vitro IgE production of peripheral blood mononuclear cells (PBMC) following IL-4 and anti-CD40 stimulation before IVIG was 6.6+/-3.1 ng/mL (SD) and 4.3+/-3.1 ng/mL (P = .1641) after six IVIG treatments. There were no significant trends in lymphocyte proliferative responses to PHA (phytohemaglutinin), Candida, tetanus, and anti-CD3 monoclonal antibody. Radioallergosorbent (RAST) testing showed no clear changes from positivity to negativity. We conclude that IVIG was of no clear clinical benefit in these nine patients and did not significantly decrease Ig

Oral triazolam pretreatment for intravenous sedation.

PubMed Central

Stopperich, P. S.; Moore, P. A.; Finder, R. L.; McGirl, B. E.; Weyant, R. J.

1993-01-01

This double-blind, controlled clinical trial assessed the anxiety relief provided by oral triazolam given before intravenous sedation. Twenty-two healthy adults undergoing third-molar surgery with intravenous sedation were enrolled in this study. Subjects were randomly assigned to receive either 0.25 mg of triazolam p.o. or an identically appearing placebo 45 to 60 min before venipuncture. Immediately before test drug administration, subjects completed the Corah Anxiety Scale, a Visual Analog Scale (VAS) assessing state anxiety, and the Interval Scale of Anxiety Response (ISAR). The VAS and ISAR were repeated immediately before venipuncture. Intravenous sedation medications consisted of fentanyl, midazolam, and methohexital. At 24 hr, assessments of the venipuncture and global experience were obtained. Results indicated that the characteristics of the triazolam and placebo patients were similar at baseline. With triazolam pretreatment, both the VAS and ISAR scores decreased significantly. Dose requirements for conscious sedation medications were decreased in the triazolam group. Patients rated the venipuncture experience significantly less unpleasant when pretreated with triazolam, and global ratings of the overall surgical experience favored triazolam. An oral-intravenous combination sedation technique using 0.25 mg of triazolam may have a significant therapeutic advantage for outpatient oral surgery. PMID:7943920

Study of the newborn feeding behaviors and fentanyl concentration in colostrum after an analgesic dose of epidural and intravenous fentanyl in cesarean section.

PubMed

Goma, Hala M; Said, Reem N; El-Ela, Amr M

2008-05-01

To compare the effects of epidural and intravenous fentanyl on breast feeding behaviors and fentanyl concentration in the colostrum after an analgesic dose. This study was conducted at the Obstetrics Department of Kasr El-Aini Hospital-Cairo University, Cairo, Egypt. The studied mothers were 100 multipara, who have been subjected to cesarean section, and have a previous history of successful breast feeding. The study was conducted from May 2005 to May 2007. They were divided into 2 groups: group I included 50 patients who received epidural anesthesia with fentanyl, and group II included 50 patients who received spinal anesthesia with intravenous fentanyl, and both groups were observed for initial breast feeding behaviors of newborns, and fentanyl concentration in the colostrum at 45 minutes, and 24 hours after birth. The study included 100 multipara, 2 samples of colostrum were taken from each patients at 45 minutes, and at 24 hours. The levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, reaching 0.40+/-0.059 ng/ml in the epidural group, and 0.19+/-0.019 ng/ml in intravenous fentanyl group. There was no statistical difference in breast feeding behaviors at birth, or at 24 hours of age in both groups. Although the levels of fentanyl concentration were greatest at 45 minutes of the initial sampling time, it can be used safely as intravenous or epidural without affecting the initial breast feeding behaviors of the newborn.

Low-Dose Intravenous Paracetamol for Patent Ductus Arteriosus in Indomethacin-Resistant or Contraindicated Preterm Infants: Three Cases Reports.

PubMed

Matsumura, Shun; Oshima, Ayumi; Fujinuma, Sumie; Tanaka, Kosuke; Nagano, Nobuhiko; Miyake, Fuyu; Masutani, Satoshi; Tamura, Masanori; Ueda, Keiko; Namba, Fumihiko

2017-10-01

Background  Although indomethacin (IND) is the standard treatment for hemodynamically significant patent ductus arteriosus (hsPDA) in Japan, it may be associated with renal impairment and gastrointestinal complications. The use of paracetamol for hsPDA closure has recently increased. Unlike IND, paracetamol does not have a peripheral vasoconstrictive effect and can be given to infants with contraindications to IND. Based on limited data available from randomized trials, paracetamol and IND seem to have similar effects. However, there have been no reports of the use of paracetamol for hsPDA in Japan. Cases  Our drug administration protocol was approved by the institutional ethics committee after purchasing a clinical trial insurance. In three premature infants in whom IND was contraindicated or ineffective, a 7.5 mg/kg of paracetamol was intravenously administered every 6 hour for 3 days after obtaining parental consents. A temporary hsPDA closure was observed in two of the three infants. However, all three infants eventually needed surgical closure. No side effects, such as hepatic and renal dysfunctions, and adverse events were reported. Conclusion  The intravenous administration of paracetamol was safe and feasible in premature infants with hsPDA. Future clinical trials with optimized dose and timing of administration are needed.

Multiple-, But Not Single-, Dose of Parecoxib Reduces Shoulder Pain after Gynecologic Laparoscopy

PubMed Central

Zhang, Hufei; Shu, Haihua; Yang, Lu; Cao, Minghui; Zhang, Jingjun; Liu, Kexuan; Xiao, Liangcan; Zhang, Xuyu

2012-01-01

Background: The aim of this study was to investigate effect of single- and multiple-dose of parecoxib on shoulder pain after gynecologic laparoscopy. Methods: 126 patients requiring elective gynecologic laparoscopy were randomly allocated to three groups. Group M (multiple-dose): receiving parecoxib 40mg at 30min before the end of surgery, at 8 and 20hr after surgery, respectively; Group S (single-dose): receiving parecoxib 40mg at 30min before the end of surgery and normal saline at the corresponding time points; Group C (control): receiving normal saline at the same three time points. The shoulder pain was evaluated, both at rest and with motion, at postoperative 6, 24 and 48hr. The impact of shoulder pain on patients' recovery (activity, mood, walking and sleep) was also evaluated. Meanwhile, rescue analgesics and complications were recorded. Results: The overall incidence of shoulder pain in group M (37.5%) was lower than that in group C (61.9%) (difference=-24.4%; 95% CI: 3.4~45.4%; P=0.023). Whereas, single-dose regimen (61.0%) showed no significant reduction (difference with control=-0.9%; 95% CI: -21.9~20.0%; P=0.931). Moreover, multiple-dose regimen reduced the maximal intensity of shoulder pain and the impact for activity and mood in comparison to the control. Multiple-dose of parecoxib decreased the consumption of rescue analgesics. The complications were similar among all groups and no severe complications were observed. Conclusions: Multiple-, but not single-, dose of parecoxib may attenuate the incidence and intensity of shoulder pain and thereby improve patients' quality of recovery following gynecologic laparoscopy. PMID:23136538

Inversion-based propofol dosing for intravenous induction of hypnosis

NASA Astrophysics Data System (ADS)

Padula, F.; Ionescu, C.; Latronico, N.; Paltenghi, M.; Visioli, A.; Vivacqua, G.

2016-10-01

In this paper we propose an inversion-based methodology for the computation of a feedforward action for the propofol intravenous administration during the induction of hypnosis in general anesthesia. In particular, the typical initial bolus is substituted with a command signal that is obtained by predefining a desired output and by applying an input-output inversion procedure. The robustness of the method has been tested by considering a set of patients with different model parameters, which is representative of a large population.

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

Intravenous Alcohol Self-Administration in the P Rat

PubMed Central

Windisch, Kyle A.; Kosobud, Ann E. K.; Czachowski, Cristine L.

2014-01-01

Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally “relevant” effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding “non-pharmacological” effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol’s effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous

Intravenous alcohol self-administration in the P rat.

PubMed

Windisch, Kyle A; Kosobud, Ann E K; Czachowski, Cristine L

2014-08-01

Alcohol consumption produces a complex array of effects that can be divided into two types: the explicit pharmacological effects of ethanol (which can be temporally separate from time of intake) and the more temporally "relevant" effects (primarily olfactory and taste) that bridge the time from intake to onset of the pharmacological effects. Intravenous (IV) self-administration of ethanol limits the confounding "non-pharmacological" effects associated with oral consumption, allows for controlled and precise dosing, and bypasses first order absorption kinetics, allowing for more direct and better-controlled assessment of alcohol's effect on the brain. IV ethanol self-administration has been reliably demonstrated in mouse and human experimental models; however, models of IV self-administration have been historically problematic in the rat. An operant multiple-schedule study design was used to elucidate the role of each component of a compound IV-ethanol plus oral-sucrose reinforcer. Male alcohol-preferring P rats had free access to both food and water during all IV self-administration sessions. Animals were trained to press a lever for orally delivered 1% sucrose (1S) on a fixed ratio 4 schedule, and then surgically implanted with an indwelling jugular catheter. Animals were then trained to respond on a multiple FR4-FR4 schedule composed of alternating 2.5-min components across 30-min sessions. For the multiple schedule, two components were used: an oral 1S only and an oral 1S plus IV 20% ethanol (25 mg/kg/injection). Average total ethanol intake was 0.47 ± 0.04 g/kg. We found significantly higher earning of sucrose-only reinforcers and greater sucrose-lever error responding relative to the compound oral-sucrose plus IV-ethanol reinforcer. These response patterns suggest that sucrose, not ethanol, was responsible for driving overall responding. The work with a compound IV ethanol-oral sucrose reinforcer presented here suggests that the existing intravenous ethanol

Multiple intravenous injections of allogeneic equine mesenchymal stem cells do not induce a systemic inflammatory response but do alter lymphocyte subsets in healthy horses.

PubMed

Kol, Amir; Wood, Joshua A; Carrade Holt, Danielle D; Gillette, Jessica A; Bohannon-Worsley, Laurie K; Puchalski, Sarah M; Walker, Naomi J; Clark, Kaitlin C; Watson, Johanna L; Borjesson, Dori L

2015-04-15

Intravenous (IV) injection of mesenchymal stem cells (MSCs) is used to treat systemic human diseases and disorders but is not routinely used in equine therapy. In horses, MSCs are isolated primarily from adipose tissue (AT) or bone marrow (BM) and used for treatment of orthopedic injuries through one or more local injections. The objective of this study was to determine the safety and lymphocyte response to multiple allogeneic IV injections of either AT-derived MSCs (AT-MSCs) or BM-derived MSCs (BM-MSCs) to healthy horses. We injected three doses of 25 × 10(6) allogeneic MSCs from either AT or BM (a total of 75 × 10(6) MSCs per horse) into five and five, respectively, healthy horses. Horses were followed up for 35 days after the first MSC infusion. We evaluated host inflammatory and immune response, including total leukocyte numbers, serum cytokine concentration, and splenic lymphocyte subsets. Repeated injection of allogeneic AT-MSCs or BM-MSCs did not elicit any clinical adverse effects. Repeated BM-MSC injection resulted in increased blood CD8(+) T-cell numbers. Multiple BM-MSC injections also increased splenic regulatory T cell numbers compared with AT-MSC-injected horses but not controls. These data demonstrate that multiple IV injections of allogeneic MSCs are well tolerated by healthy horses. No clinical signs or clinico-pathologic measurements of organ toxicity or systemic inflammatory response were recorded. Increased numbers of circulating CD8(+) T cells after multiple IV injections of allogeneic BM-MSCs may indicate a mild allo-antigen-directed cytotoxic response. Safety and efficacy of allogeneic MSC IV infusions in sick horses remain to be determined.

Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report.

PubMed

Dilrukshi, M D S A; Ratnayake, C A P; Gnanathasan, C A

2017-08-08

Fixed drug combination of isoniazid and rifampicin is a rare cause of poisoning even in endemic countries for tuberculosis infection. Severe poisoning can cause severe morbidity and mortality if not treated promptly. Though intravenous pyridoxine is the preferred antidote for severe standard isoniazid poisoning it is not freely available even in best of care centers. We describe a case of severe poisoning with fixed drug combination of isoniazid and rifampicin successfully managed with oral pyridoxine at national hospital of Sri Lanka. A 22 year old, Sri Lankan female presented to a local hospital 1 h after self-ingestion of 28 tablets of fixed drug combination of isoniazid and rifampicin which contained 4.2 g of standard isoniazid and 7.2 g of rifampicin. One and half hours after ingestion she developed generalized tonic-clonic seizure with loss of consciousness. She was given intravenous diazepam 5 mg immediately and transferred to national hospital of Sri Lanka, for further care. Upon arrival to tertiary care hospital in 3.5 h of poisoning she had persistent vomiting, dizziness and headache. On examination, she was drowsy but arousable, orange-red discoloration of the body was noted even with the dark skin complexion. She also had orange-red colour urine and vomitus. Pulse rate was 104 beats/min, blood pressure 130/80 mmHg, respiratory rate was 20 breaths/min. The arterial blood gas analysis revealed compensated metabolic acidosis and mildly elevated lactic acid level. Considering the clinical presentation with neurological toxicity and the large amount of isoniazid dose ingested, crushed oral tablets of pyridoxine 4.2 g (equal to standard isoniazid dose ingested) administered immediately via a nasogastric tube since intravenous preparation was not available in the hospital. Simultaneously forced diuresis using intravenous 0.9% saline was commenced in order to enhance excretion of toxic metabolites via kidneys. She had no recurrence of seizures but had

Smart syringe pumps for drug infusion during dental intravenous sedation

PubMed Central

Lee, Kiyoung

2016-01-01

Dentists often sedate patients in order to reduce their dental phobia and stress during dental treatment. Sedatives are administered through various routes such as oral, inhalation, and intravenous routes. Intravenous administration has the advantage of rapid onset of action, predictable duration of action, and easy titration. Typically, midazolam, propofol or dexmedetomidine are used as intravenous sedatives. Administration of these sedatives via infusion by using a syringe pump is more effective and successful than infusing them as a bolus. However, during intravenous infusion of sedatives or opioids using a syringe pump, fatal accidents may occur due to the clinician's carelessness. To prevent such risks, smart syringe pumps have been introduced clinically. They allow clinicians to perform effective sedation by using a computer to control the dose of the drug being infused. To ensure patient safety, various alarm features along with a drug library, which provides drug information and prevents excessive infusion by limiting the dose, have been added to smart pumps. In addition, programmed infusion systems and target-controlled infusion systems have also been developed to enable effective administration of sedatives. Patient-controlled infusion, which allows a patient to control his/her level of sedation through self-infusion, has also been developed. Safer and more successful sedation may be achieved by fully utilizing these new features of the smart pump. PMID:28884149

Conversion from intravenous to oral medications: assessment of a computerized intervention for hospitalized patients.

PubMed

Fischer, Michael A; Solomon, Daniel H; Teich, Jonathan M; Avorn, Jerry

2003-11-24

Many hospitalized patients continue to receive intravenous medications longer than necessary. Earlier conversion from the intravenous to the oral route could increase patient safety and comfort, reduce costs, and facilitate earlier discharge from the hospital without compromising clinical care. We examined the effect of a computer-based intervention to prompt physicians to switch appropriate patients from intravenous to oral medications. This study was performed at Brigham and Women's Hospital, an academic tertiary care hospital at which all medications are ordered online. We targeted 5 medications with equal oral and intravenous bioavailability: fluconazole, levofloxacin, metronidazole, ranitidine, and amiodarone. We used the hospital's computerized order entry system to prompt physicians to convert appropriate intravenous medications to the oral route. We measured the total use of the targeted medications via each route in the 4 months before and after the implementation of the intervention. We also measured the rate at which physicians responded to the intervention when prompted. The average intravenous defined daily dose declined by 11.1% (P =.002) from the preintervention to the postintervention period, while the average oral defined daily dose increased by 3.7% (P =.002). Length of stay, case-mix index, and total drug use at the hospital increased during the study period. The average total monthly use of the intravenous preparation of all of the targeted medications declined in the 4 months after the intervention began, compared with the 4 months before. In 35.6% of 1045 orders for which a prompt was generated, the physician either made a conversion from the intravenous to the oral version or canceled the order altogether. Computer-generated reminders can produce a substantial reduction in excessive use of targeted intravenous medications. As online prescribing becomes more common, this approach can be used to reduce excess use of intravenous medications

The Reinforcing and Subjective Effects of Intravenous and Intranasal Buprenorphine in Heroin Users

PubMed Central

Jones, Jermaine D.; Madera, Gabriela; Comer, Sandra D.

2014-01-01

Abuse of buprenorphine (BUP) by the intravenous (IV) route has been documented in several studies, and reports of intranasal (IN) abuse are increasing. However, no studies have directly compared the effects of BUP when it is administered intranasally and intravenously. The present secondary analysis used data from two separate studies to compare the reinforcing and subjective effects of IV and IN buprenorphine. One study evaluated IV buprenorphine (N=13) and the other evaluated IN buprenorphine (N=12). Participants were maintained on 2 mg sublingual (SL) BUP and tested with each intranasal or intravenous buprenorphine test dose (0 mg, 2 mg, 4 mg, 8 mg, and 16 mg). During morning laboratory sessions, participants received money (US $20) and sample doses of IN or IV BUP, and then completed subjective effects questionnaires. Later that day, they completed a self-administration task to receive 10% portions of the drug and/or money they previously sampled. In general, positive subjective ratings for both IV and IN BUP were significantly greater than placebo, with IV BUP having a greater effect than IN BUP. All active BUP doses (IV and IN) maintained significantly higher progressive ratio breakpoint values than placebo, but breakpoint values for IV BUP were greater than for IN BUP. Buprenorphine is an effective maintenance treatment for opioid dependence, valued for its ability to reduce the positive subjective effects of other opioids. Nevertheless, the present data demonstrate that in participants maintained on a low dose of SL BUP, the medication itself has abuse liability when used intravenously or intranasally. PMID:24793093

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

PubMed Central

Hawke, Roy L.; Schrieber, Sarah J.; Soule, Tedi A.; Wen, Zhiming; Smith, Philip C.; Reddy, K. Rajender; Wahed, Abdus S.; Belle, Steven H.; Afdhal, Nezam H.; Navarro, Victor J.; Berman, Josh; Liu, Qi-Ying; Doo, Edward; Fried, Michael W.

2011-01-01

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. PMID:19841158

Cardiovascular effects, induction and recovery characteristics and alfaxalone dose assessment in alfaxalone versus alfaxalone-fentanyl total intravenous anaesthesia in dogs.

PubMed

Dehuisser, Virginie; Bosmans, Tim; Kitshoff, Adriaan; Duchateau, Luc; de Rooster, Hilde; Polis, Ingeborgh

2017-11-01

To compare cardiovascular effects and anaesthetic quality of alfaxalone alone or in combination with a fentanyl constant rate infusion (CRI) when used for total intravenous anaesthesia (TIVA) in dogs. Prospective, blinded, randomized, experimental study. A group of 12 intact female dogs. Following intramuscular dexmedetomidine (10 μg kg -1 ) and methadone (0.1 mg kg -1 ) administration, anaesthesia was induced intravenously with alfaxalone (2 mg kg -1 ) (group AP) or alfaxalone (2 mg kg -1 ) preceded by fentanyl (2 μg kg -1 ) (group AF). Anaesthetic maintenance was obtained with an alfaxalone variable rate infusion (VRI) started at 0.15 mg kg -1 minute -1 (group AP) or an alfaxalone VRI (same starting rate) combined with a CRI of fentanyl (10 μg kg -1 hour -1 ) (group AF). The alfaxalone VRI was adjusted every 5 minutes, based on clinical assessment. Cardiovascular parameters (recorded every 5 minutes) and recovery characteristics (using a numerical rating scale) were compared between groups. A mixed model statistical approach was used to compare the mean VRI alfaxalone dose and cardiovascular parameters between groups; recovery scores were analysed using the Wilcoxon rank-sum test (α = 0.05). The mean CRI alfaxalone dose for anaesthetic maintenance differed significantly between treatments [0.16 ± 0.01 mg kg -1 minute -1 (group AP) versus 0.13 ± 0.01 mg kg -1 minute -1 (group AF)]. Overall heart rate, systolic, mean and diastolic arterial pressures were lower in group AF than in group AP (p < 0.0001, p = 0.0058, p < 0.0001 and p < 0.0001, respectively. Recovery quality scores did not differ significantly and were poor in both groups. In combination with a fentanyl CRI, an alfaxalone TIVA provides a cardiovascular stable anaesthesia in dogs. The addition of fentanyl results in a significant dose reduction. The quality of anaesthetic recovery remains poor. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia

High-dose intravenously administered iron versus orally administered iron in blood donors with iron deficiency: study protocol for a randomised, controlled trial.

PubMed

Macher, Susanne; Drexler, Camilla; Lindenau, Ines; Sareban, Nazanin; Schlenke, Peter; Amrein, Karin

2016-10-28

About 2-3 % of the population participates in blood donation programmes. Each whole blood donation or ten apheresis donations cause a loss of 200-250 mg of iron. As a result, one of the most common risks of regular blood donors is iron deficiency. Although this has been known for decades, in most countries, iron status is currently not assessed or treated in this population. Premenopausal women are particularly affected, as they have lower iron reserves and higher daily requirements. Besides anaemia, iron deficiency may lead to fatigue and impaired cognitive and physical performance. Current iron preparations for intravenous administration are well tolerated and allow for application of large doses up to 1 g in one visit. Our hypothesis is that in blood donors with iron deficiency, intravenously administered iron is more efficient and as safe as oral iron supplementation. Since anaemia is one of the most frequent reasons for permanent or intermittent donor deferral, maintaining an iron-replete donor pool may help to prevent shortages in blood supply and to avoid iron deficiency-related comorbidities. In this randomised clinical trial we include male and female blood donors aged ≥18 and ≤65 years with a ferritin value of ≤30 ng/ml. Stratified by gender, participants are randomized with a web-based randomisation tool in a 1:1 ratio to either 1 g of intravenously administered ferric carboxymaltose or 10 g of iron fumarate supplements at one to two daily doses of 100 mg each. Eight to 12 weeks after the first visit, iron status, blood count and symptoms are assessed in both groups. The primary endpoint is the difference in transferrin saturation (%) following the intervention between both groups. Secondary endpoints include other parameters of iron metabolism and red blood cell count, the number of patients with drug-related adverse events, and subjective symptoms including those of the restless legs syndrome, quality of life, and fatigue. Iron

Unexplained abdominal pain as a driver for inappropriate therapeutics: an audit on the use of intravenous proton pump inhibitors

PubMed Central

Wong, Yin Yen; Low, Yong Chia; Lau, Hui Ling; Chin, Kin-Fah; Mahadeva, Sanjiv

2014-01-01

Background. Proton pump inhibitors (PPIs) are currently the most effective agents for acid-related disorders. However, studies show that 25–75% of patients receiving intravenous PPIs had no appropriate justification, indicating high rates of inappropriate prescribing. Objective. To examine the appropriate use of intravenous PPIs in accordance with guidelines and the efficacy of a prescribing awareness intervention at an Asian teaching institution. Setting. Prospective audit in a tertiary hospital in Malaysia. Method. Every 4th intravenous PPI prescription received in the pharmacy was screened against hospital guidelines. Interventions for incorrect indication/dose/duration were performed. Patients’ demographic data, medical history and the use of intravenous PPI were collected. Included were all adult inpatients prescribed intravenous PPI. Main Outcome Measure. Proportion of appropriate IV PPI prescriptions. Results. Data for 106 patients were collected. Most patients were male [65(61.3%)], Chinese [50(47.2%)], with mean age ± SD = 60.3 ± 18.0 years. Most intravenous PPI prescriptions were initiated by junior doctors from the surgical [47(44.3%)] and medical [42(39.6%)] departments. Only 50/106(47.2%) patients had upper gastrointestinal endoscopy/surgery performed to verify the source of bleeding. Unexplained abdominal pain [81(76.4%)] was the main driver for prescribing intravenous PPIs empirically, out of which 73(68.9%) were for suspected upper gastrointestinal bleed. Overall, intravenous PPI was found to be inappropriately prescribed in 56(52.8%) patients for indication, dose or duration. Interventions on the use of intravenous PPI were most effective when performed by senior doctors (100%), followed by clinical pharmacists (50%), and inpatient pharmacists (37.5%, p = 0.027). Conclusion. Inappropriate intravenous PPI usage is still prevalent despite the enforcement of hospital guidelines. The promotion of prescribing awareness and evidence

Unexplained abdominal pain as a driver for inappropriate therapeutics: an audit on the use of intravenous proton pump inhibitors.

PubMed

Lai, Pauline Siew Mei; Wong, Yin Yen; Low, Yong Chia; Lau, Hui Ling; Chin, Kin-Fah; Mahadeva, Sanjiv

2014-01-01

Background. Proton pump inhibitors (PPIs) are currently the most effective agents for acid-related disorders. However, studies show that 25-75% of patients receiving intravenous PPIs had no appropriate justification, indicating high rates of inappropriate prescribing. Objective. To examine the appropriate use of intravenous PPIs in accordance with guidelines and the efficacy of a prescribing awareness intervention at an Asian teaching institution. Setting. Prospective audit in a tertiary hospital in Malaysia. Method. Every 4th intravenous PPI prescription received in the pharmacy was screened against hospital guidelines. Interventions for incorrect indication/dose/duration were performed. Patients' demographic data, medical history and the use of intravenous PPI were collected. Included were all adult inpatients prescribed intravenous PPI. Main Outcome Measure. Proportion of appropriate IV PPI prescriptions. Results. Data for 106 patients were collected. Most patients were male [65(61.3%)], Chinese [50(47.2%)], with mean age ± SD = 60.3 ± 18.0 years. Most intravenous PPI prescriptions were initiated by junior doctors from the surgical [47(44.3%)] and medical [42(39.6%)] departments. Only 50/106(47.2%) patients had upper gastrointestinal endoscopy/surgery performed to verify the source of bleeding. Unexplained abdominal pain [81(76.4%)] was the main driver for prescribing intravenous PPIs empirically, out of which 73(68.9%) were for suspected upper gastrointestinal bleed. Overall, intravenous PPI was found to be inappropriately prescribed in 56(52.8%) patients for indication, dose or duration. Interventions on the use of intravenous PPI were most effective when performed by senior doctors (100%), followed by clinical pharmacists (50%), and inpatient pharmacists (37.5%, p = 0.027). Conclusion. Inappropriate intravenous PPI usage is still prevalent despite the enforcement of hospital guidelines. The promotion of prescribing awareness and evidence-based prescribing

Disposition, metabolism and mass balance of delafloxacin in healthy human volunteers following intravenous administration.

PubMed

McEwen, Andrew; Lawrence, Laura; Hoover, Randy; Stevens, Lloyd; Mair, Stuart; Ford, Gill; Williams, Dylan; Wood, Stuart

2015-01-01

1. The pharmacokinetics and disposition of delafloxacin was investigated following a single intravenous (300 mg, 100 µCi) dose to healthy male subjects. 2. Mean Cmax, AUC0-∞, Tmax and t1/2 values for delafloxacin were 8.98 µg/mL, 21.31 µg h/mL, 1 h and 2.35 h, respectively, after intravenous dosing. 3. Radioactivity was predominantly excreted via the kidney with 66% of the radioactive dose recovered in the urine. Approximately 29% of the radioactivity was recovered in the faeces, giving an overall mean recovery of 94% administered radioactivity. 4. The predominant circulating components were identified as delafloxacin and a direct glucuronide conjugate of delafloxacin.

High-pressure liquid chromatography and microbiological assay of serum ofloxacin levels in adults receiving intravenous and oral therapy for skin infections.

PubMed Central

Auten, G M; Preheim, L C; Sookpranee, M; Bittner, M J; Sookpranee, T; Vibhagool, A

1991-01-01

Thirty-two adults hospitalized with skin and skin structure infections received intravenous ofloxacin followed by oral ofloxacin. The standard treatment was 400 mg every 12 h. One patient with renal failure received 400 mg every 24 h. Serum ofloxacin levels were measured (1.5 h postdose and 1 h predose) during intravenous (32 patients) and oral (30 patients) therapy. Levels were assayed by high-pressure liquid chromatography (HPLC) and microbiological assay (MBA). Mean levels +/- standard deviation (in micrograms per milliliter) when measured by MBA after intravenous dosing were (postdose versus predose) 6.23 +/- 2.49 versus 2.42 +/- 1.56, and those after oral dosing were 6.17 +/- 3.25 versus 3.49 +/- 2.77. When measured by HPLC, mean levels +/- standard deviation after intravenous dosing were 5.81 +/- 2.08 versus 2.14 +/- 1.26 and those after oral dosing were 5.63 +/- 2.92 versus 3.41 +/- 2.98. There were no significant differences between levels achieved with oral or intravenous dosing when measured by either MBA or HPLC. Levels in serum did not correlate with side effects. The MICs for 50 and 90% of the 40 aerobic pathogens isolated from 21 patients were 0.5 and 2.0 micrograms/ml, respectively. Cure or improvement was achieved in 30 patients. Intravenous and oral administration of ofloxacin yielded similar levels in serum which were safe and effective in the therapy of skin infections in adult patients. PMID:1810189

Magnesium sulphate for prevention of eclampsia: are intramuscular and intravenous regimens equivalent? A population pharmacokinetic study.

PubMed

Salinger, D H; Mundle, S; Regi, A; Bracken, H; Winikoff, B; Vicini, P; Easterling, T

2013-06-01

To compare magnesium sulphate concentrations achieved by intramuscular and intravenous regimens used for the prevention of eclampsia. Low-resource obstetric hospitals in Nagpur and Vellore, India. Pregnant women at risk for eclampsia due to hypertensive disease. A pharmacokinetic study was performed as part of a randomised trial that enrolled 300 women comparing intramuscular and intravenous maintenance regimens of magnesium dosing. Data from 258 enrolled women were analysed in the pharmacokinetic study. A single sample was drawn per woman with the expectation of using samples in a pooled data analysis. Pharmacokinetic parameters of magnesium distribution and clearance. Magnesium clearance was estimated to be 48.1 dl/hour, volume of distribution to be 156 dl and intramuscular bioavailability to be 86.2%. The intramuscular regimen produced higher initial serum concentrations, consistent with a substantially larger loading dose. At steady state, magnesium concentrations in the intramuscular and intravenous groups were comparable. With either regimen, a substantial number of women would be expected to have serum concentrations lower than those generally held to be therapeutic. Clinical implications were that a larger loading dose for the intravenous regimen should be considered; where feasible, individualised dosing of magnesium sulphate would reduce the variability in serum concentrations and might result in more women with clinically effective magnesium concentrations; and lower dose magnesium sulphate regimens should be considered with caution. © 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.

Safety of Intravenous Application of Mistletoe (Viscum album L.) Preparations in Oncology: An Observational Study

PubMed Central

Steele, Megan L.; Axtner, Jan; Happe, Antje; Kröz, Matthias; Matthes, Harald; Schad, Friedemann

2014-01-01

Background. Traditional mistletoe therapy in cancer patients involves subcutaneous applications of Viscum album L. preparations, with doses slowly increasing based on patient responses. Intravenous infusion of high doses may improve therapeutic outcomes and is becoming more common. Little is known about the safety of this “off-label” application of mistletoe. Methods. An observational study was performed within the Network Oncology. Treatment with intravenous mistletoe applications is described. The frequency of adverse drug reactions (ADRs) to intravenous mistletoe applications was calculated and compared to ADR data from a study on subcutaneous applications. Results. Of 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%). No serious ADRs occurred. ADRs were more frequently reported to i.v. mistletoe administered alone (4.3%), versus prior to chemotherapy (1.6%). ADR frequency differed with respect to preparation type, with Iscador preparations showing a higher relative frequency, compared to Abnoba viscum and Helixor. Overall, patients were almost two times less likely to experience an ADR to intravenous compared to subcutaneous application of mistletoe. Conclusion. Intravenous mistletoe therapy was found to be safe and prospective studies for efficacy are recommended. PMID:24955100

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

Intravenous Carbamazepine for Adults With Seizures.

PubMed

Vickery, P Brittany; Tillery, Erika E; DeFalco, Alicia Potter

2018-03-01

To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions, and place in therapy of the intravenous (IV) formulation of carbamazepine (Carnexiv) for the treatment of seizures in adult patients. A comprehensive PubMed and EBSCOhost search (1945 to August 2017) was performed utilizing the keywords carbamazepine, Carnexiv, carbamazepine intravenous, IV carbamazepine, seizures, epilepsy, and seizure disorder. Additional data were obtained from literature review citations, manufacturer's product labeling, and Lundbeck website as well as Clinicaltrials.gov and governmental sources. All English-language trials evaluating IV carbamazepine were analyzed for this review. IV carbamazepine is FDA approved as temporary replacement therapy for treatment of adult seizures. Based on a phase I trial and pooled data from 2 open-label bioavailability studies comparing oral with IV dosing, there was no noted indication of loss of seizure control in patients switched to short-term replacement antiepileptic drug therapy with IV carbamazepine. The recommended dose of IV carbamazepine is 70% of the patient's oral dose, given every 6 hours via 30-minute infusions. The adverse effect profile of IV carbamazepine is similar to that of the oral formulation, with the exception of added infusion-site reactions. IV carbamazepine is a reasonable option for adults with generalized tonic-clonic or focal seizures, previously stabilized on oral carbamazepine, who are unable to tolerate oral medications for up to 7 days. Unknown acquisition cost and lack of availability in the United States limit its use currently.

Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration.

PubMed

Rawlins, M D; Henderson, D B; Hijab, A R

1977-04-20

Plasma paracetamol concentrations were measured in 6 volunteers after single intravenous (1000 mg) and oral (500 mg, 1000 mg and 2000 mg) doses of the drug. Paracetamol levels declined multiphasically with a mean clearance after intravenous administration of 352 +/- 40 ml/min. A two-compartment open model appeared to describe the decline adequately. Comparison of the areas under the plasma concentration-time curves (AUC) indicated that oral bioavailability increased from 0.63 +/- 0.02 after 500 mg, to 0.89 +/- 0.04 and 0.87 +/- 0.08 after 1000 mg and 2000 mg, respectively. As a consequence of the incomplete bioavailability of paracetamol, as well as its multicompartmental distribution, accurate estimates of its distribution volume and clearance cannot be obtained if the drug is given orally. However, an estimate of its total plasma clearance may be derived from the AUC after a 500 mg oral dose.

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed Central

Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-01-01

Background Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Methodology/Principal findings Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38–4.13%) and 0.35% (95% CI: 0.06–1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Conclusions/Significance Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use

Neutropenia induced by high-dose intravenous benzylpenicillin in treating neurosyphilis: Does it really matter?

PubMed

Peng, Rui-Rui; Wu, Juan; Zhao, Wei; Qi, Tengfei; Shi, Mei; Guan, Zhifang; Lu, Haikong; Long, Fuquan; Gao, Zixiao; Zhang, Sufang; Zhou, Pingyu

2017-03-01

Prompt therapy with high-dose intravenous benzylpenicillin for a prolonged period is critical for neurosyphilis patients to avoid irreversible sequelae. However, life-threatening neutropenia has been reported as a complication of prolonged therapy with high doses of benzylpenicillin when treating other diseases. This study aimed to investigate the incidence, presentation, management and prognosis of benzylpenicillin-induced neutropenia in treating neurosyphilis based on a large sample of syphilis patients in Shanghai. Between 1st January 2013 and 31st December 2015, 1367 patients with neurosyphilis were treated with benzylpenicillin, 578 of whom were eligible for recruitment to this study. Among patients without medical co-morbidities, the total incidence of benzylpenicillin-induced neutropenia and severe neutropenia was 2.42% (95% CI: 1.38-4.13%) and 0.35% (95% CI: 0.06-1.39%), respectively. The treatment duration before onset of neutropenia ranged from 10 to 14 days, with a total cumulative dose of between 240 and 324 megaunits of benzylpenicillin. Neutropenia was accompanied by symptoms of chills and fever (5 patients), fatigue (2 patients), cough (1 patient), sore throat (1 patient), diarrhea (1 patient) and erythematous rash (1 patient). The severity of neutropenia was not associated with age, gender or type of neurosyphilis (p>0.05). Neutropenia, even when severe, was often tolerated and normalized within one week. A more serious neutropenia did not occur when reinstituting benzylpenicillin in patients with mild or moderate neutropenia nor when ceftriaxone was used three months after patients had previously experienced severe neutropenia. Benzylpenicillin-induced neutropenia was uncommon in our cohort of patients. Continuation of therapy was possible with intensive surveillance for those with mild or moderate neutropenia. For severe neutropenia, it is not essential to aggressively use hematopoietic growth factors or broad-spectrum antibiotics for patients in

Optimization of a therapeutic protocol for intravenous injection of human mesenchymal stem cells after cerebral ischemia in adult rats.

PubMed

Omori, Yoshinori; Honmou, Osamu; Harada, Kuniaki; Suzuki, Junpei; Houkin, Kiyohiro; Kocsis, Jeffery D

2008-10-21

The systemic injection of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has therapeutic benefits after cerebral artery occlusion in rats, and may have multiple therapeutic effects at various sites and times within the lesion as the cells respond to a particular pathological microenvironment. However, the comparative therapeutic benefits of multiple injections of hMSCs at different time points after cerebral artery occlusion in rats remain unclear. In this study, we induced middle cerebral artery occlusion (MCAO) in rats using intra-luminal vascular occlusion, and infused hMSCs intravenously at a single 6 h time point (low and high cell doses) and various multiple time points after MCAO. From MRI analyses lesion volume was reduced in all hMSC cell injection groups as compared to serum alone injections. However, the greatest therapeutic benefit was achieved following a single high cell dose injection at 6 h post-MCAO, rather than multiple lower cell infusions over multiple time points. Three-dimensional analysis of capillary vessels in the lesion indicated that the capillary volume was equally increased in all of the cell-injected groups. Thus, differences in functional outcome in the hMSC transplantation subgroups are not likely the result of differences in angiogenesis, but rather from differences in neuroprotective effects.

Intravenous Lacosamide in Pediatric Status Epilepticus: An Open-Label Efficacy and Safety Study.

PubMed

Poddar, Karan; Sharma, Rohan; Ng, Yu-Tze

2016-08-01

Lacosamide is an antiepilepsy drug approved by the Food and Drug Administration for patients aged 17 years and older for partial-onset seizures as monotherapy or adjunctive therapy. We reviewed the use of intravenous lacosamide in children aged less than 17 years with status epilepticus. Children who received at least one dose of intravenous lacosamide for status epilepticus at our tertiary care children's hospital from December 2011 to March 2014 were studied. Status epilepticus was defined as continuous seizure activity for longer than 20 minutes or two or more recurrent seizures without regaining baseline level of awareness. Efficacy was defined as seizure freedom or more than 50% reduction of seizures within 24 hours of administering lacosamide. Nine children with a mean age of 5.7 years (range: three months to 16 years) were included. The mean initial or loading dose was 8.7 mg/kg, with seven of nine patients receiving a dose of 10 mg/kg. The average total amount of intravenous lacosamide administered within the initial 24 hours was 13.8 mg/kg. Lacosamide was found to be efficacious in seven of nine (77.8%) patients. Four patients (44.4%) became seizure free. Two patients continued to have status epilepticus within 24 hours of lacosamide administration. Bradycardia was observed in one patient. In children with status epilepticus, intravenous lacosamide was efficacious in 78% of the patients and 44% become seizure free. In addition, no significant adverse reactions were observed. An appropriate safe, effective initial, or loading dose may be 10 mg/kg. Copyright © 2016 Elsevier Inc. All rights reserved.

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

PubMed

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups

Pharmacokinetics of 14 C-ortho-phenylphenol following intravenous administration in pigs.

PubMed

Nixon, Emma; Brooks, James D; Routh, Patricia A; Chittenden, Jason T; Baynes, Ronald E

2017-04-01

Workers in the USA are exposed to industrial formulations, which may be toxic. These formulations often contain preservatives or biocides such as ortho-phenylphenol (OPP). There are limited data describing OPP following intravenous administration to assess truly the clearance of this chemical in humans and other species. In vivo experiments were conducted in pigs to determine related pharmacokinetic parameters. 14 C-OPP was administered as an intravenous bolus dose. Blood, feces, urine and tissue samples were collected for analysis by liquid scintillation. Data were analyzed using non-compartmental and compartmental pharmacokinetic model approaches. These data fitted a three-compartment model and showed that the half-life of 14 C-OPP following the intravenous bolus in pigs was 46.26 ± 10.01 h. The kidneys play a crucial role in clearance of 14 C-OPP with a large percentage of the dose being found in the urine (70.3 ± 6.9% dose). Comparisons with other species suggest that 14 C-OPP clearance in pigs (2.48 ml h -1  kg -1 ) is less than that in humans (18.87 ml h -1  kg -1 ) and rats (35.51 ml h -1  kg -1 ). Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Pharmacokinetics of intravenous tramadol in dogs

PubMed Central

McMillan, Chantal J.; Livingston, Alex; Clark, Chris R.; Dowling, Patricia M.; Taylor, Susan M.; Duke, Tanya; Terlinden, Rolf

2008-01-01

The purpose of this study was to determine the pharmacokinetics of tramadol and the active metabolite mono-O-desmethyltramadol (M1) in 6 healthy male mixed breed dogs following intravenous injection of tramadol at 3 different dose levels. Verification of the metabolism to the active metabolite M1, to which most of the analgesic activity of this agent is attributed to, was a primary goal. Quantification of the parent compound and the M1 metabolite was performed using gas chromatography. Pharmacodynamic evaluations were performed at the time of patient sampling and included assessment of sedation, and evaluation for depression of heart and respiratory rates. This study confirmed that while these dogs were able to produce the active M1 metabolite following intravenous administration of tramadol, the M1 concentrations were lower than previously reported in research beagles. Adverse effects were minimal, with mild dose-related sedation in all dogs and nausea in 1 dog. Analgesia was not documented with the method of assessment used in this study. Tramadol may be useful in canine patients, but additional studies in the canine population are required to more accurately determine the effective clinical use of the drug in dogs and quantification of M1 concentrations in a wider population of patients. PMID:18783021

Single Intravenous Dose of Novel Flurbiprofen-Loaded Proniosome Formulations Provides Prolonged Systemic Exposure and Anti-inflammatory Effect.

PubMed

Verma, Preeti; Prajapati, Sunil K; Yadav, Rajbharan; Senyschyn, Danielle; Shea, Peter R; Trevaskis, Natalie L

2016-11-07

Vesicular and colloidal delivery systems can be designed to control drug release spatially and temporally to improve drug efficacy and side effect profiles. Niosomes (vesicles prepared from nonionic surfactants in aqueous media) are gaining interest as an alternative vesicular delivery system as they offer advantages such as biocompatibility, chemical stability, low cost, high purity, and versatility. However, the physical stability of niosomes, like other vesicular systems, is limited by vesicle fusion, aggregation, and leakage. Proniosomes (dehydrated powder or gel formulations that spontaneously form niosomes on hydration with aqueous media) can overcome these physical stability problems and are more convenient for sterilization, storage, transport, distribution, and dosing. Proniosomes have mostly been explored for their potential to enhance transdermal and oral absorption. In this study we assess, for the first time, the potential for hydrated proniosomes to sustain systemic exposure and therapeutic effect after intravenous delivery. Proniosomes carrying the anti-inflammatory drug, flurbiprofen, were prepared by spraying different nonionic surfactants (span 20, span 40, and span 60 in varying ratios with span 80) and cholesterol onto a sorbitol carrier. The proniosome powders were characterized for surface morphology and flow properties. Niosome formation was assessed at three different hydration temperatures (25, 37, and 45 °C), and the niosomes were assessed for vesicle size, entrapment efficiency, and sterility. OLP proniosomes prepared with a high ratio of span 80 to span 20 were found to spontaneously form vesicles of small size and high drug loading on hydration with aqueous media. The OLP derived niosomes successfully sustained in vitro drug release, in vivo pharmacokinetics, and the anti-inflammatory effect of flurbiprofen in an acute (rat paw edema) model of inflammation when compared to a control solution formulation. The study demonstrates that

Triple dose of gadolinium-DTPA and delayed MRI in patients with benign multiple sclerosis.

PubMed Central

Filippi, M; Capra, R; Campi, A; Colombo, B; Prandini, F; Marcianò, N; Gasparotti, R; Comi, G

1996-01-01

OBJECTIVES--To evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) or delayed MRI increase the number, size, and conspicuousness of enhancing lesions in patients with benign multiple sclerosis. METHODS--T1 weighted brain MRI was carried out on 20 patients with benign multiple sclerosis (expanded disability status scale < 3 with a disease duration > 10 years) in two sessions. In the first session, one scan was obtained before and two scans five to seven minutes and 20-30 minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, the same procedure was repeated with 0.3 mmol/kg Gd-DTPA (triple dose). RESULTS--Nine enhancing lesions were found in seven patients (35%) using the standard dose of Gd-DTPA. The numbers of enhancing lesions increased to 13 (P = 0.03) and the number of patients with such lesions to eight (40%) on the delayed standard dose scans. On the early triple dose scans, we found 19 enhancing lesions in 10 patients (50%). The number of enhancing lesions was significantly higher (P = 0.01) than that obtained with the early standard dose. The number of enhancing lesions was 18 and the number of "active" patients 11 (55%) on the delayed triple dose scans. The enhancing areas increased progressively from the early standard dose scans to the delayed triple dose scans. The contrast ratios of the lesions detected in early standard dose scans was lower than those of lesions present in the early (P = 0.01) and delayed (P = 0.04) triple dose scans. CONCLUSIONS--More enhancing lesions were detected in patients with benign multiple sclerosis with both delay of MRI and the use of triple dose of Gd-DTPA suggesting that the amount of inflammation in the lesions of such patients is mild and heterogeneous. Images PMID:8778257

Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

PubMed Central

Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

2016-01-01

ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients.

PubMed

Canavese, Caterina; Petrarulo, Michele; Massarenti, Paola; Berutti, Silvia; Fenoglio, Roberta; Pauletto, Daniela; Lanfranco, Giacomo; Bergamo, Daniela; Sandri, Luisa; Marangella, Martino

2005-03-01

Ascorbate supplementation for patients on regular dialysis treatment (RDT) is advised to obviate deficiency and improve epoetin response in those with functional iron deficiency. However, clear-cut safety concerns regarding hyperoxalemia are still poorly understood. This study tries to establish safety/efficacy profiles of ascorbate and oxalate during long-term intravenous ascorbate supplementation. A prospective study was performed in 30 patients on RDT showing ascorbate deficiency (plasma ascorbate < 2.6 mg/L [<15 micromol/L]): 18 patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. Plasma ascorbate and oxalate assays and dialytic balance determinations were performed (ion chromatography and reverse-phase high-performance liquid chromatography, respectively) at baseline, during treatment, and 12 months after withdrawal. Plasma ascorbate levels increased dose dependently with supplementation (1.6 +/- 0.8 mg/L [9.1 +/- 4.6 mumol/L] at baseline, 2.8 +/- 1.8 mg/L [15.9 +/- 10.1 micromol/L]) with 250 mg of ascorbate, and 6.6 +/- 2.8 mg/L [37.5 +/- 16.0 micromol/L] with 500 mg/wk of ascorbate), but only normalized with greater dosages for several months in 94% of patients. Baseline plasma oxalate levels increased from 3.2 +/- 0.8 mg/L (35.8 +/- 8.8 micromol/L) to 3.6 +/- 0.8 mg/L (39.5 +/- 9.1 micromol/L) and 4.5 +/- 0.9 mg/L (50.3 +/- 10.4 micromol/L) with 250 and 500 mg, respectively ( P < 0.001). The calcium oxalate saturation threshold was exceeded by 7 of 18 patients (40%) during 6 months therapy with 500 mg/wk. Ascorbate dialysis removal increased from 37.8 +/- 23.2 mg (215 +/- 132 micromol) to 99.6 +/- 51.7 mg (566 +/- 294 micromol) during supplementation (P < 0.001), with corresponding increases in oxalate removal from 82.5 +/- 33.2 mg (917 +/- 369 micromol) to 111.2 +/- 32.6 mg/L (1,236 +/- 362 micromol; P < 0.01). Withdrawal reverted plasma

Randomized controlled trial of intravenous acetaminophen for postcesarean delivery pain control.

PubMed

Altenau, Brie; Crisp, Catrina C; Devaiah, C Ganga; Lambers, Donna S

2017-09-01

Cesarean delivery is a common surgery in the United States, with 1.3 million performed during 2009. 1 Obstetricians must balance the growing concern with opioid abuse, dependence, and side effects with optimal postoperative pain control. Intravenous acetaminophen may represent an additional method to decrease the reliance on opioid medications and improve postoperative pain following cesarean delivery. The objective of the study was to determine whether the administration of intravenous acetaminophen following routine scheduled cesarean delivery would decrease the need for narcotic medications to control postoperative pain. This was an institutional review board-approved, double-blind, placebo-controlled, randomized trial, registered on clinicaltrials.gov (number 02046382). Women scheduled to undergo cesarean delivery with regional anesthesia at term were recruited. All perioperative and postpartum care was standardized via study order sets. Study patients were given all medications in a standardized manner receiving either acetaminophen 1000 mg intravenously or 100 mL saline (placebo) every 8 hours for 48 hours for a total of 6 doses. The pharmacy prepared intravenous acetaminophen and saline in identical administration bags labeled study drug to ensure blinding. The initial dose of study drug was given within 60 minutes of skin incision. Quantity of breakthrough and scheduled analgesic medications and self-reported pain levels on the Faces Pain Scale (0-10) before and after study drug administration were collected. Patient demographics were extracted from the chart. Power calculation determined that 45 patients per arm were required to detect a 30% reduction in postcesarean narcotic requirement with 80% power and a significance level of P = .05. A total of 133 patients were consented for the study. Twenty-nine were excluded and 104 patients completed the study: 57 received intravenous acetaminophen and 47 received placebo. There were no differences in baseline

Intravenous immunoglobulin therapy for refractory recurrent pericarditis.

PubMed

del Fresno, M Rosa; Peralta, Julio E; Granados, Miguel Ángel; Enríquez, Eugenia; Domínguez-Pinilla, Nerea; de Inocencio, Jaime

2014-11-01

Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy. Copyright © 2014 by the American Academy of Pediatrics.

Bioavailability of diazepam after intravenous, oral and rectal administration in adult epileptic patients.

PubMed Central

Dhillon, S; Oxley, J; Richens, A

1982-01-01

1 The absorption of single doses of diazepam in six adult epileptic subjects following intravenous, oral and rectal administration were studied in order to evaluate the usefulness of the latter in emergency situations in the adult. 2 Diazepam tablets (Valium, Roche) and rectal solution (Valium solution for intravenous administration) produced similar peak serum concentrations after delays of 15-90 min. 3 Two suppository formulations showed statistically significant differences in absorption characteristics. 4 Serum diazepam levels above 400 ng ml-1 (suggested to be necessary for a satisfactory anticonvulsant effect) were reached in only a few subjects after rectal doses of 10-20 mg of solution, and then usually after a delay of over 2 h. PMID:7059446

Successful outcome after intravenous gasoline injection.

PubMed

Domej, Wolfgang; Mitterhammer, Heike; Stauber, Rudolf; Kaufmann, Peter; Smolle, Karl Heinz

2007-12-01

Gasoline, ingested intentionally or accidentally, is toxic. The majority of reported cases of gasoline intoxication involve oral ingestion or inhalation. Data are scarce on complications and outcomes following hydrocarbon poisoning by intravenous injection. Following a suicide attempt by intravenous self-injection of 10 ml of gasoline, a 26-year-old medical student was admitted to the intensive care unit (ICU) with hemoptysis, symptoms of acute respiratory failure, chest pain, and severe abdominal cramps. Gas exchange was severely impaired and a chest x-ray indicated chemical pneumonitis. Initial treatment consisted of mechanical ventilation, supportive hyperventilation, administration of nitrogen oxide (NO), and prednisone. Unfortunately, the patient developed multi-organ dysfunction syndrome (MODS) complicated by life-threatening severe vasoplegia within 24 hours after gasoline injection. High doses of vasopressors along with massive amounts of parenteral fluids were necessary. Despite fluid replacement, renal function worsened and required hemofiltration on 5 sequential days. After 12 days of intensive care management, the patient recovered completely and was discharged to a psychiatric care facility. Intravenous gasoline injection causes major injury to the lungs, the organ bearing the first capillary bed encountered. Treatment of gasoline poisoning is symptomatic because no specific antidote is available. Early and aggressive supportive care may be conducive to a favorable outcome with minimal residual pulmonary sequelae.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease.

PubMed

Reinisch, Walter; Altorjay, Istvan; Zsigmond, Ferenc; Primas, Christian; Vogelsang, Harald; Novacek, Gottfried; Reinisch, Sieglinde; Thomsen, Lars L

2015-01-01

Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500-2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease

PubMed Central

Reinisch, Walter; Altorjay, Istvan; Zsigmond, Ferenc; Primas, Christian; Vogelsang, Harald; Novacek, Gottfried; Reinisch, Sieglinde; Thomsen, Lars L.

2015-01-01

Abstract Objective. Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. Material and methods. This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500–2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. Results. A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. Conclusion. Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues. PMID:25900645

Pharmacokinetic study of single- and multiple-dosing with metolazone tablets in healthy Chinese population.

PubMed

Li, Xueqing; Wang, Rutao; Liu, Yang; Liu, Yun; Zheng, Heng; Feng, Yabo; Zhao, Na; Geng, Hongbin; Zhang, Wanzhi; Wen, Aidong

2017-11-16

Metolazone is a diuretic, saluretic and antihypertensive chemical compound from the quinazoline category that possesses medicinal features similar to those of other thiazide diuretic drugs. However, the pharmacokinetics of metolazone in the Chinese population has rarely been studied. This study aimed to examine the pharmacokinetic characteristics, safety characteristic, and tolerability of metolazone in healthy Chinese subjects after single and multiple doses taken orally as well as the effects that food and gender have on oral metolazone pharmacokinetic parameters. An open-label, randomized, and single- and multiple-dosing investigation was performed in healthy Chinese subjects. The investigation included 3 study groups: the 0.5 mg, 1 mg and 2 mg dose groups were the single-dose study groups in the first stage. Eligible volunteers were randomly and orally administered a single 0.5 mg, 1 mg, or 2 mg metolazone tablet. The 0.5 mg dose group was also part of the multiple-dose study group, and the 1 mg dose group was the food-effect study group in the second stage. Human plasma samples were gathered pre-dosing and up to 48 h after dosing. The human plasma sample concentration of metolazone was quantified using a validated liquid chromatography tandem mass spectrometry method. Pharmacokinetic data were calculated by a noncompartmental analysis method using WinNonlin version 6.4. Tolerability was evaluated based on adverse events, medical examination, 12-lead ECG, and other clinical laboratory exams. Thirty eligible subjects (15 men and 15 women) were registered in our investigation and completed all of the study stages. The AUC and C max showed dose proportionality after a single dose based on the linear-regression analysis. A comparison of the pharmacokinetic data revealed that the differences between the male and female groups were not statistically significant. The t max of metolazone was increased by approximately 100% in the fed condition. Metolazone was

Efficacy of prophylactic doses of intravenous nitroglycerin in preventing myocardial ischemia under general anesthesia: A systematic review and meta-analysis with trial sequential analysis.

PubMed

Hoshijima, Hiroshi; Denawa, Yohei; Mihara, Takahiro; Takeuchi, Risa; Kuratani, Norifumi; Mieda, Tsutomu; Iwase, Yoshinori; Shiga, Toshiya; Wajima, Zen'ichiro; Nagasaka, Hiroshi

2017-08-01

To evaluate the efficacy of intravenous nitroglycerin (TNG) in preventing intraoperative myocardial ischemia (MI) under general anesthesia. Moreover, we analyzed the hemodynamic changes in heart rate (HR), mean blood pressure (MBP), and pulmonary capillary wedge pressure (PCWP) associated with TNG administration both before and after the induction of anesthesia. Meta-analysis. Operating room, cardiac surgery or non-cardiac surgery, all surgeries were elective measurements. We performed a computerized search of articles on PubMed, Scopus, and the Cochrane Central Register of Controlled Trials. Meta-analysis was performed using Review Manager. The data from the individual trials were combined using a random-effects model to calculate either the pooled relative risk (RR) or the weighted mean difference (WMD) with 95% confidence interval (CI). We conducted trial sequential analysis (TSA). The primary outcome was the incidence of MI and the secondary outcomes were hemodynamic changes (HR, MBP, and PCWP). Using electronic databases, we selected 10 trials with a total of 353 patients for our review. Prophylactic intravenous TNG did not significantly decrease the incidence of MI (RR=0.61; CI, 0.33 to 1.13; P=0.12; I 2 =55). TSA corrected the CI to 0.05 to 7.39 and showed that 9.5% of the required information size was achieved. In terms of hemodynamic changes, intravenous TNG significantly reduced MBP in comparison with the placebo (MBP pre-induction: WMD=-7.27; 95% CI -14.2 to -0.33; P=0.04; I 2 =97%; MBP post-induction: WMD=-5.13; 95% CI -9.17 to -1.09; P=0.01; I 2 =73%). Our analyses showed that prophylactic intravenous TNG does not reduce the incidence of intraoperative MI. Moreover, TSA suggests that further studies are necessary to confirm the results (GRADE: very low). Prophylactic doses of intravenous TNG significantly reduced the MBP both pre and post anesthesia induction (GRADE: very low). Copyright © 2017 Elsevier Inc. All rights reserved.

A randomized trial of one versus three doses of Augmentin as wound prophylaxis in at-risk abdominal surgery.

PubMed Central

Bates, T.; Roberts, J. V.; Smith, K.; German, K. A.

1992-01-01

In a randomized prospective trial of prophylactic antibiotics in at-risk abdominal surgery, one dose of intravenous Augmentin (amoxycillin 250 mg and clavulanic acid 125 mg) on induction has been compared with three 8 hourly doses in 900 patients. Wound infection rates which included minor and delayed infections were very similar in those given one dose: 48/449 (10.7%) compared with those given three doses: 49/451 (10.9%) 95% confidence limits - 4.25% + 3.9%. There were more septic and sepsis-related deaths in those patients given one dose (14 deaths) than in those given three doses (7 deaths) P > 0.1 95% CL - 0.4% + 3.0%. However, there were more very elderly patients in the one dose group: 64% of the deaths were aged over 80 and all but one had an emergency operation. There was no difference in the other outcome measures studied which included non-fatal deep sepsis, length of postoperative hospital stay, duration of postoperative fever or the use of antibiotics for postoperative infection. One dose of a suitable intravenous antibiotic gives prophylaxis against wound infection in at-risk abdominal surgery which is at least as effective as multiple doses. However, there may be a risk of overwhelming systemic sepsis in very elderly patients having emergency surgery. PMID:1461853

Effect of intravenous amino acids on interdigestive antroduodenal motility and small bowel transit time.

PubMed

Gielkens, H A; van den Biggelaar, A; Vecht, J; Onkenhout, W; Lamers, C B; Masclee, A A

1999-02-01

Patients on total parenteral nutrition have an increased risk of developing gallstones because of gall bladder hypomotility. High dose amino acids may prevent biliary stasis by stimulating gall bladder emptying. To investigate whether intravenous amino acids also influence antroduodenal motility. Eight healthy volunteers received, on three separate occasions, intravenous saline (control), low dose amino acids (LDA), or high dose amino acids (HDA). Antroduodenal motility was recorded by perfusion manometry and duodenocaecal transit time (DCTT) using the lactulose breath hydrogen test. DCTT was significantly prolonged during LDA and HDA treatment compared with control. The interdigestive motor pattern was maintained and migrating motor complex (MMC) cycle length was significantly reduced during HDA compared with control and LDA due to a significant reduction in phase II duration. Significantly fewer phase IIIs originated in the gastric antrum during LDA and HDA compared with control. Duodenal phase II motility index was significantly reduced during HDA, but not during LDA, compared with control. Separate intravenous infusion of high doses of amino acids in healthy volunteers: (1) modulates interdigestive antroduodenal motility; (2) shortens MMC cycle length due to a reduced duration of phase II with a lower contractile incidence both in the antrum and duodenum (phase I remains unchanged whereas the effect on phase III is diverse: in the antrum phase III is suppressed and in the duodenum the frequency is increased); and (3) prolongs interdigestive DCTT.

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits.

PubMed

Cox, Daniel T C; Shanahan, Danielle F; Hudson, Hannah L; Fuller, Richard A; Anderson, Karen; Hancock, Steven; Gaston, Kevin J

2017-02-09

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare.

Single- and multiple-dose pharmacokinetics, pharmacodynamics, and safety of apixaban in healthy Chinese subjects

PubMed Central

Cui, Yimin; Song, Yan; Wang, Jessie; Yu, Zhigang; Schuster, Alan; Barrett, Yu Chen; Frost, Charles

2013-01-01

Background The pharmacokinetics (PK), pharmacodynamics (PD), and safety of apixaban were assessed in healthy Chinese subjects in this randomized, placebo-controlled, double-blind, single-sequence, single- and multiple-dose study. Subjects and methods Eighteen subjects 18–45 years of age were randomly assigned (2:1 ratio) to receive apixaban or matched placebo. Subjects received a single 10 mg dose of apixaban or placebo on day 1, followed by 10 mg apixaban or placebo twice daily for 6 days (days 4–9). The PK and PD of apixaban were assessed by collecting plasma samples for 72 hours following the dose on day 1 and the morning dose on day 9, and measuring apixaban concentration and anti-Xa activity. Safety was assessed via physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory evaluations. Results PK analysis showed similar characteristics of apixaban after single and multiple doses, including a median time to maximum concentration of ~3 hours, mean elimination half-life of ~11 hours, and renal clearance of ~1.2 L/hour. The accumulation index was 1.7, consistent with twice-daily dosing and the observed elimination half-life. Single-dose data predict multiple-dose PK, therefore apixaban PK are time-independent. The relationship between anti-Xa activity and plasma apixaban concentrations appears to be linear. Apixaban was safe and well tolerated, with no bleeding-related adverse events reported. Conclusion Apixaban was safe and well tolerated in healthy Chinese subjects. Apixaban PK and PD were predictable and consistent with findings from previous studies in Asian and non-Asian subjects. The administration of apixaban does not require any dose modification based on race. PMID:24353445

Association of an Opioid Standard of Practice Intervention With Intravenous Opioid Exposure in Hospitalized Patients.

PubMed

Ackerman, Adam L; O'Connor, Patrick G; Doyle, Deirdre L; Marranca, Sheyla M; Haight, Carolyn L; Day, Christine E; Fogerty, Robert L

2018-06-01

Opioids are commonly used to treat pain in hospitalized patients; however, intravenous administration carries an increased risk of adverse effects compared with oral administration. The subcutaneous route is an effective method of opioid delivery with favorable pharmacokinetics. To assess an intervention to reduce intravenous opioid use, total parenteral opioid exposure, and the rate of patients administered parenteral opioids. A pilot study was conducted in an adult general medical unit in an urban academic medical center. Attending physicians, nurse practitioners, and physician assistants who prescribed drugs were the participants. Use of opioids was compared between a 6-month control period and 3 months following education for the prescribers on opioid routes of administration. Adoption of a local opioid standard of practice, preferring the oral and subcutaneous routes over intravenous administration, and education for prescribers and nursing staff on awareness of the subcutaneous route was implemented. The primary outcome was a reduction in intravenous doses administered per patient-day. Secondary measures included total parenteral and overall opioid doses per patient-day, parenteral and overall opioid exposure per patient-day, and daily rate of patients receiving parenteral opioids. Pain scores were measured on a standard 0- to 10-point Likert scale over the first 5 days of hospitalization. The control period included 4500 patient-days, and the intervention period included 2459 patient-days. Of 127 patients in the intervention group, 59 (46.5%) were men; mean (SD) age was 57.6 (18.5) years. Intravenous opioid doses were reduced by 84% (0.06 vs 0.39 doses per patient-day, P < .001), and doses of all parenteral opioids were reduced by 55% (0.18 vs 0.39 doses per patient-day, P < .001). In addition, mean (SD) daily parenteral opioid exposure decreased by 49% (2.88 [0.72] vs 5.67 [1.14] morphine-milligram equivalents [MMEs] per patient-day). The daily rate

Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review.

PubMed

Harel, Ziv; Kamel, Kamel S

2016-01-01

Hyperkalemia is a common electrolyte disorder that can result in fatal cardiac arrhythmias. Despite the importance of insulin as a lifesaving intervention in the treatment of hyperkalemia in an emergency setting, there is no consensus on the dose or the method (bolus or infusion) of its administration. Our aim was to review data in the literature to determine the optimal dose and route of administration of insulin in the management of emergency hyperkalemia. We searched several databases from their date of inception through February 2015 for eligible articles published in any language. We included any study that reported on the use of insulin in the management of hyperkalemia. We identified eleven studies. In seven studies, 10 units of regular insulin was administered (bolus in five studies, infusion in two studies), in one study 12 units of regular insulin was infused over 30 minutes, and in three studies 20 units of regular insulin was infused over 60 minutes. The majority of included studies were biased. There was no statistically significant difference in mean decrease in serum potassium (K+) concentration at 60 minutes between studies in which insulin was administered as an infusion of 20 units over 60 minutes and studies in which 10 units of insulin was administered as a bolus (0.79±0.25 mmol/L versus 0.78±0.25 mmol/L, P = 0.98) or studies in which 10 units of insulin was administered as an infusion (0.79±0.25 mmol/L versus 0.39±0.09 mmol/L, P = 0.1). Almost one fifth of the study population experienced an episode of hypoglycemia. The limited data available in the literature shows no statistically significant difference between the different regimens of insulin used to acutely lower serum K+ concentration. Accordingly, 10 units of short acting insulin given intravenously may be used in cases of hyperkalemia. Alternatively, 20 units of short acting insulin may be given as a continuous intravenous infusion over 60 minutes in patients with severe

Optimal Dose and Method of Administration of Intravenous Insulin in the Management of Emergency Hyperkalemia: A Systematic Review

PubMed Central

Harel, Ziv; Kamel, Kamel S.

2016-01-01

Background and Objectives Hyperkalemia is a common electrolyte disorder that can result in fatal cardiac arrhythmias. Despite the importance of insulin as a lifesaving intervention in the treatment of hyperkalemia in an emergency setting, there is no consensus on the dose or the method (bolus or infusion) of its administration. Our aim was to review data in the literature to determine the optimal dose and route of administration of insulin in the management of emergency hyperkalemia. Design, Setting, Participants, & Measurements We searched several databases from their date of inception through February 2015 for eligible articles published in any language. We included any study that reported on the use of insulin in the management of hyperkalemia. Results We identified eleven studies. In seven studies, 10 units of regular insulin was administered (bolus in five studies, infusion in two studies), in one study 12 units of regular insulin was infused over 30 minutes, and in three studies 20 units of regular insulin was infused over 60 minutes. The majority of included studies were biased. There was no statistically significant difference in mean decrease in serum potassium (K+) concentration at 60 minutes between studies in which insulin was administered as an infusion of 20 units over 60 minutes and studies in which 10 units of insulin was administered as a bolus (0.79±0.25 mmol/L versus 0.78±0.25 mmol/L, P = 0.98) or studies in which 10 units of insulin was administered as an infusion (0.79±0.25 mmol/L versus 0.39±0.09 mmol/L, P = 0.1). Almost one fifth of the study population experienced an episode of hypoglycemia. Conclusion The limited data available in the literature shows no statistically significant difference between the different regimens of insulin used to acutely lower serum K+ concentration. Accordingly, 10 units of short acting insulin given intravenously may be used in cases of hyperkalemia. Alternatively, 20 units of short acting insulin may be

Single‐dose intravenous iron in Southeast Asian heart failure patients: A pilot randomized placebo‐controlled study (PRACTICE‐ASIA‐HF)

PubMed Central

Yeo, Poh Shuan Daniel; Hadi, Farid Abdul; Cushway, Timothy; Lee, Kim Yee; Yin, Fang Fang; Ching, Anne; Li, Ruili; Loh, Seet Yoong; Lim, Shir Lynn; Wong, Raymond Ching‐Chiew; Tai, Bee Choo; Richards, Arthur Mark; Lam, Carolyn S.P.

2018-01-01

Abstract Aims Iron deficiency is highly prevalent in Southeast Asians with heart failure (HF) and associated with worse outcomes. This trial aimed to assess the effect of intravenous iron in Southeast Asians hospitalized with decompensated HF. Methods and results Fifty patients hospitalized for acute decompensated HF, regardless of ejection fraction, with iron deficiency (defined as serum ferritin <300 ng/mL if transferrin saturation is <20%) were randomized to receive either one dose of intravenous ferric carboxymaltose (FCM) 1000 mg or placebo (0.9% saline) following HF stabilization and before discharge in two Singapore tertiary centres. The primary endpoint was difference in 6‐min walk test (6MWT) distance over 12 weeks, while secondary endpoints were quality of life assessed using validated Kansas City Cardiomyopathy Questionnaire (KCCQ) and Visual Analogue Scale (VAS). Improvement in 6MWT distance at Week 12 was observed in both FCM and placebo groups (from 252 ± 123 to 334 ± 128 m and from 243 ± 67 to 301 ± 83 m, respectively). Unadjusted analysis showed 6MWT distance for FCM exceeded that for placebo, but adjustment for baseline covariates and time attenuated this effect {adjusted mean difference between groups: 0.88 m [95% confidence interval (CI) −30.2 to 32.0, P = 0.956]}. KCCQ overall summary and VAS were similar in both groups [adjusted mean difference: KCCQ −1.48 (95% CI −8.27 to 5.31, P = 0.670) and VAS 0.26 (95% CI −0.33 to 0.86, P = 0.386)]. FCM was well tolerated with no serious treatment‐related adverse events. Conclusions Intravenous FCM administered pre‐discharge in Southeast Asians hospitalized with decompensated HF is clinically feasible. Changes in 6MWT distance should be measured beyond Week 12 to account for background therapy effects. PMID:29345426

Is combined topical with intravenous tranexamic acid superior than topical, intravenous tranexamic acid alone and control groups for blood loss controlling after total knee arthroplasty: A meta-analysis.

PubMed

Lin, Chunmei; Qi, Yingmei; Jie, Li; Li, Hong-Biao; Zhao, Xi-Cheng; Qin, Lei; Jiang, Xin-Qiang; Zhang, Zhen-Hua; Ma, Liping

2016-12-01

pooled meta-analysis indicated that combined TXA can decrease the amount of total blood loss with mean 107.65 mL with statistically significant(MD = -107.65, 95% CI: -525.55 to -239.9141.85, P = 0.001). The pooled results indicated that combined topical with intravenous TXA can decrease the need for transfusion (RR = 0.34, 95% CI: 0.23-0.50, P < 0.001). There is no significant difference between combined topical with intravenous TXA with topical or intravenous TXA (P > 0.05) in terms of need for transfusion and the occurrence of DVT. Compared with topical, intravenous TXA alone or control group, combined topical with TXA, can decrease the total blood loss and subsequent need for transfusion without increasing the occurrence of DVT. The dose and timing to administration TXA is different, and more randomized controlled trials are warranted to clarify the optimal dosing and time to administration TXA.

Intravenous zoledronate for osteoporosis: less might be more

PubMed Central

Grey, Andrew

2016-01-01

Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken. PMID:27493690

Intravenous zoledronate for osteoporosis: less might be more.

PubMed

Grey, Andrew

2016-08-01

Annual administration of 5 mg intravenous zoledronate is moderately effective in reducing fracture risk in older adults, decreasing the relative risk of clinical fracture by 33%. However, almost 10 years after its approval for use in clinical practice there remain very substantial uncertainties about the optimal treatment regimen, that is, the lowest dose and/or longest dosing interval that is efficacious. Several pieces of clinical research suggest that the current recommendation for annual administration of 5 mg zoledronate might represent overtreatment. Clinical trials to clarify the optimal use of zoledronate for reduction of fracture risk should be undertaken.

Single- and multiple-dose pharmacokinetics of dapoxetine hydrochloride, a novel agent for the treatment of premature ejaculation.

PubMed

Modi, Nishit B; Dresser, Mark J; Simon, Mary; Lin, Denise; Desai, Dhaval; Gupta, Suneel

2006-03-01

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.

Regional cerebral energy metabolism during intravenous anesthesia with etomidate, ketamine or thiopental

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

Davis, D.W.

1987-01-01

Regional brain glucose utilization (rCMRglc) was measured in rats during steady-state levels of intravenous anesthesia to determine if alterations in brain function due to anesthesia could provide information on the mechanisms of anesthesia. Intravenous anesthetics from three different chemical classes were studied: etomidate, ketamine and thiopental. All rCMRglc experiments were conducted in freely moving rats in isolation chambers, with the use of (6-/sup 14/C) glucose and guantitative autoradiography. Etomidate caused a rostral-to-caudal gradient of depression of rCMRglc. The four doses of etomidate did not differ in their effects on energy metabolism. Sub-anesthetic (5 mg kg/sup -1/) and anesthetic (30 mgmore » kg /sup -1/) doses of ketamine produced markedly different patterns of behavior. Brain energy metabolism during the sub-anesthetic dose was stimulated in most regions, while the anesthetic dose selectively stimulated the hippocampus, leaving most brain regions unaffected. Thiopental produced a dose-dependent reduction of rCMRglc in all gray matter regions. No brain region was selectively affected. Comparison of the drug-specific alterations of cerebral energy metabolism suggests these anesthetics do not act through a common mechanism. The hypothesis that each acts by binding to specific cell membrane receptors is consistent with these observations.« less

Low-dose intravenous ketamine for postcardiac surgery pain: Effect on opioid consumption and the incidence of chronic pain.

PubMed

Cogan, Jennifer; Lalumière, Geneviève; Vargas-Schaffer, Grisell; Deschamps, Alain; Yegin, Zeynep

2017-01-01

Recent meta-analyses have concluded that low-dose intravenous ketamine infusions (LDKIs) during the postoperative period may help to decrease acute and chronic postoperative pain after major surgery. This study aims to evaluate the level of pain at least 3 months after surgery for patients treated with a postoperative LDKI versus patients who were not treated with a postoperative LDKI. Administrative and Ethics Board approval were obtained for this study. We performed a retrospective chart review for all patients receiving LDKI, and equal number of age-, sex-, and surgery-matched patients who did not receive LDKI. Low-dose ketamine was prepared using 100 mg of ketamine in 100 ml of normal saline and run between 50 and 200 mcg/kg/h. We reviewed 115 patients with LDKI and 115 without LDKI. The average age was 63.1 years, 73% of the patients were men and sex was evenly distributed between LDKI and non-LDKI. The average duration of the ketamine infusions was 26.8 h with the average dose being 169.9 mg. At an average of 9 months after surgery, 42% of the ketamine group and 38% of the nonketamine group stated that they had had pain on discharge. Of these patients, 30% of the ketamine group and 26% of the nonketamine group still had pain at the time of the phone call. Women in both groups had more acute and chronic pain than men. These results show that LDKI does not promote a decrease in long-term postoperative pain.

Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

PubMed Central

Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

2017-01-01

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study.

PubMed

Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

2017-01-01

The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3 + , CD4 + , CD8 + , and CD19 + ) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray.

PubMed

Stott, C G; White, L; Wright, S; Wilbraham, D; Guy, G W

2013-05-01

A Phase I study to assess the single and multipledose pharmacokinetics (PKs) and safety and tolerability of oromucosally administered Δ(9)-tetrahydrocannabinol (THC)/cannabidiol (CBD) spray, an endocannabinoid system modulator, in healthy male subjects. Subjects received either single doses of THC/CBD spray as multiple sprays [2 (5.4 mg THC and 5.0 mg CBD), 4 (10.8 mg THC and 10.0 mg CBD) or 8 (21.6 mg THC and 20.0 mg CBD) daily sprays] or multiple doses of THC/CBD spray (2, 4 or 8 sprays once daily) for nine consecutive days, following fasting for a minimum of 10 h overnight prior to each dosing. Plasma samples were analyzed by gas chromatography-mass spectrometry for CBD, THC, and its primary metabolite 11-hydroxy-THC, and various PK parameters were investigated. Δ(9)-Tetrahydrocannabinol and CBD were rapidly absorbed following single-dose administration. With increasing single and multiple doses of THC/CBD spray, the mean peak plasma concentration (Cmax) increased for all analytes. There was evidence of dose-proportionality in the single but not the multiple dosing data sets. The bioavailability of THC was greater than CBD at single and multiple doses, and there was no evidence of accumulation for any analyte with multiple dosing. Inter-subject variability ranged from moderate to high for all PK parameters in this study. The time to peak plasma concentration (Tmax) was longest for all analytes in the eight spray group, but was similar in the two and four spray groups. THC/CBD spray was well-tolerated in this study and no serious adverse events were reported. The mean Cmax values (<12 ng/mL) recorded in this study were well below those reported in patients who smoked/inhaled cannabis, which is reassuring since elevated Cmax values are linked to significant psychoactivity. There was also no evidence of accumulation on repeated dosing.

Pharmacokinetics and bactericidal activities of one 800-milligram dose versus two 400-milligram doses of intravenously administered pefloxacin in healthy volunteers.

PubMed Central

Petitjean, O; Pangon, B; Brion, N; Tod, M; Chaplain, C; Le Gros, V; Louchahi, K; Allouch, P

1993-01-01

Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions. PMID:8494368

Doses of Nearby Nature Simultaneously Associated with Multiple Health Benefits

PubMed Central

Cox, Daniel T. C.; Shanahan, Danielle F.; Hudson, Hannah L.; Fuller, Richard A.; Anderson, Karen; Hancock, Steven; Gaston, Kevin J.

2017-01-01

Exposure to nature provides a wide range of health benefits. A significant proportion of these are delivered close to home, because this offers an immediate and easily accessible opportunity for people to experience nature. However, there is limited information to guide recommendations on its management and appropriate use. We apply a nature dose-response framework to quantify the simultaneous association between exposure to nearby nature and multiple health benefits. We surveyed ca. 1000 respondents in Southern England, UK, to determine relationships between (a) nature dose type, that is the frequency and duration (time spent in private green space) and intensity (quantity of neighbourhood vegetation cover) of nature exposure and (b) health outcomes, including mental, physical and social health, physical behaviour and nature orientation. We then modelled dose-response relationships between dose type and self-reported depression. We demonstrate positive relationships between nature dose and mental and social health, increased physical activity and nature orientation. Dose-response analysis showed that lower levels of depression were associated with minimum thresholds of weekly nature dose. Nearby nature is associated with quantifiable health benefits, with potential for lowering the human and financial costs of ill health. Dose-response analysis has the potential to guide minimum and optimum recommendations on the management and use of nearby nature for preventative healthcare. PMID:28208789

21 CFR 320.27 - Guidelines on the design of a multiple-dose in vivo bioavailability study.

Code of Federal Regulations, 2011 CFR

2011-04-01

... vivo bioavailability study. 320.27 Section 320.27 Food and Drugs FOOD AND DRUG ADMINISTRATION... Guidelines on the design of a multiple-dose in vivo bioavailability study. (a) Basic principles. (1) In... labeling of the test product. (3) A multiple-dose study may be required to determine the bioavailability of...

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

PubMed Central

2012-01-01

Introduction Tumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters. Methods In this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo. Results Seventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment. Conclusions The safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies. PMID:22340283

Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats.

PubMed

Abelson, Klas S P; Höglund, A Urban

2002-04-01

Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10-300 microg/kg) and atropine (0.1, 10, 5000 microg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2-C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 microg/kg), or subcutaneously with oxotremorine (30, 100, 300 microg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 microg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 microg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

Pharmacokinetics of multiple doses of transdermal flunixin meglumine in adult Holstein dairy cows.

PubMed

Kleinhenz, M D; Gorden, P J; Smith, J S; Schleining, J A; Kleinhenz, K E; Wulf, L L; Sidhu, P K; Rea, D; Coetzee, J F

2018-06-01

A transdermal formulation of the nonsteroidal anti-inflammatory drug, flunixin meglumine, has been approved in the United States and Canada for single-dose administration. Transdermal flunixin meglumine was administered to 10 adult Holstein cows in their second or third lactation at the label dose of 3.33 mg/kg every 24 hr for three total treatments. Plasma flunixin concentrations were determined using high-pressure liquid chromatography with mass spectroscopy (HPLC-MS). Pharmacokinetic analysis was completed on each individual animal with noncompartmental methods using computer software. The time to maximum drug concentration (Tmax) was 2.81 hr, and the maximum drug concentration was 1.08 μg/ml. The mean terminal half-life (T½) was determined to be 5.20 hr. Clearance per fraction absorbed (Cl/F) was calculated to be 0.294 L/hr kg -1 , and volume of distribution of fraction (Vz/F) absorbed was 2.20 L/kg. The mean accumulation factor was 1.10 after three doses. This indicates changes in dosing may not be required when giving multiple doses of flunixin transdermal. Further work is required to investigate the clinical efficacy of transdermal flunixin after multiple daily doses. © 2018 John Wiley & Sons Ltd.

Dose escalation study to evaluate safety, tolerability and efficacy of intravenous etoposide phosphate administration in 27 dogs with multicentric lymphoma

PubMed Central

Hordeaux, Juliette; Bouchaert, Emmanuel; Gomes, Bruno

2017-01-01

Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans’ solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas. PMID:28505195

Multiple etiologies of axonal sensory motor polyneuropathy in a renal transplant recipient: a case report

PubMed Central

2011-01-01

Introduction Neurological complications leading to morbidity and mortality are not frequent in renal transplant recipients. Here, we report a renal transplant recipient who presented with diminished strength in his limbs probably due to multiple etiologies of axonal sensorimotor polyneuropathy, which resolved with intravenous immunoglobulin. Case presentation A 49-year-old Iranian male renal transplant recipient with previous history of autosomal dominant polycystic kidney disease presented with diminished strength in his limbs one month after surgery. Our patient was on cyclosporine A, mycophenolate mofetil and prednisone. Although a detected hypophosphatemia was corrected with supplemental phosphate, the loss of strength was still slowly progressive and diffuse muscular atrophy was remarkable in his trunk, upper limb and pelvic girdle. Meanwhile, his cranial nerves were intact. Post-transplant diabetes mellitus was diagnosed and insulin therapy was initiated. In addition, as a high serum cyclosporine level was detected, the dose of cyclosporine was reduced. Our patient was also put on intravenous ganciclovir due to positive serum cytomegalovirus immunoglobulin M antibody. Despite the reduction of oral cyclosporine dose along with medical therapy for the cytomegalovirus infection and diabetes mellitus, his muscular weakness and atrophy did not improve. One week after administration of intravenous immunoglobulin, a significant improvement was noted in his muscular weakness. Conclusion A remarkable response to intravenous immunoglobulin is compatible with an immunological basis for the present condition (post-transplant polyneuropathy). In cases of post-transplant polyneuropathy with a high clinical suspicion of immunological origin, administration of intravenous immunoglobulin may be recommended. PMID:22032472

Intravenous iron isomaltoside 1000 administered by high single-dose infusions or standard medical care for the treatment of fatigue in women after postpartum haemorrhage: study protocol for a randomised controlled trial.

PubMed

Holm, Charlotte; Thomsen, Lars Lykke; Norgaard, Astrid; Langhoff-Roos, Jens

2015-01-14

Postpartum haemorrhage can lead to iron deficiency with and without anaemia, the clinical consequences of which include physical fatigue. Although oral iron is the standard treatment, it is often associated with gastrointestinal side effects and poor compliance. To date, no published randomised controlled studies have compared the clinical efficacy and safety of standard medical care with intravenous administration of iron supplementation after postpartum haemorrhage.The primary objective of this study is to compare the efficacy of an intravenous high single-dose of iron isomaltoside 1000 with standard medical care on physical fatigue in women with postpartum haemorrhage. In a single centre, open-labelled, randomised trial, women with postpartum haemorrhage exceeding 700 mL will be allocated to either a single dose of 1,200 mg of iron isomaltoside 1000 or standard medical care. Healthy parturients with a singleton pregnancy will be included within 48 hours after delivery.Participants will complete structured questionnaires that focus on several dimensions of fatigue and mental health (Multidimensional Fatigue Inventory, Edinburgh Postnatal Depression Scale and the Postpartum Questionnaire), at inclusion and at follow-up visits after three days, one week, three weeks, eight weeks, and 12 weeks postpartum. The primary endpoint is the aggregated change in physical fatigue score within 12 weeks postpartum, as measured by a subscale of the Multidimensional Fatigue Inventory. The primary objective will be considered to have been met if an intravenous high single dose of iron isomaltoside 1000 is shown to be superior to standard medical care in women after postpartum haemorrhage regarding physical fatigue.For claiming superiority, we set the minimal clinically relevant difference between the mean scores at 1.8, and the assumed standard deviation at 4.2. Hence, 87 participants per treatment group are needed in order to demonstrate superiority; to provide an extra margin

Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen.

PubMed

Singla, Neil K; Parulan, Cherri; Samson, Roselle; Hutchinson, Joel; Bushnell, Rick; Beja, Evelyn G; Ang, Robert; Royal, Mike A

2012-09-01

This is the first study to compare plasma and cerebrospinal fluid (CSF) pharmacokinetics of intravenous (IV), oral (PO), or rectal (PR) formulations of acetaminophen. Healthy male subjects (N = 6) were randomized to receive a single dose of IV (OFIRMEV(®) ; Cadence) 1,000 mg (15 minute infusion), PO (2 Tylenol(®) 500 mg caplets; McNeil Consumer Healthcare), or PR acetaminophen (2 Feverall(®) 650 mg suppositories; Actavis) with a 1-day washout period between doses. The 1,300 mg PR concentrations were standardized to 1,000 mg. Acetaminophen plasma and CSF levels were obtained at T0, 0.25, 0.5, 0.75, 1, 2, 3, 4, and 6 hours. IV acetaminophen showed earlier and higher plasma and CSF levels compared with PO or PR administration. CSF bioavailability over 6 hours (AUC(0-6)) for IV, PO, and PR 1 g was 24.9, 14.2, and 10.3 μg·h/mL, respectively. No treatment-related adverse events were reported. One subject was replaced because of premature failure of his lumbar spinal catheter. The mean CSF level in the IV group was similar to plasma from 3 to 4 hours and higher from 4 hours on. Absorption phase, variability in plasma, and CSF were greater in PO and PR groups than variability with IV administration. These results demonstrate that earlier and greater CSF penetration occurs as a result of the earlier and higher plasma peak with IV administration compared with PO or PR. © 2012 Lotus Clinical Research, LLC. Pain Practice © 2012 World Institute of Pain.

Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone.

PubMed

Fort, J G; Abruzzo, J L

1988-09-01

We describe a patient with polyarteritis nodosa who, despite therapy with daily doses of oral prednisone and cyclophosphamide, developed acute renal failure. Renal histopathologic examination demonstrated crescentic glomerulonephritis. Treatment with intravenous pulse cyclophosphamide and methylprednisolone resulted in clinical improvement and significant recovery of renal function.

Evaluation of an antibiotic intravenous to oral sequential therapy program.

PubMed

Pablos, Ana I; Escobar, Ismael; Albiñana, Sandra; Serrano, Olga; Ferrari, José M; Herreros de Tejada, Alberto

2005-01-01

This study was designed to analyse the drug consumption difference and economic impact of an antibiotic sequential therapy focused on quinolones. We studied the consumption of quinolones (ofloxacin/levofloxacin and ciprofloxacin) 6 months before and after the implementation of a sequential therapy program in hospitalised patients. It was calculated for each antibiotic, in its oral and intravenous forms, in defined daily dose (DDD/100 stays per day) and economical terms (drug acquisition cost). At the beginning of the program ofloxacin was replaced by levofloxacin and, since their clinical uses are similar, the consumption of both drugs was compared during the period. In economic terms, the consumption of intravenous quinolones decreased 60% whereas the consumption of oral quinolones increased 66%. In DDD/100 stays per day, intravenous forms consumption decreased 53% and oral forms consumption increased 36%. Focusing on quinolones, the implementation of a sequential therapy program based on promoting an early switch from intravenous to oral regimen has proved its capacity to alter the utilisation profile of these antibiotics. The program has permitted the hospital a global saving of 41420 dollars for these drugs during the period of time considered. Copyright (c) 2004 John Wiley & Sons, Ltd.

Postoperative administration of landiolol hydrochloride for patients with supraventricular arrhythmia: the efficacy of sustained intravenous infusion at a low dose.

PubMed

Wariishi, Seiichiro; Yamashita, Koichi; Nishimori, Hideaki; Fukutomi, Takashi; Yamamoto, Masaki; Radhakrishnan, Geethalakshmi; Sasaguri, Shiro

2009-11-01

The purpose of this study was to investigate the efficacy of landiolol hydrochloride, a short-acting beta(1) blocker, by initiating its administration at a low dose (5 microg kg(-1) min(-1)) in patients with postoperative supraventricular arrhythmia. The efficacy of landiolol was evaluated in 38 patients who, after developing postoperative atrial flutter or fibrillation, with sinus tachycardia and two patients who had a history of paroxysmal atrial fibrillation with frequent atrial extrasystole. The heart rate and blood pressure before and 2 h after the administration of landiolol were compared. A return to the sinus rhythm from supraventricular arrhythmia was noted in 89%. The heart rate was reduced from 137+/-26 bpm (before landiolol administration) to 93+/-18 bpm (2 h after the start of the medication, P<0.01). As an agent to correct an arrhythmic condition, landiolol successfully raised the systolic blood pressure from 108+/-24 mmHg (before medication) to 120+/-19 mmHg (2 h after the medication was started, P<0.05). Continuous intravenous infusion of landiolol at a low dose was found to be effective for postoperative supraventricular arrhythmia.

A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion.

PubMed

Shimada, Shigeki; Takeda, Masamitsu; Nishihira, Jun; Kaneuchi, Masanori; Sakuragi, Noriaki; Minakami, Hisanori; Yamada, Hideto

2009-11-01

A high dose of intravenous immunoglobulin (HIVIg) therapy is effective in various diseases such as autoimmune diseases, and also is expected to have efficacy in recurrent spontaneous abortion (RSA). The aim of this study was to understand immunological mechanisms of this therapy. By flowcytometric analyses, we examined phenotypic changes of a variety of immunological cells including natural killer (NK) cells, cytotoxic T cells, regulatory T cells and macrophages in peripheral blood of RSA women with HIVIg therapy (n = 8). Expression percentages of inhibitory CD94 on NK cells significantly (P = 0.01) increased after the therapy (58.8 +/- 21.4% versus 71.0 +/- 17.6%). Mechanisms of possible efficacy of HIVIg therapy for RSA may include enhancement of CD94 expression and subsequent suppression of NK cell cytotoxicity.

Intravenous insertion site protection: moisture accumulation in intravenous site protectors.

PubMed

Lee, W E; Vallino, L M

1996-01-01

Stabilizing the intravenous catheter after insertion is a significant part of intravenous therapy. Dislodgments of the cannula from its optimal position in the vein can lead to complications such as phlebitis, thrombophlebitis, infiltration, and infection. Intravenous site protector shields are designed to protect the catheter from impact and tissue trauma at the insertion site. Nurses have requested ventilation in these shields to avoid moisture build up that may increase the risk of infections. To address this issue, experimental laboratory testing was performed to determine if moisture accumulation as evidenced by increased weight of the shield and visible evidence of condensation occurred. No moisture condensation problems with the ventilated intravenous site protectors were found.

Low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS): study protocol for a randomized controlled trial.

PubMed

Goebel, Andreas; Shenker, Nicholas; Padfield, Nick; Shoukrey, Karim; McCabe, Candida; Serpell, Mick; Sanders, Mark; Murphy, Caroline; Ejibe, Amaka; Milligan, Holly; Kelly, Joanna; Ambler, Gareth

2014-10-24

Longstanding complex regional pain syndrome (CRPS) is refractory to treatment with established analgesic drugs in most cases, and for many patients, alternative pain treatment approaches, such as with neuromodulation devices or rehabilitation methods, also do not work. The development of novel, effective treatment technologies is, therefore, important. There are preliminary data suggesting that low-dose immunoglobulin treatment may significantly reduce pain from longstanding CRPS. LIPS is a multicentre (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. Participants with moderate or severe CRPS of between 1 and 5 years duration will be randomly allocated to receive IVIg 0.5 g/kg (IntratectTM 50 g/l solution for infusion) or matching placebo administered day 1 and day 22 after randomisation, followed by two optional doses of open-label medication on day 43 after randomisation and on day 64 after randomisation. The primary outcome is the patients' pain intensity in the IVIG group compared with the placebo group, between 6 and 42 days after randomisation. The primary trial objective is to confirm the efficacy and confidently determine the effect size of the IVIG treatment technology in this group of patients. ISRCTN42179756 (Registered 28 June 13).

Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy.

PubMed

Letko, Erik; Yeh, Steven; Foster, C Stephen; Pleyer, Uwe; Brigell, Mitchell; Grosskreutz, Cynthia L

2015-05-01

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibited promising activity in a proof-of-concept study when administered in intravenous (IV) doses to patients with active, chronic, noninfectious uveitis. This study compared the efficacy and safety of different IV and subcutaneous (SC) doses of secukinumab in patients with noninfectious uveitis. Multicenter, randomized, double-masked, dose-ranging, phase 2 clinical trial. Thirty-seven patients with active noninfectious intermediate uveitis, posterior uveitis, or panuveitis who required corticosteroid-sparing immunosuppressive therapy. Patients were randomized to secukinumab 300 mg SC every 2 weeks for 4 doses, secukinumab 10 mg/kg IV every 2 weeks for 4 doses, or secukinumab 30 mg/kg IV every 4 weeks for 2 doses. Intravenous or SC saline was administered to maintain masking. Efficacy was assessed on day 57 (2-4 weeks after last dose). Percentage of patients with treatment response, defined as (1) at least a 2-grade reduction in vitreous haze score or trace or absent vitreous haze in the study eye without an increase in corticosteroid dose and without uveitis worsening or (2) reduction in corticosteroid dosages to prespecified levels without uveitis worsening. Percentage of patients with remission, defined as anterior chamber cell and vitreous haze scores of 0 or 0.5+ in both eyes without corticosteroid therapy or uveitis worsening. Secukinumab 30 mg/kg IV and 10 mg/kg IV, compared with the 300 mg SC dose, produced higher responder rates (72.7% and 61.5% vs. 33.3%, respectively) and remission rates (27.3% and 38.5% vs. 16.7%, respectively). Statistical and clinical superiority for the 30 mg/kg IV dose compared with the 300 mg SC dose was established in a Bayesian probability model. Other measures, including time to response onset, change in visual acuity, and change in vitreous haze score, showed numeric trends favoring IV dosing. Secukinumab, administered in IV or SC formulations, appeared

Urinary symptoms following external beam radiotherapy of the prostate: Dose-symptom correlates with multiple-event and event-count models.

PubMed

Yahya, Noorazrul; Ebert, Martin A; Bulsara, Max; House, Michael J; Kennedy, Angel; Joseph, David J; Denham, James W

2015-11-01

This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events. Urinary symptoms (dysuria, haematuria, incontinence and frequency) from 754 participants from TROG 03.04-RADAR trial were analysed. Relative (R1-R75 Gy) and absolute (A60-A75Gy) bladder dose-surface area receiving more than a threshold dose and equivalent uniform dose using exponent a (range: a ∈[1 … 100]) were derived. The dose-symptom correlates were analysed using; peak-symptom (logistic), multiple-event (generalised estimating equation) and event-count (negative binomial regression) models. Stronger dose-symptom correlates were found for incontinence and frequency using multiple-event and/or event-count models. For dysuria and haematuria, similar or better relationships were found using peak-symptom models. Dysuria, haematuria and high grade (⩾ 2) incontinence were associated to high dose (R61-R71 Gy). Frequency and low grade (⩾ 1) incontinence were associated to low and intermediate dose-surface parameters (R13-R41Gy). Frequency showed a parallel behaviour (a=1) while dysuria, haematuria and incontinence showed a more serial behaviour (a=4 to a ⩾ 100). Relative dose-surface showed stronger dose-symptom associations. For certain endpoints, the multiple-event and event-count models provide stronger correlates over peak-symptom models. Accounting for multiple events may be advantageous for a more complete understanding of urinary dose-symptom relationships. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Outcomes of Substituting Oral Fludarabine for Intravenous Fludarabine in Combination with Cytarabine and Filgrastim for Treatment of Primary Refractory or Relapsed Acute Leukemias.

PubMed

Demichelis-Gómez, Roberta; Crespo-Solís, Erick; Pérez-Jacobo, Luis Fernando; Valencia-Rocha, Ubaldo Rafael; Rosas-López, Adriana

2015-01-01

Treatment of relapsed/refractory acute myeloid or lymphoid leukemia consists of salvage chemotherapy followed by allogeneic hematopoietic stem-cell transplantation. Intravenous fludarabine, cytarabine, and filgrastim is an effective regimen in this setting. In view of the lack of availability of intravenous fludarabine in Mexico from 2009-2013, we substituted an equivalent oral fludarabine dose (40 mg) for the intravenous formulation. This is a retrospective comparison of the toxicity and effectiveness of oral fludarabine, cytarabine, and filgrastim versus intravenous fludarabine, cytarabine and filgrastim. A total of 44 patients with relapsed/refractory acute myeloid leukemia or acute lymphoid leukemia treated in an academic medical center from 2005-2013 with oral fludarabine, cytarabine and filgrastim (21 patients) or intravenous fludarabine, cytarabine and filgrastim (23 patients) were included in the analysis. There was a trend towards a higher complete remission rate and a longer overall survival following intravenous fludarabine, cytarabine, and filgrastim as compared with oral fludarabine, cytarabine, and filgrastim: complete remission rates 39.1 vs. 23.8% (p = 0.342) and overall survival 6.14 vs. 10.78 months (p = 0.363), respectively. A higher incidence of neutropenic fever (100 vs. 76.2%; p = 0.019) and septic shock (34.8 vs. 0%; p = 0.003) and a longer hospitalization (26.8 vs. 19.4 days; p = 0.046) were observed with intravenous fludarabine, cytarabine, and filgrastim. In multivariate analysis, factors associated with a shorter survival were septic shock (HR: 3.93; 95% CI: 1.67-9.25; p = 0.002) and a higher number of previous treatments (HR: 2.5; 95% CI: 1.26-4.99; p = 0.009). Complete remission was associated with better survival (HR: 0.18; 95% CI: 0.08-0.44; p < 0.001). Further studies are needed to determine the optimal dose and timing of oral fludarabine when given as part of the fludarabine, cytarabine, and filgrastim regimen for relapsed

Intravenous zoledronic acid for the treatment of osteoporosis: The evidence of its therapeutic effect

PubMed Central

Lewiecki, E Michael

2010-01-01

Introduction: Osteoporosis is a disease characterized by low bone mineral density and poor bone quality resulting in reduced bone strength and increased risk of fracture. Oral bisphosphonates, first-line therapy for most patients with osteoporosis, are associated with suboptimal adherence to therapy due to factors that include a complex dosing regimen and gastrointestinal intolerance in some patients. Intravenous bisphosphonates address these limitations through infrequent injectable dosing that assures 100% bioavailability. Intravenous zoledronic acid is the newest bisphosphonate to be approved for the treatment of osteoporosis. Aims: This review assesses the evidence for the therapeutic effects of intravenous zoledronic acid for the treatment of osteoporosis. Evidence review: Zoledronic acid 5 mg administered as an annual 15-min intravenous infusion has been shown to reduce the risk of vertebral fractures, hip fractures, and other fractures in a three-year randomized, double-blind, placebo-controlled trial in women with postmenopausal osteoporosis. In a randomized, double-blind, placebo-controlled trial in women and men with a recent surgical repair of low-trauma hip fracture, it reduced the risk of new clinical fractures and improved survival. In both studies, zoledronic acid was associated with a good safety profile and was generally well tolerated. Zoledronic acid has the potential to improve clinical outcomes by reducing the risk of fracture in patients with osteoporosis. Clinical value: Intravenous zoledronic acid 5 mg every 12 months reduces fracture risk in women with postmenopausal osteoporosis and in women and men with recent low-trauma hip fracture. PMID:20694061

Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

PubMed

Lacasse, Claude; Gamble, Kathryn C; Boothe, Dawn M

2013-09-01

Pharmacokinetic data were determined after a single dose of meloxicam in red-tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/- 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species.

Hanford Technical Basis for Multiple Dosimetry Effective Dose Methodology

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

Hill, Robin L.; Rathbone, Bruce A.

2010-08-01

The current method at Hanford for dealing with the results from multiple dosimeters worn during non-uniform irradiation is to use a compartmentalization method to calculate the effective dose (E). The method, as documented in the current version of Section 6.9.3 in the 'Hanford External Dosimetry Technical Basis Manual, PNL-MA-842,' is based on the compartmentalization method presented in the 1997 ANSI/HPS N13.41 standard, 'Criteria for Performing Multiple Dosimetry.' With the adoption of the ICRP 60 methodology in the 2007 revision to 10 CFR 835 came changes that have a direct affect on the compartmentalization method described in the 1997 ANSI/HPS N13.41more » standard, and, thus, to the method used at Hanford. The ANSI/HPS N13.41 standard committee is in the process of updating the standard, but the changes to the standard have not yet been approved. And, the drafts of the revision of the standard tend to align more with ICRP 60 than with the changes specified in the 2007 revision to 10 CFR 835. Therefore, a revised method for calculating effective dose from non-uniform external irradiation using a compartmental method was developed using the tissue weighting factors and remainder organs specified in 10 CFR 835 (2007).« less

Comparative pharmacokinetics of oxytetracycline in blunt-snout bream (Megalobrama amblycephala) with single and multiple-dose oral administration.

PubMed

Li, Ru-Qin; Ren, Yu-Wei; Li, Jing; Huang, Can; Shao, Jun-Hui; Chen, Xiao-Xuan; Wu, Zhi-Xin

2015-06-01

Research into the pharmacokinetics and residue elimination of oxytetracycline (OTC) is important both to determine the optimal dosage regimens and to establish a safe withdrawal time in fish. A depletion study is presented here for OTC in Megalobrama amblycephala with a single-dose (100 mg/kg) and multiple-dose (100 mg/kg for five consecutive days) oral administration. The study was conducted at 25 °C. As a result, a one-compartment model was developed. For the single dose, the absorption half-life was 5.79, 9.40, 6.96, and 8.06 h in the plasma, liver, kidney, and muscle, respectively. However, the absorption half-life was 3.62, 7.33, 4.59, and 6.02 h with multiple-dose oral administration. The elimination half-time in the plasma, liver, kidney, and muscle was 58.63, 126.43, 65.1, and 58.85 h when M. amblycephala was treated with a single dose. However, the elimination half-time changed to 91.75, 214.87, 126.22, and 135.84 h with multiple-dose oral administration.

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

PubMed Central

D'Souza, Deepak Cyril; Fridberg, Daniel J; Skosnik, Patrick D; Williams, Ashley; Roach, Brian; Singh, Nagendra; Carbuto, Michelle; Elander, Jacqueline; Schnakenberg, Ashley; Pittman, Brian; Sewell, R Andrew; Ranganathan, Mohini; Mathalon, Daniel

2012-01-01

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball' P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high' in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact

Pharmacodynamic and pharmacokinetic effects of the intravenous CB1 receptor agonist Org 26828 in healthy male volunteers.

PubMed

Zuurman, Lineke; Passier, Paul C C M; de Kam, Marieke L; Kleijn, Huub J; Cohen, Adam F; van Gerven, Joop M A

2010-11-01

An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 μg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 μg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 μg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.

The Safety of Intravenous Cyclophosphamide in the Treatment of Rheumatic Diseases.

PubMed

Woytala, Patryk J; Morgiel, Ewa; Łuczak, Anna; Czesak-Woytala, Katarzyna; Wiland, Piotr

2016-01-01

The therapeutic effects of cyclophosphamide (CP) in the treatment of systemic rheumatic diseases are related to its immune suppressive activity. However effective, the application of CP is restricted due to multiple adverse effects. This retrospective study was conducted to determine the frequency of adverse effects attributed to CP toxicity. The study involved 65 patients (17 male; 48 female) receiving intravenous CP between October 2007 and December 2010. The mean age at onset was 51.2 years (range 19-77 years). The most common diagnoses were systemic sclerosis (20), systemic lupus erythematosus (13) and vasculitis (13). The indications for treatment with CP were interstitial lung disease in the course of systemic diseases (33), vasculitis (24), glomerulonephritis (5) and changes in the central nervous system (3). The patients were administered 400-1000 mg CP in intravenous infusions at 2-16 week intervals, with the addition of sodium 2-sulfanylethanesulfonate (mesna) before and after each pulse. Out of 65 patients 40 (60%) reported adverse effects: infections in 24 (37%), nausea in 19 (29%), vomiting in 11 (17%), abdominal pain in 7 (11%) and pancytopenia in one, leading to cessation of the therapy. No association was found between the frequency of side effects and the treatment duration (p = 0.632), age (p = 0.852), diagnosis (p = 0.171) or nominal dose (p = 0.321). As knowledge about CP continues to increase, this medication remains a safe way to treat many rheumatic diseases.

Intravenous Therapy.

ERIC Educational Resources Information Center

Galliart, Barbara

Intended for teaching licensed practical nurses, this curriculum guide provides information related to the equipment and skills required for nursing care of patients needing intravenous (IV) therapy. It also explains the roles and responsibilities of the licensed practical nurse with regard to intravenous therapy. Each of the 15 instructional…

Safety and Feasibility of Long-term Intravenous Sodium Nitrite Infusion in Healthy Volunteers

PubMed Central

Pluta, Ryszard M.; Oldfield, Edward H.; Bakhtian, Kamran D.; Fathi, Ali Reza; Smith, René K.; DeVroom, Hetty L.; Nahavandi, Masoud; Woo, Sukyung; Figg, William D.; Lonser, Russell R.

2011-01-01

Background Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. Methodology Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8±9.2 years (range, 21–56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 µg/kg/hr; maximal dose of 533.8 µg/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. Findings The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 µg/kg/hr. Dose limiting toxicity occurred at 446 µg/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S-nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. Conclusion Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. Clinical Trial Registration Information http

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.

Dose-escalation of human anti-interferon-α receptor monoclonal antibody MEDI-546 in subjects with systemic sclerosis: a phase 1, multicenter, open label study

PubMed Central

2014-01-01

Introduction Type I interferons (IFNs) are implicated in the pathogenesis of systemic sclerosis (SSc). MEDI-546 is an investigational human monoclonal antibody directed against the type I IFN receptor. This Phase 1 study evaluated the safety/tolerability, pharmacokinetics (PK), immunogenicity, and pharmacodynamics (PD) of single and multiple intravenous doses of MEDI-546 in adults with SSc. Methods Subjects (≥18 years) with SSc were enrolled in an open-label, dose-escalation study to receive single (0.1, 0.3, 1.0, 3.0, 10.0, or 20.0 mg/kg), or 4 weekly intravenous doses (0.3, 1.0, or 5.0 mg/kg/week) of MEDI-546. Subjects were followed for 12 weeks. Safety assessments included adverse events (AEs), laboratory results, and viral monitoring. Blood samples were collected from all subjects for determination of PK, presence of anti-drug antibodies (ADAs), and expression of type I IFN-inducible genes. Results Of 34 subjects (mean age 47.4 years), 32 completed treatment and 33 completed the study. Overall, 148 treatment-emergent AEs (TEAEs) were reported (68.9% mild, 27.7% moderate). TEAEs included one grade 1 infusion reaction (5.0 mg/kg/week multiple dose). Of 4 treatment-emergent serious AEs (skin ulcer, osteomyelitis, vertigo, and chronic myelogenous leukemia (CML)), only CML (1.0 mg/kg/week multiple dose) was considered possibly treatment-related. MEDI-546 exhibited non-linear PK at lower doses. ADAs were detected in 5 subjects; no apparent impact on PK was observed. Peak inhibition of the type I IFN signature in whole blood was achieved within 1 day and in skin after 7 days. Conclusion The safety/tolerability, PK, and PD profiles observed in this study support further clinical development of MEDI-546. Trial Registration ClinicalTrials.gov NCT00930683 PMID:24559157

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

PubMed

Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

1995-07-01

In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality.

The pharmacokinetic and safety profiles of blonanserin in healthy Chinese volunteers after single fasting doses and single and multiple postprandial doses.

PubMed

Chen, Xia; Wang, Hongyun; Jiang, Ji; Chen, Rui; Zhou, Ying; Zhong, Wen; Liu, Hongzhong; Hu, Pei

2014-03-01

Blonanserin is a novel atypical antipsychotic drug acting as a mixed serotonin 5-HT2A and dopamine D2 receptor antagonist. This study investigated the pharmacokinetics and safety of blonanserin in healthy Chinese males. This was an open-label trial with two parts. Twenty-four subjects were enrolled in part A to receive a single fasting dose of 4 or 8 mg blonanserin (each n = 12); part B recruited 12 subjects and administered single and sequentially twice-daily multiple postprandial doses of blonanserin 2 mg for 9 days. Serial blood samples were taken for the bioassay of plasma blonanserin and its four metabolites during both sub-studies. Safety was assessed, including repeat measurements of fasting serum prolactin, insulin, triglyceride and cholesterol. Blonanserin was rapidly absorbed, accompanied with immediate plasma concentration elevation of the N-oxide form (M2) and gradual rises of the N-deethylated form (M1) and its downstream metabolites. The mean elimination half-life of blonanserin (7.7-11.9 h) was much longer than that of M2 (1.2-1.3 h) but shorter than that of M1 (26.4-31.4 h) after single fasting doses. After food intake, a single dose of 2 mg blonanserin resulted in total exposure and peak concentrations of blonanserin similar to those observed with a single fasting dose of blonanserin 4 mg. Moreover, the relationship of metabolite over parent compound ratio was different between M1 and M2 after single and multiple postprandial administrations (single dose vs multiple dose: M1, 0.33 vs 0.75; M2, 0.13 vs 0.067). Mild but transient increases of prolactin, insulin and triglyceride were observed. The pharmacokinetics of blonanserin in Chinese subjects were similar to those observed in Japanese subjects. This study suggested that food intake not only increases the bioavailability of blonanserin but differently affects the pharmacokinetics of its metabolites as well. The drug was safe and well tolerated in healthy Chinese males.

Pharmacokinetics, microbial response, and pulmonary outcomes of multidose intravenous azithromycin in preterm infants at risk for Ureaplasma respiratory colonization.

PubMed

Merchan, L Marcela; Hassan, Hazem E; Terrin, Michael L; Waites, Ken B; Kaufman, David A; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J; Schelonka, Robert; Magder, Laurence S; Shukla, Sagar; Eddington, Natalie D; Viscardi, Rose M

2015-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg(0.75), 1.88 liters · kg, 1.79 liters/h · kg(0.75), and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼ 4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating

Pharmacokinetics, Microbial Response, and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

PubMed Central

Merchan, L. Marcela; Hassan, Hazem E.; Terrin, Michael L.; Waites, Ken B.; Kaufman, David A.; Ambalavanan, Namasivayam; Donohue, Pamela; Dulkerian, Susan J.; Schelonka, Robert; Magder, Laurence S.; Shukla, Sagar; Eddington, Natalie D.

2014-01-01

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg0.75, 1.88 liters · kg, 1.79 liters/h · kg0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC24)/MIC90 value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp

Phage therapy dosing: The problem(s) with multiplicity of infection (MOI).

PubMed

Abedon, Stephen T

2016-01-01

The concept of bacteriophage multiplicity of infection (MOI) - ratios of phages to bacteria - historically has been less easily applied than many phage workers would prefer or, perhaps, may be aware. Here, toward clarification of the concept, I discuss multiplicity of infection in terms of semantics, history, mathematics, pharmacology, and actual practice. For phage therapy and other biocontrol purposes it is desirable, especially, not to solely employ MOI to describe what phage quantities have been applied during dosing. Why? Bacterial densities can change between bacterial challenge and phage application, may not be easily determined immediately prior to phage dosing, and/or target bacterial populations may not be homogeneous with regard to phage access and thereby inconsistent in terms of what MOI individual bacteria experience. Toward experiment reproducibility and as practiced generally for antibacterial application, phage dosing instead should be described in terms of concentrations of formulations (phage titers) as well as volumes applied and, in many cases, absolute numbers of phages delivered. Such an approach typically will be far more desirable from a pharmacological perspective than solely indicating ratios of agents to bacteria. This essay was adapted, with permission, from an appendix of the 2011 monograph, Bacteriophages and Biofilms , Nova Science Publishers.

The Cardiovascular Effect of Single Injection and Toxicologic Effects of Repetitive 2-Week Intravenous Administration of Activin A/BMP-2 Chimera in Beagle Dog.

PubMed

Lee, Jae Hyup; Choe, Senyon; Han, Shihuan

2018-02-01

This study was performed for the purpose to evaluate the effect of activin A/BMP-2 chimera (AB204) on cardiovascular system and toxicological effect in beagle dogs. When administered AB204 at the dose of 0.32 mg/kg via intravenous injection in beagle dogs, there were no changes in systolic, diastolic and mean blood pressure as well as in pulse rate, in addition that there were no differences in ORS complex, PR interval, R-R interval, QT interval and QTcV interval on the electrocardiography. Also, when administered AB204 at the doses of 0.25 and 0.5 mg/kg/day via repetitive intravenous injection for 2 weeks, it did not cause any significant changes in general symptoms, weight, food intake, ophthalmologic abnormality, urine, hematology, serum biochemistry, organ weight and autopsy values. Therefore, AB204 did not affect cardiovascular functions including blood pressure, pulse rate and ECG, when administered at the dose of ≤0.32 mg/kg via single intravenous injection in male beagle dogs. When it was administered at the dose of 0.5 mg/kg repetitive intravenous injection for 2 weeks, it did not show any toxicity.

Pharmacodynamic Effects of Single and Multiple Doses of Empagliflozin in Patients With Type 2 Diabetes.

PubMed

Heise, Tim; Jordan, Jens; Wanner, Christoph; Heer, Martina; Macha, Sreeraj; Mattheus, Michaela; Lund, Søren S; Woerle, Hans J; Broedl, Uli C

2016-10-01

Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes. In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P < 0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P < 0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P < 0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020). Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Achieving Consistent Multiple Daily Low-Dose Bacillus anthracis Spore Inhalation Exposures in the Rabbit Model

PubMed Central

Barnewall, Roy E.; Comer, Jason E.; Miller, Brian D.; Gutting, Bradford W.; Wolfe, Daniel N.; Director-Myska, Alison E.; Nichols, Tonya L.; Taft, Sarah C.

2012-01-01

Repeated low-level exposures to biological agents could occur before or after the remediation of an environmental release. This is especially true for persistent agents such as B. anthracis spores, the causative agent of anthrax. Studies were conducted to examine aerosol methods needed for consistent daily low aerosol concentrations to deliver a low-dose (less than 106 colony forming units (CFU) of B. anthracis spores) and included a pilot feasibility characterization study, acute exposure study, and a multiple 15 day exposure study. This manuscript focuses on the state-of-the-science aerosol methodologies used to generate and aerosolize consistent daily low aerosol concentrations and resultant low inhalation doses to rabbits. The pilot feasibility characterization study determined that the aerosol system was consistent and capable of producing very low aerosol concentrations. In the acute, single day exposure experiment, targeted inhaled doses of 1 × 102, 1 × 103, 1 × 104, and 1 × 105 CFU were used. In the multiple daily exposure experiment, rabbits were exposed multiple days to targeted inhaled doses of 1 × 102, 1 × 103, and 1 × 104 CFU. In all studies, targeted inhaled doses remained consistent from rabbit-to-rabbit and day-to-day. The aerosol system produced aerosolized spores within the optimal mass median aerodynamic diameter particle size range to reach deep lung alveoli. Consistency of the inhaled dose was aided by monitoring and recording respiratory parameters during the exposure with real-time plethysmography. Overall, the presented results show that the animal aerosol system was stable and highly reproducible between different studies and over multiple exposure days. PMID:22919662

Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats.

PubMed

Cheng, Chen; Lin, Jia-zhen; Li, Li; Yang, Jun-ling; Jia, Wei-wei; Huang, Yu-hong; Du, Fei-fei; Wang, Feng-qing; Li, Mei-juan; Li, Yan-fen; Xu, Fang; Zhang, Na-ting; Olaleye, Olajide E; Sun, Yan; Li, Jian; Sun, Chang-hai; Zhang, Gui-ping; Li, Chuan

2016-04-01

Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

ASSESSING POPULATION EXPOSURES TO MULTIPLE AIR POLLUTANTS USING A MECHANISTIC SOURCE-TO-DOSE MODELING FRAMEWORK

EPA Science Inventory

The Modeling Environment for Total Risks studies (MENTOR) system, combined with an extension of the SHEDS (Stochastic Human Exposure and Dose Simulation) methodology, provide a mechanistically consistent framework for conducting source-to-dose exposure assessments of multiple pol...

Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial.

PubMed

Goebel, Andreas; Bisla, Jatinder; Carganillo, Roy; Frank, Bernhard; Gupta, Rima; Kelly, Joanna; McCabe, Candy; Murphy, Caroline; Padfield, Nick; Phillips, Ceri; Sanders, Mark; Serpell, Mick; Shenker, Nick; Shoukrey, Karim; Wyatt, Lynne; Ambler, Gareth

2017-10-03

Two small trials suggest that low-dose intravenous immunoglobulin (IVIg) may improve the symptoms of complex regional pain syndrome (CRPS), a rare posttraumatic pain condition. To confirm the efficacy of low-dose IVIg compared with placebo in reducing pain during a 6-week period in adult patients who had CRPS from 1 to 5 years. 1:1 parallel, randomized, placebo-controlled, multicenter trial for 6 weeks, with an optional 6-week open extension. Patients were randomly assigned to 1 of 2 study groups between 27 August 2013 and 28 October 2015; the last patient completed follow-up on 21 March 2016. Patients, providers, researchers, and outcome assessors were blinded to treatment assignment. (ISRCTN42179756). 7 secondary and tertiary care pain management centers in the United Kingdom. 111 patients with moderate or severe CRPS of 1 to 5 years' duration. IVIg, 0.5 g/kg of body weight, or visually indistinguishable placebo of 0.1% albumin in saline on days 1 and 22 after randomization. The primary outcome was 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale. Secondary outcomes were pain interference and quality of life. The primary analysis sample consisted of 108 eligible patients, 103 of whom had outcome data. Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, -0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of -1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events. Results do not apply to patients who have had CRPS for less than 1 year or more

[Toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (4). 6-month repeated dose intravenous toxicity study in rats with 1-month recovery test].

PubMed

Yamaguchi, K; Aze, Y; Shimizu, K; Shichino, Y; Oku, H; Mori, H; Shinomiya, K; Ueda, H; Suzuki, Y; Oida, H; Nishibata, K; Tanaka, M; Yanagizawa, Y; Nanba, T; Nishiyama, K; Yonezawa, H; Fujita, T

1998-07-01

A 6-month repeated dose toxicity study with 1-month recovery test of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley (SD) rats. The rats of both sexes were administered ONO-5046.Na intravenously at a daily dose of 0 (vehicle control), 18.75, 37.5 or 75 mg/kg. ONO-5046.Na did not affect clinical signs, body weight, food consumption, opthalmology, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathology at any dose. These results indicate that the NOAEL of ONO-5046.Na in rats is 75 mg/kg/day for both sexes in this study.

Efficacy of multiple exposure with low level He-Ne laser dose on acute wound healing: a pre-clinical study

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

Investigations on the use of Low Level Laser Therapy (LLLT) for wound healing especially with the red laser light have demonstrated its pro-healing potential on a variety of pre-clinical and surgical wounds. However, until now, in LLLT the effect of multiple exposure of low dose laser irradiation on acute wound healing on well-designed pre-clinical model is not much explored. The present study aimed to investigate the effect of multiple exposure of low dose Helium Neon laser on healing progression of full thickness excision wounds in Swiss albino mice. Further, the efficacy of the multiple exposure of low dose laser irradiation was compared with the single exposure of optimum dose. Full thickness excision wounds (circular) of 15 mm diameter were created, and subsequently illuminated with the multiple exposures (1, 2, 3, 4 and 5 exposure/ week until healing) of He-Ne (632.8 nm, 4.02 mWcm-2) laser at 0.5 Jcm-2 along with single exposure of optimum laser dose (2 J/cm-2) and un-illuminated controls. Classical biophysical parameters such as contraction kinetics, area under the curve and the mean healing time were documented as the assessment parameters to examine the efficacy of multiple exposures with low level laser dose. Experimental findings substantiated that either single or multiple exposures of 0.5 J/cm2 failed to produce any detectable alterations on wound contraction, area under the curve and mean healing time compared to single exposure of optimum dose (2 Jcm-2) and un-illuminated controls. Single exposure of optimum, laser dose was found to be ideal for acute wound healing.

Blockade of the High-Affinity Interleukin-2 Receptors with Daclizumab High-Yield Process: Pharmacokinetic/Pharmacodynamic Analysis of Single- and Multiple-Dose Phase I Trials.

PubMed

Minocha, Mukul; Tran, Jonathan Q; Sheridan, James P; Othman, Ahmed A

2016-01-01

Daclizumab high-yield process (DAC HYP) is a humanized monoclonal antibody that selectively blocks the α-subunit (CD25) of the high-affinity interleukin-2 receptors, and has shown robust efficacy as a treatment for multiple sclerosis (MS). This work quantitatively characterized the relationship between DAC HYP serum concentrations and saturation of CD25 expressed on antigen-rich target T cells in blood. Serial pharmacokinetic and 968 CD25 measurements from three double-blind, randomized, placebo-controlled, phase I studies of DAC HYP (50-300 mg subcutaneous and 200-400 mg intravenous doses or placebo) in healthy volunteers (n = 95) were analyzed using nonlinear mixed-effects modeling. CD25 occupancy was determined using flow cytometry and a fluorescently-labeled DAC HYP-competing antibody. CD25 occupancy was described using a direct inhibitory sigmoidal maximum effect (E max) model (where DAC HYP fully inhibited CD25 labeling with competing antibody). Two IC50 (serum concentration corresponding to 50 % of maximal inhibition) parameters were used to describe rapid CD25 saturation at initiation of dosing and apparently slower desaturation during DAC HYP washout. Parameter estimates (95 % bootstrap confidence intervals) were: baseline CD25 labeling, 47 % (45-48); DAC HYP IC50(saturation), 0.023 µg/mL (0.005-0.073); IC50(desaturation) 0.86 µg/mL (0.74-0.98); Hill coefficient 5.6 (4.3-6.8). Based on the developed model, the 150 mg monthly subcutaneous regimen of DAC HYP in subjects with MS is predicted to saturate CD25 on target effector T cells within a few hours of dosing and maintain CD25 saturation during the entire dosing interval. Free CD25 levels return to baseline within 4-6 months of the last DAC HYP dose.

Intravenous human immunoglobulin for treatment of folliculitis decalvans.

PubMed

Ismail, Nuriah; Ralph, Nicola; Murphy, Gillian

2015-10-01

We report a case of folliculitis decalvans (FD) successfully treated with intravenous human immunoglobulin (HIG). Many conventional treatments with topical agents and oral antibiotics had failed to achieve disease remission, treatment with HIG at a dose of 2 g/kg for the first month, reduced to 1 g/kg for second to fourth months was therefore started, which resulted in rapid improvement and ultimately complete resolution of FD. Clinical improvement was noted after the first infusion of HIG and remission of inflammation was achieved after the fourth infusion. Disease remission was sustained for six months following the last HIG infusion. The exact mechanism of action of HIG is poorly understood. However, it is thought to act as an immunomodulatory agent by altering different components of immune functions. To our knowledge, this is the first case reported in the literature of FD successfully treated with intravenous HIG.

Phase I study of intravenous 4-hydroxyanisole.

PubMed

Rustin, G J; Stratford, M R; Lamont, A; Bleehen, N; Philip, P A; Howells, N; Watfa, R R; Slack, J A

1992-01-01

4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 mumol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.

The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta.

PubMed

Biggin, Andrew; Zheng, Linda; Briody, Julie N; Coorey, Craig P; Munns, Craig F

2015-01-01

Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI. © 2015 S. Karger AG, Basel.

Covariates of intravenous paracetamol pharmacokinetics in adults

PubMed Central

2014-01-01

Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

Impact of intravenous contrast used in computed tomography on radiation dose to carotid arteries and thyroid in intensity-modulated radiation therapy planning for nasopharyngeal carcinoma

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

Lee, Victor Ho Fun, E-mail: vhflee@hku.hk; Ng, Sherry Chor Yi; Kwong, Dora Lai Wan

The aim of this study was to investigate if intravenous contrast injection affected the radiation doses to carotid arteries and thyroid during intensity-modulated radiation therapy (IMRT) planning for nasopharyngeal carcinoma (NPC). Thirty consecutive patients with NPC underwent plain computed tomography (CT) followed by repeated scanning after contrast injection. Carotid arteries (common, external, internal), thyroid, target volumes, and other organs-at-risk (OARs), as well as IMRT planning, were based on contrast-enhanced CT (CE-CT) images. All these structures and the IMRT plans were then copied and transferred to the non–contrast-enhanced CT (NCE-CT) images, and dose calculation without optimization was performed again. The radiationmore » doses to the carotid arteries and the thyroid based on CE-CT and NCE-CT were then compared. Based on CE-CT, no statistical differences, despite minute numeric decreases, were noted in all dosimetric parameters (minimum, maximum, mean, median, D05, and D01) of the target volumes, the OARs, the carotid arteries, and the thyroid compared with NCE-CT. Our results suggested that compared with NCE-CT planning, CE-CT scanning should be performed during IMRT for better target and OAR delineation, without discernible change in radiation doses.« less

Comparison of the pharmacokinetics of imipenem after intravenous and intrathecal administration in rabbits.

PubMed

Wang, Y; Qiu, L; Dong, J; Wang, B; Shi, Z; Liu, B; Wang, W; Zhang, J; Cai, S; Ye, G; Cai, X

2013-03-01

Intrathecal administration of antibiotics has potentially high effectiveness for the treatment for severe intracranial infections, particularly nosocomial meningitis. The use of intrathecal injection of antibiotics has been reported mostly in case reports. However, there is sparse data regarding the pharmacokinetics of antibiotics after intrathecal administration. This study investigated whether intrathecal injection is an effective method for the administration of imipenem. The pharmacokinetics of imipenem after intrathecal and intravenous administration of 1:1 imipenem: cilastatin (IMI/CIL) to rabbits were compared. The AUC0-t in the cerebrospinal fluid for intrathecal administration was approximately twice that of an equal dose of intravenous administration at doses of 0.35, 0.7, and 1.4 mg/kg. Brain concentrations of imipenem after intrathecal injection were three times greater than observed after intravenous injection and remained high for at least 8 hours post-injection. Elimination of imipenem after administration by either route was primarily via urine, but a transient surge of imipenem in bile and intestinal tissue was observed. Results indicate that there is a clinical potential for intrathecally administered IMI/CIL. Further studies are warranted to investigate the potential for seizure and to assess the translatability of the rabbit model to human treatment.

Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons.

PubMed

Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y

2011-05-01

The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.

[Toxicity studies of landiolol hydrochloride (ONO-1101) (2). 4-week repeated dose intravenous toxicity study in rats with 4-week recovery test].

PubMed

Yamaguchi, K; Yanagi, H; Shimizu, K; Sakai, M; Nishibata, K; Oida, H; Shinomiya, K; Suzuki, Y; Yonezawa, H; Fujita, T

1997-12-01

4-week repeated dose toxicity study with 4-week recovery test of landiolol hydrochloride (ONO-1101), a novel ultra short acting beta-blocker, was conducted in Sprague-Dawley (SD) rats. ONO-1101 was administered intravenously to rats of both sexes at a dose level of 0 (control), 12.5, 25, 50 or 100 mg/kg/day. In the 100 mg/kg/day group, bradypnea or dyspnea was seen in all animals, pale in ear, eye and foot, tremor, reddish lacrimation and loss of righting reflex were also observed in some animals right after administration, and then those signs disappeared within 1 min after administration. During the treatment period, 3/20 animals of each sex in the 100 mg/kg/day showed clonic convulsion and died within 2 min after administration. No clinical changes were seen in the 50 mg/kg/day group or lower. Histopathological findings showed atrophy of the submaxillary gland in females and vessel-wall thickening and perivascular fibrosis of the injection site (tail) in both sexes at 100 mg/kg/day, however those changes were reversible. ONO-1101 did not effect on body weight, food consumption, ophthalmology, urinalysis, hematology, blood chemistry, organ weights or necropsy at any doses. These results indicate that the no-adverse-effect level of ONO-1101 in rats is 50 mg/kg/day for both sexes in this study.

Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

PubMed

Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

2016-02-01

Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Multiple Testing, Cumulative Radiation Dose, and Clinical Indications in Patients Undergoing Myocardial Perfusion Imaging

PubMed Central

Einstein, Andrew J.; Weiner, Shepard D.; Bernheim, Adam; Kulon, Michal; Bokhari, Sabahat; Johnson, Lynne L.; Moses, Jeffrey W.; Balter, Stephen

2013-01-01

Context Myocardial perfusion imaging (MPI) is the single medical test with the highest radiation burden to the US population. While many patients undergoing MPI receive repeat MPI testing, or additional procedures involving ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with reasons for testing. Objective To characterize procedure counts, cumulative estimated effective doses of radiation, and clinical indications, for patients undergoing MPI. Design, Setting, Patients Retrospective cohort study evaluating, for 1097 consecutive patients undergoing index MPI during the first 100 days of 2006 at Columbia University Medical Center, all preceding medical imaging procedures involving ionizing radiation undergone beginning October 1988, and all subsequent procedures through June 2008, at that center. Main Outcome Measures Cumulative estimated effective dose of radiation, number of procedures involving radiation, and indications for testing. Results Patients underwent a median (interquartile range, mean) of 15 (6–32, 23.9) procedures involving radiation exposure; 4 (2–8, 6.5) were high-dose (≥3 mSv, i.e. one year's background radiation), including 1 (1–2, 1.8) MPI studies per patient. 31% of patients received cumulative estimated effective dose from all medical sources >100mSv. Multiple MPIs were performed in 39% of patients, for whom cumulative estimated effective dose was 121 (81–189, 149) mSv. Men and whites had higher cumulative estimated effective doses, and there was a trend towards men being more likely to undergo multiple MPIs than women (40.8% vs. 36.6%, Odds ratio 1.29, 95% confidence interval 0.98–1.69). Over 80% of initial and 90% of repeat MPI exams were performed in patients with known cardiac disease or symptoms consistent with it. Conclusion In this institution, multiple testing with MPI was very common, and in many patients associated with very high cumulative

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

PubMed

Funk, Felix; Ryle, Peter; Canclini, Camillo; Neiser, Susann; Geisser, Peter

2010-01-01

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow

Use of Subcutaneous and Intraperitoneal Administration Methods to Facilitate Cassette Dosing in Microdialysis Studies in Rats.

PubMed

Durk, Matthew R; Deshmukh, Gauri; Valle, Nicole; Ding, Xiao; Liederer, Bianca M; Liu, Xingrong

2018-07-01

Microdialysis is a powerful technique allowing for real-time measurement of unbound drug concentrations in brain interstitial fluid in conscious animals. Use of microdialysis in drug discovery is limited by high resource requirement and low throughput, but this may be improved by cassette dosing. Administering multiple compounds intravenously of diverse physiochemical properties, it is often very challenging and time consuming to identify a vehicle that can dissolve all of the compounds. To overcome this limitation, the present study explores the possibility of administering a cassette dose of nine diverse compounds (carbamazepine, citalopram, desmethylclozapine, diphenhydramine, gabapentin, metoclopramide, naltrexone, quinidine, and risperidone) in suspension, rather than in solution, by intraperitoneal and subcutaneous routes, and determining if this is a viable option for assessing blood-brain barrier penetration in microdialysis studies. Repeated hourly subcutaneous dosing during the 6-hour microdialysis study allowed for the best attainment of distributional equilibrium between brain and plasma, resulting in less than a 2-fold difference in the unbound brain to unbound plasma concentration ratio for the cassette dosing method versus discrete dosing. Both subcutaneous and intraperitoneal repeated dosing can provide a more practical substitute for intravenous dosing in determining brain penetration of a cassette of diverse compounds in brain microdialysis studies. The results from the present study demonstrate that dosing compounds in suspension represents a practical approach to eliminating the technical challenge and labor-intensive step of preparation of solutions of a mixture of compounds and will enable the use of the cassette brain microdialysis method in a central nervous system drug discovery setting. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Intravenous immunoglobulin in treatment of cardiac tamponade in a patient with systemic lupus erythematosus.

PubMed

Grenader, Tal; Shavit, Linda

2004-12-01

We describe a 23-year-old female patient with a history of systemic lupus erythematosus and pulmonary hypertension who developed a large pericardial effusion with cardiac tamponade. Invasive interventions such as pericardial window or pericardiectomy were ruled out because of the posterior localization of the effusion and high risk of general anesthesia in a patient with severe pulmonary hypertension. The patient received high-dose steroids intravenously with no response. A 5-day course of intravenous immunoglobulin resulted in gradual decrease of the pericardial effusion and resolution of cardiac tamponade within 2 weeks.

Intravenous vaiproate therapy.

PubMed

Shah, Nilesh; Shenoy, Sujit; Gawde, Pradnya

2003-10-01

Four cases of acute manic episode (bipolar-l disorder), not responding to oral valproate or other mood stabilizer and neuroleptics were given injection valproate intravenously. Three out of 4 patients showed good response and tolerance to intravenous valporate.

Single- and Multiple-dose Pharmacokinetics of a Lorcaserin Extended-release Tablet.

PubMed

Christopher, Ronald; Morgan, Mike; Ferry, Jim; Rege, Bhaskar; Tang, Yong; Kristensen, Allan; Shanahan, William

2016-10-01

Lorcaserin is a serotonin 2C receptor agonist indicated for chronic weight management as an adjunct to diet and exercise. The initial approved formulation is a 10-mg, immediate-release (IR) tablet for administration BID. These studies investigated the single- and multiple-dose pharmacokinetic properties of a new, recently US Food and Drug Administration-approved, extended-release, 20-mg once-daily formulation. We performed 2 separate 2-period, 2-sequence crossover studies in 36 healthy adults: a study comparing the IR formulation to the extended-release formulation under fasting conditions and a study comparing the extended-release formulation under fed and fasted conditions. Compared with lorcaserin IR, the T max after a single dose of lorcaserin extended-release was greater (median, 12 vs 3 hours), and the C max was 26% lower (38.8 vs 52.3 ng/mL). AUC data were bioequivalent for the 2 formulations in both single- and multiple-dose regimens, confirming no formulation effect on lorcaserin bioavailability. In fasted and fed conditions, T max after a single dose was identical (median, 12 hours), but C max was approximately 45% higher in the fed state (mean, 38.5 ng/mL fasted vs 56.1 ng/mL fed). However, at steady state, C max and AUC were determined to be bioequivalent between the fasted and fed states, indicating no clinically relevant food effect on the pharmacokinetic properties of lorcaserin extended-release. The safety profile was consistent between the 2 formulations. Overall, the results indicate that lorcaserin extended-release is a suitable once-daily alternative to the approved IR BID formulation. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Influence of Al³⁺ addition on the flocculation and sedimentation of activated sludge: comparison of single and multiple dosing patterns.

PubMed

Wen, Yue; Zheng, Wanlin; Yang, Yundi; Cao, Asheng; Zhou, Qi

2015-05-15

In this study, the flocculation and sedimentation performance of activated sludge (AS) with single and multiple dosing of trivalent aluminum (Al(3+)) were studied. The AS samples were cultivated in sequencing batch reactors at 22 °C. The dosages of Al(3+) were 0.00, 0.125, 0.5, 1.0, and 1.5 meq/L for single dosing, and 0.1 meq/L for multiple dosing. Under single dosing conditions, as Al(3+) dosage increased, the zeta potential, total interaction energy, and effluent turbidity decreased, whereas the sludge volume index (SVI) increased, indicating that single Al(3+) dosing could enhance sludge flocculation, but deteriorate sedimentation. By comparison, adding an equal amount of Al(3+) through multiple dosing achieved a similar reduction in turbidity, but the zeta potential was higher, while the loosely bound extracellular polymeric substances (LB-EPS) content and SVI remarkably declined. Although the difference in the flocculation performances between the two dosing patterns was not significant, the underlying mechanisms were quite distinct: the interaction energy played a more important role under single dosing conditions, whereas multiple dosing was more effective in reducing the EPS content. Multiple dosing, which allows sufficient time for sludge restructuring and floc aggregation, could simultaneously optimize sludge flocculation and sedimentation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin.

PubMed Central

Richter, C; Schnabel, A; Csernok, E; De Groot, K; Reinhold-Keller, E; Gross, W L

1995-01-01

In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality. PMID:7621588

Intravenous Vaiproate Therapy

PubMed Central

Shah, Nilesh; Shenoy, Sujit; Gawde, Pradnya

2003-01-01

Four cases of acute manic episode (bipolar-l disorder), not responding to oral valproate or other mood stabilizer and neuroleptics were given injection valproate intravenously. Three out of 4 patients showed good response and tolerance to intravenous valporate. PMID:21206868

[Toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (1). Single-dose intravenous toxicity studies in rats and dogs].

PubMed

Yanagi, H; Yamaguchi, K; Shimizu, K; Shichino, Y; Nishiyama, K; Mori, H; Shinomiya, K; Ueda, H; Suzuki, Y; Yonezawa, H; Fujita, T

1998-07-01

Single-dose toxicity studies of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, were conducted in Sprague-Dawley (SD) rats and beagle dogs. The rats of both sexes were administered ONO-5046.Na intravenously at a single dose of 150, 300 or 450 mg/kg. The male dogs were also given ONO-5046.Na at a single dose of 75 or 150 mg/kg. In the rat study, hypoactivity, bradypnea and paleness of limbs and pinna were observed at doses of 300 mg/kg and above. In particular, one of six female rats in the 450 mg/kg group showed clonic convulsion and died. In surviving animals, those signs disappeared within 3 hr after administration. No effect on body weight gain was seen in either group. Necropsy findings showed a slight foamy fluid in the bronchus, hemorrhage at the right knee joint muscle, tendon and lung in a dead animal. In the dog study, no effects on clinical signs, body weight, food consumption and blood biochemistry were seen in any animals of the 75 and 150 mg/kg groups. It is concluded that the approximate lethal doses are 450 mg/kg in rats and 150 mg/kg and above in dogs.

Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication.

PubMed

Ten Broeke, R; Mestrom, E; Woo, L; Kreeftenberg, H

2016-06-01

This case report describes the possible benefit of intravenous lipid emulsion in two patients surviving a severe intoxication with hydroxychloroquine in a dose that was previously considered to be lethal. The first case involves a 25-year-old female who ingested 17.5 grams of hydroxychloroquine, approximately one hour before presentation. An ECG showed QRS widening and the lab results showed hypokalaemia. She became unconscious, and developed hypotension and eventually apnoea. After intubation, supportive care consisted of norepinephrine and supplementation of potassium. Moreover, sodium bicarbonate and intravenous lipid emulsion were started to prevent cardiac toxicity. After these interventions, haemodynamic stability was established within a few hours. Although cardiomyopathy was confirmed, the patient recovered after two weeks. The second case concerns a 25-year-old male who took 5 grams of hydroxychloroquine. At presentation, two hours after intake, he showed QTc prolongation and hypokalaemia. The patient was treated with the usual supportive care and, although presentation to hospital was later, with intravenous lipid emulsion. Also this patient recovered. In conclusion, these cases show the benefit of supplemental intravenous lipid emulsion to prevent cardiac toxicity after a severe intoxication with hydroxychloroquine.

Pharmacokinetics, metabolism and urinary detection time of flunixin after intravenous administration in camels.

PubMed

Wasfi, I A; Boni, N S; Abdel Hadi, A; Elghazali, M; Zorob, O; Alkatheeri, N A; Barezaiq, I M

1998-06-01

The pharmacokinetics of flunixin were determined after an intravenous dose of 1.1 mg/kg body weight in six camels and 2.2 mg/kg body weight in four camels. The data obtained (mean +/- SEM) for the low and high dose, respectively, were as follows: The elimination half-lives (t1/2 beta) were 3.76 +/- 0.24 and 4.08 +/- 0.49 h, the steady state volumes of distribution (Vdss) were 320.61 +/- 38.53 and 348.84 +/- 35.36 mL/kg body weight, total body clearances (ClT) were 88.96 +/- 6.63 and 84.86 +/- 4.95 mL/h/kg body weight and renal clearances (Clr) were 0.52 +/- 0.09 and 0.62 +/- 0.18 mL/h/kg body weight. A hydroxylated metabolite of flunixin was identified by gas chromatography/mass spectrometry (GC/MS) under electron and chemical ionization and its major fragmentation pattern was verified by tandem mass spectrometry (GC/MS/MS) using neutral loss, daughter and parent scan modes. The detection times for flunixin and its hydroxylated metabolite in urine after an intravenous (i.v.) dose of 2.2 mg/kg body weight were 96 and 48 h, respectively.

Intravenous flurbiprofen axetil can increase analgesic effect in refractory cancer pain

PubMed Central

Wu, Hongyang; Chen, Zhendong; Sun, Guoping; Gu, Kangsheng; Pan, Yueyin; Hao, Jiqing; Du, Yingying; Ning, Jie

2009-01-01

Background The aim of this study was to investigate the analgesic effects of intravenous flurbiprofen axetil for the refractory pain in cancer patients. Methods 2109 patients were screened from the department of medical oncology, the first affiliated hospital of Anhui medical university in China between October of 2007 and October of 2008. Thirty-seven cases of cancer patients who had bad effect from anaesthetic drugs were received administration of intravenous flurbiprofen axetil with dose of 50 mg/5 ml/day. The pain score was evaluated for pre- and post- treatment by Pain Faces Scale criteria, and the side effects were also observed. Results Intravenous flurbiprofen axetil increased the analgesic effects. The total effective rate was 92%. The side effects, such as abdominal pain, alimentary tract bleeding which were found in using NSAIDs or constipation, nausea, vomit, sleepiness which were found in using opioid drugs did not be found. Conclusion Intravenous flurbiprofen axetil could provide better analgesia effects and few side effects to patients with refractory cancer pain. It could also increase analgesia effects when combining with anesthetic drugs in treatment of moderate or severe pain, especially breakthrough pain, and suit to patients who can not take oral drugs for the reason of constipation and psychosomatic symptoms. PMID:19267934

Dose accumulation of multiple high dose rate prostate brachytherapy treatments in two commercially available image registration systems.

PubMed

Poder, Joel; Yuen, Johnson; Howie, Andrew; Bece, Andrej; Bucci, Joseph

2017-11-01

The purpose of this study was to assess whether deformable image registration (DIR) is required for dose accumulation of multiple high dose rate prostate brachytherapy (HDRPBT) plans treated with the same catheter pattern on two different CT datasets. DIR was applied to 20 HDRPBT patients' planning CT images who received two treatment fractions on sequential days, on two different CT datasets, with the same implant. Quality of DIR in Velocity and MIM image registration systems was assessed by calculating the Dice Similarity Coefficient (DSC) and mean distance to agreement (MDA) for the prostate, urethra and rectum contours. Accumulated doses from each system were then calculated using the same DIR technique and dose volume histogram (DVH) parameters compared to manual addition with no DIR. The average DSC was found to be 0.83 (Velocity) and 0.84 (MIM), 0.80 (Velocity) and 0.80 (MIM), 0.80 (Velocity) and 0.81 (MIM), for the prostate, rectum and urethra contours, respectively. The average difference in calculated DVH parameters between the two systems using dose accumulation was less than 1%, and there was no statistically significant difference found between deformably accumulated doses in the two systems versus manual DVH addition with no DIR. Contour propagation using DIR in velocity and MIM was shown to be at least equivalent to inter-observer contouring variability on CT. The results also indicate that dose accumulation through manual addition of DVH parameters may be sufficient for HDRPBT treatments treated with the same catheter pattern on two different CT datasets. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

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.

Comparative oncology evaluation of intravenous recombinant oncolytic Vesicular Stomatitis Virus therapy in spontaneous canine cancer

PubMed Central

Naik, Shruthi; Galyon, Gina D.; Jenks, Nathan J.; Steele, Michael B.; Miller, Amber C.; Allstadt, Sara D.; Suksanpaisan, Lukkana; Peng, Kah Whye; Federspiel, Mark J.; Russell, Stephen J.; LeBlanc, Amy K.

2017-01-01

Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single shot systemic therapy with a VSV-IFNβ-NIS, a novel recombinant oncolytic Vesicular stomatitis virus (VSV), can induce curative remission in tumor bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNβ-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNβ-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNβ-NIS is well-tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNβ-NIS therapy, and provided preliminary evidence of clinical efficacy, and potential biomarkers that correlate with therapeutic response. PMID:29158470

The shortened infusion time of intravenous ibuprofen part 1: a multicenter, open-label, surveillance trial to evaluate safety and efficacy.

PubMed

Bergese, Sergio D; Candiotti, Keith; Ayad, Sabry S; Soghomonyan, Suren; Gan, Tong J

2015-02-01

The main purpose of the study was to determine the safety profile and efficacy of intravenous ibuprofen administered over 5 to 10 minutes for the treatment of pain or fever in hospitalized patients. Current evidence supports the use of intravenous infusions of ibuprofen to control pain and reduce the opioid requirements associated with surgical pain. Current dosing guidelines recommend that the drug be administered over 30 minutes. However, a more rapid infusion might yield additional benefits. The safety profile and efficacy of a shortened infusion time requires additional study. This was a Phase IV multicenter, open-label, surveillance clinical study. Thirteen clinical centers located in the United States enrolled a total of 150 adult hospitalized patients with pain or fever. Patients experiencing pain received 800 mg intravenous ibuprofen infused over 5 to 10 minutes every 6 hours for up to 24 hours (4 doses) and patients experiencing fever received 400 mg intravenous ibuprofen infused over 5 to 10 minutes every 4 hours for up to 24 hours (6 doses). Vital signs, adverse events, and pain scores were assessed. The exclusion criteria included inadequate intravenous access; patients younger than 18 years of age; history of allergy or hypersensitivity to any component of intravenous ibuprofen, aspirin, or other nonsteroid anti-inflammatory drugs; active hemorrhage or clinically significant bleeding; pregnancy or nursing; and patients in the perioperative period in the setting of coronary artery bypass graft surgery. Adverse events were reported for 43 of 150 patients (29%). The most common adverse events experienced by patients were infusion site pain in 22 of 150 patients (15%) and flatulence (8 of 150 [5%]). Four patients (3%) discontinued the study drug due to infusion-site pain. In the patients experiencing fever, temperature decreased from baseline over 4 hours (mean [SD] reduction of 1.5 [1.25]°F). In patients experiencing pain, patient-reported visual analog

[Influence of iron nanoparticles on cardiac performance and hemodynamics in rabbits after intravenous administration in acute experiment].

PubMed

Doroshenko, A M

2014-01-01

Iron nanoparticles are possessed by high potential in the creation of effective and safe antianemic drugs due to the enhanced biological activity of metal nanoparticles. As a step of intravenous dosage form development the study of short-term effects of iron nanoparticles on the cardiovascular system is important. Dose-dependent changes of systemic hemodynamics' parameters were established in acute experiment on rabbits after several intravenous injections of zero-valent iron nanoparticles solution.

Salicylic acid plasma levels following multiple doses of Norgesic Forte and aspirin.

PubMed

Harrison, L I; Kehe, C R; Goldlust, M B; Kvam, D C; Bianchine, J R

1983-01-01

Plasma salicyclic acid levels from the recommended multiple dose regimen of Norgesic Forte (orphenadrine citrate, aspirin, and caffeine) were compared to those from an equivalent multiple dose regimen of aspirin alone in 24 volunteers. The drugs were administered double-blind so that side effects could also be compared. No statistically significant differences were found between Norgesic Forte and aspirin in peak or trough levels, time to peak level, area under the curve, or mean steady-state level of salicylic acid. Mean steady-state levels averaged 154 +/- 46 (+/- SD) and 152 +/- 49 micrograms/ml on days 5 and 10 following Norgesic Forte versus 161 +/- 49 and 154 +/- 47 micrograms/ml following aspirin. Thus, the aspirin in Norgesic Forte provides an anti-inflammatory amount of salicylic acid equivalent to that of plain aspirin. There was no evidence that the combination of orphenadrine citrate, caffeine, and aspirin in Norgesic Forte caused increased or unusual side effects compared with aspirin alone.

Dose-response characteristics of intravenous ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats.

PubMed

Radford, Kennett D; Park, Thomas Y; Lee, Bong Hyo; Moran, Sean; Osborne, Lisa A; Choi, Kwang H

2017-02-01

Clinicians administer subanesthetic intravenous (IV) ketamine infusions for treatment of refractory depression, chronic pain, and post-traumatic stress disorder in humans. However, ketamine is administered via the subcutaneous (SC) or intraperitoneal (IP) routes to rodents in most pre-clinical research, which may limit translational application. The present study characterized the dose-response of a subanesthetic IV ketamine bolus (2 and 5mg/kg) and 1-h infusion (5, 10, and 20mg/kg/h) on dissociative stereotypy, locomotion, sensorimotor gating, and thermal nociception in male Sprague-Dawley rats. The secondary aim was to measure ketamine and norketamine plasma concentrations following IV ketamine bolus at 1, 20, and 50min and at the conclusion of the 1-h infusion using liquid chromatography/mass spectrometry. The results showed that ketamine bolus and infusions produced dose-dependent dissociative stereotypy. Bolus (2 and 5mg/kg) and 20mg/kg/h infusion increased locomotor activity while 5mg/kg/h infusion decreased locomotor activity. Both 10 and 20mg/kg/h infusions reduced the acoustic startle reflex, while 5mg/kg bolus and 20mg/kg/h infusion impaired pre-pulse inhibition. Ketamine 5mg/kg bolus and the 10 and 20mg/kg/h infusions induced significant and prolonged antinociception to the hotplate test. Plasma concentrations of ketamine decreased quickly after bolus while norketamine levels increased from 1 to 20min and plateaued from 20 to 50min. The peak ketamine plasma concentrations [ng/ml] were similar between 5mg/kg bolus [4100] vs. 20mg/kg/h infusion [3900], and 2mg/kg bolus [1700] vs. 10mg/kg/h infusion [1500]. These results support the findings from previous ketamine injection studies and further validate the feasibility of administering subanesthetic doses of IV ketamine infusion to rats for neuropharmacological studies. Published by Elsevier Inc.

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

PubMed Central

Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; LaCreta, Frank

2013-01-01

Aim Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels – apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily– with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). Results Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ∼3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3–1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. PMID:23451769

Estimation of effective dose and lifetime attributable risk from multiple head CT scans in ventriculoperitoneal shunted children.

PubMed

Aw-Zoretic, J; Seth, D; Katzman, G; Sammet, S

2014-10-01

The purpose of this review is to determine the averaged effective dose and lifetime attributable risk factor from multiple head computed tomography (CT) dose data on children with ventriculoperitoneal shunts (VPS). A total of 422 paediatric head CT exams were found between October 2008 and January 2011 and retrospectively reviewed. The CT dose data was weighted with the latest IRCP 103 conversion factor to obtain the effective dose per study and the averaged effective dose was calculated. Estimates of the lifetime attributable risk were also calculated from the averaged effective dose using a conversion factor from the latest BEIR VII report. Our study found the highest effective doses in neonates and the lowest effective doses were observed in the 10-18 years age group. We estimated a 0.007% potential increase risk in neonates and 0.001% potential increased risk in teenagers over the base risk. Multiple head CTs in children equates to a slight potential increase risk in lifetime attributable risk over the baseline risk for cancer, slightly higher in neonates relative to teenagers. The potential risks versus clinical benefit must be assessed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Randomized equivalence study evaluating the possibility of switching hemodialysis patients receiving subcutaneous human erythropoietin directly to intravenous darbepoetin alfa.

PubMed

Chazot, Charles; Terrat, Jean Claude; Dumoulin, Alexandre; Ang, Kim-Seng; Gassia, Jean Paul; Chedid, Khalil; Maurice, Francois; Canaud, Bernard

2009-02-01

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied. To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis. In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route. Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference -0.5 [90% CI -12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 microg/L in the 3 groups during the whole study, and darbepoetin was well tolerated. This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Pharmacokinetics of intravenous levofloxacin administered at 750 milligrams in obese adults.

PubMed

Cook, Aaron M; Martin, Craig; Adams, Val R; Morehead, R Scott

2011-07-01

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing.

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing.

PubMed

Karaboyas, Angelo; Zee, Jarcy; Morgenstern, Hal; Nolen, Jacqueline G; Hakim, Raymond; Kalantar-Zadeh, Kamyar; Zager, Philip; Pisoni, Ronald L; Port, Friedrich K; Robinson, Bruce M

2015-10-07

Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients' changes in ferritin over time. Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009-2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of these changes in ferritin on health outcomes requires further investigation. Copyright © 2015 by

Understanding the Recent Increase in Ferritin Levels in United States Dialysis Patients: Potential Impact of Changes in Intravenous Iron and Erythropoiesis-Stimulating Agent Dosing

PubMed Central

Zee, Jarcy; Morgenstern, Hal; Nolen, Jacqueline G.; Hakim, Raymond; Kalantar-Zadeh, Kamyar; Zager, Philip; Pisoni, Ronald L.; Port, Friedrich K.; Robinson, Bruce M.

2015-01-01

Background and objectives Anemia management changed substantially among dialysis patients in the United States around the time of implementation of the new Centers for Medicare & Medicaid Services bundled payment system and erythropoiesis-stimulating agent (ESA) label change in 2011. Among these, average ferritin levels increased dramatically and have remained high since; this study sought to gain understanding of this sustained rise in ferritin levels. Design, setting, participants, & measurements Trends in mean ferritin, hemoglobin, IV iron dose, and ESA dose from 2009 to 2013 were examined in 9735 patients from 91 United States Dialysis Outcomes and Practice Patterns Study facilities. Linear mixed models were used to assess the extent to which intravenous (IV) iron and ESA dose accounted for patients’ changes in ferritin over time. Results Mean ESA dose and hemoglobin levels declined throughout the study. Mean IV iron dose increased from 210 mg/mo in 2009–2010 to a peak of 280 mg/mo in 2011, then declined back to 200 mg/mo and remained stable from 2012 to 2013. Mean ferritin increased from 601 ng/ml in the third quarter of 2009 to 887 ng/ml in the first quarter of 2012; models suggest that higher IV iron dosing was a primary determinant during 2011, but lower ESA doses contributed to the sustained high ferritin levels thereafter. In a subset of 17 facilities that decreased IV iron dose in 2011, mean ferritin rose by 120 ng/ml to 764 ng/ml, which appeared to be primarily due to ESA reduction. Together, changes in IV iron and ESA doses accounted for 46% of the increase in ferritin over the study period. Conclusions In contrast to expectations, the rise in average IV iron dose did not persist beyond 2011. The sustained rise in ferritin levels in United States dialysis patients after policy changes in 2011, to average levels well in excess of 800 ng/ml, appeared to be partly due to reductions in ESA dosing and not solely IV iron dosing practices. The effect of

Pharmacokinetics of butafosfan after intravenous and intramuscular administration in piglets.

PubMed

Sun, F; Wang, J; Yang, S; Zhang, S; Shen, J; Xingyuan, C

2017-04-01

The pharmacokinetics and bioavailability of butafosfan in piglets were investigated following intravenous and intramuscular administration at a single dose of 10 mg/kg body weight. Plasma concentration-time data and relevant parameters were best described by noncompartmental analysis after intravenous and intramuscular injection. The data were analyzed through WinNolin 6.3 software. After intravenous administration, the mean pharmacokinetic parameters were determined as T 1/2λz of 3.30 h, Cl of 0.16 L kg/h, AUC of 64.49 ± 15.07 μg h/mL, V ss of 0.81 ± 0.44/kg, and MRT of 1.51 ± 0.27 h. Following intramuscular administration, the C max (28.11 μg/mL) was achieved at T max (0.31 h) with an absolute availability of 74.69%. Other major parameters including AUC and MRT were 48.29 ± 21.67 μg h/mL and 1.74 ± 0.29 h, respectively. © 2016 John Wiley & Sons Ltd.

Elucidating Rifampin’s Inducing and Inhibiting Effects on Glyburide Pharmacokinetics and Blood Glucose in Healthy Volunteers: Unmasking the Differential Effect of Enzyme Induction and Transporter Inhibition for a Drug and Its Primary Metabolite

PubMed Central

Zheng, HX; Huang, Y; Frassetto, LA; Benet, LZ

2013-01-01

The effects of single doses of intravenous ciprofloxacin and rifampin, multiple doses of rifampin, on glyburide exposure and effect on blood glucose levels in 9 healthy volunteers were investigated. The single intravenous dose of rifampin significantly increased the AUCs of glyburide and metabolite. Blood glucose levels dropped significantly in comparison to when glyburide was dosed alone. Multiple doses of rifampin induced liver enzymes leading to a marked decrease in glyburide exposure and in blood glucose measurements. When intravenous rifampin was given after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect, however, relative changes in AUC for glyburide and its hydroxyl metabolite were the same as that seen under non-induced conditions. The studies reported here demonstrate how measurements of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and characterizing enzymatic versus transporter mechanisms. PMID:18843263

Effects of low doses of americium 241 on animals

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

Rudnitskaya, E.I.; Moskalev, Yu.I.

1979-10-01

The long term effects of low doses of americium 241 on dogs and rats were investigated. Americium chloride was administered intravenously to dogs and intraperitoneally to rats in varying doses. The biological radiation effects were determined at autopsy. Survival times were reported.

Comparison of oral and intravenous Ibuprofen for medical closure of patent ductus arteriosus: which one is better?

PubMed

Olukman, Ozgur; Calkavur, Sebnem; Ercan, Gulten; Atlihan, Fusun; Oner, Taliha; Tavli, Vedide; Kultursay, Nilgun

2012-01-01

Intravenous ibuprofen is an expensive drug that is being used currently for treating and preventing patent ductus arteriosus. Although oral ibuprofen is much cheaper, there is limited data published about its safety and efficacy. The aim of this study was to compare two forms of ibuprofen in terms of safety and efficacy in closure of patent ductus arteriosus. This is a single-center retrospective study. Data were collected from patients' files of preterm infants who were hospitalized at the Neonatal Intensive Care Unit of Dr. Behcet Uz Children's Hospital between April 2009 and June 2010. Six hundred sixty infants were evaluated by echocardiography between 24 and 48 postnatal hours. Clinically and hemodynamically significant ductus arteriosus was defined in 66 infants with gestational age less than 32 weeks and birth weight less than 1500 g. Oral or intravenous ibuprofen (loading dose: 10 mg/kg on day 1, followed by maintenance dose: 5 mg/kg on days 2 and 3) was administered. Treatment success was defined as a completely closed duct without reopening on follow-up. Drug-associated renal, gastrointestinal, cerebral, hematological, and metabolic side effects were monitored and compared between treatment groups. Ductal closure rates were 100% and 97.6%, respectively, in the oral and intravenous groups. Hypernatremia was the remarkable side effect in the intravenous group, whereas bronchopulmonary dysplasia and septicemia were prominent in the oral group. No statistically significant difference could be demonstrated between the groups in terms of mortality rates. Oral ibuprofen therapy is as efficacious as intravenous ibuprofen with some concerns about increased sepsis and bronchopulmonary dysplasia incidence. However, comprehensive and large-scale pharmacokinetic studies are required in order to prove this efficacy. On the other hand, intravenous ibuprofen still remains to be the drug of choice for patent ductus arteriosus but only with meticulous control of serum

Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

PubMed

Clark, Robert E; Kuczenski, Ronald; Segal, David S

2007-07-01

Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

Featured Article: Serum [Met5]-enkephalin levels are reduced in multiple sclerosis and restored by low-dose naltrexone.

PubMed

Ludwig, Michael D; Zagon, Ian S; McLaughlin, Patricia J

2017-09-01

Low-dose naltrexone is a widely used off-label therapeutic prescribed for a variety of immune-related disorders. The mechanism underlying low-dose naltrexone's efficacy for fatigue, Crohn's disease, fibromyalgia, and multiple sclerosis is, in part, intermittent blockade of opioid receptors followed by upregulation of endogenous opioids. Short, intermittent blockade by naltrexone specifically blocks the opioid growth factor receptor resulting in biofeedback events that increase production of the endogenous opioid growth factor (OGF) (chemically termed [Met 5 ]-enkephalin) facilitating interactions between opioid growth factor and opioid growth factor receptor that ultimately, result in inhibited cell proliferation. Preclinical studies have reported that enkephalin levels are deficient in animal models of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Our hypothesis is that serum enkephalin levels are diminished in humans with multiple sclerosis and experimental autoimmune encephalomyelitis mice, and that change in serum opioid growth factor levels may serve as a reasonable candidate biomarker for the onset of experimental autoimmune encephalomyelitis and response to therapy. To address this, we designed a two-part study to measure endogenous opioids in multiple sclerosis patients, and to investigate the temporal pattern of decline in serum enkephalin concentrations in mice with chronic progressive experimental autoimmune encephalomyelitis and treated with low-dose naltrexone. For comparison, we investigated whether low-dose naltrexone exposure in normal mice also resulted in altered enkephalin levels. In both animal models, we monitored tactile and heat sensitivity, as well as differential white blood cell counts as indicators of inflammation. Serum [Met 5 ]-enkephalin levels were lower in humans with multiple sclerosis relative to non-multiple sclerosis patients, and low-dose naltrexone restored their levels. In experimental

Contrast agent choice for intravenous coronary angiography

NASA Astrophysics Data System (ADS)

Zeman, H. D.; Siddons, D. P.

1990-05-01

The screening of the general population for coronary artery disease would be practical if a method existed for visualizing the extent of occlusion after an intravenous injection of contrast agent. Measurements performed with monochromatic synchrotron radiation X-rays and an iodine-containing contrast agent at the Stanford Synchrotron Radiation Laboratory have shown that such an intravenous angiography procedure would be possible with an adequately intense monochromatic X-ray source. Because of the size and cost of synchrotron radiation facilities it would be desirable to make the most efficient use of the intensity available, while reducing as much as possible the radiation dose experienced by the patient. By choosing contrast agents containing elements with a higher atomic number than iodine, it is possible to both improve the image quality and reduce the patient radiation dose, while using the same synchrotron radiation source. By using Si monochromator crystals with a small mosaic spread, it is possible to increase the X-ray flux available for imaging by over an order of magnitude, without any changes in the storage ring or wiggler magnet. The most critical imaging task for intravenous coronary angiography utilizing synchrotron radiation X-rays is visualizing a coronary artery through the left ventricle or aorta which also contain contrast agent. Calculations have been made of the signal to noise ratio expected for this imaging task for various contrast agents with atomic numbers between that of iodine and bismuth. The X-ray energy spectrum of the X-17 superconduction wiggler beam line at the National Synchrotron Light Source at Brookhaven National Laboratory has been used for these calculations. Both perfect Si crystals and Si crystals with a small mosaic spread are considered as monochromators. Contrast agents containing Gd or Yb seem to have about the optimal calculated signal to noise ratio. Gd-DTPA is already approved for use as a contrast agent for

The comparison of the diuretic and natriuretic efficacy of continuous and bolus intravenous furosemide in patients with chronic kidney disease.

PubMed

Sanjay, Srinivas; Annigeri, Rajeev A; Seshadri, Rajagopalan; Rao, Budithi Subba; Prakash, Kowdle C; Mani, Muthu Krishna

2008-06-01

To compare natriuretic, kaliuretic, diuretic and free water clearance efficacy of continuous versus bolus intravenous furosemide administration in patients with chronic renal insufficiency. In a prospective randomized cross-over trial, 42 patients of chronic renal insufficiency were randomized to receive the same dose of intravenous furosemide as bolus and continuous infusion. The effects of bolus and intravenous administration of furosemide on the volume of urine, sodium and potassium excretion were assessed. Mean age was 53.6 +/- 14 years and 23 (55%) were male. The mean modification of diet in renal disease glomerular filtration rate was 20.5 +/- 17 mL/min per 1.73 m(2). The urinary excretion of sodium in intravenous bolus and infusion was 98.1 +/- 78 and 114.4 +/- 100 mmol, respectively (P = 0.001). Total urinary volume following bolus and infusion of furosemide was 1064 +/- 627 and 1170 +/- 764 mL, respectively (0.001). The excretion of potassium was similar in bolus (15.8 +/- 16.6) and infusion (14.3 +/- 9) administration (P = 0.11). The fractional excretion of sodium was higher following infusion (16.63 +/- 16.1) than bolus administration (12.87 +/- 9) of furosemide (P = 0.016). Continuous intravenous infusion of furosemide has significantly better natriuretic and diuretic effect than bolus administration of the same dose of the drug in patients with advanced chronic renal insufficiency.

Urinary calculi composed of uric acid, cystine, and mineral salts: differentiation with dual-energy CT at a radiation dose comparable to that of intravenous pyelography.

PubMed

Thomas, Christoph; Heuschmid, Martin; Schilling, David; Ketelsen, Dominik; Tsiflikas, Ilias; Stenzl, Arnulf; Claussen, Claus D; Schlemmer, Heinz-Peter

2010-11-01

To retrospectively evaluate radiation dose, image quality, and the ability to differentiate urinary calculi of differing compositions by using low-dose dual-energy computed tomography (CT). The institutional review board approved this retrospective study; informed consent was waived. A low-dose dual-energy CT protocol (tube voltage and reference effective tube current-time product, 140 kV and 23 mAs and 80 kV and 105 mAs; collimation, 64 × 0.6 mm; pitch, 0.7) for the detection of urinary calculi was implemented into routine clinical care. All patients (n = 112) who were examined with this protocol from July 2008 to August 2009 were included. The composition of urinary calculi was assessed by using commercially available postprocessing software and was compared with results of the reference standard (ex vivo infrared spectroscopy) in 40 patients for whom the reference standard was available. Effective doses were calculated. Image quality was rated subjectively and objectively and was correlated with patient size expressed as body cross-sectional area at the level of acquisition by using Spearman correlation coefficients. One calcified concrement in the distal ureter of an obese patient was mistakenly interpreted as mixed calcified and uric acid. One struvite calculus was falsely interpreted as cystine. All other uric acid, cystine, and calcium-containing calculi were correctly identified by using dual-energy CT. The mean radiation dose was 2.7 mSv. The average image quality was rated as acceptable, with a decrease in image quality in larger patients. Low-dose unenhanced dual-source dual-energy CT can help differentiate between calcified, uric acid, and cystine calculi at a radiation dose comparable to that of conventional intravenous pyelography. Because of decreased image quality in obese patients, only nonobese patients should be examined with this protocol. © RSNA, 2010.

Synthesis and dose interval dependent hepatotoxicity evaluation of intravenously administered polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticle on Wistar rats.

PubMed

Rajan, Balan; Sathish, Shanmugam; Balakumar, Subramanian; Devaki, Thiruvengadam

2015-03-01

Superparamagnetic iron oxide nanoparticles are being used in medical imaging, drug delivery, cancer therapy, and so on. However, there is a direct need to identify any nanotoxicity associated with these nanoparticles. However uncommon, drug-induced liver injury (DILI) is a major health concern that challenges pharmaceutical industry and drug regulatory agencies alike. In this study we have synthesized and evaluated the dose interval dependent hepatotoxicity of polyethylene glycol-8000 coated ultra-small superparamagnetic iron oxide nanoparticles (PUSPIOs). To assess the hepatotoxicity of intravenously injected PUSPIOs, alterations in basic clinical parameters, hematological parameters, hemolysis assay, serum levels of liver marker enzymes, serum and liver lipid peroxidation (LPO) levels, enzymatic antioxidant levels, and finally histology of liver, kidney, spleen, lung, brain, and heart tissues were studied in control and experimental Wistar rat groups over a 30-day period. The results of our study showed a significant increase in the aspartate transaminase (AST) enzyme activity at a dose of 10mg/kg b.w. PUSPIOs twice a week. Besides, alanine transaminase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) enzyme activity showed a slender increase when compared with control experimental groups. A significant increase in the serum and liver LPO levels at a dose of 10mg/kg b.w. PUSPIOs twice a week was also observed. Histological analyses of liver, kidney, spleen, lung, brain and heart tissue samples showed no obvious uncharacteristic changes. In conclusion, PUSPIOs were found to posses excellent biocompatibility and Wistar rats showed much better drug tolerance to the dose of 10mg/kg b.w. per week than the dose of 10mg/kg b.w. twice a week for the period of 30 days. Copyright © 2015 Elsevier B.V. All rights reserved.

Update of a comparative analysis of cost minimization following the introduction of newly available intravenous iron therapies in hospital practice

PubMed Central

Bhandari, Sunil

2011-01-01

Background The clinical need to be able to administer high doses of intravenous iron conveniently as a rapid infusion has been addressed by the recent introduction of ferric carboxymaltose and subsequently iron isomaltoside 1000. Neither requires a test dose. The maximum dose of ferric carboxymaltose is 1000 mg. The maximum dose of iron isomaltoside 1000 is based on 20 mg/kg body weight without a specified ceiling dose, thereby increasing the scope of being able to achieve total iron repletion with a single infusion. This ability to give high doses of iron is important in the context of managing iron deficiency anemia, which is associated with a number of clinical conditions where demands for iron are high. It is also an important component of the strategy as an alternative to blood transfusion. Affordability is a key issue for health services. Recent price changes affecting iron sucrose and ferric carboxymaltose, plus modifications to the manufacturers’ prescribing information, have provoked this update. Methods This study is a comparative analysis of the costs of acquiring and administering the newly available intravenous iron formulations against standard treatments in the hospital setting. The costs include the medication, nursing costs, equipment, and patient transportation. Three dosage levels (600 mg, 1000 mg, and 1600 mg) are considered. Results and conclusion The traditional standard treatments, blood and iron sucrose, cost more than the alternative intravenous iron preparations across the dose spectrum and sensitivities. Low molecular weight iron dextran is the least expensive option at the 1600 mg dose level but has the caveat of a prolonged administration time and requirement for a test dose. At 600 mg and 1000 mg dose levels, both iron isomaltoside 1000 and ferric carboxymaltose are more economical than low molecular weight iron dextran. Iron isomaltoside 1000 is less expensive than ferric carboxymaltose at all dose levels. Newly available iron

The impact of using an intravenous workflow management system (IVWMS) on cost and patient safety.

PubMed

Lin, Alex C; Deng, Yihong; Thaibah, Hilal; Hingl, John; Penm, Jonathan; Ivey, Marianne F; Thomas, Mark

2018-07-01

The aim of this study was to determine the financial costs associated with wasted and missing doses before and after the implementation of an intravenous workflow management system (IVWMS) and to quantify the number and the rate of detected intravenous (IV) preparation errors. A retrospective analysis of the sample hospital information system database was conducted using three months of data before and after the implementation of an IVWMS System (DoseEdge ® ) which uses barcode scanning and photographic technologies to track and verify each step of the preparation process. The financial impact associated with wasted and missing >IV doses was determined by combining drug acquisition, labor, accessory, and disposal costs. The intercepted error reports and pharmacist detected error reports were drawn from the IVWMS to quantify the number of errors by defined error categories. The total number of IV doses prepared before and after the implementation of the IVWMS system were 110,963 and 101,765 doses, respectively. The adoption of the IVWMS significantly reduced the amount of wasted and missing IV doses by 14,176 and 2268 doses, respectively (p < 0.001). The overall cost savings of using the system was $144,019 over 3 months. The total number of errors detected was 1160 (1.14%) after using the IVWMS. The implementation of the IVWMS facilitated workflow changes that led to a positive impact on cost and patient safety. The implementation of the IVWMS increased patient safety by enforcing standard operating procedures and bar code verifications. Published by Elsevier B.V.

Comparative pharmacokinetics study of orientin in rat plasma by UHPLC-MS/MS after intravenous administration of single orientin and Trollius chinensis Bunge extract.

PubMed

Zhao, Nan; Sun, Qi; Song, Yang; Wang, Lin; Zhang, Tingjian; Meng, Fanhao

2018-04-01

Orientin showed a broad array of biological activities, and it is the major bioactive compound in the Trollius chinensis Bunge. The aim of this study was to investigate the comparative pharmacokinetics of orientin after intravenous administration of single orientin and T. chinensis Bunge extract. Sample preparation involved a simple one-step deproteinization procedure with acetonitrile. Chromatographic separation was achieved on a Waters BEH C 18 column with a mobile phase consisting of acetonitrile and water containing 0.1% formic acid in an isocratic elution way. The detection was accomplished in multiple reaction monitoring mode with positive electrospray ionization. The pharmacokinetic properties of orientin were compared after intravenous administrations of pure orientin and T. chinensis Bunge extract to rats with approximately the same dosage of 10 mg/kg. The results of the study indicate that the pharmacokinetics of orientin in rat plasma show significant differences between two groups. This is useful for the clinical uses of therapeutic dosing of orientin and T. chinensis Bunge. Copyright © 2017 John Wiley & Sons, Ltd.

Scurvy in an alcoholic patient treated with intravenous vitamins

PubMed Central

Ong, John; Randhawa, Rabinder

2014-01-01

Vitamin C deficiency is rare in developed countries but there is an increased prevalence in chronic alcohol abusers. In the UK, it is common practice to treat patients with chronic alcoholism who are admitted to hospital with intravenous vitamins B1, B2, B3, B6 and C for 2–3 days, followed by oral thiamine and vitamin B-compound tablets. This is a case of a 57-year-old man with a history of chronic alcoholism and chronic obstructive lung disease who was admitted to the intensive care unit for pneumonia requiring ventilatory support. He was given high doses of intravenous vitamins B1, B2, B3, B6 and C for 3 days then oral thiamine and vitamin B compound tablets but developed scurvy 4 days later. He was restarted on oral vitamin C supplementation and showed signs of improvement within 3 days of treatment. PMID:24728889

Pharmacokinetics of doxycycline in laying hens after intravenous and oral administration.

PubMed

Yang, F; Si, H B; Wang, Y Q; Zhao, Z S; Zhou, B H; Hao, X Q

2016-08-01

The pharmacokinetics of doxycycline in laying hens was investigated after a single intravenous (IV) or an oral (PO) dose at 20 mg/kg body weight. The concentrations of doxycycline in plasma samples were determined by high-performance liquid chromatography with an ultraviolet detector, and pharmacokinetic parameters were calculated using a compartmental model method. The disposition of doxycycline after one single IV injection was best described by a two-compartment open model and the main pharmacokinetic parameters were as follows: volume of distribution (Vd) was 865.15 ± 127.64 ml/kg, distribution rate constant (α) was (2.28 ± 0.38) 1/h, elimination rate constant (β) was 0.08 ± 0.02 1/h and total body clearance (Cl) was104.11 ± 18.32 ml/h/kg, while after PO administration, the concentration versus time curve was best described by a one-compartment open model and absorption rate constant (Ka), peak concentration (Cmax), time to reach Cmax (tmax) and absolute bioavailability (F) were 2.55 ± 1.40 1/h, 5.88 ± 0.70 μg/ml, 1.73 ± 0.75 h and 52.33%, respectively. The profile of doxycycline exhibited favourable pharmacokinetic characteristics in laying hens, such as quick absorption and slow distribution and elimination, though oral bioavailability was relatively low. A multiple-dosing regimen (a dose of 20 mg/kg/d for 3 consecutive days) of doxycycline was recommended to treat infections in laying hens. But a further study should be conducted to determine the withdrawal time of doxycycline in eggs.

First administration to man of Org 25435, an intravenous anaesthetic: A Phase 1 Clinical Trial.

PubMed

Rigby-Jones, Ann E; Sneyd, J Robert; Vijn, Peter; Boen, Patrick; Cross, Maurice

2010-06-29

Org 25435 is a new water-soluble alpha-amino acid ester intravenous anaesthetic which proved satisfactory in animal studies. This study aimed to assess the safety, tolerability and efficacy of Org 25435 and to obtain preliminary pharmacodynamic and pharmacokinetic data. In the Short Infusion study 8 healthy male volunteers received a 1 minute infusion of 0.25, 0.5, 1.0, or 2.0 mg/kg (n = 2 per group); a further 10 received 3.0 mg/kg (n = 5) or 4.0 mg/kg (n = 5). Following preliminary pharmacokinetic modelling 7 subjects received a titrated 30 minute Target Controlled Infusion (TCI), total dose 5.8-20 mg/kg. Within the Short Infusion study, all subjects were successfully anaesthetised at 3 and 4 mg/kg. Within the TCI study 5 subjects were anaesthetised and 2 showed signs of sedation. Org 25435 caused hypotension and tachycardia at doses over 2 mg/kg. Recovery from anaesthesia after a 30 min administration of Org 25435 was slow (13.7 min). Pharmacokinetic modelling suggests that the context sensitive half-time of Org 25435 is slightly shorter than that of propofol in infusions up to 20 minutes but progressively longer thereafter. Org 25435 is an effective intravenous anaesthetic in man at doses of 3 and 4 mg/kg given over 1 minute. Longer infusions can maintain anaesthesia but recovery is slow. Hypotension and tachycardia during anaesthesia and slow recovery of consciousness after cessation of drug administration suggest this compound has no advantages over currently available intravenous anaesthetics.

PUNISHING AND CARDIOVASCULAR EFFECTS OF INTRAVENOUS HISTAMINE IN RATS: PHARMACOLOGICAL SELECTIVITY

PubMed Central

Podlesnik, Christopher A.; Jimenez-Gomez, Corina

2014-01-01

Although drugs may serve as reinforcers or punishers of operant behavior, the punishing function has received much less experimental attention than the reinforcing function. A sensitive method for studying drug-induced punishment is to assess choice for a punished response over an unpunished response. In these experiments, rats chose between pressing one lever and receiving a sucrose pellet or pressing another lever and receiving a sucrose pellet plus an intravenous injection of histamine. When sucrose was delivered equally frequently for either the punished or the unpunished response, rats selected the unpunished lever consistently, but decreases in the punished response did not differ as a function of intravenous histamine dose (0.1–1 mg/kg/inj). Changing the procedure so that sucrose was delivered on the unpunished lever with p = .5 increased the rats’ responding on the punished lever with saline injections. In addition, the same range of histamine doses produced a much larger range of responses on the punished lever that was dose dependent. Using these procedures to assess the receptors mediating histamine’s effects, the histamine H1-receptor antagonists, pyrilamine and ketotifen, antagonized the punishing effect of histamine, but the histamine H2-receptor antagonist ranitidine did not. However, ranitidine pretreatments reduced histamine-induced heart-rate increases to a greater extent than did the histamine H1-receptor antagonists when administered at the same doses examined under conditions of histamine punishment. Overall, the present findings extend the general hypothesis that activation of histamine H1-receptors mediates the punishing effects of histamine. They also introduce methods for rapidly assessing pharmacological mechanisms underlying drug-induced punishment. PMID:23982898

A reliable model of intravenous MDMA self-administration in naïve mice.

PubMed

Trigo, José Manuel; Panayi, Fany; Soria, Guadalupe; Maldonado, Rafael; Robledo, Patricia

2006-01-01

MDMA is one of the most widely consumed recreational drugs in Europe. However, the mechanisms involved in the reinforcing properties of MDMA are still unclear. In this sense, the establishment of a reliable model of MDMA self-administration in mice could represent an important approach to study the neuronal substrates associated with MDMA reward by using genetically modified mice. To develop a reliable model of operant intravenous MDMA self-administration in drug-naïve mice. Mice were trained to acquire intravenous self-administration of MDMA at different doses (0, 0.06, 0.125, 0.25, 0.5 and 1.0 mg/kg/infusion) on a FR1 schedule of reinforcement for 15 consecutive days. The motivational value of different doses of MDMA (0.125, 0.25 and 0.5 mg/kg/infusion) was then tested using a progressive ratio paradigm. Finally, [3H]-mazindol autoradiographic studies were carried out in order to quantitatively assess presynaptic dopamine transporter (DAT) binding sites in the striatum of mice trained to self-administer MDMA (0 and 1.0 mg/kg/infusion) during 15 days. The latency for discrimination between the active and inactive holes, as well as the number of animals acquiring stability criteria, varied as a function of the dose of MDMA. The mice responding for intermediate doses (0.125, 0.25 and 0.5 mg/kg/infusion) discriminated earlier than those responding for low (0.06 mg/kg/infusion) or high (1.0 mg/kg/infusion) doses. The percentage of animals achieving stability criteria increased with days of testing and was inversely proportional to the dose of MDMA. The breaking points achieved for doses of 0.125 and 0.25 mg/kg/infusion were significantly higher than for a dose of 0.5 mg/kg/infusion. No significant DAT neurotoxicity was observed in the striatum of animals self-administering MDMA at a dose of 1 mg/kg/infusion. The present results show that MDMA can be reliably self-administered by drug-naïve mice.

A randomized, double-blinded, controlled trial of the effects of fluid rate and/or presence of dextrose in intravenous fluids on the labor course of nulliparas.

PubMed

Fong, Alex; Serra, Allison E; Caballero, Deysi; Garite, Thomas J; Shrivastava, Vineet K

2017-08-01

Prolonged labor has been demonstrated to increase adverse maternal and neonatal outcome. A practice that may decrease the risk of prolonged labor is the modification of fluid intake during labor. Several studies demonstrated that increased hydration in labor as well as addition of dextrose-containing fluids may be associated with a decrease in length of labor. The purpose of our study was to characterize whether high-dose intravenous fluids, standard-dose fluids with dextrose, or high-dose fluids with dextrose show a difference in the duration of labor in nulliparas. Nulliparous subjects with singletons who presented in active labor were randomized to 1 of 3 groups of intravenous fluids: 250 mL/h of normal saline, 125 mL/h of 5% dextrose in normal saline, or 250 mL/h of 2.5% dextrose in normal saline. The primary outcome was total length of labor from initiation of intravenous fluid in vaginally delivered subjects. Secondary outcomes included cesarean delivery rate and length of second stage of labor, among other maternal and neonatal outcomes. In all, 274 subjects who met inclusion criteria were enrolled. There were no differences in baseline characteristics among the 3 groups. There was no difference in the primary outcome of total length of labor in vaginally delivered subjects among the 3 groups. First stage of labor duration, second stage of labor duration, and cesarean delivery rates were also equivalent. There were no differences identified in other secondary outcomes including clinical chorioamnionitis, postpartum hemorrhage, blood loss, Apgar scores, or neonatal intensive care admission. There is no difference in length of labor or delivery outcomes when comparing high-dose intravenous fluids, addition of dextrose, or use of high-dose intravenous fluids with dextrose in nulliparous women who present in active labor. Copyright © 2017 Elsevier Inc. All rights reserved.

Safety and pharmacokinetics of oral cannabidiol when administered concomitantly with intravenous fentanyl in humans

PubMed Central

Manini, Alex F.; Yiannoulos, Georgia; Bergamaschi, Mateus M.; Hernandez, Stephanie; Olmedo, Ruben; Barnes, Allan J.; Winkel, Gary; Sinha, Rajita; Jutras-Aswad, Didier; Huestis, Marilyn A.; Hurd, Yasmin L.

2015-01-01

Objectives Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects. Methods This double-blind, placebo-controlled cross-over study of CBD co-administered with intravenous fentanyl, was conducted at the Clinical Research Center in Mount Sinai Hospital, a tertiary care medical center in New York City. Participants were healthy volunteers aged 21–65 years with prior opioid exposure, regardless of route. Blood samples were obtained before and after 400 or 800 mg CBD pretreatment, followed by a single 0.5 (Session 1) or 1.0mcg/Kg (Session 2) intravenous fentanyl dose. The primary outcome was the Systematic Assessment for Treatment Emergent Events (SAFTEE) to assess safety and adverse effects. CBD peak plasma concentrations, time to reach peak plasma concentrations (tmax), and area under the curve (AUC) were measured. Results SAFTEE data were similar between groups without respiratory depression or cardiovascular complications during any test session. Following low dose CBD, tmax occurred at 3 and 1.5h (Sessions 1 and 2, respectively). Following high dose CBD, tmax occurred at 3 and 4h in Sessions 1 and 2, respectively. There were no significant differences in plasma CBD or cortisol (AUC p=NS) between sessions. Conclusions CBD does not exacerbate adverse effects associated with intravenous fentanyl administration. Co-administration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse. PMID:25748562

Anaphylaxis following intravenous ranitidine: a rare adverse reaction of a common drug.

PubMed

Chopra, Deepti; Arora, Pooja; Khan, Shamimullah; Dwivedi, Shridhar

2014-01-01

Ranitidine hydrochloride is a widely used drug that is generally well-tolerated. Anaphylaxis is rarely observed with ranitidine. We report a case who developed severe anaphylaxis following single dose of intravenous ranitidine. The article highlights the importance of recognition of this serious adverse event and re-emphasizes the need for cautious use of drugs, especially in those with known history of allergy.

Pharmacokinetics of Intravenous Levofloxacin Administered at 750 Milligrams in Obese Adults ▿

PubMed Central

Cook, Aaron M.; Martin, Craig; Adams, Val R.; Morehead, R. Scott

2011-01-01

The physiochemical properties of levofloxacin suggest that it is an agent which may exhibit altered pharmacokinetics in obese individuals. The purpose of this study was to describe the pharmacokinetics of a single 750-mg intravenous dose of levofloxacin in both hospitalized and ambulatory obese individuals. The hypothesis was that a standard dose of levofloxacin in obese individuals would achieve serum concentrations likely to be therapeutic. A single levofloxacin dose of 750 mg was infused over 90 min, and seven serial serum samples were subsequently obtained to evaluate the pharmacokinetics after the first dose. The peak concentrations of levofloxacin were comparable to those seen with normal-weight individuals. However, the area under the concentration-time curve and clearance were quite variable. Accelerated clearance was evident in the ambulatory obese individuals. Further investigation of the effects of obesity on the pharmacokinetics of levofloxacin is necessary to ensure optimal dosing. PMID:21576432

The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.

PubMed

Honkavaara, J M; Restitutti, F; Raekallio, M R; Kuusela, E K; Vainio, O M

2011-08-01

Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 μg/kg [D]), MK-467 (250 μg/kg [M250] or dexmedetomidine (10 μg/kg) with increasing doses of MK-467 (250 μg/kg [DM250], 500 μg/kg [DM500] and 750 μg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidine's systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function. © 2010 Blackwell Publishing Ltd.

Pilocarpine disposition and salivary flow responses following intravenous administration to dogs.

PubMed

Weaver, M L; Tanzer, J M; Kramer, P A

1992-08-01

Oral doses of pilocarpine increase salivary flow rates in patients afflicted with xerostomia (dry mouth). This study examined the pharmacokinetics of and a pharmacodynamic response (salivation) to intravenous pilocarpine nitrate administration in dogs. Disposition was linear over a dose range of 225-600 micrograms/kg; plasma concentrations were 10-120 micrograms/L. Elimination was rapid and generally biphasic, with a terminal elimination half-life of approximately 1.3 hr. The systemic clearance of pilocarpine was high (2.22 +/- 0.49 L/kg/hr) and its steady-state volume of distribution (2.30 +/- 0.64 L/kg) was comparable to that of many other basic drugs. All doses of pilocarpine induced measurable submaxillary and parotid salivary flow rates which could be maintained constant over time. Cumulative submaxillary saliva flow was linearly related to total pilocarpine dose. Plasma pilocarpine concentration was linearly related to both steady-state and postinfusion submaxillary salivary flow rates.

Cost-effectiveness of oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin in the emergency department.

PubMed

Rudis, Maria I; Touchette, Daniel R; Swadron, Stuart P; Chiu, Amy P; Orlinsky, Michael

2004-03-01

Oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin are all commonly used for loading phenytoin in the emergency department (ED). The cost-effectiveness of each was compared for patients presenting with seizures and subtherapeutic phenytoin concentrations. A simple decision tree was developed to determine the treatment costs associated with each of 3 loading techniques. We determined effectiveness by comparing adverse event rates and by calculating the time to safe ED discharge. Time to safe ED discharge was defined as the time at which therapeutic concentrations of phenytoin (>or=10 mg/L) were achieved with an absence of any adverse events that precluded discharge. The comparative cost-effectiveness of alternatives to oral phenytoin was determined by combining net costs and number of adverse events, expressed as cost per adverse events avoided. Cost-effectiveness was also determined by comparing the net costs of each loading technique required to achieve the time to safe ED discharge, expressed as cost per hour of ED time saved. The outcomes and costs were primarily derived from a prospective, randomized controlled trial, augmented by time-motion studies and alternate-cost sources. Costs included the cost of drugs, supplies, and personnel. Analyses were also performed in scenarios incorporating labor costs and savings from using a lower-urgency area of the ED. The mean number of adverse events per patient for oral phenytoin, intravenous phenytoin, and intravenous fosphenytoin was 1.06, 1.93, and 2.13, respectively. Mean time to safe ED discharge in the 3 groups was 6.4 hours, 1.7 hours, and 1.3 hours. Cost per patient was 2.83 dollars, 21.16 dollars, and 175.19 dollars, respectively, and did not differ substantially in the Labor and Triage (lower-urgency area of ED) scenarios. When the measure of effectiveness was adverse events, oral phenytoin dominated intravenous phenytoin and intravenous fosphenytoin, with a lower cost and number of adverse

Role of Intravenous Ferric Carboxy-maltose in Pregnant Women with Iron Deficiency Anaemia.

PubMed

Mishra, Vineet; Gandhi, Khusaili; Roy, Priyankur; Hokabaj, Shaheen; Shah, Kunur N

2017-09-08

Iron deficiency is a common nutritional deficiency amongst women of childbearing age. Peri-partum iron deficiency anaemia is associated with significant maternal, foetal and infant morbidity. Current options for treatment include oral iron, which can be ineffective and poorly tolerated, and red blood cell transfusions, which carry an inherent risk and should be avoided. Ferric carboxymaltose is a modern treatment option. The study was designed to assess the safety and efficacy of intravenous ferric carboxymaltose for correction of iron deficiency anaemia in pregnant women. A prospective study was conducted at Institute of Kidney Disease and Research Centre, Ahmedabad from January 2014 to December 2016. Antenatal women (108) with iron deficiency anaemia were the study subjects. Socio-demographic profile was recorded and anaemia was assessed based on recent haemoglobin reports. Iron deficiency was diagnosed on basis of serum ferritin value. Intravenous ferric carboxymaltose as per total correction dose (maximum 1500mg) was administered to all women; the improvement in haemoglobin levels were assessed after 3 weeks of total dose infusion. Most of the women(n= 45, 41.7%), were in the age group of 27-30 years. Most of the women (n = 64, 59.3%) had moderate anaemia as per WHO guidelines. Mean haemoglobin levels significantly increased over a period of 3 weeks after Ferric carboxymaltose administrationand no serious life threatening adverse events were observed. Intravenous ferric carboxymaltose was safe and effective in pregnent women with iron deficiency anaemia.

Home intravenous therapy: Part I--Issues.

PubMed

McAbee, R R; Grupp, K; Horn, B

1991-01-01

Concerns related to providing home intravenous therapy were among the top ten clinical problems identified by Northwest Medicare-certified home care agencies in a 1986 survey. This paper addresses issues related to home intravenous therapy and provides lists of resources for the development of home intravenous therapy programs. Part I of the paper covers concerns related to intravenous therapy as expressed by home care agencies in the Northwest and synthesized the literature about home intravenous therapies. Survey results are presented, followed by a discussion of client and caregiver concerns. These include: discharge planning, client admission criteria and client and caregiver education. Standards, staffing, and staff education issues are discussed followed by sections on economics, marketing regulations and legal and ethical concerns. Finally, there is a discussion of issues related to specific types of intravenous therapies: parenteral nutrition, antibiotic therapy; chemotherapy; blood and blood component therapy and other less frequently used types of intravenous therapies. Each therapy is discussed with regard to complications, client and caregiver instruction and financial considerations. Part II of the paper is a resource guide which lists resources that agencies may use to develop a home intravenous therapy program. In the first section, national organizations and journals and books concerned with intravenous therapy are listed as well as journal articles, guidelines and guidebooks and client and provider educational materials. National and regional product and service representatives of intravenous therapy related companies are also listed. In the second section, addresses for the State Boards of Nursing are given for Alaska, Idaho, Montana, Oregon and Washington. Each state section includes a list of those agencies who indicated in the 1988 survey that they would be willing to share materials. In addition, product and service vendors of intravenous

Intravenously injected human multilineage-differentiating stress-enduring cells selectively engraft into mouse aortic aneurysms and attenuate dilatation by differentiating into multiple cell types.

PubMed

Hosoyama, Katsuhiro; Wakao, Shohei; Kushida, Yoshihiro; Ogura, Fumitaka; Maeda, Kay; Adachi, Osamu; Kawamoto, Shunsuke; Dezawa, Mari; Saiki, Yoshikatsu

2018-06-01

Aortic aneurysms result from the degradation of multiple components represented by endothelial cells, vascular smooth muscle cells, and elastic fibers. Cells that can replenish these components are desirable for cell-based therapy. Intravenously injected multilineage-differentiating stress-enduring (Muse) cells, endogenous nontumorigenic pluripotent-like stem cells, reportedly integrate into the damaged site and repair the tissue through spontaneous differentiation into tissue-compatible cells. We evaluated the therapeutic efficacy of Muse cells in a murine aortic aneurysm model. Human bone marrow Muse cells, isolated as stage-specific embryonic antigen-3 + from bone marrow mesenchymal stem cells, or non-Muse cells (stage-specific embryonic antigen-3 - cells in mesenchymal stem cells), bone marrow mesenchymal stem cells, or vehicle was intravenously injected at day 0, day 7, and 2 weeks (20,000 cells/injection) after inducing aortic aneurysms by periaortic incubation of CaCl 2 and elastase in severe combined immunodeficient mice. At 8 weeks, infusion of human Muse cells attenuated aneurysm dilation, and the aneurysmal size in the Muse group corresponded to approximately 62.5%, 55.6%, and 45.6% in the non-Muse, mesenchymal stem cell, and vehicle groups, respectively. Multiphoton laser confocal microscopy revealed that infused Muse cells migrated into aneurysmal tissue from the adventitial side and penetrated toward the luminal side. Histologic analysis demonstrated robust preservation of elastic fibers and spontaneous differentiation into endothelial cells and vascular smooth muscle cells. After intravenous injection, Muse cells homed and expanded to the aneurysm from the adventitial side. Subsequently, Muse cells differentiated spontaneously into vascular smooth muscle cells and endothelial cells, and elastic fibers were preserved. These Muse cell features together led to substantial attenuation of aneurysmal dilation. Copyright © 2018 The American Association

Administration costs of intravenous biologic drugs for rheumatoid arthritis.

PubMed

Soini, Erkki J; Leussu, Miina; Hallinen, Taru

2013-01-01

Cost-effectiveness studies explicitly reporting infusion times, drug-specific administration costs for infusions or real-payer intravenous drug cost are few in number. Yet, administration costs for infusions are needed in the health economic evaluations assessing intravenously-administered drugs. To estimate the drug-specific administration and total cost of biologic intravenous rheumatoid arthritis (RA) drugs in the adult population and to compare the obtained costs with published cost estimates. Cost price data for the infusions and drugs were systematically collected from the 2011 Finnish price lists. All Finnish hospitals with available price lists were included. Drug administration and total costs (administration cost + drug price) per infusion were analysed separately from the public health care payer's perspective. Further adjustments for drug brand, dose, and hospital type were done using regression methods in order to improve the comparability between drugs. Annual expected drug administration and total costs were estimated. A literature search not limited to RA was performed to obtain the per infusion administration cost estimates used in publications. The published costs were converted to Finnish values using base-year purchasing power parities and indexing to the year 2011. Information from 19 (95%) health districts was obtained (107 analysable prices out of 176 observations). The average drug administration cost for infliximab, rituximab, abatacept, and tocilizumab infusion in RA were €355.91; €561.21; €334.00; and €293.96, respectively. The regression-adjusted (dose, hospital type; using semi-log ordinary least squares) mean administration costs for infliximab and rituximab infusions in RA were €289.12 (95% CI €222.61-375.48) and €542.28 (95% CI €307.23-957.09). The respective expected annual drug administration costs were €2312.96 for infliximab during the first year, €1879.28 for infliximab during the forthcoming years, and �

[Use of intravenous iron infusion in a gastroenterology day hospital: Indications, dosage and adverse effects].

PubMed

Dosal, Angelina; Calvet, Xavier; Moreno, Laura; López, María; Figuerola, Ariadna; Ruíz, Miquel Angel; Suárez, David; Gené, Emili; Miquel, Mireia; Villoria, Albert

2010-01-01

There are no data in the literature on the use of intravenous iron infusion in gastroenterology day hospitals. To determine the indications, dosage and tolerance of intravenous iron infusion in outpatients attending a gastroenterology day hospital. We retrospectively reviewed the medical records of patients who received intravenous iron infusion between August 2007 and July 2008. The indications, dosage, transfusion requirements, adverse effects and patients' clinical and laboratory data were recorded. During the study period, 111 patients (41% women, with a mean age of 63.8 ± 18 years) received intravenous iron infusions. The main causes of anemia indicating iron administration were portal hypertensive gastropathy (n=55), inflammatory bowel disease (n=22) and intestinal angiodysplasia (n=12). The patients received a total of 557 iron infusions with a mean dose of 1033 mg iron per patient. There were no adverse effects. Despite the treatment, 46 patients required transfusion. Iron and transfusion requirements and mortality were significantly higher in patients with liver cirrhosis than in the remainder of the study group. Intravenous iron therapy is frequently used in the gastroenterology day hospital. Most infusions were administered in patients with chronic iron loss. Patients with liver cirrhosis had the most severe anemia and underlying disease and the highest mortality.

Distribution of creatinine following intravenous and oral administration to rats.

PubMed

Watanabe, J; Hirate, J; Iwamoto, K; Ozeki, S

1981-05-01

To evaluate the distribution of creatinine in rats, urinary, fecal and expiratory excretion, plasma levels and whole-body autoradiography following intravenous or oral administration of [carbonyl-14C]creatinine was investigated. More than 90% of the exogeneous creatinine was excreted in the urine in 24 hr following intravenous administration, and both fecal and expiratory excretion were only about 1%. In case of oral administration, however, it was found that expiratory excretion could not be neglected, ranging from about 1 to 30%. Plasma creatinine concentration-time curves following the intravenous administration (70.4 micrograms/kg or 400 mg/kg as creatinine) were analyzed according to a two-compartment open model. There were significant but very small differences in the pharmacokinetic parameters for these two doses. When these parameters were compared with those of urea, k12 and k21, which are transfer rate constants between compartment 1 and 2, for creatinine were significantly smaller than those of urea. On the other hand, k10 was larger in creatinine. Furthermore, (V'd)extrap for creatinine was about three times that of urea. Whole-body autoradiograms at 5 minutes following intravenous administration showed that exogeneous creatinine distributes with higher concentrations in liver, lung and kidney than in muscle and fat. This results was remarkably different from that of urea which distributes almost uniformly throughout the body at the same time. This difference observed in the autoradiograms would be the consequence of the fact that urea has larger k12 and k21 than creatinine.

Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose.

PubMed

Jiménez-Juan, Laura; Nguyen, Elsie T; Wintersperger, Bernd J; Moshonov, Hadas; Crean, Andrew M; Deva, Djeven P; Paul, Narinder S; Torres, Felipe S

2013-01-01

The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR ≥ 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1-2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 ± 4.5 bpm vs. 69.6 ± 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 ± 3.9 bpm vs. 67.4 ± 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 ± 2.9 vs. 6.1 ± 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality.

Multiple oral dosing of ketoconazole increases dog exposure to ivermectin.

PubMed

Hugnet, Christophe; Lespine, Anne; Alvinerie, Michel

2007-01-01

The parasiticide ivermectin and the antimicrobial drug ketoconazole are macrolides that interact with P-glycoprotein. We investigated the effects of ketoconazole at a clinical dose on the pharmacokinetics of ivermectin, a CYP3A substrate with low hepatic clearance. Beagle dogs received a single subcutaneous injection of ivermectin at 0.05 mg/kg alone (n=6) or in combination with a daily oral dose of ketoconazole 10 mg/kg over 5 days before and after ivermectin administration (n=6). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis. Co-administered ketoconazole induced a higher plasma concentration and longer residence time of ivermectin in dogs, leading to a substantial increase in the overall exposure of the animal to the drug. Ketoconazole does not interfere with the production of the ivermectin metabolite but it may rather inhibit the elimination of the parental drug by interfering with P-gp transport. Multiple oral dosing of ketoconazole dramatically altered the pharmacokinetics of ivermectin in dogs leading to an increase in systemic exposure to the drug. Neurotoxicity of ivermectin means that inhibition of the P-gp function at the blood-brain barrier during polytherapy using P-gp inhibitors must be taken into consideration.

Oral and Intravenous Fumonisin Exposure in Pigs—A Single-Dose Treatment Experiment Evaluating Toxicokinetics and Detoxification

PubMed Central

Schertz, Hanna; Kluess, Jeannette; Frahm, Jana; Schatzmayr, Dian; Dohnal, Ilse; Bichl, Gerlinde; Schwartz-Zimmermann, Heidi; Breves, Gerhard; Dänicke, Sven

2018-01-01

We examined the toxicokinetics of fumonisin B1 (FB1) and its main metabolites after single dose application intravenously (iv) of 139 nmol FB1 or hydrolyzed FB1 (HFB1)/kg bodyweight (BW) in barrows (BW: 34.4 kg ± 2.7 kg), as well as the toxicokinetics of FB1, FB2, FB3 and FB1 bioavailability from oral exposure (3425 nmol FB1/kg BW, on top of ration). Additionally, detoxification efficacy of FumD (240 U/kg feed; 3321 nmol FB1/kg BW), a fumonisin esterase, was examined for oral fumonisin application. Urine and feces were collected quantitatively and serum samples were taken over a period of 120 h. Serum toxicokinetics of FB1iv showed a short distribution half-life of 6 min followed by a longer elimination half-life of 36 min. After HFB1iv administration, serum clearance was three times higher compared to FB1iv group (5.6 and 1.8 L/kg/h respectively) which together with a 5-times higher volume of distribution indicates that HFB1 is more rapidly cleared from systemic circulation but distributed more extensively into the extravasal space than FB1. The bioavailability of FB1 in orally exposed pigs was 5.2% (incl. metabolites). Moreover, we found a significant reduction of FB1 bioavailability by 90% caused by the action of fumonisin esterase in the gastrointestinal tract, clearly demonstrating the efficacy of FumD. PMID:29621161

Pharmacokinetics and bioavailability of denaverine hydrochloride in healthy subjects following intravenous, oral and rectal single doses.

PubMed

Staab, Alexander; Schug, Barbara S; Larsimont, Véronique; Elze, Martina; Thümmler, Daniela; Mutschler, Ernst; Blume, Henning

2003-02-01

The neurotropic-musculotropic spasmolytic agent denaverine hydrochloride is used mainly in the treatment of smooth muscle spasms of the gastrointestinal and urogenital tract. Despite its commercial availability as a solution for intravenous or intramuscular administration (ampoule) and as a suppository formulation, no pharmacokinetic data in man was available to date. Therefore, the objectives of this clinical trial were to determine the basic pharmacokinetic parameters of denaverine after intravenous administration, to assess the feasibility of using the oral route of administration and to characterise the bioavailability of the suppository formulation. To achieve this, healthy subjects received 50 mg denaverine hydrochloride intravenously, orally and rectally in aqueous solutions and rectally as suppository in an open, randomised crossover design. Total body clearance, volume of distribution at steady-state and half-life of denaverine are 5.7 ml/min per kg, 7.1 l/kg and 33.8 h, respectively. The absolute bioavailability after oral administration of an aqueous solution is 37%. First-pass metabolism leading to the formation of N-monodemethyl denaverine was found to be one reason for the incomplete bioavailability after oral administration. Rectal administration of an aqueous solution of denaverine hydrochloride resulted in a decreased rate (median of C(max) ratios: 26%, difference in median t(max) values: 1.9 h) and extent (31%) of bioavailability compared to oral administration. Using the suppository formulation led to a further reduction in rate (median of C(max) ratios: 30%, difference in median t(max) values: 3 h) and extent (42%) of bioavailability compared to the rectal solution.

Balanced conscious sedation with intravenous induction and inhalational maintenance for patients requiring endoscopic and/or surgical procedures.

PubMed

Lahoud, G Y; Hopkins, P M

2007-02-01

The use of inhalation sedation with sub-anaesthetic concentrations of sevoflurane and nitrous oxide mixture is expected to reduce amounts of intravenous sedative drugs needed to produce a balanced sedation with the benefits of having reduced side-effects. Eighty-two patients requiring endoscopic and/or surgical procedures under conscious sedation and local anaesthesia were recruited for this pilot study. Conscious sedation was induced with a titrated dose of midazolam and propofol given intravenously until the clinical end-point of conscious sedation was achieved. Subsequently, during the procedure, the patient was asked to breathe sevoflurane 0.1-0.3% and a fixed ratio of 40% nitrous oxide in oxygen given through a face mask. In 78 patients (95.1%), the treatment was completed successfully. Patients were discharged back to the wards within 4-16 min (10.1) without significant side-effects. Treatment was satisfactorily accepted by 38 patients (48.7%) and considered excellent by 40 patients (51.3%). The use of titrated doses of intravenous sedative drugs for induction of conscious sedation followed by the use of low concentrations (0.1-0.3%) of sevoflurane combined with 40% nitrous oxide for maintenance of conscious sedation in patients requiring endoscopic and/or surgical procedures under local anaesthesia, has the potential advantages of reducing amounts of intravenous sedative drugs, less likelihood of problems from drug side-effects and fast recovery and discharge time. Further investigations to establish the technique are currently in progress.

A Double-Blind Placebo-Controlled Crossover Trial of Intravenous Magnesium Sulfate for Foscarnet-Induced Ionized Hypocalcemia and Hypomagnesemia in Patients with AIDS and Cytomegalovirus Infection

PubMed Central

Huycke, Mark M.; Naguib, M. Tarek; Stroemmel, Mathias M.; Blick, Kenneth; Monti, Katherine; Martin-Munley, Sarah; Kaufman, Chris

2000-01-01

Foscarnet (trisodium phosphonoformate hexahydrate) is an antiviral agent used to treat cytomegalovirus disease in immunocompromised patients. One common side effect is acute ionized hypocalcemia and hypomagnesemia following intravenous administration. Foscarnet-induced ionized hypomagnesemia might contribute to ionized hypocalcemia by impairing excretion of preformed parathyroid hormone (PTH) or by producing target organ resistance. Prevention of ionized hypomagnesemia following foscarnet administration could blunt the development of ionized hypocalcemia. To determine whether intravenous magnesium ameliorates the decline in ionized calcium and/or magnesium following foscarnet infusions, MgSO4 at doses of 1, 2, and 3 g was administered in a double-blind, placebo-controlled, randomized, crossover trial to 12 patients with AIDS and cytomegalovirus disease. Overall, increasing doses of MgSO4 reduced or eliminated foscarnet-induced acute ionized hypomagnesemia. Supplementation, however, had no discernible effect on foscarnet-induced ionized hypocalcemia despite significant increases in serum PTH levels. No dose-related, clinically significant adverse events were found, suggesting that intravenous supplementation with up to 3 g of MgSO4 was safe in this chronically ill population. Since parenteral MgSO4 did not alter foscarnet-induced ionized hypocalcemia or symptoms associated with foscarnet, routine intravenous supplementation for patients with normal serum magnesium levels is not recommended during treatment with foscarnet. PMID:10898688

Pharmacokinetic Interpretation of Cephradine Levels in Serum After Intravenous and Extravascular Administration in Humans

PubMed Central

Rattie, Elisabeth S.; Bernardo, Peter D.; Ravin, Louis J.

1976-01-01

Pharmacokinetic parameters were calculated from intravenous data based upon a two-compartment open model. These parameters were subsequently used to determine the absorption rates and bioavailability of cephradine administered intramuscularly and orally. The results indicate that cephradine obeys dose-independent kinetics and that biological availability is complete from all dosage forms. PMID:984770

Anaphylaxis following intravenous ranitidine: A rare adverse reaction of a common drug

PubMed Central

Chopra, Deepti; Arora, Pooja; Khan, Shamimullah; Dwivedi, Shridhar

2014-01-01

Ranitidine hydrochloride is a widely used drug that is generally well-tolerated. Anaphylaxis is rarely observed with ranitidine. We report a case who developed severe anaphylaxis following single dose of intravenous ranitidine. The article highlights the importance of recognition of this serious adverse event and re-emphasizes the need for cautious use of drugs, especially in those with known history of allergy. PMID:24741203

Pharmacokinetics of tilmicosin in beef cattle following intravenous and subcutaneous administration.

PubMed

Lombardi, K R; Portillo, T; Hassfurther, R; Hunter, R P

2011-12-01

The intravenous pharmacokinetic profile of tilmicosin is yet to be achieved because of the cardiovascular effects of tilmicosin. This study summarizes two pharmacokinetic studies that provided complete pharmacokinetic profile of tilmicosin in cattle. The first study was a pharmacokinetic study of tilmicosin in beef calves dosed by i.v. infusion over 5 h. The second study was a subcutaneous (s.c.) pharmacokinetic study comparing the pharmacokinetic profile of tilmicosin in light (approximately 170 kg) and heavy (approximately 335 kg) beef cattle and comparing the labeled dose range of 10 or 20 mg/kg dose. The data from the two different studies were used to calculate bioavailability values, which support the assumption that tilmicosin is 100% bioavailable in cattle. The results from the second study showed that the weight of an animal when administered tilmicosin does not have a significant effect on exposure, but did demonstrate that doubling the dose of tilmicosin administered doubles the systemic exposure to tilmicosin. © 2011 Blackwell Publishing Ltd.

Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil.

PubMed

Bergman, Ebba; Lundahl, Anna; Fridblom, Patrik; Hedeland, Mikael; Bondesson, Ulf; Knutson, Lars; Lennernäs, Hans

2009-12-01

The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 +/- 3.5 and 35.7 +/- 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC(bile)/AUC(VH) ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC(50) values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 +/- 0.06; TII, 0.46 +/- 0.13) and increased the AUC(VP) and AUC(VH) by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and f(e, bile) were reduced by approximately 50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.

Thoracic paravertebral block versus intravenous patient-controlled analgesia for pain treatment in patients with multiple rib fractures.

PubMed

Yeying, Ge; Liyong, Yuan; Yuebo, Chen; Yu, Zhang; Guangao, Ye; Weihu, Ma; Liujun, Zhao

2017-12-01

Objectives To assess the effect of thoracic paravertebral block (PVB) on pain management and preservation of pulmonary function compared with intravenous, patient-controlled analgesia (IVPCA) in patients with multiple rib fractures (MRFs). Methods Ninety patients with unilateral MRFs were included in this prospective study and randomly assigned to the TPVB or IVPCA group. The visual analogue scale (VAS) pain score, blood gas analysis, and bedside spirometry were measured and recorded at different time points after analgesia. Results TPVB and IVPCA provided good pain relief. VAS scores were significantly lower in the TPVB group than in the IVPCA group at rest and during coughing ( P < 0.05). Patients in the TPVB group had a higher PaO 2 and PaO 2 /FiO 2 and lower P (A-a) O 2 compared with the IVPCA group ( P < 0.05). Moreover, patients in the TPVB group showed higher FVC, FEV1/FVC, and PEFR, and fewer complications than did the IVPCA group ( P < 0.05). Conclusion TPVB is superior to IVPCA in pain relief and preservation of pulmonary function in patients with MRFs.

Pharmacokinetics of valproic acid after oral and intravenous administration

PubMed Central

Perucca, E.; Gatti, G.; Frigo, G. M.; Crema, A.

1978-01-01

1 The kinetics of sodium valproate (di-n-propyl-acetate, Depakine®) have been studied in six healthy volunteers after administration of single oral and intravenous doses (800 mg). 2 Kinetic parameters were similar for both routes of administration. In all subjects absorption was rapid and complete. Half-lives ranged from 11-15 h. Apparent volumes of distribution were relatively low (0.147 ± 0.004 l/kg) and showed little variation amongst individuals. 3 The factors responsible for the poor correlation between dosage and serum levels during chronic treatment and therapeutic implications are discussed.

Effect of antiarrhythmic therapy with intravenous loading dose of amiodarone: evidence for an altered response in diabetic patients.

PubMed

Iervasi, G; Clerico, A; Bonini, R; Nannipieri, M; Manfredi, C; Sabatino, L; Biagini, A; Donato, L

1998-01-01

Amiodarone, a potent class III antiarrhythmic agent with adrenergic antagonism properties, is administered increasingly to diabetic patients with cardiac arrhythmias refractory to all other available forms of therapy. Because a large percentage of diabetic patients show a perturbed autonomic regulation of the cardiovascular system, including a pertubed regulation of heart rate, we studied the antiarrhythmic response as well as the early effects (within 5 days) on heart rate of an intravenous amiodarone loading dose in diabetic patients. Seven type II (noninsulin-dependent) diabetic patients (age 64.7 +/- 9.7 years), affected by uncontrolled atrial fibrilation or atrial flutter, were enrolled for the study and a group of 12 well-matched (for age, sex and arrhythmia) nondiabetic patients served as a control group. It was found that before amiodarone administration, nondiabetic patients showed significantly wider variations in the circadian rhythm of heart rate values than diabetic patients (p = 0.0062, unpaired t-test). In all patients but one (who was nondiabetic), amiodarone treatment resulted in a cardioversion to sinus rhythm. After amiodarone administration, nondiabetic patients showed a significantly greater decrease (p = 0.0011) in heart rate values in comparison with the diabetic group (-35% vs. -20% on average, at the end of the study). Furthermore, in nondiabetic patients there was also an earlier significant fall (within the first 4 h after the start of treatment with amiodarone, p < 0.001) in the heart rate values in comparison with diabetic patients, in whom a significant decrease (p < 0.001) was found only at the 4th day. A significant (p = 0.0004), more rapid onset of the antiarrhythmic response to the drug was found in nondiabetic patients (6.8 +/- 6.0 h) in comparison with diabetic patients (98.0 +/- 14.8 h). Our findings suggest that the antiarrhythmic effects of amiodarone in diabetic patients with uncontrolled atrial fibrilation or atrial flutter

Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles.

PubMed

Carlander, Ulrika; Li, Dingsheng; Jolliet, Olivier; Emond, Claude; Johanson, Gunnar

2016-01-01

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

PubMed

Li, Xiaojiao; Liu, Chang; Wu, Min; Zhang, Hong; Sun, Yanfu; Cheng, Longmei; Chen, Hong; Liu, Chengjiao; Yang, Lizhi; Zhang, Qi; Cao, Yuchen; Gu, Jingkai; Ding, Yanhua

2016-08-01

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Clinical and pharmacokinetic results with a new ultrashort-acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers

PubMed Central

Ericsson, H; Fakt, C; Jolin-Mellgård, Å; Nordlander, M; Sohtell, L; Sunzel, M; Regårdh, C G

1999-01-01

Aims To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug. Methods Twenty-five subjects were enrolled in the study and twenty-one of them were included twice, resulting in a total of forty-six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min−1 kg−1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non-compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine. Results Clevidipine was administered up to a target dose rate of 48 nmol min−1 kg−1, where a pre-determined escape criterion was reached (HR>120 beats min−1) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non-compartmental analysis was 0.125 l min−1 kg−1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min−1 kg−1, and the volume of distribution at steady state was 0.56 l kg−1. The initial half-life, contributing by more than 80% to the total area under the blood concentration-time curve following i.v. bolus administration, was 1.8 min, and the terminal half-life was 9

Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma

PubMed Central

Weisel, Katja C.; Dimopoulos, Meletios A.; Moreau, Philippe; Lacy, Martha Q.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Banos, Anne; Oriol, Albert; Alegre, Adrian; Chen, Christine; Cavo, Michele; Garderet, Laurent; Ivanova, Valentina; Martinez-Lopez, Joaquin; Knop, Stefan; Yu, Xin; Hong, Kevin; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Miguel, Jesus San

2016-01-01

Pomalidomide + low-dose dexamethasone is effective and well tolerated for refractory or relapsed and refractory multiple myeloma after bortezomib and lenalidomide failure. The phase III trial MM-003 compared pomalidomide + low-dose dexamethasone with high-dose dexamethasone. This subanalysis grouped patients by baseline creatinine clearance ≥ 30 − < 60 mL/min (n=93, pomalidomide + low-dose dexamethasone; n=56, high-dose dexamethasone) or ≥ 60 mL/min (n=205, pomalidomide + low-dose dexamethasone; n=93, high-dose dexamethasone). Median progression-free survival was similar for both subgroups and favored pomalidomide + low-dose dexamethasone versus high-dose dexamethasone: 4.0 versus 1.9 months in the group with baseline creatinine clearance ≥ 30 − < 60 mL/min (P<0.001) and 4.0 versus 2.0 months in the group with baseline creatinine clearance ≥ 60 mL/min (P<0.001). Median overall survival for pomalidomide + low-dose dexamethasone versus high-dose dexamethasone was 10.4 versus 4.9 months (P=0.030) and 15.5 versus 9.2 months (P=0.133), respectively. Improved renal function, defined as an increase in creatinine clearance from < 60 to ≥ 60 mL/min, was similar in pomalidomide + low-dose dexamethasone and high-dose dexamethasone patients (42% and 47%, respectively). Improvement in progression-free and overall survival in these patients was comparable with that in patients without renal impairment. There was no increase in discontinuations of therapy, dose modifications, and adverse events in patients with moderate renal impairment. Pomalidomide at a starting dose of 4 mg + low-dose dexamethasone is well tolerated in patients with refractory or relapsed and refractory multiple myeloma, and of comparable efficacy if moderate renal impairment is present. This trial was registered with clinicaltrials.gov identifier 01311687 and EudraCT identifier 2010-019820-30. PMID:27081177

Cabotegravir long acting injection protects macaques against intravenous challenge with SIVmac251.

PubMed

Andrews, Chasity D; Bernard, Leslie St; Poon, Amanda Yee; Mohri, Hiroshi; Gettie, Natanya; Spreen, William R; Gettie, Agegnehu; Russell-Lodrigue, Kasi; Blanchard, James; Hong, Zhi; Ho, David D; Markowitz, Martin

2017-02-20

We evaluated the effectiveness of cabotegravir (CAB; GSK1265744 or GSK744) long acting as preexposure prophylaxis (PrEP) against intravenous simian immunodeficiency virus (SIV) challenge in a model that mimics blood transfusions based on the per-act probability of infection. CAB long acting is an integrase strand transfer inhibitor formulated as a 200 mg/ml injectable nanoparticle suspension that is an effective PrEP agent against rectal and vaginal simian/human immunodeficiency virus transmission in macaques. Three groups of rhesus macaques (n = 8 per group) were injected intramuscularly with CAB long acting and challenged intravenously with 17 animal infectious dose 50% SIVmac251 on week 2. Group 1 was injected with 50 mg/kg on week 0 and 4 to evaluate the protective efficacy of the CAB long-acting dose used in macaque studies mimicking sexual transmission. Group 2 was injected with 50 mg/kg on week 0 to evaluate the necessity of the second injection of CAB long acting for protection against intravenous challenge. Group 3 was injected with 25 mg/kg on week 0 and 50 mg/kg on week 4 to correlate CAB plasma concentrations at the time of challenge with protection. Five additional macaques remained untreated as controls. CAB long acting was highly protective with 21 of the 24 CAB long-acting-treated macaques remaining aviremic, resulting in 88% protection. The plasma CAB concentration at the time of virus challenge appeared to be more important for protection than sustaining therapeutic plasma concentrations with the second CAB long acting injection. These results support the clinical investigation of CAB long acting as PrEP in people who inject drugs.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

PubMed

Gabardi, Steven; Catella, Jennifer; Martin, Spencer T; Perrone, Ronald; Chandraker, Anil; Magee, Colm C; McDevitt-Potter, Lisa M

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation. The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisolone 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m²) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m²) and no adverse events. The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting, long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAs have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2

[The efficacy of intravenous lacosamide in psychiatric hospital].

PubMed

Vakula, I N; Bojko, E O; Vorona, U A; Storozhuk, J A; Nikiforova, E U; Nikiforova, D I; Glazunova, T I

2016-01-01

To evaluate the efficacy and tolerability of intravenous lacosamide (vimpat) in inpatients with frequent partial-onset seizures and affective and cognitive disorders. Fifteen patients were enrolled including 14 patients diagnosed with «organic personality disorder associated with epilepsy» (cryptogenic or symptomatic epilepsy with frequent partial-onset and/or secondary-generalized seizures (serial seizures in some cases) and 1 patient with a preliminary diagnosis of «organic schizophrenia-like disorder», which was changed for «organic personality disorder associated with epilepsy» after examination. Patients were treated with 2--3 antiepileptic drugs (AEDs), but no one of them received earlier lacosamide. Lacosamide was used intravenously in drops in the dose of 200 or 400 mg daily during 5 days. In 4 patients with marked personality disorders, the frequency of seizures decreased by 75%, no seizures were noted after 2--3 days of treatment in 11 patients. A positive effect of lacosamide on the affective sphere and quality-of-life was observed in 11 (73.4%) patients with epilepsy. Mild and moderate adverse effects were found only in 2 patients. It has been concluded that lacosamide demonstrates the high efficacy in patients with frequent drug-resistant seizures.

High-dose methylprednisolone pulse therapy for treatment of refractory intestinal involvement caused by Henoch-Schönlein purpura: a case report.

PubMed

Kang, Hyun Sik; Chung, Hee Sup; Kang, Ki-Soo; Han, Kyoung Hee

2015-03-24

Henoch-Schönlein purpura is an immunoglobulin A-mediated, small vascular inflammatory disease that can be associated with palpable purpura, arthralgia, abdominal pain, or nephritis. The presence of purpura facilitates the diagnosis of Henoch-Schönlein purpura at the onset of associated symptoms, whereas the absence of purpura makes the diagnosis challenging. It is important to diagnose Henoch-Schönlein purpura with delayed-onset skin purpura to avoid unnecessary surgery for acute abdomen. Most cases of Henoch-Schönlein purpura with severe abdominal pain are treated with low-dose steroids and intravenous immunoglobulin. A 15-year-old Korean girl complained of severe abdominal pain and delayed-onset purpura on admission. Henoch-Schönlein purpura was diagnosed based on endoscopic findings of hemorrhagic duodenitis and duodenal vasculitis and abdominal computed tomography findings of edematous bowels. Two common initial treatments, a low-dose steroid and intravenous immunoglobulin, were administered, but there was no improvement for 1 month. Subsequently, we used high-dose intravenous methylprednisolone pulse therapy (30 mg/kg/day, with a maximum of 1g/day), which dramatically alleviated her abdominal symptoms. High-dose intravenous methylprednisolone pulse therapy can be used as the ultimate treatment for delayed-onset Henoch-Schönlein purpura with severe abdominal pain when symptoms do not improve after low-dose steroid and intravenous immunoglobulin treatments.

Brief Report: The Euro-Lupus Low-Dose Intravenous Cyclophosphamide Regimen Does Not Impact the Ovarian Reserve, as Measured by Serum Levels of Anti-Müllerian Hormone.

PubMed

Tamirou, Farah; Husson, Séverine Nieuwland; Gruson, Damien; Debiève, Frédéric; Lauwerys, Bernard R; Houssiau, Frédéric A

2017-06-01

The Euro-Lupus regimen of low-dose intravenous cyclophosphamide (IV CYC) (cumulative dose of 3 gm) was developed to reduce gonadal toxicity. To address the possibility of a marginal effect on the ovarian reserve, we measured serum titers of anti-Müllerian hormone (AMH) in patients with systemic lupus erythematosus (SLE) treated with the Euro-Lupus regimen and compared them with those measured in patients who were treated with higher doses of IV CYC or were never treated with IV CYC. Serum AMH levels were measured by enzyme-linked immunosorbent assay in a cohort of 155 premenopausal SLE patients; 30 of these patients had been treated with the Euro-Lupus regimen, and 24 had received higher doses of IV CYC. None had received oral CYC. AMH levels were age-adjusted using a slope computed from levels measured across the group of SLE patients who had not been treated with IV CYC. Demographic and clinical data were collected. Serum titers of AMH measured in SLE patients treated with the Euro-Lupus IV CYC regimen (median dose 1.46 ng/ml) did not differ from those measured in patients never treated with the cytotoxic drug (median 1.85 ng/ml). As expected, patients given >6 gm of IV CYC had significantly lower serum titers of AMH (median 0.83 ng/ml) compared with those never treated with IV CYC (P = 0.047). Median serum AMH titers did not change before (1.24 ng/ml) and after (2.50 ng/ml) treatment with the Euro-Lupus IV CYC regimen in the subset of patients for whom paired samples could be tested (P = 0.43). The Euro-Lupus regimen of low-dose IV CYC does not impact the ovarian reserve of SLE patients and can therefore be proposed as treatment in patients seeking to become pregnant. © 2017, American College of Rheumatology.

Resolving the paradigm crisis in intravenous iron and erythropoietin management.

PubMed

Besarab, A

2006-05-01

Despite the proven benefits of intravenous (i.v.) iron therapy in anemia management, it remains underutilized in the hemodialysis population. Although overall i.v. iron usage continues to increase slowly, monthly usage statistics compiled by the US Renal Data System suggest that clinicians are not implementing continued dosing regimens following repletion of iron stores. Continued therapy with i.v. iron represents a key opportunity to improve patient outcomes and increase the efficiency of anemia treatment. Regular administration of low doses of i.v. iron prevents the recurrence of iron deficiency, enhances response to recombinant human erythropoietin therapy, minimizes fluctuation of hemoglobin levels, hematocrit levels, and iron stores, and may reduce overall costs of care. This article reviews the importance of i.v. iron dosing on a regular basis in the hemodialysis patient with iron-deficiency anemia and explores reasons why some clinicians may still be reluctant to employ these protocols in the hemodialysis setting.

Single and Multiple Ascending-dose Studies of Oral Delafloxacin: Effects of Food, Sex, and Age.

PubMed

Hoover, Randall; Hunt, Thomas; Benedict, Michael; Paulson, Susan K; Lawrence, Laura; Cammarata, Sue; Sun, Eugene

2016-01-01

The objective of this report is describe the results of 2 studies that examined the pharmacokinetic parameters, safety profile, and tolerability of single and multiple ascending doses of oral delafloxacin and the effects of food, sex, and age on oral delafloxacin pharmacokinetic parameters, safety profile, and tolerability. The first study contained 3 parts and used unformulated delafloxacin in a capsule. Part 1 was a randomized, double-blind, placebo-controlled, single (50, 100, 200, 400, 800, 1200, and 1600 mg) ascending-dose study of oral delafloxacin in healthy men. Part 2 was a single-dose crossover study in which 20 men received 250 mg delafloxacin with or without food. Part 2 also included a parallel group, double-blind, placebo-controlled study in 16 women and 16 elderly men and women who were randomized (3:1) to receive 250 mg delafloxacin or placebo. Part 3 was a randomized, double-blind, placebo-controlled, multiple (100, 200, 400, 800, 1200 mg once daily for 5 days) ascending-dose study of oral delafloxacin in healthy men. The second study was a single-dose, randomized, 3-period crossover study in which participants received 900 mg delafloxacin (2 × 450-mg tablets) under fasted conditions, with a high-fat meal, or fasted with a high-fat meal 2 hours after dosing. Serial blood samples were collected, and plasma pharmacokinetic parameters of delafloxacin were determined. Delafloxacin Cmax and AUC0-∞ increased with increasing oral dose over the dose range of 50 to 1600 mg. The increases in delafloxacin AUC0-∞ were dose proportional at doses of ≥200 mg. Steady state was reached by day 3 of dosing with minimal accumulation of delafloxacin. The Cmax of delafloxacin was decreased slightly in the presence of food. No sex difference in delafloxacin pharmacokinetic parameters was observed. In the elderly men and women, mean delafloxacin Cmax and AUC0-∞ were 35% higher than observed for young adults, which could be partially explained by a decrease in

TH-AB-207A-03: Skin Dose to Patients Receiving Multiple CTA and CT Exams of the Head

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

Nawfel, RD; Young, G

Purpose: To measure patient skin dose from CT angiography (CTA) and CT exams of the head, and determine if patients having multiple exams could receive cumulative doses that approach or exceed deterministic thresholds. Methods: This study was HIPAA compliant and conducted with IRB approval. Patient skin doses were measured over a 4 month period using nanoDot OSL dosimeters placed on the head of 52 patients for two CT scanners. On each scanner, 26 patients received CT exams (scanner 1: 10 females, 16 males, mean age 64.2 years; scanner 2: 18 females, 8 males, mean age 61.2 years). CT exam dosemore » metrics, CTDIvol and dose-length product (DLP) were recorded for each exam. Additionally, skin dose was measured on an acrylic skull phantom in each scanner and on a neuro-interventional imaging system using clinical protocols. Measured dose data was used to estimate peak skin dose (PSD) for 4 patients receiving multiple exams including CTA, head CT, and cerebral angiography. Results: For scanner 1, the mean PSD for CTA exams (98.9 ± 5.3 mGy) and for routine head CT exams (39.2 ± 3.7 mGy) agreed reasonably well with the PSD measured on the phantom, 105.4 mGy and 40.0 mGy, respectively. Similarly for scanner 2, the mean PSD for CTA exams (98.8 ± 7.4 mGy) and for routine head CT exams (42.9 ± 9.4 mGy) compared well with phantom measurements, 95.2 mGy and 37.6 mGy, respectively. In addition, the mean PSD was comparable between scanners for corresponding patient exams, CTA and routine head CT respectively. PSD estimates ranged from 1.9 – 4.5 Gy among 4 patients receiving multiple exams. Conclusion: Patients having several exams including both CTA and routine head CT may receive cumulative doses approaching or exceeding the threshold for single dose deterministic effects.« less

Bioavailability of dexmedetomidine after extravascular doses in healthy subjects

PubMed Central

Anttila, Markku; Penttilä, Jani; Helminen, Antti; Vuorilehto, Lauri; Scheinin, Harry

2003-01-01

Aim To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects. Methods Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data). Results Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively. Conclusion Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug. PMID:14616431

Pharmacokinetics of intravenous and subcutaneous cefovecin in alpacas.

PubMed

Cox, S; Sommardahl, C; Seddighi, R; Videla, R; Hayes, J; Pistole, N; Hamill, M; Doherty, T

2015-08-01

The purpose of this study was to determine the pharmacokinetics of cefovecin after intravenous and subcutaneous dose of 8 mg/kg to alpacas. Bacterial infections requiring long-term antibiotic therapy such as neonatal bacteremia, pneumonia, peritonitis, dental, and uterine infections are a significant cause of morbidity and mortality in this species. However, few antimicrobials have been evaluated and proven to have favorable pharmacokinetics for therapeutic use. Most antimicrobials that are currently used require daily injections for many days. Cefovecin is a long-acting cephalosporin that is formulated for subcutaneous administration, and its long-elimination half-life allows for 14-day dosing intervals in dogs and cats. The properties of cefovecin may be advantageous for medical treatment of camelids due to its broad spectrum, route of administration, and long duration of activity. Pharmacokinetic evaluation of antimicrobial drugs in camelids is essential for the proper treatment and prevention of bacterial disease, and to minimize development of antibiotic resistant bacterial strains due to inadequate antibiotic concentrations. Cefovecin mean half-life, volume of distribution at steady-state, and clearance after intravenous administration were 10.3 h, 86 mL/kg, and 7.07 mL·h/kg. The bioavailability was 143%, while half-life, C(max), and T(max) were 16.9 h, 108 μg/mL, and 2.8 h following subcutaneous administration. In the absence of additional microbial susceptibility data for alpaca pathogens, the current cefovecin dosage regimen prescribed for dogs (8 mg/kg SC every 14 days) may need to be optimized for the treatment of infections in this species. © 2014 John Wiley & Sons Ltd.

Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate.

PubMed

Nakayama, Masafumi; Chikamori, Taishiro; Uchiyama, Takashi; Kimura, Yo; Hijikata, Nobuhiro; Ito, Ryosuke; Yuhara, Mikio; Sato, Hideaki; Kobori, Yuichi; Yamashina, Akira

2018-04-01

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 μg/kg/min (normal dose) and 170 μg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

Induction of anti-glioma NK cell response following multiple low-dose intracerebral CpG therapy

PubMed Central

Alizadeh, Darya; Zhang, Leying; Brown, Christine E.; Farrukh, Omar; Jensen, Michael C.; Badie, Behnam

2010-01-01

Purpose Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG-ODN) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. These studies, however, have used high doses of CpG-ODN which can induce toxicity in a clinical setting. The goal of this study was to evaluate the anti-tumor efficacy of multiple low-dose intratumoral CpG- ODN in a glioma model. Experimental Design Mice bearing four-day old intracranial GL261 gliomas received a single or multiple (two or four) intratumoral injections of CpG-ODN (3 μg) every 4 days. Tumor growth was measured by bioluminescent imaging, brain histology, and animal survival. Flow cytometry and cytotoxicity assays were used to assess anti-glioma immune response. Results Two and four intracranial injections of low-dose CpG-ODN, but not a single injection, eradicated gliomas in 70% of mice. Moreover, surviving animals exhibited durable tumor free remission (> 3 months), and were protected from intracranial rechallenge with GL21 gliomas, demonstrating the capacity for long-term anti-tumor immunity. Although most inflammatory cells appeared to increase, activated NK cells (i.e. NK+CD107a+) were more frequent than CD8+CD107a+ in the brains of rechallenged CpG-ODN-treated animals and demonstrated a stronger in vitro cytotoxicity against GL261 target cells. Leukocyte depletion studies confirmed that NK cells played an important role in the initial CpG-ODN anti-tumor response, but both CD8 and NK cells were equally important in long-term immunity against gliomas. Conclusions These findings suggest that multiple low-dose intratumoral injections of CpG-ODN can eradicate intracranial gliomas possibly through mechanisms involving NK mediated effector function. PMID:20570924

Understanding the causes of intravenous medication administration errors in hospitals: a qualitative critical incident study

PubMed Central

Keers, Richard N; Williams, Steven D; Cooke, Jonathan; Ashcroft, Darren M

2015-01-01

Objectives To investigate the underlying causes of intravenous medication administration errors (MAEs) in National Health Service (NHS) hospitals. Setting Two NHS teaching hospitals in the North West of England. Participants Twenty nurses working in a range of inpatient clinical environments were identified and recruited using purposive sampling at each study site. Primary outcome measures Semistructured interviews were conducted with nurse participants using the critical incident technique, where they were asked to discuss perceived causes of intravenous MAEs that they had been directly involved with. Transcribed interviews were analysed using the Framework approach and emerging themes were categorised according to Reason's model of accident causation. Results In total, 21 intravenous MAEs were discussed containing 23 individual active failures which included slips and lapses (n=11), mistakes (n=8) and deliberate violations of policy (n=4). Each active failure was associated with a range of error and violation provoking conditions. The working environment was implicated when nurses lacked healthcare team support and/or were exposed to a perceived increased workload during ward rounds, shift changes or emergencies. Nurses frequently reported that the quality of intravenous dose-checking activities was compromised due to high perceived workload and working relationships. Nurses described using approaches such as subconscious functioning and prioritising to manage their duties, which at times contributed to errors. Conclusions Complex interactions between active and latent failures can lead to intravenous MAEs in hospitals. Future interventions may need to be multimodal in design in order to mitigate these risks and reduce the burden of intravenous MAEs. PMID:25770226

Randomized clinical trial of an intravenous hydromorphone titration protocol versus usual care for management of acute pain in older emergency department patients.

PubMed

Chang, Andrew K; Bijur, Polly E; Davitt, Michelle; Gallagher, E John

2013-09-01

Opioid titration is an effective strategy for treating pain; however, titration is generally impractical in the busy emergency department (ED) setting. Our objective was to test a rapid, two-step, hydromorphone titration protocol against usual care in older patients presenting to the ED with acute severe pain. This was a prospective, randomized clinical trial of patients 65 years of age and older presenting to an adult, urban, academic ED with acute severe pain. The study was registered at http://www.clinicaltrials.gov (NCT01429285). Patients randomized to the hydromorphone titration protocol initially received 0.5 mg intravenous hydromorphone. Patients randomized to usual care received any dose of any intravenous opioid. At 15 min, patients in both groups were asked, 'Do you want more pain medication?' Patients in the hydromorphone titration group who answered 'yes' received a second dose of 0.5 mg intravenous hydromorphone. Patients in the usual care group who answered 'yes' had their ED attending physician notified, who then could administer any (or no) additional medication. The primary efficacy outcome was satisfactory analgesia defined a priori as the patient declining additional analgesia at least once when asked at 15 or 60 min after administration of the initial opioid. Dose was calculated in morphine equivalent units (MEU: 1 mg hydromorphone = 7 mg morphine). The need for naloxone to reverse adverse opioid effects was the primary safety outcome. 83.0 % of 153 patients in the hydromorphone titration group achieved satisfactory analgesia compared with 82.5 % of 166 patients in the usual care group (p = 0.91). Patients in the hydromorphone titration group received lower mean initial doses of opioids at baseline than patients in the usual care group (3.5 MEU vs. 4.7 MEU, respectively; p ≤ 0.001) and lower total opioids through 60 min (5.3 MEU vs. 6.0 MEU; p = 0.03). No patient needed naloxone. Low-dose titration of intravenous hydromorphone in increments of

Dose- and time-dependent pharmacokinetics of apigenin trimethyl ether.

PubMed

Elhennawy, Mai Gamal; Lin, Hai-Shu

2018-06-15

Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Upon single intravenous administration (2 mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8 mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45 mg/kg, much longer mean residence time (MRT 0→last ), higher dose-normalized maximal plasma concentration (C max /Dose) and exposure (AUC/Dose) were observed at 15 and/or 45 mg/kg. One-week daily oral administration of ATE at 15 mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2 mg/kg) and oral administration (15 mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger. Copyright © 2018 Elsevier B.V. All rights reserved.

Treatment of a mild chronic case of ciguatera fish poisoning with intravenous mannitol, a case study.

PubMed

Mitchell, Gary

2005-03-01

This article describes a recent case of ciguatera poisoning treated with intravenous mannitol. Mannitol has been used with good effect in non-controlled studies in acutely severely poisoned patients, but is not described in the treatment of chronic or milder poisoning. Our patient was a 35-year-old Niuean man who had eaten a ciguatoxic fish two weeks previously. His symptoms were not severe but were very unpleasant and restricted his ability to work. He was given a single dose of mannitol (0.66g/kg) as an intravenous infusion over two hours. His symptoms dramatically improved within 24 hours, and within a few days he felt virtually back to his former self. He experienced no side effects to the mannitol. It is suggested that intravenous mannitol may prove to be a useful treatment for mild to moderate ciguatera poisoning, and for patients who present late for treatment.

Intravenous Levetiracetam in the Rat Pilocarpine-Induced Status Epilepticus Model: Behavioral, Physiological and Histological Studies

PubMed Central

Zheng, Yi; Moussally, Jon; Cash, Sydney S.; Karnam, Havisha B.; Cole, Andrew J.

2010-01-01

Purpose Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an antiepileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. Methods We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 minutes after the onset of behavioral status epilepticus, animals were treated with LEV (200–1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. Results When administered 30 minutes after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4 minutes to 23.6 minutes. When administered 10 minutes after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Conclusions Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG

Intravenous levetiracetam in the rat pilocarpine-induced status epilepticus model: behavioral, physiological and histological studies.

PubMed

Zheng, Yi; Moussally, Jon; Cash, Sydney S; Karnam, Havisha B; Cole, Andrew J

2010-01-01

Status epilepticus is a neurological emergency associated with neuronal injury, lasting behavioral disturbance, and a high rate of mortality. Intravenous levetiracetam (LEV), an anti-epileptic drug approved to treat partial seizures, has recently been introduced. We sought to determine the effect of LEV administered intravenously in a chemoconvulsant model of status epilepticus. We examined the effect of intravenous LEV in the rat lithium-pilocarpine model of status epilepticus. Ten or 30 min after the onset of behavioral status epilepticus, animals were treated with LEV (200-1200 mg/kg i.v.) administered in a single bolus. Behavioral responses were recorded. Selected animals had continuous EEG recording before, during and after the administration of LEV. Some animals were sacrificed 24 h after the experiment and processed for histochemical assessment of neuronal injury. When administered 30 min after the onset of behavioral epileptic seizures, transient attenuation of ictal behavior was observed in animals treated with 800 mg/kg or more of LEV. The duration of behavioral attenuation increased sharply as the dose rose to 1000 mg/kg or higher, from a mean of 4-23.6 min. When administered 10 min after seizure onset, 400 mg/kg of LEV resulted in transient ictal behavioral attenuation, and higher doses caused relatively longer periods of attenuation. Pretreatment with LEV prior to pilocarpine also delayed the onset of seizures. EEG recordings, however, showed no significant attenuation of ictal discharge. By contrast, TUNEL staining demonstrated less neuronal injury in hippocampii and other limbic structures in animals that responded behaviorally to LEV. Intravenous administration of LEV in a chemoconvulsant model of status epilepticus results in attenuation of behavioral manifestations of seizure discharge and in reduction of neuronal injury but does not significantly alter ictal discharge recorded by EEG. Copyright 2009 Elsevier Ltd. All rights reserved.

Repeated intravenous doxapram induces phrenic motor facilitation

PubMed Central

Sandhu, MS; Lee, KZ; Gonzalez-Rothi, EJ; Fuller, DD

2013-01-01

Doxapram is a respiratory stimulant used to treat hypoventilation. Here we investigated whether doxapram could also trigger respiratory neuroplasticity. Specifically, we hypothesized that intermittent delivery of doxapram at low doses would lead to long-lasting increases (i.e., facilitation) of phrenic motor output in anesthetized, vagotomized, and mechanically-ventilated rats. Doxapram was delivered intravenously in a single bolus (2 or 6 mg/kg) or as a series of 3 injections (2 mg/kg) at 5 min intervals. Control groups received pH-matched saline injections (vehicle) or no treatment (anesthesia time control). Doxapram evoked an immediate increase in phrenic output in all groups, but a persistent increase in burst amplitude only occurred after repeated dosing with 2 mg/kg. At 60 min following the last injection, phrenic burst amplitude was 168±24% of baseline (%BL) in the group receiving 3 injections (P < 0.05 vs. controls), but was 103±8%BL and 112±4%BL in the groups receiving a single dose of 2 or 6 mg/kg, respectively. Following bilateral section of the carotid sinus nerves, the acute phrenic response to doxapram (2 mg/kg) was reduced by 68% suggesting that at low doses the drug was acting primarily via the carotid chemoreceptors. We conclude that intermittent application of doxapram can trigger phrenic neuroplasticity, and this approach might be of use in the context of respiratory rehabilitation following neurologic injury. PMID:24013015

A PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR intravenous and ingested DIMETHYLARSINIC ACID (DMAV) IN MICE.

EPA Science Inventory

A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was ...

Leukoencephalopathy in childhood hematopoietic neoplasm caused by moderate-dose methotrexate and prophylactic cranial radiotherapy - an MR analysis

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

Matsumoto, Ko; Takahashi, Shoki; Higano, Shuichi

1995-07-15

The main purpose of this study was to determine influential factors related to minor leukoencephalopathy (LEP) caused by moderate-dose methotrexate (MTX) and prophylactic cranial radiotherapy (CRT) in childhood hematopoietic malignancies. We also compared the incidence of LEP following this treatment to that reported in the literature following treatment with high-dose MTX alone. Thirty-eight pediatric patients of hematopoietic malignancies (37 acute lymphoblastic leukemias, 1 non-Hodgkin lymphoma) who were given CRT (18-24 Gy) as well as prophylactic intrathecal and per os MTX were studied for leukoencephalopathy by magnetic resonance (MR) imaging. All the patients were free from grave neuropsychiatric disturbances. The datamore » were examined to elucidate the influential ones of five factors (patients` age, doses of intrathecal and per os MTX, dose of CRT, interval between treatment, and MR study) to develop LEP using multiple regression analysis. To compare the effect of moderate-dose MTX and prophylactic CRT on LEP to that of high-dose MTX alone, we conducted a literature review. Seven out of 38 patients (18%) developed LEP. From multiple regression analysis and partial correlation coefficients, the age and CRT dose seemed influential in the subsequent development of LEP. The incidence of LEP following treatment with moderate-dose MTX and prophylactic CRT appears to be less than that reported in the literature following treatment with intravenous high-dose MTX. However, even moderate-dose MTX in combination with CRT can result in a significant incidence of MR-detectable LEP, particularly in children 6 years of age or younger receiving 24 Gy. Leukoencephalopathy was caused by moderate-dose MTX and prophylactic CRT in pediatric patients, probably less frequently than by high-dose MTX treatment alone. The influential factors were patient`s age and CRT dose. 26 refs., 6 figs., 2 tabs.« less

A prospective, within-patient, crossover study of continuous intravenous and subcutaneous morphine for chronic cancer pain.

PubMed

Nelson, K A; Glare, P A; Walsh, D; Groh, E S

1997-05-01

The dose, efficacy, and side effects of continuous intravenous infusion (CIVI) of morphine were compared with continuous subcutaneous infusion (CSCI) of morphine in patients with chronic cancer pain. Eligible patients were referred to the Palliative Care Program and were receiving a stable dose of CIVI of morphine. The design was a within-patient, one-way crossover; in which each patient provided data before and after a switch from CIVI to CSCI of morphine. "Rescue" doses were 50% of the hourly dose given every 2 hours as needed. Morphine was infused intravenously (i.v.) and subcutaneously (s.c.) via a McGaw/AccuPro Volumetric Infusion Pump. After baseline data, including side effects and pain assessment, were obtained, patients were evaluated twice daily for toxicity and analgesic efficacy. Those who had a stable CIVI dose for 48 consecutive hr were crossed over to the CSCI at the same dose as the intravenous (i.v.) phase. A stable dose was defined as no dose change, four or less rescue doses in the previous 24 hr, and a pain rating of none or mild. CIVI was considered equal to CSCI if these criteria were maintained for 96 consecutive hr. Fifty-seven patients were entered, and 40 were evaluable (15 women and 25 men). The median age was 67 (range 30-83 years). All 40 participants, after maintaining a stable dose throughout the i.v. phase, crossed to the s.c. phase and remained on s.c. for at least 48 hr. Thirty-two patients maintained a stable dose throughout the i.v. and s.c. phases. The mean stable i.v. dose (day 2) was 5.05 mg/hr, and the mean stable s.c. dose (day 4) was 5.7 mg/hr (P = 0.01). The mean number of rescue doses on day 2 was 0.83 per 24 hr versus 0.80 per 24 hours on day 4 (P = 0.6). The mean categorical pain score on day 2 was 0.83, and on day 4, 0.85 (P = 0.7). The mean visual analogue scale (VAS) on day 2 was 22.9 mm versus 17.6 mm on day 4 (P = 0.1). The mean incidence of side effects on day 2 was 1.7, and on day 4, 2.0 (P = 0.2). No patient was

Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study.

PubMed

Demirol, Aygul; Gurgan, Timur

2009-08-01

To compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols for poor-responder patients in intracytoplasmic sperm injection-ET cycles. A randomized, prospective study. Center for assisted reproductive technology in Turkey. Ninety patients with poor ovarian response in a minimum of two previous IVF cycles. All women were prospectively randomized into two groups by computer-assisted randomization. The patients in group 1 were stimulated according to the microdose flare-up protocol (n = 45), while the patients in group 2 were stimulated according to antagonist multiple-dose protocol (n = 45). The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in group 2, while the number of oocytes retrieved was significantly greater in group 1. Although the fertilization and clinical pregnancy rates were nonsignificantly higher in group 1 compared with group 2, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). The microdose flare-up protocol seems to have a better outcome in poor-responder patients, with a significantly higher mean number of mature oocytes retrieved and higher implantation rate.

Multi organ failure following intravenous gasoline for suicide: a case report.

PubMed

Mahmoodpoor, Ata; Soleimanpour, Hassan; Hamishehkar, Hadi

2012-01-01

Hydrocarbons are ubiquitous in daily life and include plant and animal fats, alcohols, solvents, natural gas, petroleum derivates. Majority of intoxication reports of hydrocarbons are due to inhalation or ingestion, but there is few reports about intravenous injection of gasoline. We report a 58 year-old man who injected gasoline intravenously for suicide. He developed soft tissue necrosis of forearm and bilateral pulmonary infiltration. He underwent fasciotomy and extensive debridement of necrotic tissues, at the operation room. He was intubated and mechanically ventilated because of acute lung injury. He developed acute kidney injury after 2 days. These symptoms seem to be due to extravasation of gasoline from vessels which lead to inflammation, cell damage and organ failure. The patient developed multi organ failure which unfortunately did not respond to our treatment and he died at day 21. Management of gasoline intoxication depends on the rout of exposure. Like other types of toxications, intravenous toxication has pulmonary involvement, however in this case we had multiple organ involvement. It seems that in such cases we should consider early end organ targeted therapy to stop the future organ failure. © 2012 Tehran University of Medical Sciences. All rights reserved.

Single-dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study.

PubMed

Holm, C; Thomsen, L L; Norgaard, A; Langhoff-Roos, J

2017-02-01

There are no randomized trials comparing intravenous iron to RBC transfusion for the treatment of severe postpartum anaemia. The objectives of this study were to evaluate the feasibility of randomizing women with severe postpartum anaemia secondary to postpartum haemorrhage to RBC transfusion or intravenous iron, and to describe patient-reported outcomes, and haematological and iron parameters. Women with a postpartum haemorrhage exceeding 1000 ml and an Hb between 5·6 and 8·1 g/dl were randomized to 1500 mg of intravenous iron (n = 7) isomaltoside or RBC transfusion (n = 6). Participants completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and blood samples were drawn at inclusion, daily during the first week and at weeks 3, 8 and 12. We screened 162 women and included 13 (8%). There was no significant difference between groups in fatigue or depression scores. RBC transfusion was associated with a higher Hb on day 1, inhibition of reticulocytosis during the first week and low iron levels. Intravenous iron was associated with increased reticulocytosis during the first week, repleted iron stores and a higher Hb in weeks 3-12. This pilot study shows that intravenous iron could be an attractive alternative to RBC transfusion in severe postpartum anaemia, and that a larger trial is needed and feasible. © 2016 The Authors. Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.

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.

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

PubMed

Shapiro, Geoffrey I; Bell-McGuinn, Katherine M; Molina, Julian R; Bendell, Johanna; Spicer, James; Kwak, Eunice L; Pandya, Susan S; Millham, Robert; Borzillo, Gary; Pierce, Kristen J; Han, Lixin; Houk, Brett E; Gallo, Jorge D; Alsina, Maria; Braña, Irene; Tabernero, Josep

2015-04-15

To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. ©2015 American Association for Cancer Research.

Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus.

PubMed

Gokmen, Tulin; Erdeve, Omer; Altug, Nahide; Oguz, Serife Suna; Uras, Nurdan; Dilmen, Ugur

2011-04-01

To compare oral ibuprofen with intravenous ibuprofen for closure of patent ductus arteriosus in very low birth weight (VLBW) preterm infants. In a prospective, randomized study, 102 VLBW preterm infants with patent ductus arteriosus received either intravenous or oral ibuprofen at an initial dose of 10 mg/kg, followed by 5 mg/kg at 24 and 48 hours. The success rate and evaluation of renal tolerance using cystatin-C were the major outcomes. Patent ductus arteriosus closure rate was significantly higher with oral ibuprofen (84.6% versus 62%) after the first course of the treatment (P = .011). The cystatin-C level increased significantly after treatment in the oral group (P = .001), but did not change with intravenous ibuprofen (P = .4). Oral ibuprofen is more effective than intravenous ibuprofen for ductal closure in VLBW infants. The increase in the cystatin-C level with oral treatment suggests that patients with borderline renal function should be evaluated and followed closely. Copyright © 2011 Mosby, Inc. All rights reserved.

[Vasopressin intravenous infusion causes dose dependent adverse cardiovascular effects in anesthetized dogs.

PubMed

Martins, Luiz Cláudio; Sabha, Maricene; Paganelli, Maria Ondina; Coelho, Otávio Rizzi; Ferreira-Melo, Silvia Elaine; Moreira, Marcos Mello; Cavalho, Adriana Camargo de; Araujo, Sebastião; Moreno Junior, Heitor

2010-01-15

BACKGROUND: Arginine vasopressin (AVP) has been broadly used in the management of vasodilatory shock. However, there are many concerns regarding its clinical use, especially in high doses, as it can be associated with adverse cardiovascular events. OBJECTIVE: To investigate the cardiovascular effects of AVP in continuous IV infusion on hemodynamic parameters in dogs. METHODS: Sixteen healthy mongrel dogs, anesthetized with pentobarbital were intravascularly catheterized, and randomly assigned to: control (saline-placebo; n=8) and AVP (n=8) groups. The study group was infused with AVP for three consecutive 10-minute periods at logarithmically increasing doses (0.01; 0.1 and 1.0U/kg/min), at them 20-min intervals. Heart rate (HR) and intravascular pressures were continuously recorded. Cardiac output was measured by the thermodilution method. RESULTS: No significant hemodynamic effects were observed during 0.01U/kg/min of AVP infusion, but at higher doses (0.1 and 1.0U/kg/min) a progressive increase in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) were observed, with a significant decrease in HR and the cardiac index (CI). A significant increase in the pulmonary vascular resistance index (PVRI) was also observed with the 1.0U/kg/min dose, mainly due to the decrease in the CI. CONCLUSION: AVP, when administered at doses between 0.1 and 1.0U/kg/min, induced significant increases in MAP and SVRI, with negative inotropic and chronotropic effects in healthy animals. Although these doses are ten to thousand times greater than those routinely used for the management of vasodilatory shock, our data confirm that AVP might be used carefully and under strict hemodynamic monitoring in clinical practice, especially if doses higher than 0.01 U/kg/min are needed. Martins, LC et al.

Distribution of flunixin residues in muscles of dairy cattle dosed with lipopolysaccharide or saline and treated with flunixin by intravenous or intramuscular injection

USDA-ARS?s Scientific Manuscript database

Twenty dairy cows received flunixin meglumine at 2.2 mg/kg bw, administered once daily by either the intravenous (IV) or intra muscular (IM) route for three consecutive days with either intravenous normal saline (NS) or lipopolysaccharide (LPS) providing a balanced design with five animals per group...

Using higher doses to compensate for tubing residuals in extended-infusion piperacillin-tazobactam.

PubMed

Lam, Wendy J; Bhowmick, Tanaya; Gross, Alan; Vanschooneveld, Trevor C; Weinstein, Melvin P

2013-06-01

To mathematically assess drug losses due to infusion line residuals and evaluate methods to compensate for drug loss due to residual volumes in intravenous pump tubing. Literature was accessed through Ovid MEDLINE (1996-February 2013), using combinations of the search terms tubing residuals, residual volume, residual medication, intravenous infusions, intravenous injections, piperacillin, piperacillin-tazobactam, β-lactams, equipment design, infusion pumps, extended infusion, extended administration, and prolonged infusion. In addition, select reference citations from publications identified were reviewed. All articles that involved extended-infusion piperacillin-tazobactam implementation strategies were included in the review. Infusion pump characteristics and tubing residuals can affect extended-infusion piperacillin-tazobactam dosing strategies. Two studies addressing tubing residuals were identified. Both studies recommended increasing infusion volumes to compensate for tubing residuals. One study also recommended decreasing infusion-line dead space by using alternative infusion pump systems. Study calculations suggest that higher doses of piperacillin-tazobactam may be used to account for medication left in tubing residuals if alternative infusion pump systems cannot be obtained, and increased infusion volumes are not an option. Extended-infusion piperacillin-tazobactam has been used as a method of maximizing pharmacodynamic target attainment. Use of higher doses of piperacillin-tazobactam may be a reasonable method to compensate for drug loss due to residual volumes in large-bore intravenous pump tubing.

Mercury poisoning through intravenous administration: Two case reports with literature review.

PubMed

Lu, Qiuying; Liu, Zilong; Chen, Xiaorui

2017-11-01

Metallic mercury poisoning through intravenous injection is rare, especially for a homicide attempt. Diagnosis and treatment of the disease are challenging. A 34-year-old male presented with pyrexia, chill, fatigue, body aches, and pain of the dorsal aspect of right foot. Another case is that of a 29-year-old male who committed suicide by injecting himself metallic mercury 15 g intravenously and presented with dizzy, dyspnea, fatigue, sweatiness, and waist soreness. The patient's condition in case 1 was deteriorated after initial treatment. Imaging studies revealed multiple high-density spots throughout the body especially in the lungs. On further questioning, the patient's girlfriend acknowledged that she injected him about 40 g mercury intravenously 11 days ago. The diagnosis was then confirmed with a urinary mercury concentration of 4828 mg/L. Surgical excision, continuous blood purification, plasma exchange, alveolar lavage, and chelation were performed successively in case 1. Blood irrigation and chelation therapy were performed in case 2. The laboratory test results and organ function of the patient in case 1 gradually returned to normal. However, in case 2, the patient's dyspnea was getting worse and he finally died due to toxic encephalopathy and respiratory failure. Early diagnosis and appropriate treatment are critical for intravenous mercury poisoning. It should be concerned about the combined use of chelation agents and other treatments, such as surgical excision, hemodialysis and plasma exchange in clinical settings.

Development of a Monte Carlo multiple source model for inclusion in a dose calculation auditing tool.

PubMed

Faught, Austin M; Davidson, Scott E; Fontenot, Jonas; Kry, Stephen F; Etzel, Carol; Ibbott, Geoffrey S; Followill, David S

2017-09-01

The Imaging and Radiation Oncology Core Houston (IROC-H) (formerly the Radiological Physics Center) has reported varying levels of agreement in their anthropomorphic phantom audits. There is reason to believe one source of error in this observed disagreement is the accuracy of the dose calculation algorithms and heterogeneity corrections used. To audit this component of the radiotherapy treatment process, an independent dose calculation tool is needed. Monte Carlo multiple source models for Elekta 6 MV and 10 MV therapeutic x-ray beams were commissioned based on measurement of central axis depth dose data for a 10 × 10 cm 2 field size and dose profiles for a 40 × 40 cm 2 field size. The models were validated against open field measurements consisting of depth dose data and dose profiles for field sizes ranging from 3 × 3 cm 2 to 30 × 30 cm 2 . The models were then benchmarked against measurements in IROC-H's anthropomorphic head and neck and lung phantoms. Validation results showed 97.9% and 96.8% of depth dose data passed a ±2% Van Dyk criterion for 6 MV and 10 MV models respectively. Dose profile comparisons showed an average agreement using a ±2%/2 mm criterion of 98.0% and 99.0% for 6 MV and 10 MV models respectively. Phantom plan comparisons were evaluated using ±3%/2 mm gamma criterion, and averaged passing rates between Monte Carlo and measurements were 87.4% and 89.9% for 6 MV and 10 MV models respectively. Accurate multiple source models for Elekta 6 MV and 10 MV x-ray beams have been developed for inclusion in an independent dose calculation tool for use in clinical trial audits. © 2017 American Association of Physicists in Medicine.

SU-G-201-17: Verification of Dose Distributions From High-Dose-Rate Brachytherapy Ir-192 Source Using a Multiple-Array-Diode-Detector (MapCheck2)

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

Harpool, K; De La Fuente Herman, T; Ahmad, S

Purpose: To investigate quantitatively the accuracy of dose distributions for the Ir-192 high-dose-rate (HDR) brachytherapy source calculated by the Brachytherapy-Planning system (BPS) and measured using a multiple-array-diode-detector in a heterogeneous medium. Methods: A two-dimensional diode-array-detector system (MapCheck2) was scanned with a catheter and the CT-images were loaded into the Varian-Brachytherapy-Planning which uses TG-43-formalism for dose calculation. Treatment plans were calculated for different combinations of one dwell-position and varying irradiation times and different-dwell positions and fixed irradiation time with the source placed 12mm from the diode-array plane. The calculated dose distributions were compared to the measured doses with MapCheck2 delivered bymore » an Ir-192-source from a Nucletron-Microselectron-V2-remote-after-loader. The linearity of MapCheck2 was tested for a range of dwell-times (2–600 seconds). The angular effect was tested with 30 seconds irradiation delivered to the central-diode and then moving the source away in increments of 10mm. Results: Large differences were found between calculated and measured dose distributions. These differences are mainly due to absence of heterogeneity in the dose calculation and diode-artifacts in the measurements. The dose differences between measured and calculated due to heterogeneity ranged from 5%–12% depending on the position of the source relative to the diodes in MapCheck2 and different heterogeneities in the beam path. The linearity test of the diode-detector showed 3.98%, 2.61%, and 2.27% over-response at short irradiation times of 2, 5, and 10 seconds, respectively, and within 2% for 20 to 600 seconds (p-value=0.05) which depends strongly on MapCheck2 noise. The angular dependency was more pronounced at acute angles ranging up to 34% at 5.7 degrees. Conclusion: Large deviations between measured and calculated dose distributions for HDR-brachytherapy with Ir-192 may

Intravenous nicotine self-administration and cue-induced reinstatement in mice: Effects of nicotine dose, rate of drug infusion and prior instrumental training

PubMed Central

Fowler, Christie D.; Kenny, Paul J.

2011-01-01

Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg/kg/infusion) before access to higher doses, a slower rate of drug delivery (3-sec versus 1-sec infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressing for nicotine (0.03–0.4 mg/kg/infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-sec (FR5TO20) reinforcement schedule consumed the drug according to an inverted ‘U’-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice. PMID:21640128

Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution

PubMed Central

Heinemann, Günter; Fichtl, Burckhard; Vogt, Wolfgang

2003-01-01

Aims Vanadium is currently undergoing clinical trials as an oral drug in patients with noninsulin-dependent diabetes mellitus. Furthermore, vanadium occurs in elevated concentrations in the blood of patients receiving intravenous albumin solutions containing large amounts of the metal ion as an impurity. The present study was performed to examine the pharmacokinetics of vanadium in humans following a single intravenous (i.v.) dose of a commercial albumin solution containing a high amount of vanadium. Methods The study was conducted in five healthy volunteer subjects who received intravenously 90 ml of a commercial 20% albumin infusion solution containing 47.6 µg vanadium as an impurity. Vanadium concentrations in serum and urine were determined by electrothermal atomic absorption spectrometry. Results Vanadium serum concentrations after i.v. administration were measured for 31 days. The data could be fitted by a triexponential function corresponding formally to a three-compartment model. There was an initial rapid decrease in serum concentrations with half-lives of 1.2 and 26 h. This was followed by a long-terminal half-life time of 10 days. The terminal phase accounted for about 80% of the total area under the serum concentration-time curve (AUC). The mean apparent volume of distribution of the central compartment was found to be 10 l. The volume of distribution at steady state was 54 l, and total clearance was 0.15 l h−1. Vanadium was mainly excreted by the kidneys. About 52% of the dose was recovered in the urine after 12 days. Conclusions This study provides data on vanadium pharmacokinetics in healthy humans. PMID:12630973

[Adult-onset Still's disease with pulmonary and cardiac involvement and response to intravenous immunoglobulin].

PubMed

Neto, Nilton Salles Rosa; Waldrich, Leandro; de Carvalho, Jozélio Freire; Pereira, Rosa Maria Rodrigues

2009-01-01

Cardiopulmonary manifestations of adult-onset Still's disease (AOSD) include pericarditis, pleural effusion, transient pulmonary infiltrates, pulmonary interstitial disease and myocarditis. Serositis are common but pneumonitis and myocarditis are not and bring elevated risk of mortality. They may manifest on disease onset or flares. Previously reported cases were treated with high-dose glucocorticoids and immunosupressants and, when refractory, intravenous immunoglobulin (IVIG). We report an AOSD patient whose flare presented with severe pleupneumonitis and myopericarditis and, following nonresponse to a methylprednisolone pulse, high dose of prednisone and cyclosporine A, recovered after a 2-day 1g/kg/day IVIG infusion.

Plasma, salivary and urinary cortisol levels following physiological and stress doses of hydrocortisone in normal volunteers.

PubMed

Jung, Caroline; Greco, Santo; Nguyen, Hanh H T; Ho, Jui T; Lewis, John G; Torpy, David J; Inder, Warrick J

2014-11-26

Glucocorticoid replacement is essential in patients with primary and secondary adrenal insufficiency, but many patients remain on higher than recommended dose regimens. There is no uniformly accepted method to monitor the dose in individual patients. We have compared cortisol concentrations in plasma, saliva and urine achieved following "physiological" and "stress" doses of hydrocortisone as potential methods for monitoring glucocorticoid replacement. Cortisol profiles were measured in plasma, saliva and urine following "physiological" (20 mg oral) or "stress" (50 mg intravenous) doses of hydrocortisone in dexamethasone-suppressed healthy subjects (8 in each group), compared to endogenous cortisol levels (12 subjects). Total plasma cortisol was measured half-hourly, and salivary cortisol and urinary cortisol:creatinine ratio were measured hourly from time 0 (between 0830 and 0900) to 5 h. Endogenous plasma corticosteroid-binding globulin (CBG) levels were measured at time 0 and 5 h, and hourly from time 0 to 5 h following administration of oral or intravenous hydrocortisone. Plasma free cortisol was calculated using Coolens' equation. Plasma, salivary and urine cortisol at 2 h after oral hydrocortisone gave a good indication of peak cortisol concentrations, which were uniformly supraphysiological. Intravenous hydrocortisone administration achieved very high 30 minute cortisol concentrations. Total plasma cortisol correlated significantly with both saliva and urine cortisol after oral and intravenous hydrocortisone (P <0.0001, correlation coefficient between 0.61 and 0.94). There was no difference in CBG levels across the sampling period. An oral dose of hydrocortisone 20 mg is supraphysiological for routine maintenance, while stress doses above 50 mg 6-hourly would rarely be necessary in managing acute illness. Salivary cortisol and urinary cortisol:creatinine ratio may provide useful alternatives to plasma cortisol measurements to monitor replacement doses in

Impact of concomitant dexamethasone dosing schedule on bortezomib-induced peripheral neuropathy in multiple myeloma.

PubMed

Kumar, Shaji K; Laubach, Jacob P; Giove, Thomas J; Quick, Maureen; Neuwirth, Rachel; Yung, Godwin; Rajkumar, S Vincent; Richardson, Paul G

2017-09-01

Peripheral neuropathy (PN) is the most troublesome adverse event associated with the proteasome inhibitor bortezomib. Studies suggest an inflammatory aetiology for bortezomib-induced PN (BiPN) and it has been hypothesized that reducing inflammation with concomitant dexamethasone may reduce BiPN incidence and/or severity. We retrospectively analysed PN rates from 32 studies (2697 patients with previously untreated multiple myeloma) incorporating bortezomib and differing dexamethasone schedules: partnered dosing (days of and after bortezomib), weekly dosing, and other dosing schedules (e.g. days 1-4, 8-11). Pooled overall PN rates were 45·5%, 63·9%, and 47·5%, respectively, with 5·3%, 11·0%, and 9·6% grade ≥3. Adjusting for potential confounders (age, gender, presence of thalidomide, bortezomib treatment duration), PN rates in patients on partnered dosing schedules appeared lower than in patients on weekly or other dosing schedules. Analyses conducted using patient-level data suggest that cumulative dexamethasone dose, a potential confounding factor, is unlikely to have influenced the analyses. Findings were similar in a separate pooled analysis excluding data from regimens incorporating thalidomide, when pooled overall PN rates were 50·1%, 63·9%, and 48·3%, respectively, with 4·2%, 11·0%, and 8·6% grade ≥3. These findings suggest that partnered dexamethasone dosing may result in less severe BiPN compared with alternative dexamethasone dosing schedules. © 2017 John Wiley & Sons Ltd.

Intravenous ibuprofen: the first injectable product for the treatment of pain and fever

PubMed Central

Bookstaver, P Brandon; Miller, April D; Rudisill, Celeste N; Norris, LeAnn B

2010-01-01

This paper reviews the current data on the use of the first approved intravenous ibuprofen product for the management of post-operative pain and fever in the United States. The management of acute and post-operative pain and fever with nonsteroidal anti-inflammatory agents (NSAIDs) is well documented. A search in Medline and International Pharmaceutical Abstracts of articles until the end of November 2009 and references of all citations were conducted. Available manufacturer data on file were also analyzed for this report. Several randomized controlled studies have demonstrated the opioid-sparing and analgesic effects of 400 and 800 mg doses of intravenous ibuprofen in a series of post-operative patient populations. Two recent studies have also noted the improvement in fever curves in critically ill and burn patients. These data, along with pharmacokinetic and pharmacologic properties, are explored in this review, which addresses the clinical utility of a parenteral NSAID in a hospitalized patient for post-operative pain management and fever reduction. Further data on intravenous ibuprofen are needed to define long-term utilization, management of acute pain, and use in special populations. PMID:21197311

HIV-1 Expression Within Resting CD4+ T Cells After Multiple Doses of Vorinostat

PubMed Central

Archin, Nancy M.; Bateson, Rosalie; Tripathy, Manoj K.; Crooks, Amanda M.; Yang, Kuo-Hsiung; Dahl, Noelle P.; Kearney, Mary F.; Anderson, Elizabeth M.; Coffin, John M.; Strain, Matthew C.; Richman, Douglas D.; Robertson, Kevin R.; Kashuba, Angela D.; Bosch, Ronald J.; Hazuda, Daria J.; Kuruc, Joann D.; Eron, Joseph J.; Margolis, David M.

2014-01-01

Background. A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4+ T cells of treated, aviremic human immunodeficiency virus (HIV)–positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. Methods. Five participants in whom resting CD4+ T-cell–associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4+ T cells were assayed. Results. VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. Conclusions. Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥24 hours. The optimal schedule for VOR administration is still to be defined. PMID:24620025

Intravenous Sedation with Low-Dose Dexmedetomidine: Its Potential for Use in Dentistry

PubMed Central

Ogawa, Sachie; Seino, Hiroaki; Ito, Hiroshi; Yamazaki, Shinya; Ganzberg, Steven; Kawaai, Hiroyoshi

2008-01-01

This study investigated the physiologic and sedative parameters associated with a low-dose infusion of dexmedetomidine (Dex). Thirteen healthy volunteers were sedated with Dex at a loading dose of 6 mcg/kg/h for 5 minutes and a continuous infusion dose of 0.2 mcg/kg/h for 25 minutes. The recovery process was observed for 60 minutes post infusion. The tidal volume decreased significantly despite nonsignificant changes in respiratory rate, minute ventilation, oxygen saturation, and end-tidal carbon dioxide. The mean arterial pressure and heart rate also decreased significantly but within clinically acceptable levels. Amnesia to pin prick was present in 69% of subjects. A Trieger dot test plot error ratio did not show a significant change at 30 minutes post infusion despite a continued significant decrease in bispectral index. We conclude that sedation with a low dose of Dex appears to be safe and potentially efficacious for young healthy patients undergoing dental procedures. PMID:18788843

Intravenous pyelogram

MedlinePlus

... is Performed An IVP can be used to evaluate: An abdominal injury Bladder and kidney infections Blood ... IVP Images Kidney anatomy Kidney - blood and urine flow Intravenous pyelogram References Bishoff JT, Rastinehad AR. Urinary ...

The use of a low dose hydrocortisone to prevent pulmonary embolism in patients with multiple trauma.

PubMed

Chaari, Anis; Ghadhoune, Hatem; Chakroune, Olfa; Abid, Hanen; Turki, Olfa; Bahloul, Mabrouk; Bouaziz, Mounir

2013-08-01

Venous thromboembolism events are common in trauma patients. Immediate acute inflammation following injury triggers coagulation cascade and may increase the risk of pulmonary embolism (PE) in this population. We aimed to evaluate whether early low-dose steroids prevent symptomatic PE onset in multiple trauma patients. The medical surgical intensive care unit of Habib Bourguiba University Hospital (Sfax--Tunisia). Comparative study of two cohorts: a retrospective cohort of patients who didn't receive early low-dose steroids (steroid (-) group) and a prospective cohort of patients who received hydrocortisone with a dose of 100 mg/8 h for a scheduled period of 7 days (steroid (+) group). All adult patients admitted in our intensive care unit (ICU) for multiple trauma with predicted duration of mechanical ventilation over 48 h were included. Evaluation of the impact of low-dose steroids on the incidence of symptomatic PE. We included 175 patients: 92 in the steroids (-) group and 83 in the steroids (+) group. PE was diagnosed in 15 patients (8.5 %). The incidence of PE was significantly lower in steroid (+) group (3.6 vs 13 %; p = 0.013). In multivariate analysis, independent factors predicting PE onset were meningeal hemorrhage [OR = 14.7; 95 % CI (2.2-96.3); p = 0.013] and pelvic ring trauma [OR = 8; 95 % CI (1.8-36.4); p = 0.007] whereas low-dose steroids were significantly associated with a protective effect [OR = 0.2; 95 % CI (0.05-0.77); p = 0.019]. There was no significant difference between steroids (+) and steroids (-) groups neither in terms of mean ICU length of stay (LOS) (respectively 11 ± 9.7 and 12.3 ± 10.7 days; p = 0.372) nor in terms of ICU mortality (respectively 29.3 and 24.1 %; p = 0.434). Steroids are effective in reducing the incidence of PE in multiple trauma patients. However, no significant benefice was found on ICU mortality.

Effect of the NEP inhibitor SCH32615 on airway responses to intravenous substance P in guinea pigs.

PubMed

Shore, S A; Martins, M A; Drazen, J M

1992-11-01

We examined the effects of the selective neutral endopeptidase (NEP) inhibitor SCH32615 on airway responses to rapid intravenous infusions of substance P (SP) and neurokinin A (NKA) and on recovery of administered tachykinins from arterial blood in anesthetized mechanically ventilated guinea pigs. SCH32615, in doses that cause a marked increase in the magnitude of bronchoconstriction induced by infused NKA, had little effect on the changes in pulmonary conductance (GL) or dynamic compliance induced by SP. In animals in which SCH32615 (1 mg/kg) was administered in combination with the angiotensin-converting enzyme (ACE) inhibitor captopril (5.7 mg/kg), the dose of SP required to decrease GL by 50% was fourfold less than in animals that received captopril alone (P < 0.005). SP measured in arterial blood withdrawn within 45 s of intravenous administration of this tachykinin was not different in control and SCH32615-treated animals, whereas captopril caused an approximately threefold increase in SP concentrations (P < 0.005). When SCH32615 and captopril were administered together, significantly more SP was recovered than when captopril or SCH32615 was administered alone (P < 0.0005). Our results are consistent with the hypothesis that both NEP and ACE contribute to the degradation of intravenously infused SP. ACE degradation of SP is sufficient to limit SP-induced bronchoconstriction even in the presence of specific NEP inhibition.

Acute Toxicity of Amorphous Silica Nanoparticles in Intravenously Exposed ICR Mice

PubMed Central

Wang, Wen; Jin, Minghua; Du, Zhongjun; Li, Yanbo; Duan, Junchao; Yu, Yongbo; Sun, Zhiwei

2013-01-01

This study aimed to evaluate the acute toxicity of intravenously administrated amorphous silica nanoparticles (SNPs) in mice. The lethal dose, 50 (LD50), of intravenously administrated SNPs was calculated in mice using Dixon's up-and-down method (262.45±33.78 mg/kg). The acute toxicity was evaluated at 14 d after intravenous injection of SNPs at 29.5, 103.5 and 177.5 mg/kg in mice. A silicon content analysis using ICP-OES found that SNPs mainly distributed in the resident macrophages of the liver (10.24%ID/g), spleen (34.78%ID/g) and lung (1.96%ID/g). TEM imaging showed only a small amount in the hepatocytes of the liver and in the capillary endothelial cells of the lung and kidney. The levels of serum LDH, AST and ALT were all elevated in the SNP treated groups. A histological examination showed lymphocytic infiltration, granuloma formation, and hydropic degeneration in liver hepatocytes; megakaryocyte hyperplasia in the spleen; and pneumonemia and pulmonary interstitial thickening in the lung of the SNP treated groups. A CD68 immunohistochemistry stain indicated SNPs induced macrophage proliferation in the liver and spleen. The results suggest injuries induced by the SNPs in the liver, spleen and lungs. Mononuclear phagocytic cells played an important role in the injury process. PMID:23593469

Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

PubMed

Cvrčková, Fatima; Luštinec, Jiří; Žárský, Viktor

2015-01-01

We usually expect the dose-response curves of biological responses to quantifiable stimuli to be simple, either monotonic or exhibiting a single maximum or minimum. Deviations are often viewed as experimental noise. However, detailed measurements in plant primary tissue cultures (stem pith explants of kale and tobacco) exposed to varying doses of sucrose, cytokinins (BA or kinetin) or auxins (IAA or NAA) revealed that growth and several biochemical parameters exhibit multiple reproducible, statistically significant maxima over a wide range of exogenous substance concentrations. This results in complex, non-monotonic dose-response curves, reminiscent of previous reports of analogous observations in both metazoan and plant systems responding to diverse pharmacological treatments. These findings suggest the existence of a hitherto neglected class of biological phenomena resulting in dose-response curves exhibiting periodic patterns of maxima and minima, whose causes remain so far uncharacterized, partly due to insufficient sampling frequency used in many studies.

Pharmacokinetics of voriconazole after oral administration of single and multiple doses in African grey parrots (Psittacus erithacus timneh).

PubMed

Flammer, Keven; Nettifee Osborne, Julie A; Webb, Donna J; Foster, Laura E; Dillard, Stacy L; Davis, Jennifer L

2008-01-01

To determine the pharmacokinetics and safety of orally administered voriconazole in African grey parrots. 20 clinically normal Timneh African grey parrots (Psittacus erithacus timneh). In single-dose trials, 12 parrots were each administered 6, 12, and 18 mg of voriconazole/kg orally and plasma concentrations of voriconazole were determined via high-pressure liquid chromatography. In a multiple-dose trial, voriconazole (18 mg/kg) was administered orally to 6 birds every 12 hours for 9 days; a control group (2 birds) received tap water. Treatment effects were assessed via observation, clinicopathologic analyses (3 assessments), and measurement of trough plasma voriconazole concentrations (2 assessments). Voriconazole's elimination half-life was short (1.1 to 1.6 hours). Higher doses resulted in disproportional increases in the maximum plasma voriconazole concentration and area under the curve. Trough plasma voriconazole concentrations achieved in the multiple-dose trial were lower than those achieved after administration of single doses. Polyuria (the only adverse treatment effect) developed in treated and control birds but was more severe in the treatment group. In African grey parrots, voriconazole has dose-dependent pharmacokinetics and may induce its own metabolism. Oral administration of 12 to 18 mg of voriconazole/kg twice daily is a rational starting dose for treatment of African grey parrots infected with Aspergillus or other fungal organisms that have a minimal inhibitory concentration for voriconazole < or = 0.4 microg/mL. Higher doses may be needed to maintain plasma voriconazole concentrations during long-term treatment. Safety and efficacy of various voriconazole treatment regimens in this species require investigation.

Rash, fever, and chills after intravenous fluorescein angiography.

PubMed

Johnson, R N; McDonald, H R; Schatz, H

1998-12-01

To report a previously unreported complication associated with intravenous injection of fluorescein dye. Case report. A 75-year-old man developed a unique complication after intravenous injection of fluorescein dye for angiography. Two hours after receiving an intravenous injection of fluorescein for angiography, the patient developed a fever, rash, and chills. Admission to a hospital and careful systemic evaluation determined that this reaction was a noninfectious allergic response to intravenous fluorescein dye injection. A delayed allergic response to intravenous fluorescein dye injection can occur.

Administration of Intravenous Inf liximab for Prevention of Peritoneal Adhesions Formation in Rats.

PubMed

Nikeghbalian, Saman; Vafaei, Homeira; Moradian, Farid; Kazemi, Kourosh; Tanideh, Nader; Shayan, Leila; Nikeghbalian, Zahra

2015-07-01

To investigate the effects of intravenous infliximab in preventing the formation of peritoneal adhesions in an animal model of rat. This was an experimental study being performed in animal laboratory of Shiraz University of Medical Sciences during 2012. Sixty albino rats were randomly assigned in to three groups by Random Design Method. The first group received single infliximab injection (n=20), the second one received double infliximab injection (n=20) and the third received nothing (n=20), after receiving intra-peritoneal injection of talc for induction of peritoneal adhesions. All the animals were sacrificed after 6 weeks and the peritoneal adhesions were evaluated according to Nair classification. We observed that the mean adhesion grade was lower in those who received double dose of infliximib when compared to single dose and controls. However the difference did not reach a significant value (p=0.178). The grade of peritoneal adhesion was also comparable between the three study groups (p=0.103). The mean number of 1st WBC count was also comparable between three study groups (p=0.382). We observed that 2nd WBC count was also comparable between two study groups (p=0.317). Administration of intravenous infliximab after intraabdominal surgicalprocedures would not prevent the formation of peritoneal adhesions in animal model of albino rat.

Intravenous Esomeprazole for Prevention of Peptic Ulcer Rebleeding: A Randomized Trial in Chinese Patients.

PubMed

Bai, Yu; Chen, Dong-Feng; Wang, Rong-Quan; Chen, You-Xiang; Shi, Rui-Hua; Tian, De-An; Chen, Huifang; Eklund, Stefan; Li, Zhao-Shen

2015-11-01

High-dose intravenous esomeprazole is the only approved pharmacological treatment for the prevention of peptic ulcer rebleeding (currently approved in over 100 countries worldwide), but has not yet been approved in China. This study aimed to evaluate a high-dose esomeprazole intravenous regimen vs. an active control (cimetidine) for the prevention of rebleeding in Chinese patients with a high risk of peptic ulcer rebleeding who had undergone primary endoscopic hemostatic treatment. This was a parallel-group study conducted at 20 centers in China. The study comprised a randomized, double-blind, intravenous treatment phase of 72 h in which 215 patients received either high-dose esomeprazole (80 mg + 8 mg/h) or cimetidine (200 mg + 60 mg/h), followed by an open-label oral treatment phase in which all patients received esomeprazole 40 mg tablets once daily for 27 days. The primary outcome was the rate of clinically significant rebleeding within the first 72 h after initial endoscopic hemostatic therapy. Secondary outcomes included the rates of clinically significant rebleeding within 7 and 30 days; proportions of patients who had endoscopic retreatment and other surgery due to rebleeding; and number of blood units transfused. The rate of clinically significant rebleeding within 72 h was low overall (3.3%) and numerically lower in patients treated with esomeprazole compared with cimetidine (0.9% vs. 5.6%). Overall, the results of the secondary outcomes also showed a numerical trend towards superiority of esomeprazole over cimetidine. All treatments were well tolerated. In this phase 3, multicenter, randomized trial conducted in China, esomeprazole showed a numerical trend towards superior clinical benefit over cimetidine in the prevention of rebleeding in patients who had successfully undergone initial hemostatic therapy of a bleeding peptic ulcer, with a similar safety and tolerability profile. These findings suggest that esomeprazole may be an

THE EFFECTS OF INTRAVENOUS INJECTIONS OF DICHLOROETHYLSULFIDE IN RABBITS, WITH SPECIAL REFERENCE TO ITS LEUCOTOXIC ACTION

PubMed Central

Pappenheimer, Alwin M.; Vance, Morgan

1920-01-01

1. The lethal dose of dichloroethylsulfide (distilled from a German yellow cross shell), when injected intravenously into rabbits is from 0.005 to 0.01 gm. per kilo. 2. Rabbits dying within 24 hours showed extensive hemorrhages, and edema of the lungs. 3. Severe lesions of the intestinal tract were present in about one-third of the rabbits. 4. Dichloroethylsulfide injected intravenously is specifically poisonous for the hematopoietic tissues. Severe lesions are caused in the bone marrow, and the number of circulating leucocytes is markedly deminished. In animals surviving the injection regeneration occurs. The granular cells of the bone marrow seem to be more sensitive than the lymphoid cells and the erythrocytes. 5. The effect upon the blood and hematopoietic tissues is not due to the admixture of nitrobenzene or chlorobenzene in the shell filling. Injection of these substances in animals in amounts many times greater than the total dose of dichloroethylsulfide used produced no changes in the blood picture, and the subsequent injection of dichloroethylsulfide free from these solvents produced a typical reaction. PMID:19868389

Intravenous N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomized, Controlled Trials

PubMed Central

Sun, Zikai; Fu, Qiang; Cao, Longxing; Jin, Wen; Cheng, LingLing; Li, Zhiliang

2013-01-01

Background Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media. Study Design Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed. Results Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q = 17.42, P = 0.04; I2 = 48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics. Conclusion This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different

Carfilzomib-dexamethasone versus subcutaneous or intravenous bortezomib in relapsed or refractory multiple myeloma: secondary analysis of the phase 3 ENDEAVOR study.

PubMed

Goldschmidt, Hartmut; Moreau, Philippe; Ludwig, Heinz; Niesvizky, Ruben; Chng, Wee-Joo; Joshua, Douglas; Weisel, Katja; Spencer, Andrew; Orlowski, Robert Z; Feng, Shibao; Iskander, Karim S; Dimopoulos, Meletios A

2018-06-01

This is a secondary analysis of the phase 3 ENDEAVOR study comparing relapsed and/or refractory multiple myeloma (RRMM) patients receiving carfilzomib-dexamethasone (Kd) with those receiving subcutaneous (SC) bortezomib with dexamethasone (Vd) or intravenous (IV) Vd. Of Kd-treated patients, 356 Kd were pre-selected (by physician prior to randomization if to be randomized to Vd) for SC Vd (Kd [SC Vd]) and 108 for IV Vd (Kd [IV Vd], respectively. Of Vd-treated patients, 360 received SC Vd and 75 IV Vd. Kd (SC Vd) median PFS was not reached; SC Vd was 9.5 months. Median PFS for Kd (IV Vd) and IV Vd were 22.2 and 8.5 months, respectively. Median PFS was significantly longer and response rates were higher for Kd versus retreatment with bortezomib (SC or IV Vd) and in bortezomib naive patients. Overall, Kd was superior to Vd in RRMM regardless of route of bortezomib administration or prior bortezomib exposure.

Induction of anti-glioma natural killer cell response following multiple low-dose intracerebral CpG therapy.

PubMed

Alizadeh, Darya; Zhang, Leying; Brown, Christine E; Farrukh, Omar; Jensen, Michael C; Badie, Behnam

2010-07-01

Stimulation of toll-like receptor-9 by CpG oligodeoxynucleotides (CpG-ODN) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. These studies, however, have used high doses of CpG-ODN, which can induce toxicity in a clinical setting. The goal of this study was to evaluate the antitumor efficacy of multiple low-dose intratumoral CpG-ODN in a glioma model. Mice bearing 4-day-old intracranial GL261 gliomas received a single or multiple (two or four) intratumoral injections of CpG-ODN (3 microg) every 4 days. Tumor growth was measured by bioluminescent imaging, brain histology, and animal survival. Flow cytometry and cytotoxicity assays were used to assess anti-glioma immune response. Two and four intracranial injections of low-dose CpG-ODN, but not a single injection, eradicated gliomas in 70% of mice. Moreover, surviving animals exhibited durable tumor-free remission (> 3 months) and were protected from intracranial rechallenge with GL261 gliomas, showing the capacity for long-term antitumor immunity. Although most inflammatory cells seemed to increase, activated natural killer (NK) cells (i.e., NK(+)CD107a(+)) were more frequent than CD8(+)CD107a(+) in the brains of rechallenged CpG-ODN-treated animals and showed a stronger in vitro cytotoxicity against GL261 target cells. Leukocyte depletion studies confirmed that NK cells played an important role in the initial CpG-ODN antitumor response, but both CD8 and NK cells were equally important in long-term immunity against gliomas. These findings suggest that multiple low-dose intratumoral injections of CpG-ODN can eradicate intracranial gliomas possibly through mechanisms involving NK-mediated effector function.

Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

PubMed Central

Filippi, M; Campi, A; Martinelli, V; Colombo, B; Yousry, T; Canal, N; Scotti, G; Comi, G

1995-01-01

This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P < 0.0009) and the one hour delayed scans (P = 0.04). These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients. Images PMID:8530944

Randomized clinical trial of oral and intravenous versus intravenous antibiotic prophylaxis for laparoscopic colorectal resection.

PubMed

Ikeda, A; Konishi, T; Ueno, M; Fukunaga, Y; Nagayama, S; Fujimoto, Y; Akiyoshi, T; Yamaguchi, T

2016-11-01

The use of oral prophylactic antibiotics for the prevention of surgical-site infection (SSI) in patients undergoing laparoscopic surgery for colorectal cancer is controversial. The aim of this RCT was to evaluate whether intravenous perioperative antibiotics are inferior to combined preoperative oral and perioperative intravenous antibiotics in this setting. Patients undergoing elective laparoscopic colorectal resection in a single cancer centre were assigned randomly to combined preoperative oral antibiotics (metronidazole and kanamycin) and perioperative intravenous antibiotics (cefmetazole) (oral/IV group) or to perioperative intravenous antibiotics (cefmetazole) alone (IV-only group). Patients were stratified for the analyses based on type of operation (colonic surgery, anterior resection or abdominoperineal resection), preoperative use of mechanical bowel preparation, preoperative chemoradiotherapy and the presence of diabetes mellitus. The primary endpoint was the overall rate of SSI. Secondary endpoints were the rates of incisional site infection, organ/space infection, anastomotic leakage, intra-abdominal abscess, adverse events and postoperative complications. Of 540 patients offered participation in the trial in 2013-2014, 515 agreed to take part and were randomized. Some 256 patients in the IV-only group and 255 in the oral/IV group completed the treatment per protocol. The overall rate of SSI was 7·8 per cent (20 of 256) in the IV-only group and 7·8 per cent (20 of 255) in the oral/IV group, confirming that perioperative administration of intravenous antibiotics alone was not inferior to the combined regimen (P = 0·017). There were no differences in rates of incisional site infection (5·5 versus 5·9 per cent respectively), organ/space infection (2·3 versus 2·0 per cent) or other secondary endpoints between the two groups. Intravenous perioperative antimicrobial prophylaxis alone is not inferior to combined preoperative oral and intravenous

Safety of peripheral intravenous administration of vasoactive medication.

PubMed

Cardenas-Garcia, Jose; Schaub, Karen F; Belchikov, Yuly G; Narasimhan, Mangala; Koenig, Seth J; Mayo, Paul H

2015-09-01

Central venous access is commonly performed to administer vasoactive medication. The administration of vasoactive medication via peripheral intravenous access is a potential method of reducing the need for central venous access. The aim of this study was to evaluate the safety of vasoactive medication administered through peripheral intravenous access. Over a 20-month period starting in September 2012, we monitored the use of vasoactive medication via peripheral intravenous access in an 18-bed medical intensive care unit. Norepinephrine, dopamine, and phenylephrine were all approved for use through peripheral intravenous access. A total of 734 patients (age 72 ± 15 years, male/female 398/336, SAPS II score 75 ± 15) received vasoactive medication via peripheral intravenous access 783 times. Vasoactive medication used was norepinephrine (n = 506), dopamine (n = 101), and phenylephrine (n = 176). The duration of vasoactive medication via peripheral intravenous access was 49 ± 22 hours. Extravasation of the peripheral intravenous access during administration of vasoactive medication occurred in 19 patients (2%) without any tissue injury following treatment, with local phentolamine injection and application of local nitroglycerin paste. There were 95 patients (13%) receiving vasoactive medication through peripheral intravenous access who eventually required central intravenous access. Administration of norepinephrine, dopamine, or phenylephrine by peripheral intravenous access was feasible and safe in this single-center medical intensive care unit. Extravasation from the peripheral intravenous line was uncommon, and phentolamine with nitroglycerin paste were effective in preventing local ischemic injury. Clinicians should not regard the use of vasoactive medication is an automatic indication for central venous access. © 2015 Society of Hospital Medicine.

Vestibulo-ocular reflexes in rabbits: reduction by intravenous injection of diazepam.

PubMed

Barmack, N H; Pettorossi, V E

1980-11-01

We have studied the influence of intravenously administered diazepam on the horizontal (HVOR) and vertical (VVOR) vestibulo-ocular reflexes of the rabbit. The HVOR and VVOR were evoked by sinusoidal oscillation of rabbits on a rate table (0.01 to 0.8 Hz, +/- 10 degrees), and eye movements were measured with an infrared light-projection technique. The gains of the HVOR and VVOR (evoked eye velocity/head velocity) were reduced by diazepam injections of 5 microgram/kg. The dose required to produce a 50% reduction in HVOR gain was 500 microgram/kg. The time required to reduce the HVOR gain to 50% of its maximal reduction at dose of 400 microgram/kg (0.4 Hz +/- 10 degrees) was 60 s. These data suggest that diazepam might be effective as an anti-motion-sickness agent.

Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

PubMed

Lu, P; Fleischmann, R; Curtis, C; Ignatenko, S; Clarke, S H; Desai, M; Wong, S L; Grebe, K M; Black, K; Zeng, J; Stolzenbach, J; Medema, J K

2018-02-01

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

Central nervous system aspergillosis in an immunocompetent patient: cure in a hospice setting with very high-dose itraconazole.

PubMed

Palanisamy, Akilesh; Chao, Stephanie D; Fouts, Michelle; Kerr, Derek

2005-01-01

Aspergillosis of the central nervous system (CNS) is a rare condition with exceedingly high mortality. This study describes the case of an immunocompetent 42-year-old man with a history of intravenous drug use and hepatitis C who developed multiple Aspergillus lesions in the cerebellum. Despite neurosurgery and antifungal therapy with amphotericin B, he had a protracted hospital course with multiple complications, eventually developing cognitive and motor impairment due to progressive cerebellar lesions. After transfer to hospice and palliative care service, oral itraconazole was escalated to 1600 mg/day with the hope of palliating headache, nausea, and cognitive impairment. Remarkably, the patient stabilized and improved over time. After 14 months, this unprecedented high-dose regimen was discontinued, and the patient was discharged home with only mild cerebellar motor impairment.

Intravenous iron sucrose therapy for moderate to severe anaemia in pregnancy.

PubMed

Kriplani, Alka; Mahey, Reeta; Dash, Biswa Bhusan; Kulshreshta, Vidushi; Agarwal, Nutan; Bhatla, Neerja

2013-01-01

Iron deficiency anaemia (IDA) is the most common nutritional deficiency in pregnancy. Prophylactic oral iron is recommended during pregnancy to meet the increased requirement. In India, women become pregnant with low baseline haemoglobin level resulting in high incidence of moderate to severe anaemia in pregnancy where oral iron therapy cannot meet the requirement. Pregnant women with moderate anaemia are to be treated with parentral iron therapy. This study was undertaken to evaluate the response and effect of intravenous iron sucrose complex (ISC) given to pregnant women with IDA. A prospective study was conducted (June 2009 to June 2011) in the department of Obstetrics & Gynecology, All India Institute of Medical Sciences, New Delhi. One hundred pregnant women with haemoglobin between 5-9 g% with diagnosed iron deficiency attending antenatal clinic were given intravenous iron sucrose complex in a dose of 200 mg twice weekly schedule after calculating the dose requirement. The mean haemoglobin raised from 7.63 ± 0.61 to 11.20 ± 0.73 g% (P<0.001) after eight wk of therapy. There was significant rise in serum ferritin levels (from 11.2 ± 4.7 to 69 ± 23.1 μg/l) (P<0.001). Reticulocyte count increased significantly after two wk of starting therapy (from 1.5 ± 0.6 to 4.6 ± 0.8%).Other parameters including serum iron levels and red cell indices were also improved significantly. Only one woman was lost to follow up. No major side effects or anaphylactic reactions were noted during study period. Parentral iron therapy was effective in increasing haemoglobin, serum ferritin and other haematological parameters in pregnant women with moderate anaemia. Intravenous iron sucrose can be used in hospital settings and tertiary urban hospitals where it can replace intramuscular therapy due to injection related side effects. Further, long-term comparative studies are required to recommend its use at peripheral level.

Cost-effectiveness analysis of dose-dense versus standard intravenous chemotherapy for ovarian cancer: An economic analysis of results from the Gynecologic Oncology Group protocol 262 randomized controlled trial.

PubMed

Seagle, Brandon-Luke L; Shahabi, Shohreh

2017-04-01

To determine the cost-effectiveness of dose-dense versus standard intravenous adjuvant chemotherapy for ovarian cancer using results from the no-bevacizumab cohort of the Gynecologic Oncology Group protocol 262 (GOG-262) randomized controlled trial, which reported a smaller absolute progression-free survival (PFS) benefit than the prior Japanese trial. A three-state Markov decision model from a healthcare system perspective with a 21day cycle length and 28month time-horizon was used to calculate incremental cost-effectiveness ratio (ICER) values per progression-free life-year saved (PFLYS) using results from GOG-262. Costs of chemotherapy, complications, and surveillance were from Medicare or institutional data. PFS, discontinuation, and complication rates were from GOG-262. Time-dependent transition probabilities and within-cycle corrections were used. One-way and probabilistic sensitivity analyses were performed. The model produces standard and dose-dense cohorts with 84.3% and 68.3% progression event proportions at 28months, matching GOG-262 rates at the trial's median follow-up. With a median PFS of 10.3months after standard chemotherapy and a hazard ratio for progression of 0.62 after dose-dense therapy, the ICER for dose-dense chemotherapy is $8074.25 (95% confidence interval: $7615.97-$10,207.16) per PFLYS. ICER estimates are sensitive only to the hazard ratio estimate but do not exceed $100,000 per PFLYS. 99.8% of ICER estimates met a more stringent willingness-to-pay of $50,000 per PFLYS. The willingness-to-pay value at which there is a 90% probability of dose-dense treatment being cost-effective is $12,000 per PFLYS. Dose-dense adjuvant chemotherapy is robustly cost-effective for advanced ovarian cancer from a healthcare system perspective based on results from GOG-262. Copyright © 2017 Elsevier Inc. All rights reserved.