Transethosomal gels as carriers for the transdermal delivery of colchicine: statistical optimization, characterization, and ex vivo evaluation

PubMed Central

Abdulbaqi, Ibrahim M; Darwis, Yusrida; Assi, Reem Abou; Khan, Nurzalina Abdul Karim

2018-01-01

Introduction Colchicine is used for the treatment of gout, pseudo-gout, familial Mediterranean fever, and many other illnesses. Its oral administration is associated with poor bioavailability and severe gastrointestinal side effects. The drug is also known to have a low therapeutic index. Thus to overcome these drawbacks, the transdermal delivery of colchicine was investigated using transethosomal gels as potential carriers. Methods Colchicine-loaded transethosomes (TEs) were prepared by the cold method and statistically optimized using three sets of 24 factorial design experiments. The optimized formulations were incorporated into Carbopol 940® gel base. The prepared colchicine-loaded transethosomal gels were further characterized for vesicular size, dispersity, zeta potential, drug content, pH, viscosity, yield, rheological behavior, and ex vivo skin permeation through Sprague Dawley rats’ back skin. Results The results showed that the colchicine-loaded TEs had aspherical irregular shape, nanometric size range, and high entrapment efficiency. All the formulated gels exhibited non-Newtonian plastic flow without thixotropy. Colchicine-loaded transethosomal gels were able to significantly enhance the skin permeation parameters of the drug in comparison to the non-ethosomal gel. Conclusion These findings suggested that the transethosomal gels are promising carriers for the transdermal delivery of colchicine, providing an alternative route for drug administration. PMID:29670336

Transethosomal gels as carriers for the transdermal delivery of colchicine: statistical optimization, characterization, and ex vivo evaluation.

PubMed

Abdulbaqi, Ibrahim M; Darwis, Yusrida; Assi, Reem Abou; Khan, Nurzalina Abdul Karim

2018-01-01

Colchicine is used for the treatment of gout, pseudo-gout, familial Mediterranean fever, and many other illnesses. Its oral administration is associated with poor bioavailability and severe gastrointestinal side effects. The drug is also known to have a low therapeutic index. Thus to overcome these drawbacks, the transdermal delivery of colchicine was investigated using transethosomal gels as potential carriers. Colchicine-loaded transethosomes (TEs) were prepared by the cold method and statistically optimized using three sets of 24 factorial design experiments. The optimized formulations were incorporated into Carbopol 940 ® gel base. The prepared colchicine-loaded transethosomal gels were further characterized for vesicular size, dispersity, zeta potential, drug content, pH, viscosity, yield, rheological behavior, and ex vivo skin permeation through Sprague Dawley rats' back skin. The results showed that the colchicine-loaded TEs had aspherical irregular shape, nanometric size range, and high entrapment efficiency. All the formulated gels exhibited non-Newtonian plastic flow without thixotropy. Colchicine-loaded transethosomal gels were able to significantly enhance the skin permeation parameters of the drug in comparison to the non-ethosomal gel. These findings suggested that the transethosomal gels are promising carriers for the transdermal delivery of colchicine, providing an alternative route for drug administration.

Studies on a morphologically distinct colchicine-resistance variant of Entamoeba sp.

PubMed

Injeyan, H; Huebner, E; Meerovitch, E

1979-05-01

Colchicine has a temperature-dependent cytotoxic effect on Entamoeba sp. (Laredo isolate) that is most apparent when the drug is applied during the initiation of cultures at a concentration of 7.5 mM or higher. Continued transfer of cultures in medium containing progressively increasing concentrations of colchicine has resulted in a variant that grows prolifically in the presence of colchicine (7.5 mM) with a generation time comparable to that of the parent stock, Comparison of a number of parameters of the 2 variants revealed that colchicine resistance was accompanied by a change in cell shape, a reduced membrane permeability, which could partially be overcome by the addition of dimethyl sulfoxide (DMSO), and a reduced tolerance to osmotic stress. However, the parent strain and resistant variant were equally susceptible to cycloheximide and puromycin suggesting that the acquired colchicine resistance may not be explained on the basis of an entirely unspecific generalized reduced ability for drug uptake. Colchicine resistance and altered structure were found to be stable over a long period of time. The possible interdependence of these 2 parameters and their relation to cell motility in Entamoeba sp. are discussed.

Acute oral toxicity of colchicine in rats: effects of gender, vehicle matrix and pre-exposure to lipopolysaccharide.

PubMed

Wiesenfeld, Paddy L; Garthoff, Larry H; Sobotka, Thomas J; Suagee, Jessica K; Barton, Curtis N

2007-01-01

The oral toxicity of a single administration by gavage (10, 20 or 30 mg kg(-1) body weight) of colchicine (COL) was determined in young, mature male and female Sprague-Dawley rats. The effect of COL was evaluated in the presence or absence of additional treatment variables that included vehicle and lipopolysaccharide (LPS) pre-exposure. The vehicle for COL was either Half and Half cream (H & H) or saline, and each group included pretreatment with either saline or a low, minimally toxic dose (83 microg kg(-1) body weight) of LPS. Colchicine toxicity in both male and female age-matched rats was characterized by progressively more severe dose-related clinical signs of toxicity. These included mortality, decreased body weight and feed intake during the first several days after dosing, with recovery thereafter in surviving animals. There were differences in the severity of the toxic response to COL between male and female rats. The most notable sex-related difference was in COL lethality. Female rats were two times more susceptible to the lethal effects of COL than male rats. Saline or H & H delivery vehicles did not result in any apparent qualitative or quantitative differences in COL toxicity. LPS pretreatment significantly potentiated COL lethality in both males and females, although the potentiation in males was greater than in females. LPS pretreatment modestly increased the COL induced anorexic effect in surviving males, but not in surviving female animals. LPS did not appear to modulate either the body weights or clinical signs of COL induced toxicity in surviving males or females. (c) 2007 John Wiley & Sons, Ltd.

COMPARISON OF INTRACRANIAL INFUSIONS OF COLCHICINE AND IBOTENIC ACID AS MODELS OF NEURODEGENERATION IN THE BASAL FOREBRAIN

EPA Science Inventory

Colchicine and ibotenic acid were compared for their ability to roduce neurodegeneration and cognitive deficit after bilateral infusions into the nucleus basalis magnocellularis of male Long-Evans rats. our weeks post-lesion, there was no difference in locomotor activity followin...

Risk of Colchicine-Associated Myopathy in Gout: Influence of Concomitant Use of Statin.

PubMed

Kwon, Oh Chan; Hong, Seokchan; Ghang, Byeongzu; Kim, Yong-Gil; Lee, Chang-Keun; Yoo, Bin

2017-05-01

The purpose of this study was to investigate the risk of myopathy when statins are coadministered with colchicine in patients with gout. In gout patients who received colchicine with or without statin, clinical data collected included medications and history of hypertension, chronic kidney disease, and liver cirrhosis. Myopathy was defined as the presence of muscle symptoms with elevated creatine kinase or myoglobin. Multivariate analysis was performed to identify risk factors for myopathy. Inverse probability of treatment weighting (IPTW)-adjusted analysis was used to evaluate the influence of concomitant colchicine and statin use on myopathy. Of 674 patients, 486 received colchicine alone and 188 also received statin. The incidence of myopathy was not significantly higher in those on both drugs than in those on colchicine alone (2.7% vs 1.4%, P = .330). On multivariate analysis, chronic kidney disease (hazard ratio [HR] 29.056; 95% confidence interval [CI], 4.387-192.450; P <.001), liver cirrhosis (HR 10.676; 95% CI, 1.279-89.126; P = .029), higher colchicine dose (HR 20.960; 95% CI, 1.835-239.481; P = .014), and concomitant CYP3A4 inhibitor (HR 12.027; 95% CI, 2.743-52.725; P = .001) were associated with increased risk of myopathy. Concomitant use of statins, however, was not, even after adjusting for confounders (HR 1.123; 95% CI, 0.262-4.814; P = .875; IPTW-adjusted HR 0.321; 95% CI, 0.077-1.345; P = .120). Concomitant use of statin and colchicine was not associated with increased risk of myopathy. Thus, concomitant use of statin with colchicine seems to be safe from myotoxicity in gout patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of colchicine in pregnancy: a systematic review and meta-analysis.

PubMed

Indraratna, Praveen L; Virk, Sohaib; Gurram, Divya; Day, Richard O

2018-02-01

Colchicine is an anti-inflammatory agent used in the treatment of several rheumatological conditions. The use of colchicine in pregnancy is controversial. The current study aimed to systematically review and meta-analyse the existing data in the literature regarding the safety of colchicine in pregnancy. A systematic review was carried out using six electronic databases, identifying all relevant studies where colchicine was administered to pregnant women, and where pregnancy-related outcomes were measured. The primary endpoints were miscarriage and major foetal malformation. Secondary endpoints included birthweight and gestational age at birth. Four studies were included for meta-analysis. Use of colchicine throughout pregnancy was not associated with an increased incidence of miscarriage or major foetal malformations. The incidence of miscarriage was significantly lower in women who took colchicine compared with those that did not. In women with FMF who took colchicine throughout the pregnancy, there was no significant difference in birthweight or gestational age compared with those who did not take colchicine. When not limited to FMF, colchicine use was associated with a significantly lower birthweight and gestational age compared with a control group including healthy women who did not take colchicine. Colchicine therapy did not significantly increase the incidence of foetal malformations or miscarriage when taken during pregnancy. Colchicine therapy for FMF should not be withheld on this basis during pregnancy. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

PubMed

Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

2016-09-01

Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

Adverse interaction between colchicine and ketoconazole in a Chinese shar pei.

PubMed

McAlister, Amber; Center, Sharon A; Bender, Hannah; McDonough, Sean P

2014-01-01

A Chinese shar pei with a 2 yr history of episodic fever, lethargy, and shifting lameness was presumptively diagnosed with familial shar pei fever but had never been treated for the syndrome. After being presented for a superficial pyoderma with possible dermatophyte coinfection, treatment with a cephalosporin and ketoconazole were prescribed. One wk later, colchicine was initiated for familial shar pei fever using cautious dose escalation. Nevertheless, gastrointestinal toxicity, skeletal muscle myopathy, and hepatotoxicity developed within 2 wk. Abrupt resolution of gastrointestinal toxicity and myopathy followed drug withdrawal. However, escalating liver enzyme activity and hyperbilirubinemia led to liver biopsy to rule out an antecedent hepatopathy. Biopsy characterized canalicular cholestasis and colchicine-associated metaphase arrest and ring mitoses reflecting repression of mitotic spindle formation. Signs of illness completely resolved 3 mo after drug discontinuation. Although avoidable adverse interactions between ketoconazole and drugs reliant on cytochrome oxidase biotransformation and/or drug efflux mediated by multiple drug-resistant transporters are well documented in humans, these are rarely reported in veterinary patients. This case exemplifies an important and avoidable ketoconazole/colchicine drug interaction from which the patient completely recovered. The dog tested negative for the canine MDR1 loss of function mutation that also might potentiate colchicine toxicity.

Adding colchicine to immunosuppressive treatments; a potential option for biologics-refractory adult-onset Still's disease.

PubMed

Asano, Tomoyuki; Furuya, Makiko Yashiro; Sato, Shuzo; Kobayashi, Hiroko; Watanabe, Hiroshi; Suzuki, Eiji; Migita, Kiyoshi

2018-05-21

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder characterized by the classical triad of daily spiking fever, arthritis, and typical salmon-colored rash. Resistance to first-line corticosteroids and second-line disease modified anti-rheumatic-drugs defines refractory AOSD, which mostly includes the polycyclic or chronic courses of the disease. Anti-cytokine therapies are recommended in AOSD patients who are refractory to traditional treatments. This is the first report on the efficacy of colchicine in a patient with AOSD which was refractory to immunosuppressive treatments including biologics. A 24-years Japanese female patient was referred to our hospital for the flare-up of AOSD under the combined treatments with steroid, immunosuppressants, and biologics. She was diagnosed with AOSD according to the Yamaguchi criteria, based on the presence of spiking fever, polyarthralgia, skin rash, and hyperferritinemia. Interleukin-6 or tumor necrosis factor-α blockade treatments were not effective, the oral administration of colchicine was stared under the immunosuppressive treatments with steroid and cyclosporine A (CyA). Colchicine treatment silenced the disease activity of AOSD. The dose of prednisolone was successfully tapered, and the elevated levels of C-reactive protein were normalized. Remission has been maintained for 13 months with the start of oral administration of colchicine. We concluded that colchicine is an alternative treatment in patients with refractory AOSD, particularly in those with impaired therapeutic effects against anti-cytokines therapies.

Different disease subtypes with distinct clinical expression in familial Mediterranean fever: results of a cluster analysis.

PubMed

Akar, Servet; Solmaz, Dilek; Kasifoglu, Timucin; Bilge, Sule Yasar; Sari, Ismail; Gumus, Zeynep Zehra; Tunca, Mehmet

2016-02-01

The aim of this study was to evaluate whether there are clinical subgroups that may have different prognoses among FMF patients. The cumulative clinical features of a large group of FMF patients [1168 patients, 593 (50.8%) male, mean age 35.3 years (s.d. 12.4)] were studied. To analyse our data and identify groups of FMF patients with similar clinical characteristics, a two-step cluster analysis using log-likelihood distance measures was performed. For clustering the FMF patients, we evaluated the following variables: gender, current age, age at symptom onset, age at diagnosis, presence of major clinical features, variables related with therapy and family history for FMF, renal failure and carriage of M694V. Three distinct groups of FMF patients were identified. Cluster 1 was characterized by a high prevalence of arthritis, pleuritis, erysipelas-like erythema (ELE) and febrile myalgia. The dosage of colchicine and the frequency of amyloidosis were lower in cluster 1. Patients in cluster 2 had an earlier age of disease onset and diagnosis. M694V carriage and amyloidosis prevalence were the highest in cluster 2. This group of patients was using the highest dose of colchicine. Patients in cluster 3 had the lowest prevalence of arthritis, ELE and febrile myalgia. The frequencies of M694V carriage and amyloidosis were lower in cluster 3 than the overall FMF patients. Non-response to colchicine was also slightly lower in cluster 3. Patients with FMF can be clustered into distinct patterns of clinical and genetic manifestations and these patterns may have different prognostic significance. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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.

Topical Colchicine Gel versus Diclofenac Sodium Gel for the Treatment of Actinic Keratoses: A Randomized, Double-Blind Study.

PubMed

Faghihi, Gita; Elahipoor, Azam; Iraji, Fariba; Behfar, Shadi; Abtahi-Naeini, Bahareh

2016-01-01

Introduction. Actinic keratoses (AKs), a premalignant skin lesion, are a common lesion in fair skin. Although destructive treatment remains the gold standard for AKs, medical therapies may be preferable due to the comfort and reliability .This study aims to compare the effects of topical 1% colchicine gel and 3% diclofenac sodium gel in AKs. Materials and Methods. In this randomized double-blind study, 70 lesions were selected. Patients were randomized before receiving either 1% colchicine gel or 3% diclofenac sodium cream twice a day for 6 weeks. Patients were evaluated in terms of their lesion size, treatment complications, and recurrence at 7, 30, 60, and 120 days after treatment. Results. The mean of changes in the size was significant in both groups both before and after treatment (<0.001). The mean lesion size before treatment and at 30, 60, and 120 days was not different between the two groups (p > 0.05). No case of erythema was seen in the colchicine group, while erythema was seen in 22.9% (eight cases) of patients in the diclofenac sodium group (p = 0.005). Conclusions. 1% colchicine gel was a safe and effective medication with fewer side effects and lack of recurrence of the lesion.

Determination by flow cytometry polyploidy inducing-capacity of colchicine in Cajanus cajan (L.) Mill sp.

PubMed

Udensi, O U; Ontui, V

2013-07-01

The need to optimize flow cytometric analysis for the determination of ploidy level is a worthwhile venture to precisely know at what concentration of a mutagen and at what time of exposure polyploidy could be induced. Flow cytometry was used to determine the polyploidy inducing-capacity of colchicine in pigeon pea (Cajanus cajan (L.) Mill sp). Seeds of pigeon pea were soaked in three different concentrations of colchicine-5 mg, 10 and 15 mg L(-1) for 24, 48 and 72 h, respectively, while the control group was soaked in water. Treated seeds and those from the control were planted in a greenhouse using a Completely Randomized Design (CRD). Results show that colchicine induced tetraploids (4n) and mixoploids (2n+ 4n) as the concentration of colchicine increased and soaking duration. Days to seedling emergence increased as concentration of colchicine and duration of soaking increased while germination rate decreased proportionately with the increase in colchicine concentration and soaking duration but did not significantly affect percentage seedling survival. Explicitly, colchicine has the capacity of inducing polyploidy; especially tetraploids on the seeds of pigeon pea, which obviously could be harnessed for further breeding and improvement of the pigeon pea.

Pharmacokinetics and Bioavailability of Plant Lignan 7-Hydroxymatairesinol and Effects on Serum Enterolactone and Clinical Symptoms in Postmenopausal Women: A Single-Blinded, Parallel, Dose-Comparison Study

PubMed Central

Udani, Jay K.; Brown, Donald J.; Tan, Maria Olivia C.; Hardy, Mary

2013-01-01

Objective 7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. Methods A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 post-menopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Results Pharmacokinetic studies demonstrated 7-HMR Cmax = 757.08 ng/ml at 1 hour and ENL Cmax = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. Conclusion The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population. PMID:24606716

Pharmacokinetics and bioavailability of plant lignan 7-hydroxymatairesinol and effects on serum enterolactone and clinical symptoms in postmenopausal women: a single-blinded, parallel, dose-comparison study.

PubMed

Udani, Jay K; Brown, Donald J; Tan, Maria Olivia C; Hardy, Mary

2013-01-01

7-Hydroxymaitairesinol (7-HMR) is a naturally occurring plant lignan found in whole grains and the Norway spruce (Piciea abies). The purpose of this study was to evaluate the bioavailability of a proprietary 7-HMR product (HMRlignan, Linnea SA, Locarno, Switzerland) through measurement of lignan metabolites and metabolic precursors. A single-blind, parallel, pharmacokinetic and dose-comparison study was conducted on 22 postmenopausal females not receiving hormone replacement therapy. Subjects were enrolled in either a 36 mg/d (low-dose) or 72 mg/d dose (high-dose) regimen for 8 weeks. Primary measured outcomes included plasma levels of 7-HMR and enterolactone (ENL), and single-dose pharmacokinetic analysis was performed on a subset of subjects in the low-dose group. Safety data and adverse event reports were collected as well as data on hot flash frequency and severity. Pharmacokinetic studies demonstrated 7-HMR C max = 757.08 ng/ml at 1 hour and ENL C max = 4.8 ng/ml at 24 hours. From baseline to week 8, plasma 7-HMR levels increased by 191% in the low-dose group (p < 0.01) and by 1238% in the high-dose group (p < 0.05). Plasma ENL levels consistently increased as much as 157% from baseline in the low-dose group and 137% in the high-dose group. Additionally, the mean number of weekly hot flashes decreased by 50%, from 28.0/week to 14.3/week (p < 0.05) in the high-dose group. No significant safety issues were identified in this study. The results demonstrate that HMRlignan is quickly absorbed into the plasma and is metabolized to ENL in healthy postmenopausal women. Clinically, the data demonstrate a statistically significant improvement in hot flash frequency. Doses up to 72 mg/d HMRlignan for 8 weeks were safe and well tolerated in this population.

Structural and numerical chromosome aberration inducers in liver micronucleus test in rats with partial hepatectomy.

PubMed

Itoh, Satoru; Hattori, Chiharu; Nagata, Mayumi; Sanbuissho, Atsushi

2012-08-30

The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH. Copyright © 2012 Elsevier B.V. All rights reserved.

Recurrent Pericarditis: Modern Approach in 2016.

PubMed

Imazio, Massimo; Adler, Yehuda; Charron, Philippe

2016-06-01

Recurrent pericarditis is one of the most troublesome complications of pericarditis occurring in about one third of patients with a previous attack of pericarditis. The pathogenesis is presumed to be autoimmune and/or autoinflammatory in most cases. The mainstay of therapy for recurrences is physical restriction and anti-inflammatory therapy based on aspirin or NSAID plus colchicine. Corticosteroids at low to moderate doses (e.g., prednisone 0.2 to 0.5 mg/kg/day) should be considered only after failure of aspirin/NSAID (and more than one of these drugs) or for specific indications (e.g., pregnancy, systemic inflammatory diseases on steroids, renal failure, concomitant oral anticoagulant therapy). One of the most challenging issues is how to cope with patients who have recurrences despite colchicine. A small subset of patients (about 5 %) may develop corticosteroid-dependence and colchicine resistance. Among the emerging treatments, the three most common and evidence-based therapies are based on azathioprine, human intravenous immunoglobulin (IVIG), and anakinra. After failure of all options of medical therapy or for those patients who do not tolerate medical therapy or have serious adverse events related to medical therapy, the last possible option is the surgical removal of the pericardium. Total or radical pericardiectomy is recommended in these cases in experienced centers performing this surgery. A stepwise approach is recommended starting from NSAID and colchicine, corticosteroid and colchicine, a combination of the three options (NSAID, colchicine and corticosteroids), then azathioprine, IVIG, or anakinra as last medical options before pericardiectomy.

Acute renal failure associated with an accidental overdose of colchicine.

PubMed

Borrás-Blasco, J; Enriquez, R; Sirvent, A E; Amoros, F; Navarro-Ruiz, A; Reyes, A

2005-10-01

A 47-year-old man with a history of polyarticular gout was admitted to the nephrology service because of severe renal insufficiency (creatinine 6.25 mg/dl). Three days before admission he had a pain crisis in his knees and ankles and self-administered 20 x 1 mg granules of colchicine p.o. over a period of 4 - 5 hours together with six suppositories each containing 100 mg of indomethacin. The patient began vomiting within 24 hours, experienced diarrhea which persisted for three days and then came to the hospital. The patient reported oliguria during the preceding 24 hours. In hospital, attempts to correct water and electrolyte balance were initiated. The patient became stabilized hemo-dynamically, the diarrhea disappeared within 24 hours, diuresis resumed and the renal function progressively improved. Leukopenia and thrombopenia were diagnosed, the transaminases increased: AST = 79 U/l, ALT = 132 U/l on the eighth day after taking the colchicine. The serology for hepatitis A, B, C and HIV viruses was negative; the serology for CMV and VEB revealed a previous infection. After being discharged from hospital 11 days after admission, the patient presented with the following parameters: hematocrit 39%, leukocytes 5,920/microl (3 470 neutrophils), prothrombin time 13 seconds, urea 44 mg/dl, creatinine 1.29 mg/dl, AST 16 U/l and ALT 35 U/l. The patient mistakenly ingested 20 mg ofcolchicine p.o. (0.22 mg/kg). The intoxication was associated with gastroenterocolitis, dehydration and renal failure during the first three days after ingestion. The patient also developed leukopenia, thrombopenia and mild hepatocellular injury. Renal failure due to colchicine intoxication is due to various factors such as depletion of volume/hypotension, rhabdomyolysis and multiorgan failure. In this case, the hypovolemia was probably the fundamental cause of the acute renal insufficiency as demonstrated by the quick recovery after administering fluids. It is possible that indomethacin may have enhanced the toxic effect of colchicine on the kidneys and bone marrow. Some colchicine intoxications, as in this case, are caused by an error in interpreting the dose for treating an acute attack of gout. A way to prevent these errors would be to use a low-dose treatment protocol.

Micronucleated Erythrocytes in Peripheral Blood from Neonate Rats Exposed by Breastfeeding to Cyclophosphamide, Colchicine, or Cytosine-Arabinoside.

PubMed

Gómez-Meda, Belinda C; Bañales-Martínez, Luis R; Zamora-Perez, Ana L; Lemus-Varela, María de Lourdes; Trujillo, Xóchitl; Sánchez-Parada, María G; Torres-Mendoza, Blanca M; Armendáriz-Borunda, Juan; Zúñiga-González, Guillermo M

2016-01-01

Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs) and micronucleated polychromatic erythrocytes (MNPCEs) in the samples from pups in the experimental groups ( P < 0.02) and increased MNPCE frequencies in the samples from the dams ( P < 0.05). These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects.

Micronucleated Erythrocytes in Peripheral Blood from Neonate Rats Exposed by Breastfeeding to Cyclophosphamide, Colchicine, or Cytosine-Arabinoside

PubMed Central

Bañales-Martínez, Luis R.; Lemus-Varela, María de Lourdes; Trujillo, Xóchitl; Sánchez-Parada, María G.; Armendáriz-Borunda, Juan; Zúñiga-González, Guillermo M.

2016-01-01

Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs) and micronucleated polychromatic erythrocytes (MNPCEs) in the samples from pups in the experimental groups (P < 0.02) and increased MNPCE frequencies in the samples from the dams (P < 0.05). These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects. PMID:28018917

Differentiation by colchicine and vincristine sulphate of regenerative hepatocellular mitosis and tumour-associated hepatocellular mitosis.

PubMed

Parry, E W

1977-10-01

Colchicine and vincristine sulphate differentiate sharply between hepatocyte mitosis associated with the Ehrlich ascites tumour, and regenerative (post-CCl4 necrosis) hepatocyte mitosis. In the former case there is a gross depression of prophase index and a marked lowering of the overall mitotic index. In the latter, although a degree of prophase depression is evident, this is insufficient to prevent an overall substantial elevation of mitotic index due to accumulation at metaphase. Very low doses of colchicine claimed to be effective in stathmokinesis of hepatocytes under influence of hepatomitogenic tumour brei and tumour extracts, produced no discernible effect on the mitotic pattern of hepatocytes in Ehrlich ascites tumour-bearing mice nor in post-CCl4 regenerating livers. The results are discussed in the context of known features of tumour-associated hepatocellular mitosis.

Cytological diploidization of paleopolyploid genus Zea: Divergence between homoeologous chromosomes or activity of pairing regulator genes?

PubMed Central

2018-01-01

Cytological diploidization process is different in autopolyploid and allopolyploid species. Colchicine applied at the onset of meiosis suppresses the effect of pairing regulator genes resulting multivalents formation in bivalent-forming species. Colchicine treated maizes (4x = 2n = 20, AmAmBmBm) showed up to 5IV, suggesting pairing between chromosomes from genomes homoeologous Am and Bm. In untreated individuals of the alloautooctoploid Zea perennis (8x = 2n = 40, ApApAp´Ap´Bp1Bp1Bp2Bp2) the most frequent configuration was 5IV+10II (formed by A and B genomes, respectively). The colchicine treated Z. perennis show up to 10IV revealing higher affinity within genomes A and B, but any homology among them. These results suggest the presence of a paring regulator locus (PrZ) in maize and Z. perennis, whose expression is suppressed by colchicine. It could be postulated that in Z. perennis, PrZ would affect independently the genomes A and B, being relevant the threshold of homology, the fidelity of pairing in each genomes and the ploidy level. Cytological analysis of the treated hexaploid hybrids (6x = 2n = 30), with Z. perennis as a parental, strongly suggests that PrZ is less effective in only one doses. This conclusion was reinforced by the homoeologous pairing observed in untreated dihaploid maizes, which showed up to 5II. Meiotic behaviour of individuals treated with different doses of colchicine allowed to postulate that PrZ affect the homoeologous association by controlling entire genomes (Am or Bm) rather than individual chromosomes. Based on cytological and statistical results it is possible to propose that the cytological diploidization in Zea species occurs by restriction of pairing between homoeologous chromosomes or by genetical divergence of the homoeologous chromosomes, as was observed in untreated Z. mays ssp. parviglumis. These are independent but complementary systems and could be acting jointly in the same nucleus. PMID:29293518

Cytological diploidization of paleopolyploid genus Zea: Divergence between homoeologous chromosomes or activity of pairing regulator genes?

PubMed

Poggio, Lidia; González, Graciela Esther

2018-01-01

Cytological diploidization process is different in autopolyploid and allopolyploid species. Colchicine applied at the onset of meiosis suppresses the effect of pairing regulator genes resulting multivalents formation in bivalent-forming species. Colchicine treated maizes (4x = 2n = 20, AmAmBmBm) showed up to 5IV, suggesting pairing between chromosomes from genomes homoeologous Am and Bm. In untreated individuals of the alloautooctoploid Zea perennis (8x = 2n = 40, ApApAp´Ap´Bp1Bp1Bp2Bp2) the most frequent configuration was 5IV+10II (formed by A and B genomes, respectively). The colchicine treated Z. perennis show up to 10IV revealing higher affinity within genomes A and B, but any homology among them. These results suggest the presence of a paring regulator locus (PrZ) in maize and Z. perennis, whose expression is suppressed by colchicine. It could be postulated that in Z. perennis, PrZ would affect independently the genomes A and B, being relevant the threshold of homology, the fidelity of pairing in each genomes and the ploidy level. Cytological analysis of the treated hexaploid hybrids (6x = 2n = 30), with Z. perennis as a parental, strongly suggests that PrZ is less effective in only one doses. This conclusion was reinforced by the homoeologous pairing observed in untreated dihaploid maizes, which showed up to 5II. Meiotic behaviour of individuals treated with different doses of colchicine allowed to postulate that PrZ affect the homoeologous association by controlling entire genomes (Am or Bm) rather than individual chromosomes. Based on cytological and statistical results it is possible to propose that the cytological diploidization in Zea species occurs by restriction of pairing between homoeologous chromosomes or by genetical divergence of the homoeologous chromosomes, as was observed in untreated Z. mays ssp. parviglumis. These are independent but complementary systems and could be acting jointly in the same nucleus.

Chuanhu Anti-Gout Mixture versus Colchicine for Acute Gouty Arthritis: A Randomized, Double-Blind, Double-Dummy, Non-Inferiority Trial

PubMed Central

Wang, YanGang; Wang, Luan; Li, EnZe; Li, Yang; Wang, ZhongChao; Sun, XiaoFang; Yu, XiaoLong; Ma, Lin; Wang, YunLong; Wang, YouXin

2014-01-01

Background The Chuanhu anti-gout mixture has been used for many years in the treatment of gout in Chinese Traditional Medicine, and current methods for treatments for acute gouty arthritis have been either less effective or have had serious side effects. Methods In this 12-week, double-blind, double-dummy, non-inferiority study, outpatient individuals with newly diagnosed acute gouty arthritis were randomly assigned to receive Chuanhu anti-gout mixture or colchicine. Both the study investigators and the participants were masked to the treatment assignments. The primary outcome was the recurrence rate of acute gouty arthritis, and the secondary outcomes were changes in white blood cells (WHC) and C-reactive protein (CRP). This trial is registered at ISRCTN.org as trial ISRCTN65219941. Results A total of 176 patients were randomly assigned to receive either the Chuanhu anti-gout mixture or Colchicine. The overall recurrence rates in the Chuanhu anti-gout mixture group (CH group) and the Colchicine group (Col group) were 12.50% vs 14.77% (difference -2.22%, 95% confidence interval (95% CI): -10.78%~6.23%), meeting the predefined non-inferiority criterion of 15%, as did the data for WHC and CRP. The incidence of adverse events (mainly diarrhea) was less in the Col group than in the CH group (2.27% vs 28.41%, 95% CI 0.01~0.26). In addition, changes in blood uric acid, alanine aminotransferase, aspartate aminotransferase and creatinine in the CH group were significantly larger compared to those in the Col group (P<0.05). Conclusions The Chuanhu anti-gout mixture was non-inferior to colchicine for the treatment of acute gouty arthritis. The study suggested that the Chuanhu anti-gout mixture can be considered an alternative choice for the treatment of acute gouty arthritis because of its lower incidence of adverse events and its protection of kidney and renal function. PMID:25013367

Cytotoxic 3,4,5-trimethoxychalcones as mitotic arresters and cell migration inhibitors

PubMed Central

Salum, Lívia B.; Altei, Wanessa F.; Chiaradia, Louise D.; Cordeiro, Marlon N.S.; Canevarolo, Rafael R.; Melo, Carolina P.S.; Winter, Evelyn; Mattei, Bruno; Daghestani, Hikmat N.; Santos-Silva, Maria Cláudia; Creczynski-Pasa, Tânia B.; Yunes, Rosendo A.; Yunes, José A.; Andricopulo, Adriano D.; Day, Billy W.; Nunes, Ricardo J.; Vogt, Andreas

2013-01-01

Based on classical colchicine site ligands and a computational model of the colchicine binding site on beta tubulin, two classes of chalcone derivatives were designed, synthesized and evaluated for inhibition of tubulin assembly and toxicity in human cancer cell lines. Docking studies suggested that the chalcone scaffold could fit the colchicine site on tubulin in an orientation similar to that of the natural product. In particular, a 3,4,5-trimethoxyphenyl ring adjacent to the carbonyl group appeared to benefit the ligand-tubulin interaction, occupying the same subcavity as the corresponding moiety in colchicine. Consistent with modeling predictions, several 3,4,5-trimethoxychalcones showed improved cytotoxicity to murine acute lymphoblastic leukemia cells compared with a previously described parent compound, and inhibited tubulin assembly in vitro as potently as colchicine. The most potent chalcones inhibited the growth of human leukemia cell lines at nanomolar concentrations, caused microtubule destabilization and mitotic arrest in human cervical cancer cells, and inhibited human breast cancer cell migration in scratch wound and Boyden chamber assays. PMID:23524161

EFFECTS OF NGF AND FETAL CELL TRANSPLANTS ON SPATIAL LEARNING AFTER INTRADENTATE ADMINISTRATION OF COLCHICINE

EPA Science Inventory

This study was performed to assess the effects of NGF infusion alone or in combination with fetal hippocampal transplants on recovery of function after damage to hippocampal dentate granule cells. Two groups of male Fischer-344 rats received bilateral infusions of colchicine (COL...

Adherence to the 2012 American College of Rheumatology (ACR) Guidelines for Management of Gout: A Survey of Brazilian Rheumatologists

PubMed Central

Coutinho, Evandro Silva Freire; Schumacher, H. Ralph; Singh, Jasvinder A.; Schlesinger, Naomi

2015-01-01

Objective To describe the current pharmacological approach to gout treatment reported by rheumatologists in Brazil. Methods We performed a cross-sectional survey study using an online questionnaire e-mailed to 395 rheumatologists, randomly selected, from among the members of the Brazilian Society of Rheumatology. Results Three hundred and nine rheumatologists (78.2%) responded to the survey. For acute gout attacks, combination therapy (NSAIDs or steroid + colchicine) was often used, even in monoarticular involvement, and colchicine was commonly started as monotherapy after 36 hours or more from onset of attack. During an acute attack, urate-lowering therapy (ULT) was withdrawn by approximately a third of rheumatologists. Anti-inflammatory prophylaxis (98% colchicine) was initiated when ULT was started in most cases (92.4%), but its duration was varied. Most (70%) respondents considered the target serum uric acid level to be less than 6 mg/dl. Approximately 50% of rheumatologists reported starting allopurinol at doses of 100 mg daily or less and 42% reported the initial dose to be 300 mg daily in patients with normal renal function. ULT was maintained indefinitely in 76% of gout patients with tophi whereas in gout patients without tophi its use was kept indefinitely in 39.6%. Conclusion This is the first study evaluating gout treatment in a representative, random sample of Brazilian rheumatologists describing common treatment practices among these specialists. We identified several gaps in reported gout management, mainly concerning the use of colchicine and ULT and the duration of anti-inflammatory prophylaxis and ULT. Since rheumatologists are considered as opinion leaders in this disease, a program for improving quality of care for gout patients should focus on increasing their knowledge in this common disease. PMID:26274585

Fab fragments of ovine antibody to colchicine enhance its clearance in the rat.

PubMed

Peake, Philip W; Pianta, Timothy J; Succar, Lena; Fernando, Mangalee; Buckley, Nicholas A; Endre, Zoltan H

2015-06-01

Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab(™)) to protect rats against renal and other injury 24 h after colchicine ingestion. Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. Samples of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level; from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.

The Effects of Colchicine on Risk of Cardiovascular Events and Mortality Among Patients with Gout: A Cohort Study Using Electronic Medical Records Linked with Medicare Claims

PubMed Central

Solomon, Daniel H.; Liu, Chih-Chin; Kuo, I-Hsin; Zak, Agnes; Kim, Seoyoung C.

2016-01-01

Background Colchicine may have beneficial effects on cardiovascular (CV) disease, but there are sparse data on its CV effect among patients with gout. We examined the potential association between colchicine and CV risk and all-cause mortality in gout. Methods The analyses used data from an electronic medical record (EMR) database linked with Medicare claims (2006–2011). To be eligible for the study cohort, subjects must have had a diagnosis of gout in the EMR and Medicare claims. New users of colchicine were identified and followed-up from the first colchicine dispensing date. Non-users had no evidence of colchicine prescriptions during the study period and were matched to users on the start of follow-up, age, and gender. Both groups were followed for the primary outcome, a composite of myocardial infarction (MI), stroke or transient ischemic attack (TIA). We calculated hazard ratios (HRs) in Cox regression, adjusting for potential confounders. Results We matched 501 users with an equal number of non-users with a median follow-up of 16.5 months. During follow-up, 28 primary CV events were observed among users and 82 among non-users. Incidence rates per 1,000 person-years were 35.6 for users and 81.8 for non-users. After full adjustment, colchicine use was associated with a 49% lower risk (HR 0.51, 95% CI 0.30 – 0.88) in the primary CV outcome as well as a 73% reduction in all-cause mortality (HR 0.27, 95% CI 017 – 0.43). Conclusion Colchicine use was associated with a reduced risk of a CV event among patients with gout. PMID:26582823

Evaluation of the aneugenic potential of the fungicide Ferbam in mice.

PubMed

Shanthi, R; Krishnamoorthy, M

2002-01-01

Ferbam, a potent dithiocarbamate fungicide is used as a protectant against a wide variety of fungal diseases in fruits, vegetables, and ornamental plants. The wide-spread use of this chemical is likely to pollute the environment. Hence, it was planned to test the possible genotoxicity of Ferbam through its aneugenic potential in the in vivo mouse (Mus musculus) test system. Four different doses of Ferbam, namely, 7.5, 15.0, 30.0, 60.0 mg/kg body weight were administered orally to mice Mus musculus suspended in gum tragacanth representing, respectively, 1/16, 1/8, 1/4;, 1/2 th of the LD50 value. They were sacrificed at 6-, 12-, 24-, and 48-h intervals along with a distilled water negative control at 2 mg/kg body weight. Colchicine treated animals were used as positive controls. Bone marrow preparations were made following the standard Hypotonic flame dry Giemsa staining technique to study the dose and time yield effect of Ferbam. The aneugenic potential was evaluated for C-mitotic effects by scoring the mitotic index, c-mitoses frequency, anaphase reduction, and hyper/hypodiploidy induction. Ferbam showed a significant increase in the mitotic index and C-mitoses effects and anaphase decreased at the highest doses of 30 and 60 mg/kg at 12- and 24-h intervals. Colchicine induced significant effects in all the aneugenic parameters observed at all the time intervals. There was no significant induction of either hyperdiploidy or hypodiploidy by Ferbam, unlike colchicine, indicating that the fungicide Ferbam is not aneugenic in the mouse test system. Copyright 2002 Wiley-Liss, Inc.

Anticolchicine cytotoxicity enhanced by Dan Gua-Fang, a Chinese herb prescription in ECV304 in mediums.

PubMed

Heng, Xian-Pei; Chen, Ke-Ji; Hong, Zhen-Feng; He, Wei-Dong; Chu, Ke-Dan; Chen, Wen-Lie; Zheng, Hai-Xia; Yang, Liu-Qing; Chen, Ling; Guo, Fang

2011-02-01

To study the effect of anticolchicine cytotoxicity of Dan Gua-Fang, a Chinesea Chinese), a Chinese herbal compound prescription on endothelial cells of vein (ECV304) cultivated in mediums of different glucose concentrations as well as the proliferation of those cells in the same conditions, in order to reveal the value of Dan Gua-Fang in preventing and treating endothelial damage caused by hyperglycemia in diabetes mellitus. The research was designed as three stages. The growing state and morphological changes were observed when ECV304 were cultivated in the culture mediums, which have different glucose concentrations with or without Dan Gua-Fang and at the same time with or without colchicine. (1) Dan Gua-Fang at all concentrations reduced the floating cell population of ECV304 cultivated in hyperglycemia mediums. (2) Dan Gua-Fang at all concentrations and hyperglycemia both had a function of promoting "pseudopod-like" structure formation in cultivated ECV304, but the function was not superimposed in mediums containing both hyperglycemia and Dan Gua-Fang. (3) Colchicine reduced and even vanished the "pseudopod-like" structure of the endotheliocyte apparently cultivated in mediums of hyperglycemia or with Dan Gua-Fang. The "pseudopod-like" structure of the endotheliocyte emerged quickly in Dan Gua-Fang groups after colchicine was removed, but it was not the case in hyperglycemia only without Dan Gua-Fang groups. (4) Dan Gua-Fang reduced the mortality of cells cultivated in mediums containing colchicine. The cell revived to its normal state fast after colchicine was removed. Dan Gua-Fang has the functions of promoting the formation of cytoskeleton and fighting against colchicine cytotoxicity.

Induction of tetraploids from petiole explants through colchicine treatments in Echinacea purpurea L.

PubMed

Nilanthi, Dahanayake; Chen, Xiao-Lu; Zhao, Fu-Cheng; Yang, Yue-Sheng; Wu, Hong

2009-01-01

Petiole explants were obtained from in vitro grown diploid (2x = 22) Echinacea purpurea plantlets. Shoots were regenerated by culturing the explants on MS basal medium containing 0.3 mg/L benzyladenine (BA), 0.01 mg/L naphthaleneacetic acid (NAA) and four concentrations (30, 60, 120, and 240 mg/L) of colchicine for 30 days, or 120 mg/L of colchicine for various durations (7, 14, 21, and 28 days). The regenerated shoots were induced to root on MS basal medium with 0.01 mg/L NAA, and then the root-tips of the regenerated shoots were sampled for count of chromosome number. It was found that a treatment duration of >7 days was necessary for induction of tetraploid (4x = 44) shoots, and treatment with 120 mg/L colchicine for 28 days was the most efficient for induction of tetraploids, yielding 23.5% of tetraploids among all the regenerated shoots. Chimeras were observed in almost all the treatments. However, the ratio of tetraploid to diploid cells in a chimeric plant was usually low. In comparison with diploid plants, tetraploid plants in vitro had larger stomata and thicker roots with more root branches, and had prominently shorter inflorescence stalk when mature.

A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected].

PubMed

Micallef, J; Soubrouillard, C; Guet, F; Le Guern, M E; Alquier, C; Bruguerolle, B; Blin, O

2001-06-01

This paper describes the psychomotor and mnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects. Forty-eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study [corrected]. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list). Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects. These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam.

LC-MS/MS quantification of free and Fab-bound colchicine in plasma, urine and organs following colchicine administration and colchicine-specific Fab fragments treatment in Göttingen minipigs.

PubMed

Fabresse, Nicolas; Allard, Julien; Sardaby, Marine; Thompson, Adrian; Clutton, R Eddie; Eddleston, Michael; Alvarez, Jean-Claude

2017-08-15

Clinical evaluation of a colchicine specific antigen-binding fragment (Fab) in order to treat colchicine poisoning required the development of an accurate method allowing quantification of free and Fab-bound colchicine in plasma and urine, and free colchicine in tissues, to measure colchicine redistribution after Fab administration. Three methods have been developed for this purpose, and validated in plasma, urine and liver: total colchicine was determined after denaturation of Fab by dilution in water and heating; free colchicine was separated from Fab-bound colchicine by filtration with 30KDa micro-filters; tissues were homogenized in a tissue mixer. Deuterated colchicine was used as internal standard. Samples were extracted by liquid-liquid extraction and analyzed with a LC-MS/MS. LOQ were 0.5ng/mL in plasma and urine for free and total colchicine and 5pg/mg in tissues. The methods were linear in the 0.5-100ng/mL range in plasma and urine, and 5-300pg/mg in tissues with determination coefficients>0.99. Precision and accuracy of QC samples presented a CV<9.4%. The methods require only 200μL of sample and allow a high throughput due to short analytical run (2min). These methods were successfully applied to a pig intoxicated with colchicine and treated with colchicine specific Fab fragments. Copyright © 2017 Elsevier B.V. All rights reserved.

Dose finding with the sequential parallel comparison design.

PubMed

Wang, Jessie J; Ivanova, Anastasia

2014-01-01

The sequential parallel comparison design (SPCD) is a two-stage design recommended for trials with possibly high placebo response. A drug-placebo comparison in the first stage is followed in the second stage by placebo nonresponders being re-randomized between drug and placebo. We describe how SPCD can be used in trials where multiple doses of a drug or multiple treatments are compared with placebo and present two adaptive approaches. We detail how to analyze data in such trials and give recommendations about the allocation proportion to placebo in the two stages of SPCD.

Comparison of immunogenicity between inactivated and live attenuated hepatitis A vaccines: a single-blind, randomized, parallel-group clinical trial among children in Xinjiang Uighur Autonomous Region, China.

PubMed

Liu, Xue-En; Wushouer, Fuerhati; Gou, Aili; Kuerban, Mahemuti; Li, Xinlan; Sun, Yubo; Zhang, Jiamin; Liu, Yan; Li, Jie; Zhuang, Hui

2013-07-01

To compare immunogenicity among an inactivated hepatitis A vaccine (Healive(®)) with one-dose and two-dose regimens, and three kinds of live attenuated vaccines in children. A single-blind, randomized, parallel-group clinical trial was conducted among healthy children aged 1.5-6 y in Xinjiang Uighur Autonomous Region, China. Subjects were randomly assigned to 5 groups. Two groups were administered one-dose or two-dose inactivated vaccine and the remaining groups were immunized with one of three kinds of attenuated vaccines, respectively. Serum samples were collected at 6- and 12-mo follow-ups. Anti-HAV IgG was measured with a microparticle enzyme immunoassay. No significant differences were observed in seroconversion rates (seroprotection rates) among the five groups at 6 or 12 mo (p>0.05). The geometric mean concentration (GMC) of anti-HAV IgG was significantly higher in the two-dose Healive(®) group than in the one-dose Healive(®) group and the attenuated vaccine groups at 12 mo (932.4 vs. 112.7, 135.8, 203.3, 212.8 mIU/ml, respectively, p<0.05). In the one-dose Healive(®) group, the GMC was significantly lower than that in the attenuated vaccine B and C groups at 6 mo (152.6 vs. 212, 204 mIU/ml, p<0.05) and at 12 mo (112.7 vs. 203.3, 212.8, p<0.05), but was similar to the attenuated vaccine A group at 12 mo (112.7 vs. 135.8 mIU/ml, p>0.05). The GMCs were significantly higher in the 1-2 y of age group than in the 3-6 y of age group for all types of vaccines except the attenuated vaccine C (p<0.05) at 12 mo. A higher GMC of anti-HAV IgG was induced in the two-dose Healive(®) than in the one-dose and the attenuated vaccines at 12 mo. The attenuated vaccine B or C produced higher GMCs than the one-dose Healive(®) at 6-12 mo after vaccination.

Longitudinal analysis of serum interleukin-18 in patients with familial Mediterranean fever carrying MEFV mutations in exon 10.

PubMed

Wada, Taizo; Toma, Tomoko; Miyazawa, Hanae; Koizumi, Eiko; Shirahashi, Tetsujiro; Matsuda, Yusuke; Yachie, Akihiro

2018-04-01

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in the MEFV gene. Mutations in exon 10 are associated with typical FMF phenotypes, and patients with exon 10 mutations have higher serum levels of interleukin (IL)-18 both during attacks and afebrile phases, compared to those without exon 10 mutations. However, longitudinal changes of serum IL-18 in FMF have not been fully characterized. We serially evaluated serum levels of pro-inflammatory cytokines, including IL-18, in 12 patients with FMF carrying exon 10 mutations, all of whom showed typical FMF attacks. Markedly high concentrations of IL-18 were observed in all patients at diagnosis (5099±6084pg/mL). Serum IL-18 levels declined progressively after colchicine treatment in 7 patients (group A), whereas 5 patients showed continued elevation of circulating IL-18, despite declines in IL-6 and neopterin (group B). The mean follow-up times in the two groups were 4.7±3.2 and 4.8±1.5 years, respectively. The mean serum IL-18 level at the last hospital visit in group B was 4190±2610 pg/mL. There were no differences in onset age, initial IL-18 levels, and colchicine doses between the groups. FMF attacks almost disappeared in both groups, but there were trends towards more frequent subtle symptoms such as abdominal discomfort in group B. Sustained elevation of serum IL-18 may suggest the presence of persistent subclinical inflammation. Therefore, longitudinal examination of serum IL-18 may contribute to better follow-up of FMF patients with exon 10 mutations. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effect of induced polyploidy on some biochemical parameters in Cannabis sativa L.

PubMed

Bagheri, Mahsa; Mansouri, Hakimeh

2015-03-01

This study is aimed at testing the efficiency of colchicine on inducing polyploidy in Cannabis sativa L. and investigation of effects of polyploidy induction on some primary and secondary metabolites. Shoot tips were treated with three different concentrations of colchicine (0, 0.1, 0.2 % w/v) for 24 or 48 h. The biggest proportion of the almost coplanar tetraploids (43.33 %) and mixoploids (13.33 %) was obtained from the 24-h treatment in 0.2 and 0.1 % w/v, respectively. Colchicine with 0.2 % concentration and 48 h duration was more destructive than 24 h. The ploidy levels were screened with flow cytometry. The biochemical analyses showed that reducing sugars, soluble sugars, total protein, and total flavonoids increased significantly in mixoploid plants compared with tetraploid and diploid plants. Tetraploid plants had a higher amount of total proteins, total flavonoids, and starch in comparison with control plants. The results showed that polyploidization could increase the contents of tetrahydrocannabinol in mixoploid plants only, but tetraploid plants had lower amounts of this substance in comparison with diploids. Also, we found such changes in protein concentration in electrophoresis analysis. In overall, our study suggests that tetraploidization could not be useful to produce tetrahydrocannabinol for commercial use, and in this case, mixoploids are more suitable.

Induction of Tetraploids from Petiole Explants through Colchicine Treatments in Echinacea purpurea L.

PubMed Central

Nilanthi, Dahanayake; Chen, Xiao-Lu; Zhao, Fu-Cheng; Yang, Yue-Sheng; Wu, Hong

2009-01-01

Petiole explants were obtained from in vitro grown diploid (2x = 22) Echinacea purpurea plantlets. Shoots were regenerated by culturing the explants on MS basal medium containing 0.3 mg/L benzyladenine (BA), 0.01 mg/L naphthaleneacetic acid (NAA) and four concentrations (30, 60, 120, and 240 mg/L) of colchicine for 30 days, or 120 mg/L of colchicine for various durations (7, 14, 21, and 28 days). The regenerated shoots were induced to root on MS basal medium with 0.01 mg/L NAA, and then the root-tips of the regenerated shoots were sampled for count of chromosome number. It was found that a treatment duration of >7 days was necessary for induction of tetraploid (4x = 44) shoots, and treatment with 120 mg/L colchicine for 28 days was the most efficient for induction of tetraploids, yielding 23.5% of tetraploids among all the regenerated shoots. Chimeras were observed in almost all the treatments. However, the ratio of tetraploid to diploid cells in a chimeric plant was usually low. In comparison with diploid plants, tetraploid plants in vitro had larger stomata and thicker roots with more root branches, and had prominently shorter inflorescence stalk when mature. PMID:19696915

THE MECHANISM OF ACTION OF COLCHICINE

PubMed Central

Wilson, Leslie; Meza, Isaura

1973-01-01

The thermal depolymerization procedure of Stephens (1970. J. Mol. Biol. 47:353) has been employed for solubilization of Strongylocentrotus purpuratus sperm tail outer doublet microtubules with the use of a buffer during solubilization which is of optimal pH and ionic strength for the preservation of colchicine binding activity of chick embryo brain tubulin. Colchicine binding values were corrected for first-order decay during heat solubilization at 50°C (t½ = 5.4 min) and incubation with colchicine at 37°C in the presence of vinblastine sulfate (t½ = 485 min). The colchicine binding properties of heat-solubilized outer doublet tubulin were qualitatively identical with those of other soluble forms of tubulin. The solubilized tubulin (mol wt, 115,000) bound 0.9 ± 0.2 mol of colchicine per mol of tubulin, with a binding constant of 6.3 x 105 liters/mol at 37°C. The colchicine binding reaction was both time and temperature dependent, and the binding of colchicine was prevented in a competitive manner by podophyllotoxin (Ki = 1.3 x 10-6 M). The first-order decay of colchicine binding activity was substantially decreased by the addition of the vinca alkaloids, vinblastine sulfate or vincristine sulfate, thus demonstrating the presence of a vinca alkaloid binding site(s) on the outer doublet tubulin. Tubulin contained within the assembled microtubules did not decay. Intact outer doublet microtubules bound less than 0.001 mol of colchicine per mol of tubulin contained in the microtubules, under conditions where soluble tubulin would have bound 1 mol of colchicine per mol of tubulin (saturating concentration of colchicine, no decay of colchicine binding activity). The presence of colchicine had no effect on the rate of solubilization of outer doublet microtubules during incubation at 37°C. Therefore, the colchicine binding site on tubulin is blocked (not available to bind colchicine) when the tubulin is in the assembled outer doublet microtubules. PMID:4747924

A parallel-group comparison study of celecoxib with loxoprofen sodium in third mandibular molar extraction patients.

PubMed

Yamashita, Y; Sano, N; Shimohira, D; Danjo, A; Goto, M

2014-12-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely, but they may damage the upper gastrointestinal mucosa owing to their mechanism of action. Selective cyclooxygenase 2 (COX-2) inhibitors are known to have a reduced risk for such damage. In this comparative study, the efficacy and safety of the selective COX-2 inhibitor celecoxib for pain after third mandibular molar extraction were compared with those of loxoprofen sodium. This was a parallel-group comparison study; 107 patients who had undergone third mandibular molar extraction were given celecoxib and 102 were given loxoprofen. The level of pain on a visual analogue scale (VAS) 15 min and 30 min after taking the experimental drug decreased over time, with no significant difference between the two groups. The percentage of patients taking a second dose was 64.5% for celecoxib and 80.4% for loxoprofen. The time to second dose was significantly longer for celecoxib (533.5 min) than for loxoprofen (387.4 min). There was no significant difference in the patients' impression of efficacy between the two groups, with ratings of 'excellent' and 'good' for 77.4% in the loxoprofen group and 74.5% in the celecoxib group. These results demonstrate that celecoxib is of equal clinical value to loxoprofen for acute pain after third mandibular molar extraction. Copyright © 2014 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Successful treatment with humanized anti-interleukin-6 receptor antibody (tocilizumab) in a case of AA amyloidosis complicated by familial Mediterranean fever.

PubMed

Hamanoue, Satoshi; Suwabe, Tatsuya; Hoshino, Junichi; Sumida, Keiichi; Mise, Koki; Hayami, Noriko; Sawa, Naoki; Takaichi, Kenmei; Fujii, Takeshi; Ohashi, Kenichi; Yazaki, Masahide; Ikeda, Shuichi; Ubara, Yoshifumi

2016-07-01

Familial Mediterranean fever (FMF) is a well-known cause of secondary AA amyloidosis. Colchicine is generally considered to be the most effective treatment for FMF and FMF-associated amyloidosis, but the management of patients who are refractory to colchicine remains controversial. We encountered a 51-year-old Japanese man with suspected FMF, who had periodic fever with abdominal pain, polyarthritis, and nephropathy (serum creatinine of 1.9 mg/dL and 24-h protein excretion of 3.8 g). FMF was diagnosed by mutation analysis of the Mediterranean fever (MEFV) gene, which revealed that the patient was compound heterozygous for the marenostrin/pyrin variant E148Q/M694I. AA amyloidosis was diagnosed by renal and gastric biopsy. Colchicine was administered, but his arthritis persisted, and serum creatinine increased to 2.4 mg/dL. Therefore, a humanized anti-interleukin-6 receptor antibody (tocilizumab) was administered at a dose of 8 mg/kg on a monthly basis. Both arthritis and abdominal pain subsided rapidly, and C-reactive protein (CRP) decreased from 2.5 to 0.0 mg/dL. After 2 years, his serum creatinine was decreased to 1.5 mg/dL and proteinuria was improved to 0.3 g daily. In addition, repeat gastric biopsy showed a marked decrease of AA amyloidosis. This case suggests that tocilizumab could be a new therapeutic option for patients with FMF-associated AA amyloidosis if colchicine is not effective.

A comparison of simple and realistic eye models for calculation of fluence to dose conversion coefficients in a broad parallel beam incident of protons

NASA Astrophysics Data System (ADS)

Sakhaee, Mahmoud; Vejdani-Noghreiyan, Alireza; Ebrahimi-Khankook, Atiyeh

2015-01-01

Radiation induced cataract has been demonstrated among people who are exposed to ionizing radiation. To evaluate the deterministic effects of ionizing radiation on the eye lens, several papers dealing with the eye lens dose have been published. ICRP Publication 103 states that the lens of the eye may be more radiosensitive than previously considered. Detailed investigation of the response of the lens showed that there are strong differences in sensitivity to ionizing radiation exposure with respect to cataract induction among the tissues of the lens of the eye. This motivated several groups to look deeper into issue of the dose to a sensitive cell population within the lens, especially for radiations with low energy penetrability that have steep dose gradients inside the lens. Two sophisticated mathematical models of the eye including the inner structure have been designed for the accurate dose estimation in recent years. This study focuses on the calculations of the absorbed doses of different parts of the eye using the stylized models located in UF-ORNL phantom and comparison with the data calculated with the reference computational phantom in a broad parallel beam incident of protons with energies between 20 MeV and 10 GeV. The obtained results indicate that the total lens absorbed doses of reference phantom has good compliance with those of the more sensitive regions of stylized models. However, total eye absorbed dose of these models greatly differ with each other for lower energies.

Forecasting Three-Month Outcomes in a Laboratory School Comparison of Mixed Amphetamine Salts Extended Release (Adderall XR) and Atomoxetine (Strattera) in School-Aged Children with ADHD

ERIC Educational Resources Information Center

Faraone, Stephen V.; Wigal, Sharon B.; Hodgkins, Paul

2007-01-01

Objective: Compare observed and forecasted efficacy of mixed amphetamine salts extended release (MAS-XR; Adderall) with atomoxetine (Strattera) in ADHD children. Method: The authors analyze data from a randomized, double-blind, multicenter, parallel-group, forced-dose-escalation laboratory school study of children ages 6 to 12 with ADHD combined…

Novel Colchicine Derivatives and their Anti-cancer Activity.

PubMed

Johnson, Lorelei; Goping, Ing Swie; Rieger, Aja; Mane, Jonathan Y; Huzil, Torin; Banerjee, Asok; Luduena, Richard; Hassani, Bashar; Winter, Philip; Tuszynski, Jack A

2017-01-01

In this paper we provide an overview of the status of various colchicine derivatives in preclinical development with special focus on their anti-cancer activity. We discuss several groups of compounds that have been designed to differentially bind with specific affinities for tubulin β isotypes, especially in regard to βIII, which is commonly over-expressed in cancer. Computational prediction, protein-based and cell-based assays are summarized as well as some animal tests conducted on these compounds. It is concluded that an untapped potential exists for exploiting the colchicine scaffold as a pharmacophore with the possibility of increasing its affinity for tubulin isotypes overexpressed in cancer and decreasing it for normal cells thereby widening the therapeutic window. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improved growth and colchicine concentration in Gloriosa superba on mycorrhizal inoculation supplemented with phosphorus-fertilizer.

PubMed

Pandey, Devendra Kumar; Malik, Tabarak; Dey, Abhijit; Singh, Joginder; Banik, R M

2014-01-01

Gloriosa superba produces an array of alkaloids including colchicine, a compound of interest in the treatment of various diseases. The tuber of Gloriosa superba is a rich source of colchicine which has shown anti-gout, anti-inflammatory, and anti-tumor activity. However, this promising compound remains expensive and Gloriosa superba is such a good source in global scale. Increase in yield of naturally occurring colchicine is an important area of investigation. The effects of inoculation by four arbuscular mycorrhizal (AM), fungi, Glomus mossae, Glomus fasciculatum, Gigaspora margarita and Gigaspora gilmorei either alone or supplemented with P-fertilizer, on colchicine concentration in Gloriosa superba were studied. The concentration of colchicine was determined by high-performance thin layer chromatography. The four fungi significantly increased concentration of colchicine in the herb. Although there was significant increase in concentration of colchicine in non-mycorrhizal P-fertilized plants as compared to control, the extent of the increase was less compared to mycorrhizal plants grown with or without P-fertilization. This suggests that the increase in colchicine concentration may not be entirely attributed to enhanced P-nutrition and improved growth. Among the four AM fungi Glomus mossae was found to be best. The total colchicine content of plant (mg / plant) was significantly high in plants inoculated with Glomus mossae and 25 mg kg(-1)phosphorus fertilizer (348.9 mg /plant) while the control contain least colchicine (177.87 mg / plant). The study suggests a potential role of AM fungi in improving the concentration of colchicine in Gloriosa superba tuber.

Determination colchicine content in aquadest-extracted Gloriosa superba seed from Sukoharjo and Gunung Kidul

NASA Astrophysics Data System (ADS)

Rahmawati, S. I.; Susilowati, A.; Yunus, A.; Widyastuti, Y.

2018-03-01

Colchicine is a toxic alkaloid compound from the Colchicum autumnale plant. Colchicine can be used in agriculture as anti-mitosis in the procurement of plants with polyploid cells. Gloriosa superba is an herb contains colchicine as a mutagen (polyploid) potential in its parts, especially in the seeds. The aims of this research were to determine colchicine content from aquadest-extracted Gloriosa superba seed obtained from Sukoharjo and Gunung Kidul. Gloriosa superba seed samples were obtained naturally in January - April 2017. Samples were divided into immature seed samples from Mulur, Sukoharjo, Central Java and old seed samples from Krakal Beach, Gunung Kidul, Yogyakarta. Extraction seeds of Gloriosa superba using the maceration method with aquadest solvent (1: 1). Determination content of colchicine extract using TLC-Densitometry method. The results indicated that colchicine content of old seed Gloriosa superba samples 37,6 μg/μl (± 6,63) higher than colchicine content of immature seed Gloriosa superba samples 12,84 μg/μl (± 2,88)

Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein.

PubMed

Dahan, Arik; Amidon, Gordon L

2009-04-01

To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate. Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum. Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC(50) values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC(50) values of 90, 592 and 11.6 microM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability. The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.

Comparative Analyses of the β-Tubulin Gene and Molecular Modeling Reveal Molecular Insight into the Colchicine Resistance in Kinetoplastids Organisms

PubMed Central

Luis, Luis; Serrano, María Luisa; Hidalgo, Mariana; Mendoza-León, Alexis

2013-01-01

Differential susceptibility to microtubule agents has been demonstrated between mammalian cells and kinetoplastid organisms such as Leishmania spp. and Trypanosoma spp. The aims of this study were to identify and characterize the architecture of the putative colchicine binding site of Leishmania spp. and investigate the molecular basis of colchicine resistance. We cloned and sequenced the β-tubulin gene of Leishmania (Viannia) guyanensis and established the theoretical 3D model of the protein, using the crystallographic structure of the bovine protein as template. We identified mutations on the Leishmania   β-tubulin gene sequences on regions related to the putative colchicine-binding pocket, which generate amino acid substitutions and changes in the topology of this region, blocking the access of colchicine. The same mutations were found in the β-tubulin sequence of kinetoplastid organisms such as Trypanosoma cruzi, T. brucei, and T. evansi. Using molecular modelling approaches, we demonstrated that conformational changes include an elongation and torsion of an α-helix structure and displacement to the inside of the pocket of one β-sheet that hinders access of colchicine. We propose that kinetoplastid organisms show resistance to colchicine due to amino acids substitutions that generate structural changes in the putative colchicine-binding domain, which prevent colchicine access. PMID:24083244

Formulation of colchicine ointment for the treatment of acute gout.

PubMed

Maduri, Sairam; Atla, Venkateshwar Reddy

2012-11-01

In spite of being the fastest acting drug available for the control of an acute gout attack, colchicine is generally considered a last alternative in gout therapy. This is mainly due to the severe adverse effects associated with its administration through the enteral and parenteral routes, as well as its high risk/benefit ratio. The preparation of dosage forms of colchicine that can be administered by alternative routes is therefore a beneficial exercise. Among the formulable substitute dosage forms of colchicine, its ointment seems to be the best option available due to its ability to deliver the drug transdermally as well as its ease of preparation and evaluation. In this study, we prepared and tested 0.2% and 0.5% colchicine ointments for their effectiveness in delivering colchicine transdermally. Colchicine ointment was prepared using a self-formulated water-in-oil type of emulsion ointment base, with the colchicine dissolved in the water portion of the ointment base. In vitro drug release studies were carried out using the Franz diffusion test apparatus and an ultraviolet (UV)-visible spectrophotometer was used to quantify the drug in the samples. Rabbits were used as test animals for in vivo studies and the blood samples were analysed using the UV-visible spectrophotometer. Colchicine was found to be well-absorbed transdermally, although absorption was not 100%. No side effects were associated with its 0.2% formulation. Ointments containing colchicine in low concentrations may be a feasible and effective treatment option for the prevention and treatment of acute gout attacks.

An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia.

PubMed

Huang, Xinfang; Du, Hui; Gu, Jieruo; Zhao, Dongbao; Jiang, Lindi; Li, Xinfu; Zuo, Xiaoxia; Liu, Yi; Li, Zhanguo; Li, Xiangpei; Zhu, Ping; Li, Juan; Zhang, Zhiyi; Huang, Anbin; Zhang, Yuanchao; Bao, Chunde

2014-07-01

Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. Gout patients (n = 512) with serum uric acid (sUA) concentrations of at least 8.0 mg/dL were randomized to receive daily febuxostat 40 mg or 80 mg or allopurinol 300 mg for 28 weeks. Prophylaxis against gout flares with meloxicam or colchicine was provided during weeks 1 through 8. The primary endpoint was the percentage of subjects achieving a sUA concentration of <6.0 mg/dL at the last three monthly measurements. The primary endpoint was reached in 44.77% of patients receiving 80 mg of febuxostat, 27.33% of those receiving 40 mg of febuxostat, and 23.84% of those receiving allopurinol. The UL efficacy in the febuxostat 80 mg group was higher than in the allopurinol (P < 0.0001) and febuxostat 40 mg (P = 0.0008) groups. The UL efficacy of the febuxostat 40 mg group was statistically non-inferior to that of the allopurinol group. No significant change in the number of tophi was observed during the final visit relative to baseline in each treatment group. The rate of gout flares requiring treatment from weeks 9 through 28 and the incidence of adverse events was similar among treatment groups. The UL efficacy of daily febuxostat 80 mg was greater than that of febuxostat 40 mg and allopurinol 300 mg, which exhibited comparable UL efficacy. Safety of febuxostat and allopurinol was comparable at the doses tested. © 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension.

PubMed

Prins, Kurt W; Tian, Lian; Wu, Danchen; Thenappan, Thenappan; Metzger, Joseph M; Archer, Stephen L

2017-05-31

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV-targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin-2 (JPH2) expression, resulting in t-tubule derangements. Conversely, we assessed whether colchicine, a microtubule-depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline-induced PAH. Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t-tubule localization and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t-tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV-pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity. Monocrotaline-induced PAH causes RV-specific derangement of microtubules marked by reduction in JPH2 and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t-tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV-directed therapy for PAH. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

The effect of colchicine on the size and bioactive compound of microalgae Spirulina platensis

NASA Astrophysics Data System (ADS)

Mahardika, A.; Mukti, A. T.; Arief, M.

2018-04-01

Polyploidy is one of the techniques used to increase the genetic variant and once used as a breeding method of plant. Colchicine is one of the chemical which apply to produce polyploid organisms, such as plant. This study aimed to determine the effect of colchicine on the size and phycocyanin content of Spirulinaplatensis.Research was used six treatments of colchicine concentration with three replications. S. platensis were immersed in the colchicine solution for 12 hours and were observed for 5 days culture. This research was showed that colchicine concentration of 0.1 % were resulted highest diameter of S. platensis(12.57 μm) while highphycocyanin content obtained by treatment of 0.025 % (0.091 mg/ml).

Colchicine in Behçet syndrome: a longterm survey of patients in a controlled trial.

PubMed

Hamuryudan, Vedat; Hatemi, Gulen; Tascilar, Koray; Yurdakul, Sebahattin; Mat, Cem; Ozyazgan, Yilmaz; Seyahi, Emire; Ugurlu, Serdal; Yazici, Hasan

2014-04-01

To test the hypothesis that colchicine use during early disease decreases immunosuppressive use in Behçet syndrome (BS) in the long term. Patients with BS who participated in a double-blind, placebo-controlled trial of colchicine 16.6±1.1 years ago were evaluated for immunosuppressive use during the posttrial period. We could contact 90/116 patients; 28 (31%) received immunosuppressives during the posttrial period, 14 being from the colchicine arm. Posttrial colchicine use and cumulative duration were similar between patients who received immunosuppressives and those who did not. Continuous use of colchicine, even when initiated at an early disease stage, does not seem to decrease the use of immunosuppressives in the long term.

Management of Acute and Recurrent Gout: A Clinical Practice Guideline From the American College of Physicians.

PubMed

Qaseem, Amir; Harris, Russell P; Forciea, Mary Ann

2017-01-03

The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of gout. Using the ACP grading system, the committee based these recommendations on a systematic review of randomized, controlled trials; systematic reviews; and large observational studies published between January 2010 and March 2016. Clinical outcomes evaluated included pain, joint swelling and tenderness, activities of daily living, patient global assessment, recurrence, intermediate outcomes of serum urate levels, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with acute or recurrent gout. ACP recommends that clinicians choose corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine to treat patients with acute gout. (Grade: strong recommendation, high-quality evidence). ACP recommends that clinicians use low-dose colchicine when using colchicine to treat acute gout. (Grade: strong recommendation, moderate-quality evidence). ACP recommends against initiating long-term urate-lowering therapy in most patients after a first gout attack or in patients with infrequent attacks. (Grade: strong recommendation, moderate-quality evidence). ACP recommends that clinicians discuss benefits, harms, costs, and individual preferences with patients before initiating urate-lowering therapy, including concomitant prophylaxis, in patients with recurrent gout attacks. (Grade: strong recommendation, moderate-quality evidence).

Colchicine induced intraneuronal free zinc accumulation and dentate granule cell degeneration.

PubMed

Choi, Bo Young; Lee, Bo Eun; Kim, Jin Hee; Kim, Hyun Jung; Sohn, Min; Song, Hong Ki; Chung, Tae Nyoung; Suh, Sang Won

2014-08-01

Colchicine has been discovered to inhibit many inflammatory processes such as gout, familial Mediterranean fever, pericarditis and Behcet disease. Other than these beneficial anti-inflammatory effects, colchicine blocks microtubule-assisted axonal transport, which results in the selective loss of dentate granule cells of the hippocampus. The mechanism of the colchicine-induced dentate granule cell death and depletion of mossy fiber terminals still remains unclear. In the present study, we hypothesized that colchicine-induced dentate granule cell death may be caused by accumulation of labile intracellular zinc. 10 μg kg(-1) of colchicine was injected into the adult rat hippocampus and then brain sections were evaluated at 1 day or 1 week later. Neuronal cell death was evaluated by H&E staining or Fluoro-Jade B. Zinc accumulation and vesicular zinc were detected by N-(6-methoxy-8-quinolyl)-para-toluene sulfonamide (TSQ) staining. To test whether an extracellular zinc chelator can prevent this process, CaEDTA was injected into the hippocampus over a 5 min period with colchicine. To test whether other microtubule toxins also produce similar effects as colchicine, vincristine was injected into the hippocampus. The present study found that colchicine injection induced intracellular zinc accumulation in the dentate granule cells and depleted vesicular zinc from mossy fiber terminals. Injection of a zinc chelator, CaEDTA, did not block the zinc accumulation and neuronal death. Vincristine also produced intracellular zinc accumulation and neuronal death. These results suggest that colchicine-induced dentate granule cell death is caused by blocking axonal zinc flow and accumulation of intracellular labile zinc.

How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? a placebo-controlled study on comparison between 100 000 IU and 200 000 IU of oral D3 every 3 months in elderly women.

PubMed

Välimäki, Ville-Valtteri; Löyttyniemi, Eliisa; Pekkarinen, Tuula; Välimäki, Matti J

2016-06-01

Intermittent dosing may improve adherence to vitamin D therapy. Dosing regimen should maintain optimal serum 25-hydroxyvitamin D (25OHD) levels over all the year. We compared two dosing regimens, the primary outcome being the percentage of 25OHD measurements reaching the targets of 75 nmol/l or 50 nmol/l after baseline. Randomized, placebo-controlled parallel group comparison. Sixty women aged 75·0 ± 2·9 years. 100 000 IU (group 1D) or 200 000 IU (2D) of vitamin D3 or placebo orally every 3 months plus calcium 1 g daily for 1 year. Serum 25OHD, 1,25-dihydroxyvitamin D, PTH, sclerostin, ionized calcium, urinary calcium, renal function, bone turnover markers. Serum 25OHD increased, but the difference between two doses was of borderline significance (P = 0·0554; area under curve analysis). Immediate postadministrative increases were higher in the 2D vs 1D group (P < 0·05) after 3 and 6 months' dosing. In the 1D and 2D groups, 51·2% and 57·7% of all on-treatment measurements reached the target of 75 nmol/l. PTH levels differed marginally (P = 0·0759) due to tendency to lowering immediately after vitamin D boluses. Urinary calcium differed between the groups (P = 0·0193) due to increases 1 week after vitamin D dosing. The doses of 100 000 or 200 000 IU of oral cholecalciferol every 3 months were not capable of stabilizing 25OHD levels over the target of 75 nmol/l over the year. To improve the efficacy of high-dose vitamin D therapy, the interval between boluses has to be shortened instead of increasing their size. © 2016 John Wiley & Sons Ltd.

Colchicine--Update on mechanisms of action and therapeutic uses.

PubMed

Leung, Ying Ying; Yao Hui, Laura Li; Kraus, Virginia B

2015-12-01

To review the literature and provide an update on the mechanisms of action and therapeutic uses of oral colchicine in arthritis and inflammatory conditions. We performed PubMed database searches through June 2014 for relevant studies in the English literature published since the last update of colchicine in 2008. Searches encompassed colchicine mechanisms of action and clinical applications in medical conditions. A total of 381 articles were reviewed. The primary mechanism of action of colchicine is tubulin disruption. This leads to subsequent down regulation of multiple inflammatory pathways and modulation of innate immunity. Newly described mechanisms include various inhibitory effects on macrophages including the inhibition of the NACHT-LRRPYD-containing protein 3 (NALP3) inflammasome, inhibition of pore formation activated by purinergic receptors P2X7 and P2X2, and stimulation of dendritic cell maturation and antigen presentation. Colchicine also has anti-fibrotic activities and various effects on endothelial function. The therapeutic use of colchicine has extended beyond gouty arthritis and familial Mediterranean fever, to osteoarthritis, pericarditis, and atherosclerosis. Further understanding of the mechanisms of action underlying the therapeutic efficacy of colchicine will lead to its potential use in a variety of conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

Accidental overdose of insufflated colchicine.

PubMed

Baldwin, L R; Talbert, R L; Samples, R

1990-01-01

An accidental overdose of colchicine by nasal insufflation occurred when the colchicine was mistaken for methamphetamine. Colchicine insufflation is not believed to be a common practice among drug abusers; however, its physical appearance was similar enough to methamphetamine for it to be mistaken for that drug of abuse. In this case a 29-year-old White man presented to the emergency room 3 days after he 'snorted' approximately 200mg of colchicine powder. The colchicine was used as a 'root stimulator' in gardening by the patient's brother and stored in the same cabinet as the methamphetamine. Within 24 hours of exposure the patient began experiencing gastrointestinal distress and myalgia, which eventually prompted him to seek medical attention. The clinical course included hypocalcaemia (69 mg/L--day 5), hypophosphataemia (10 mg/L--day 5) and thrombocytopenia (19 X 10(3)/mm3 - day 8), all of which are consistent with colchicine toxicity. The patient improved with supportive care and electrolyte replacement, and was discharged after an 8-day hospitalisation.

Optimum conditions for detecting hepatic micronuclei caused by numerical chromosome aberration inducers in mice.

PubMed

Igarashi, Miyuki; Setoguchi, Mayumi; Takada, Sanae; Itoh, Satoru; Furuhama, Kazuhisa

2007-08-15

To ascertain an optimum condition for detecting micronuclei in the liver caused by numerical aberration inducers, either carbendazim (125-1000mg/kg, p.o.), colchicine (0.375-1.5mg/kg, i.v.), cytochalasin B (2.5-20mg/kg, i.v.), diazepam (3.13-25mg/kg, i.v.), noscapine (7.8-62.5mg/kg, i.v.), paclitaxel (1-100mg/kg, i.v.) or trichlorfon (18.75-150mg/kg, i.v.) was administered once to male Slc:ddY mice 1 day before or after partial hepatectomy (PH, Day 1). Five days after PH (on Day 6), hepatic micronuclei were determined in conjunction with classifications of the main nuclei and relative liver weights as a proliferative indicator or a dysfunction marker of cell division. Additionally, hepatocyte proliferation index (HPI) was calculated by using mono-, bi- and multinucleated cell counts. Treatment of mice with six compounds, except for colchicine, after PH showed higher incidence of micronucleated hepatocytes (MNH) than that before PH, and also increases in binucleated and multinucleated cells. Especially for carbendazim, diazepam, noscapine and trichlorfon, the dosing after PH was essential for the detecting numerical aberration. Colchicine evidently increased HPI and decreased relative liver weights without MNH induction on Day 6. On Day 8 when HPI and relative liver weights almost returned to the basal range, a significant increase in MNH was noted. This implied that the strong inhibition of colchicine on hepatocyte proliferation may obstruct the induction of MNH on Day 6. In conclusion, to detect the potential numerical aberration, exposure of mice to test chemicals should be performed 1 day after PH, during which enhanced proliferation of hepatocytes was seen, and it would be better to analyze the liver specimens on Day 6 or more post-PH.

Exploring the Origin of Differential Binding Affinities of Human Tubulin Isotypes αβII, αβIII and αβIV for DAMA-Colchicine Using Homology Modelling, Molecular Docking and Molecular Dynamics Simulations

PubMed Central

Panda, Dulal; Kunwar, Ambarish

2016-01-01

Tubulin isotypes are found to play an important role in regulating microtubule dynamics. The isotype composition is also thought to contribute in the development of drug resistance as tubulin isotypes show differential binding affinities for various anti-cancer agents. Tubulin isotypes αβII, αβIII and αβIV show differential binding affinity for colchicine. However, the origin of differential binding affinity is not well understood at the molecular level. Here, we investigate the origin of differential binding affinity of a colchicine analogue N-deacetyl-N-(2-mercaptoacetyl)-colchicine (DAMA-colchicine) for human αβII, αβIII and αβIV isotypes, employing sequence analysis, homology modeling, molecular docking, molecular dynamics simulation and MM-GBSA binding free energy calculations. The sequence analysis study shows that the residue compositions are different in the colchicine binding pocket of αβII and αβIII, whereas no such difference is present in αβIV tubulin isotypes. Further, the molecular docking and molecular dynamics simulations results show that residue differences present at the colchicine binding pocket weaken the bonding interactions and the correct binding of DAMA-colchicine at the interface of αβII and αβIII tubulin isotypes. Post molecular dynamics simulation analysis suggests that these residue variations affect the structure and dynamics of αβII and αβIII tubulin isotypes, which in turn affect the binding of DAMA-colchicine. Further, the binding free-energy calculation shows that αβIV tubulin isotype has the highest binding free-energy and αβIII has the lowest binding free-energy for DAMA-colchicine. The order of binding free-energy for DAMA-colchicine is αβIV ≃ αβII >> αβIII. Thus, our computational approaches provide an insight into the effect of residue variations on differential binding of αβII, αβIII and αβIV tubulin isotypes with DAMA-colchicine and may help to design new analogues with higher binding affinities for tubulin isotypes. PMID:27227832

Is colchicine more effective to prevent periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis episodes in Mediterranean fever gene variants?

PubMed

Gunes, Muhammed; Cekic, Sukru; Kilic, Sara Sebnem

2017-06-01

Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is the most frequent repetitive fever syndrome in childhood. It is characterized by fever episodes lasting for approximately 3-6 days, once every 3-8 weeks. Clinical and laboratory data for PFAPA syndrome patients between January 2010 and December 2014 followed up at a tertiary pediatric care hospital were reviewed. Four hundred children (256 male, 144 female; mean age at diagnosis, 4.2 ± 2.2 years), were enrolled in the study. During the episodes, mean leukocyte number was high (12 725/mm 3 ) with predominant neutrophils. The mean number of monocytes was 1256/mm 3 , and 90.2% had monocytosis. Serum amyloid A and C-reactive protein were high in 84.6% and in 77.8% of the patients, respectively. Mediterranean fever (MEFV) gene heterozygous mutation was identified in 57 of the 231 patients (24.7%) in whom genetic analysis had been performed. The most frequent mutation was heterozygous M694V (10%, n = 23). Extension of between-episode interval following prophylaxis was noted in 85% of those on regular colchicine treatment (n = 303). In the colchicine group, between-episode interval was prolonged from 18.8 ± 7.9 days (before colchicine treatment) to 49.5 ± 17.6 days on prophylactic colchicine therapy; also, prophylactic treatment was more effective in reducing episode frequency in patients with MEFV gene variant (n = 54, 96%) than in those without (n = 122, 80%; P = 0.003). This study has involved the largest number of PFAPA syndrome patients in the literature. It is particularly important to assess and to demonstrate the high rate of response to colchicine prophylaxis in PFAPA syndrome patients, especially those with MEFV variant. On blood screening, neutrophilia associated with monocytosis and low procalcitonin could contribute to diagnosis. © 2017 Japan Pediatric Society.

Idiopathic recurrent pericarditis as an immune-mediated disease: current insights into pathogenesis and emerging treatment options.

PubMed

Imazio, Massimo

2014-11-01

Idiopathic recurrent pericarditis affects 30-50% of patients with a previous attack of pericarditis. The etiopathogenesis is incompletely understood and most cases remain idiopathic with a presumed immune-mediated pathogenesis. The mainstay of therapy is aspirin or a nonsteroidal anti-inflammatory drug plus colchicine and the possible adjunct of a low-to-moderate dose of a corticosteroid in more difficult cases. Colchicine as an adjunct to anti-inflammatory therapy reduces by 50% the subsequent recurrent rate. For true refractory cases with failure of standard combination therapies, new and emerging options especially include human intravenous immunoglobulins and biological agents (i.e., anakinra). The outcome of idiopathic recurrent pericarditis is good with a negligible risk of developing constrictive pericarditis. Thus, it is important to reassure patients on their prognosis, explaining the nature of the disease and the likely course. Moreover, therapeutic choices should include less toxic agents and favor cheaper drugs whenever possible.

[Effects of direct current electric field on directional migration and arrangement of dermal fibroblasts in neonatal BALB/c mice and the mechanisms].

PubMed

Liu, Jie; Ren, Xi; Guo, Xiaowei; Sun, Huanbo; Tang, Yong; Luo, Zhenghui; Zhang, Qiong; Zhang, Dongxia; Huang, Yuesheng; Zhang, Jiaping

2016-04-01

To explore the effects of direct current electric fields on directional migration and arrangement of dermal fibroblasts in neonatal BALB/c mice and the related mechanisms. Twelve neonatal BALB/c mice were divided into 4 batches. The skin on the back of 3 neonatal mice in each batch was obtained to culture fibroblasts. Fibroblasts of the second passage were inoculated in 27 square cover slips with the concentration of 5 × 10(4) cells per mL. (1) Experiment 1. Six square cover slips inoculated with fibroblasts of the second passage were divided into electric field group (EF) and sham electric field group (SEF), with 3 cover slips in each group. The cover slips were put in live cell imaging workstation. The cells in group EF was treated with electric power with EF intensity of 200 mV/mm, while simulating process without actual power was given to SEF group (the same below) for 6 h. Cell proliferation rate was subsequently counted. (2) Experiment 2. Six cover slips were divided and underwent the same processes as in experiment 1. Cell movement locus within EF hour (EFH) 6, direction change of cell migration at EFH 0 (immediately), 1, 2, 3, 4, 5, and 6 which was denoted as cos(α), cell migration velocity within EFH 6, direction change of long axis of cell within EFH 6, and direction change of cell arrangement at EFH 0, 1, 2, 3, 4, 5, and 6 which was denoted as polarity value cos[2(θ-90)] were observed under live cell imaging workstation. After EFH 6, the morphological changes in microtubules and microfilaments were observed with immunofluorescent staining. (3) Experiment 3. Six cover slips were divided into cytochalasin D group (treated with 1 μmol/L cytochalasin D for 10 min) and colchicine group (treated with 5 μmol/L colchicine for 10 min), with 3 cover slips in each group. The morphological changes in microfilaments and microtubules were observed with the same method as in experiment 2. (4) Experiment 4. Nine cover slips were divided into control group (no reagent was added), cytochalasin D group and colchicine group (added with the same reagents as in experiment 3), with 3 cover slips in each group. Cells in the 3 groups were exposed to an EF of 200 mV/mm for 6 h. Cell movement locus within EFH 6, cell migration velocity within EFH 6, cell polarity values at EFH 0, 3, and 6, and morphological changes of cells at EFH 0 and 6 were observed. Data were processed with independent samples t-test, one-way analysis of variance, and LSD test. (1) There was no statistically significant difference in cell proliferation rate in group EF and group SEF (t=-0.24, P﹥0.05). (2) Within EFH 6, cells in group EF migrated towards the anode of EF, while cells in group SEF moved randomly. At EFH 0, the values of cos(α) of cells in the 2 groups were both 0. The absolute value of cos(α) of cells in group EF (-0.57 ± 0.06) was significantly higher than that in group SEF (0.13 ± 0.09, t=6.68, P<0.01) at EFH 1, and it was still higher than that in group SEF from EFH 2 to 6 (with t values from 5.33 to 6.83, P values below 0.01). Within EFH 6, migration velocity of cells in group EF was (0.308 ± 0.019) μm/min, which was significantly higher than that in group SEF [(0.228 ± 0.021) μm/min, t=-2.76, P<0.01]. Within EFH 6, long axis of cells in group EF was perpendicular to the direction of EF, while arrangement of cells in group SEF was irregular. Cell polarity values in group EF were significantly higher than that in group SEF from EFH 2 to 6 (with t values from -7.52 to -0.90, P values below 0.01). At EFH 6, the morphology of microfilaments and microtubules of cells in EF group was similar to that in SEF group. (3) The fluorescent intensity of microfilaments of cells in cytochalasin D group became weakened, and the filamentary structure became fuzzy. The microtubules of cells in colchicine group became fuzzy with low fluorescent intensity. (4) Within EFH 6, cells in control group migrated towards the anode of EF, while cells in cytochalasin D group and colchicine group moved randomly. Within EFH 6, there was statistically significant difference in migration velocity of cells in the 3 groups (F=6.36, P<0.01). Migration velocity of cells in cytochalasin D group and colchicine group was significantly slower than that in control group (P<0.05 or P<0.01). At EFH 0, 3, and 6, cell polarity values in the 3 groups were close (with F values from 0.99 to 1.51, P values above 0.05). At EFH 0, cells in control group were spindle; cells in cytochalasin D group were polygonal or in irregular shapes; cells in colchicine group were serrated circle or oval. At EFH 6, no morphological change was observed in cells in control group; cells in cytochalasin D group were spindle with split ends on both ends; cells in colchicine group were serrated oval. The physiologic strength of exogenous direct current EF can induce directional migration and alignment of dermal fibroblasts in neonatal BALB/c mice. Microfilaments and microtubules are necessary skeleton structure for cell directional migration induced by EF, while they are not necessary for cell directional arrangement induced by EF.

Colchicine

MedlinePlus

... of age and older. Colchicine is not a pain reliever and cannot be used to treat pain that is not caused by gout or FMF. Colchicine is in a class of medications called anti-gout agents. It works by stopping the natural processes that cause swelling ...

Microtubule-dependent changes in morphology and localization of chloride transport proteins in gill mitochondria-rich cells of the tilapia, Oreochromis mossambicus.

PubMed

Yang, Wen-Kai; Wu, Yu-Ching; Tang, Cheng-Hao; Lee, Tsung-Han

2016-08-01

The tilapia (Oreochromis mossambicus) is a euryhaline fish exhibiting adaptive changes in cell size, phenotype, and ionoregulatory functions upon salinity challenge. Na(+) /Cl(-) cotransporter (NCC) and Na(+) /K(+) /2Cl(-) cotransporter (NKCC) are localized in the apical and basolateral membranes of mitochondria-rich (MR) cells of the gills. These cells are responsible for chloride absorption (NCC) and secretion (NKCC), respectively, thus, the switch of gill NCC and NKCC expression is a crucial regulatory mechanism for salinity adaptation in tilapia. However, little is known about the interaction of cytoskeleton and these adaptive changes. In this study, we examined the time-course of changes in the localization of NKCC/NCC in the gills of tilapia transferred from fresh water (FW) to brackish water (20‰) and from seawater (SW; 35‰) to FW. The results showed that basolateral NKCC disappeared and NCC was expressed in the apical membrane of MR cells. To further clarify the process of these adaptive changes, colchicine, a specific inhibitor of microtubule-dependent cellular regulating processes was used. SW-acclimated tilapia were transferred to SW, FW, and FW with colchicine (colchicine-FW) for 96 h. Compared with the FW-treatment group, in the MR cells of colchicine-FW-treatment group, (1) the average size was significantly larger, (2) only wavy-convex-subtype apical surfaces were found, and (3) the basolateral (cytoplasmic) NKCC signals were still exhibited. Taken together, our results suggest that changes in size, phenotype, as well as the expression of NCC and NKCC cotransporters of MR cells in the tilapia are microtubule-dependent. J. Morphol. 277:1113-1122, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

TIME-DEPENDENT NEUROBIOLOGICAL EFFECTS OF COLCHICINE ADMINISTERED DIRECTLY INTO THE HIPPOCAMPUS OF RATS (JOURNAL VERSION)

EPA Science Inventory

Rats were given bilateral injections of colchicine into the dorsal and ventral hippocampus. Behavioral, neurochemical and histopathological measurements were taken up to 12 weeks after surgery. Colchicine produced a consistent increase in spontaneous motor activity, enhanced acou...

Comparison of the pharmacokinetics and safety of three formulations of infliximab (CT-P13, EU-approved reference infliximab and the US-licensed reference infliximab) in healthy subjects: a randomized, double-blind, three-arm, parallel-group, single-dose, Phase I study.

PubMed

Park, Won; Lee, Sang Joon; Yun, Jihye; Yoo, Dae Hyun

2015-01-01

To compare the pharmacokinetics (PK), safety and tolerability of biosimilar infliximab (CT-P13 [Remsima(®), Inflectra(®)]) with two formulations of the reference medicinal product (RMP) (Remicade(®)) from either Europe (EU-RMP) or the USA (US-RMP). This was a double-blind, three-arm, parallel-group study (EudraCT number: 2013-003173-10). Healthy subjects received single doses (5 mg/kg) of CT-P13 (n = 71), EU-RMP (n = 71) or US-RMP (n = 71). The primary objective was to compare the PK profiles for the three formulations. Assessments of comparative safety and tolerability were secondary objectives. Baseline demographics were well balanced across the three groups. Primary end points (Cmax, AUClast and AUCinf) were equivalent between all formulations (CT-P13 vs EU-RMP; CT-P13 vs US-RMP; EU-RMP vs US-RMP). All other PK end points supported the high similarity of the three treatments. Tolerability profiles of the formulations were similar. The PK profile of CT-P13 is highly similar to EU-RMP and US-RMP. All three formulations were equally well tolerated.

Induction of high mitotic index in Petunia suspension cultures by sequential treatment with aphidicolin and colchicine.

PubMed

Guri, A; Zelcer, A; Izhar, S

1984-12-01

Significantly higher than normal mitotic index (MI) values were induced in Petunia cell suspensions following treatments with colchicine, aphidicolin, drastic medium replacement, or a sequential application of aphidicolin and colchicine. This last treatment yielded the highest MI values: cells incubated with 30 μg/ml aphidicolin for 18 h, then cultured in drug-free medium for 8 h and finally exposed to 0.1% colchicine for 8 additional hours exhibited MI of 62.8% and 65.7% respectively, for the two cell lines in study.

Evaluation of the neuronal apoptotic pathways involved in cytoskeletal disruption-induced apoptosis.

PubMed

Jordà, Elvira G; Verdaguer, Ester; Jimenez, Andrés; Arriba, S Garcia de; Allgaier, Clemens; Pallàs, Mercè; Camins, Antoni

2005-08-01

The cytoskeleton is critical to neuronal functioning and survival. Cytoskeletal alterations are involved in several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We studied the possible pathways involved in colchicine-induced apoptosis in cerebellar granule neurons (CGNs). Although colchicine evoked an increase in caspase-3, caspase-6 and caspase-9 activation, selective caspase inhibitors did not attenuate apoptosis. Inhibitors of other cysteine proteases such as PD150606 (a calpain-specific inhibitor), Z-Phe-Ala fluoromethyl ketone (a cathepsins-inhibitors) and N(alpha)-p-tosyl-l-lysine chloromethyl ketone (serine-proteases inhibitor) also had no effect on cell death/apoptosis induced by colchicine. However, BAPTA-AM 10 microM (intracellular calcium chelator) prevented apoptosis mediated by cytoskeletal alteration. These data indicate that calcium modulates colchicine-induced apoptosis in CGNs. PARP-1 inhibitors did not prevent apoptosis mediated by colchicine. Finally, colchicine-induced apoptosis in CGNs was attenuated by kenpaullone, a cdk5 inhibitor. Kenpaullone and indirubin also prevented cdk5/p25 activation mediated by colchicine. These findings indicate that cytoskeletal alteration can compromise cdk5 activation, regulating p25 formation and suggest that cdk5 inhibitors attenuate apoptosis mediated by cytoskeletal alteration. The present data indicate the potential therapeutic value of drugs that prevent the formation of p25 for the treatment of neurodegenerative disorders.

Reductions in Use of Colchicine after FDA Enforcement of Market Exclusivity in a Commercially Insured Population.

PubMed

Kesselheim, Aaron S; Franklin, Jessica M; Kim, Seoyoung C; Seeger, John D; Solomon, Daniel H

2015-11-01

A brand-name version of colchicine (Colcrys) was introduced after its manufacturer conducted a clinical trial in acute gout patients, leading to higher prices for this drug. We analyzed the impact of the new single-source colchicine product on prescribing and patient health spending as well as incidence rates of potentially dangerous concomitant use of clarithromycin and cyclosporine after formal FDA approval. We conducted a retrospective cohort study of UnitedHealth-affiliated enrollees newly diagnosed with gout or FMF. Among gout and FMF patients separately, we assessed linear trends in colchicine prescriptions, prescription drug costs, and total health care costs from 2009 to September 2010 (market exclusivity announced) compared to January 2011 (market exclusivity enforced) through 2012. Next, we estimated trends in co-prescription within 15 days of clarithromycin, azithromycin (indicated on the Colcrys label for use in place of clarithromycin), and cyclosporine. Among gout patients, before Colcrys' market exclusivity, the odds of receiving colchicine within 30 days of gout diagnosis increased 1.4 %/month (OR: 1.014, 95 % CI: 1.011-1.018). Following FDA action, the odds decreased by 0.5 %/month (OR: 0.995, 95 % CI: 0.992-0.999) (p < 0.001). Similarly, among FMF patients, odds of initiating colchicine changed from an increase of 2.8 %/month to a decrease by 7.6 %/month (p = 0.01). Patients receiving colchicine experienced increases in average monthly prescription drug costs ($418 vs. $651, p < 0.001) and health care costs ($3,406 vs. $3,534, p < 0.001). Incidence rates of colchicine/clarithromycin co-prescription before and after FDA action did not change, while co-prescription of colchicine/cyclosporine increased after introduction of Colcrys [-0.75 monthly change in patients (95 % CI: -1.07, -0.43) vs. 0.13 (95 % CI: -0.16, 0.42), p < 0.001]. The FDA's actions were associated with a reduction in colchicine initiation and an increase in patient spending. By contrast, we did not observe any association with improvements in avoidance of potentially dangerous co-prescriptions.

Differential sensitivity of mouse oocytes to colchicine-induced aneuploidy

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

Mailhes, J.B.; Yuan, Z.P.

1987-01-01

Unpublished results from our laboratory showed that colchicine increased the incidence of hyperploid mouse metaphase II (MII) oocytes when injected at the same time as human chorionic gonadotrophin (HCG). The objective of the present study was to determine whether the time of administering colchicine influenced the incidence of aneuploidy in MII oocytes. CD-1 mice were given pregnant mare's serum (PMS) and, 48 hr later, HCG. An intraperitoneal injection of 0.2 mg/kg colchicine was given at +4, +2, 0, -2, or -4 hr relative to HCG. Oocytes were collected 17 hr post-HCG and processed, and chromosomes were subsequently C-banded. The percentagemore » of hyperploid oocytes was 0.77, 2.56, 5.71, 7.79, 3.54, and 2.70 for control, +4, +2, 0, -2, or -4 hr pre/post-HCG, respectively. Chi-square analyses of these data demonstrated that colchicine significantly increases the proportion of aneuploid oocytes, and that the relative sensitivity of colchicine-induced aneuploidy depends upon the time that this drug is administered relative to HCG.« less

Polyploid response of Artemisia annua L. to colchicine treatment

NASA Astrophysics Data System (ADS)

Yunus, A.; Parjanto; Samanhudi; Hikam, M. P.; Widyastuti, Y.

2018-03-01

Artemisia (Artemisia annua) is a a medicinal herb originated from Asia, its contains Artemisinin for malaria (caused by Plasmodium falciparum) treatment. Artemisinin content in A. annua are relatively low, ranging from 0.01% -0.5%. In order to increase the Artemisinin content, polyploid induction could be one effort to be done. For that, this experiment aims to examine the effect of colchicine on morphological characteristics and the induction of polyploidization in Artemisia plants. Polyploid induction on Artemisia annua L. seeds was performed by soaking the Artemisia seeds in colchicine (0%, 0,05%, 0,1% and 0,2%; concentration based) for 2 hours. The experimental design was Completely Randomized Design, one factor, 4 colchicine treatments and in each treatment 7 replicate. The results showed that polyploid occur in plants treated with 0.05% colchicine concentration and its morphological characteristic are 89.4 cm height, 30 branches, 15.9 CCI chlorophyll content, 0.78 cm stem diameter, and chromosome number 2n = 27. In the stomata density of polyploid plants (treated by 0.05% colchicine) was 130 number/mm2 with stomata diameter of 22.8 μm.

Colchicine for primary prevention of atrial fibrillation after open-heart surgery: Systematic review and meta-analysis.

PubMed

Lennerz, Carsten; Barman, Manish; Tantawy, Mahmoud; Sopher, Mark; Whittaker, Peter

2017-12-15

Atrial fibrillation occurs frequently after open-heart surgery. It is associated with increased morbidity and mortality, longer hospital stays, and increased healthcare costs. Prophylactic administration of colchicine may mitigate post-operative atrial fibrillation (POAF). We searched PubMed, ClinicalTrials.gov and CENTRAL databases to identify randomized controlled trials (RCTs) that; (1) compared prophylactic use of colchicine to placebo, or usual care, in patients with sinus rhythm who underwent elective open-heart surgery and (2) reported POAF-incidence. We excluded trials focused on incidence of atrial fibrillation after percutaneous interventions or colchicine treatment of diagnosed pericarditis or post-pericardiotomy-syndrome. A random-effects model was used to pool data for POAF-incidence as the primary outcome and for drug-related adverse effects, major adverse events (death and stroke), and hospital length-of-stay as secondary outcomes. We included five RCTs (1412 patients). Colchicine treatment reduced POAF-events by 30% versus placebo or usual care (18% vs. 27%, risk ratio (RR) 0.69, 95% confidence interval (CI) 0.57 to 0.84, p=0.0002). Adverse drug-related effects, especially gastrointestinal intolerance, increased with colchicine; (21% vs. 8.2%, RR 2.52, 95% CI 1.62 to 3.93, p<0.0001). However, major adverse events were unchanged (3.2% vs. 3.2%, RR 0.96, 95% CI 0.48 to 1.95, p=0.92). Length-of-stay decreased by 1.2days with colchicine (95% CI -1.89 to -0.44, p=0.002). Colchicine demonstrated superior efficacy versus usual care for prevention of atrial fibrillation after cardiac surgery. Moreover, colchicine treatment was associated with shorter hospital stays. These benefits outweigh increased risk of adverse drug-related effects; although further work is needed to minimize gastrointestinal effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Diagnosis, treatment, and prevention of gout.

PubMed

Hainer, Barry L; Matheson, Eric; Wilkes, R Travis

2014-12-15

Gout is characterized by painful joint inflammation, most commonly in the first metatarsophalangeal joint, resulting from precipitation of monosodium urate crystals in a joint space. Gout is typically diagnosed using clinical criteria from the American College of Rheumatology. Diagnosis may be confirmed by identification of monosodium urate crystals in synovial fluid of the affected joint. Acute gout may be treated with nonsteroidal anti-inflammatory drugs, corticosteroids, or colchicine. To reduce the likelihood of recurrent flares, patients should limit their consumption of certain purine-rich foods (e.g., organ meats, shellfish) and avoid alcoholic drinks (especially beer) and beverages sweetened with high-fructose corn syrup. Consumption of vegetables and low-fat or nonfat dairy products should be encouraged. The use of loop and thiazide diuretics can increase uric acid levels, whereas the use of the angiotensin receptor blocker losartan increases urinary excretion of uric acid. Reduction of uric acid levels is key to avoiding gout flares. Allopurinol and febuxostat are first-line medications for the prevention of recurrent gout, and colchicine and/or probenecid are reserved for patients who cannot tolerate first-line agents or in whom first-line agents are ineffective. Patients receiving urate-lowering medications should be treated concurrently with nonsteroidal anti-inflammatory drugs, colchicine, or low-dose corticosteroids to prevent flares. Treatment should continue for at least three months after uric acid levels fall below the target goal in those without tophi, and for six months in those with a history of tophi.

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

PubMed

Giles, Thomas D; Weber, Michael A; Basile, Jan; Gradman, Alan H; Bharucha, David B; Chen, Wei; Pattathil, Manoj

2014-05-31

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension. We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026. Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group. Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension. Forest Research Institute. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cell wall biogenesis in Oocystis: experimental alteration of microfibril assembly and orientation.

PubMed

Montezinos, D; Brown, R M

1978-01-01

Cell wall biogenesis in the unicellular green alga Oocystis apiculata has been studied. Under normal growth conditions, a cell wall with ordered microfibrils is synthesized. In each layer there are rows of parallel microfibrils. Layers are nearly perpendicular to each other. Terminal linear synthesizing complexes are located in the plasma membrane, and they are capable of bidirectional synthesis of cellulose microfibrils. Granule bands associated with the inner leaflet of the plasma membrane appear to control the orientation of newly synthesized microfibrils. Subcortical microtubules also are present during wall synthesis. Patterns of cell wall synthesis were studied after treatment with EDTA and EGTA as well as divalent cations (MgSO4, CaSO4, Cacl2). 0.1 M EDTA treatment for 15 min results in the disassociation of the terminal complexes from the ends of microfibrils. EDTA-treated cells followed by 15 min treatment with MgSO4 results in reaggregation of the linear complexes into a paired state, remote from the original ends to which they were associated. After 90 min treatment with MgSO4, normal synthesis resumes. EGTA and calcium salts do not affect the linear complexes or microfibril orientation. Treatments with colchicine and vinblastine sulphate do not depolymerize the microtubles, but the wall microfibril orientation is altered. With colchicine or vinblastine, the change in orientation from layer to layer is inhibited. The process is reversible upon removal of the drugs. Lumicolchicine has no effect upon microfibril orientation, but granule bands are disorganized. Treatment with coumarin, a known inhibitor of cellulose synthesis, causes the loss of visualization of subunits of the terminal complexes. The possibility of the existence of a membrane-associated colchicine-sensitive orientation protein for cellulose microfibrils is discussed. Transmembrane modulation of microfibril synthesis and orientation is presented.

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities Are Predicted for C-2 Analogues in the Colchicine Site

PubMed Central

2011-01-01

3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogues were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structure–activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design. PMID:22611477

Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.

PubMed

Da, Chenxiao; Telang, Nakul; Barelli, Peter; Jia, Xin; Gupton, John T; Mooberry, Susan L; Kellogg, Glen E

2012-01-12

3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.

Colchicine-induced leukopenia in a patient with familial Mediterranean fever: the cause and a possible approach.

PubMed

Ben-Chetrit, E; Navon, P

2003-01-01

A young patient with familial Mediterranean fever (FMF) developed leukopenia each time she took colchicine. However, when she discontinued the drug the white cell and the platelets counts increased but she experienced FMF attacks. Later it was found that the patient also had concomitant cytomegalovirus (CMV) infection. This complex situation posed several diagnostic and therapeutic issues concerning the real cause for the leukopenia and the possible approach to take in such conditions. We propose that when an essential drug (such as colchicine for FMF) causes leukopenia, one should look for concurrent CMV or another viral infection. If there is no such infection, it is suggested that the mechanism leading to leukopenia be clarified. In the case of bone marrow suppression, colchicine should be continued with injections of G-CSF, whereas if the bone marrow is hypercellular it is suggested to use steroids and colchicine concomitantly.

Comparison of antipyretic effectiveness of equal doses of rectal and oral acetaminophen in children.

PubMed

Karbasi, Sedigha Akhavan; Modares-Mosadegh, Moneyreh; Golestan, Motahhareh

2010-01-01

To compare a dose of oral and rectal acetaminophen and to evaluate acceptability of rectal acetaminophen, since oral and rectal acetaminophen is widely used as an antipyretic agent in febrile children and the comparative effectiveness of these two preparations is not well established. In this prospective parallel group designed study, 60 children who presented to the emergency department or outpatient pediatric clinic at a tertiary hospital and aged from 6 months to 6 years with rectal temperature over 39 degrees C were enrolled. Patients were randomly assigned to two equal-sized groups. Group 1 received 15 mg/kg acetaminophen rectally and group 2 received the same dose orally. Temperature was recorded at baseline and 1 and 3 hours after drug administration. In the first group, mean decrease in temperature, 1 and 3 hours after administration of acetaminophen was 1.07+/-0.16 (p < 0.001) and 1.74+/-0.25 degrees C (p < 0.001), respectively, and in the second group it was 1.98+/-0.19 (p < 0.001) and 1.70+/-0.14 degrees C (p < 0.001), respectively (p > 0.05). Rectal and oral acetaminophen preparations have equal antipyretic effectiveness in children. The rectal route proved to be as acceptable as the oral one among parents.

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

Pavelka, M.; Gangl, A.

The involvement of microtubules in the transepithelial transport of exogenous lipid in intestinal absorptive cells has been suggested. Using electronmicroscopic, biochemical, and radiochemical methods, researchers have studied the effects of the antimicrotubular agent colchicine on the intestinal mucosa and on the intestinal transport of endogenous lipid of rats in the fasting state. After colchicine treatment, the concentration of triglycerides in intestinal mucosa of rats fasted for 24 h doubled, and electron microscopic studies showed a striking accumulation of lipid particles in absorptive epithelial cells of the tips of jejunal villi. These findings suggest that colchicine interferes with the intestinal transepithelialmore » transport of endogenous lipoproteins. Additional studies, using an intraduodenal pulse injection of (/sup 14/C)linoleic acid, showed that colchicine does not affect the uptake of fatty acids by intestinal mucosa. However, it had divergent effects on fatty acid esterification, enhancing their incorporation into triglycerides relative to phospholipids, and caused a significant accumulation of endogenous diglycerides, triglycerides, and cholesterol esters within the absorptive intestinal epithelium. Detailed ultrastructural and morphometric studies revealed a decrease of visible microtubules, and a displacement of the smooth and rough endoplasmic reticulum and Golgi apparatus. Furthermore, it is shown that after colchicine treatment, microvilli appear at the lateral plasma membrane of intestinal absorptive cells, a change not previously reported to our knowledge. Thus, our study shows that colchicine causes significant changes in enterocyte ultrastructure and colchicine perturbs the reesterification of absorbed endogenous fatty acids and their secretion in the form of triglyceride-rich lipoproteins from the enterocyte.« less

Managing Gout Flares in the Elderly: Practical Considerations.

PubMed

Abhishek, Abhishek

2017-12-01

Gout is common in the elderly, affecting an estimated 4.7 million people aged > 60 years in the USA alone. The incidence and prevalence of gout increases, and male predisposition to gout reduces, with increasing age. The elderly have more comorbidities, and gout manifests differently, with more frequent involvement of knees, ankles, and wrists at disease onset, systemic upset, and tophi. Comorbidities and polypharmacy make the management of gout flares challenging in this population. Intra-articular corticosteroid injection remains the treatment of choice for accessible joints, oral prednisolone is preferred over low-dose colchicine, and non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided. Xanthine oxidase inhibitors (XOI) remain the first-line treatment for hyperuricemia in the elderly. Arhalofenate, an emerging uricosuric anti-inflammatory drug, prevents gout flares while reducing serum urate. It may be particularly relevant in the treatment of gout in the elderly as they are unable to tolerate long-term colchicine for flare prophylaxis and frequently have contraindications to corticosteroids and NSAIDs. However, given its modest urate-lowering effect, it can only be used in combination with an XOI, and the safety and efficacy of this drug has not been examined in the elderly or in those with chronic kidney disease. Diuretics and beta-blockers should be discontinued where feasible, whereas low-dose aspirin can be continued if otherwise indicated.

Severe hypertriglyceridemia and colchicine intoxication following suicide attempt.

PubMed

Lev, Shaul; Snyder, David; Azran, Carmil; Zolotarsky, Victor; Dahan, Arik

2017-01-01

Colchicine overdose is uncommon but potentially life threatening. Due to its serious adverse systemic effects, overdose must be recognized and treated. We report a case of an 18-year-old female who ingested 18 mg (~0.4 mg/kg) of colchicine in a suicide attempt. The patient's clinical manifestations included abdominal cramps, vomiting, pancytopenia, hypocholesterolemia, and rhabdomyolysis. Two unique manifestations of toxicity in this patient were profound and persistent, severe hypertriglyceridemia and electrolyte imbalance, mainly hypophosphatemia, with no other evident cause except the colchicine intoxication. Following intensive supportive treatment, including ventilator support, N-acetylcysteine, granulocyte colony stimulating factor, electrolyte repletion, and zinc supplementation, the patient made a complete recovery. Colchicine intoxication is a severe, life-threatening situation that should be followed closely in intensive care units. Severe changes in body functions can rapidly develop, as previously described in the literature. To our knowledge, this extremely elevated triglyceride level has never been reported without the administration of propofol, and requires further evaluation.

In vitro Induction and Generation of Tetraploid Plants of Sophora tonkinensis Gapnep

PubMed Central

Wei, Kun Hua; Xu, Jian Ping; Li, Lin Xuan; Cai, Jin Yuan; Miao, Jian Hua; Li, Min Hui

2018-01-01

Background: Sophora tonkinensis Gapnep. is an important medical plant in China. Early researches of S. tonkinensis were focused on rapid propagation and quality analysis of in vitro tissue culture plantlet, and still no research focuses on the plant breeding of and there were no excellent varieties for artificial cultivation of S. tonkinensis. Objective: To set up a method to generate and select the best varieties of S. tonkinensis by polyploid breeding after induction by colchicine treatment. Materials and Methods: The adventitious buds were submerged in different concentrations of aqueous colchicine solution for different lengths of time to induce polyploidy in the plants, and the induced buds were identified by root-tip chromosome determination and leaf characteristics comparison. The contents of matrine and oxymatrine of radix ex rhizoma in 13 selected tetraploid lines were collected after 90 days in vitro rooting culture and were evaluated to provide evidence of good qualities of tetraploid S. tonkinensis. Results: The results showed that the highest percentage of tetraploid induction was 23.33% and occurred in the 0.2% (w/v) colchicine treatment for 30 h. Fifty lines of tetraploid plants were obtained and 12 of the 13 selected tetraploid lines exhibited higher productivity of total contents of matrine and oxymatrine when compared to controls. Conclusion: The data demonstrate that polyploidy induction can be beneficial for improving the medicinal value of S. tonkinensis. SUMMARY Colchicine has a good in vitro induction effect on the tetraploid plants of Sophora tonkinensisThe leaf indices and stomatal apparatus of tetraploid plants were slightly larger than diploid plantsThe total content of matrine and oxymatrine of some tetraploid lines for 90-day-old in vitro rooting culture was higher than the diploid. Abbreviations used: MS medium: Murashige and Skoog medium; BAP: 6-benzylaminopurine; NAA: A-naphthaleneacetic acid; IAA: Indole-3-acetic acid; KT: Kinetin; IBA: Indole-3-butyric acid; ABT: Rooting power. PMID:29720823

Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

PubMed Central

Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

2011-01-01

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA. PMID:21537018

Immunoprotective effects of oral intake of heat-killed Lactobacillus pentosus strain b240 in elderly adults: a randomised, double-blind, placebo-controlled trial.

PubMed

Shinkai, Shoji; Toba, Masamichi; Saito, Takao; Sato, Ikutaro; Tsubouchi, Mina; Taira, Kiyoto; Kakumoto, Keiji; Inamatsu, Takashi; Yoshida, Hiroto; Fujiwara, Yoshinori; Fukaya, Taro; Matsumoto, Tetsuya; Tateda, Kazuhiro; Yamaguchi, Keizo; Kohda, Noriyuki; Kohno, Shigeru

2013-05-28

Oral intake of Lactobacillus pentosus strain b240 (b240) has been shown to enhance the secretion of salivary secretory IgA in elderly adults. However, its clinical benefits remain to be determined. We tested the hypothesis that b240 exerts a protective effect against the common cold in elderly adults. The design of the present study was a randomised, double-blind, placebo-controlled trial (RCT) with parallel three-group comparison. For this purpose, 300 eligible elderly adults were randomly allocated to one of three groups, namely a placebo, low-dose or high-dose b240 group. Participants in the low-dose and high-dose b240 groups were given tablets containing 2 × 10(9) or 2 × 10(10) cells, respectively, of heat-killed b240, while those in the placebo group were given tablets without b240. Each group consumed their respective tablets once daily for 20 weeks. The common cold was assessed on the basis of a diary. Change in quality of life was evaluated using the SF-36. Of the total participants, 280 completed the 20-week RCT. The accumulated incidence rate of the common cold was 47·3, 34·8 and 29·0 % for the placebo, low-dose b240 and high-dose b240 groups, respectively (P for trend = 0·012). Lower incidence rates were consistently observed throughout the experimental period in the b240 groups (log-rank test, P= 0·034). General health perception, as determined by the SF-36®, dose-dependently increased in the b240 groups ( P <0·025). In conclusion, oral intake of b240 significantly reduced the incidence rate of the common cold in elderly adults, indicating that b240 might be useful in improving resistance against infection through mucosal immunity.

Tubulin structure-based drug design for the development of novel 4β-sulfur-substituted podophyllum tubulin inhibitors with anti-tumor activity

PubMed Central

Zhao, Wei; Bai, Jia-Ke; Li, Hong-Mei; Chen, Tao; Tang, Ya-Jie

2015-01-01

The well-characterized anti-tubulin agent, podophyllotoxin (PTOX), with the 4′-position methoxyl group, targets the colchicines domain located between α- and β-tubulin. Two guanosine triphosphate (GTP) analogs of the tubulin-binding region were synthesized from PTOX, where a hydroxyl group was substituted with a carbon-sulfur bond. These compounds, 4-MP-PTOX and 4-TG-PTOX, reduce the dosage and greatly improve the therapeutic effect for microtubule damage in cancer cells. Here we characterize the anti-tubulin properties of these compounds. We found the stronger inhibition of tubulin polymerization (the concentration of 50% growth inhibition, GI50 < 2 μM) for compounds 4-TG-PTOX and 4-MP-PTOX, which were better than that of PTOX or colchicine. The cytotoxicity of two designed compounds on tumor cells was also significantly enhanced by comparing to those of PTOX and colchicines. The ΔH value of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by isothermal titration calorimetry (ITC) was found to be −7.4 and −5.3 kcal·mol−1, respectively. The wide range of enthalpy values across the series may reflect entropy/enthalpy compensation effects. Fragments 6-mercaptopurine (MP) and 6-thioguanine (TG) likely enhance the affinity of 4-MP-PTOX and 4-TG-PTOX binding to tubulin by increasing the number of binding sites. The correctness of rational drug design was strictly demonstrated by a bioactivity test. PMID:25959922

Biological Characterization of an Improved Pyrrole-Based Colchicine Site Agent Identified through Structure-Based Design

PubMed Central

Rohena, Cristina C.; Telang, Nakul S.; Da, Chenxiao; Risinger, April L.; Sikorski, James A.; Kellogg, Glen E.; Gupton, John T.

2016-01-01

A refined model of the colchicine site on tubulin was used to design an improved analog of the pyrrole parent compound, JG-03-14. The optimized compound, NT-7-16, was evaluated in biological assays that confirm that it has potent activities as a new colchicine site microtubule depolymerizer. NT-7-16 exhibits antiproliferative and cytotoxic activities against multiple cancer cell lines, with IC50 values of 10–16 nM, and it is able to overcome drug resistance mediated by the expression of P-glycoprotein and the βIII isotype of tubulin. NT-7-16 initiated the concentration-dependent loss of cellular microtubules and caused the formation of abnormal mitotic spindles, leading to mitotic accumulation. The direct interaction of NT-7-16 with purified tubulin was confirmed, and it was more potent than combretastatin A-4 in these assays. Binding studies verified that NT-7-16 binds to tubulin within the colchicine site. The antitumor effects of NT-7-16 were evaluated in an MDA-MB-435 xenograft model and it had excellent activity at concentrations that were not toxic. A second compound, NT-9-21, which contains dichloro moieties in place of the 3,5-dibromo substituents of NT-7-16, had a poorer fit within the colchicine site as predicted by modeling and the Hydropathic INTeractions score. Biological evaluations showed that NT-9-21 has 10-fold lower potency than NT-7-16, confirming the modeling predictions. These studies highlight the value of the refined colchicine-site model and identify a new pyrrole-based colchicine-site agent with potent in vitro activities and promising in vivo antitumor actions. PMID:26655304

Comparative effects of vildagliptin and sitagliptin determined by continuous glucose monitoring in patients with type 2 diabetes mellitus.

PubMed

Koyanagawa, Naohide; Miyoshi, Hideaki; Ono, Kota; Nakamura, Akinobu; Cho, Kyu Yong; Yamamoto, Kohei; Takano, Yoshinari; Dan-Noura, Midori; Atsumi, Tatsuya

2016-08-31

The dipeptidyl peptidase-4 inhibitors vildagliptin and sitagliptin are effective in treating patients with type 2 diabetes mellitus. Patients receiving standard doses of sitagliptin plus insulin may require increased doses of sitagliptin or switching to vildagliptin to improve blood glucose control. This study compared the effects of increasing sitagliptin and switching to vildagliptin in type 2 diabetes patients receiving standard doses of sitagliptin plus insulin. This prospective, randomized, parallel-group comparison trial enrolled 33 type 2 diabetes patients receiving 50 mg sitagliptin once daily plus insulin. Seventeen patients were randomized to 50 mg vildagliptin twice daily, and 16 to 100 mg sitagliptin once daily, and evaluated by continuous glucose monitoring at baseline and after 8 weeks. The primary end-point was the change in mean amplitude of glycemic excursions (MAGE). MAGE decreased from baseline in both the vildagliptin (-13.4 ± 35.7 mg/dL) and sitagliptin (-8.4 ± 24.3 mg/dL) groups, but neither within- nor between-group changes were statistically significant. Similarly, the areas under the curve for blood glucose levels ≥180 mg/dL and <70 mg/dL tended to improve in both groups, but these differences were not statistically significant. In contrast, HbA1c was significantly reduced only in the vildagliptin group, from 7.1 ± 0.6% at baseline to 6.8 ± 0.6% at 8 weeks (p=0.006). Increasing sitagliptin dose and switching to vildagliptin had limited effects in improving MAGE in type 2 diabetic patients treated with standard doses of sitagliptin.

Colchicine promotes a change in chromosome structure without loss of sister chromatid cohesion in prometaphase I-arrested bivalents.

PubMed

Rodríguez, E M; Parra, M T; Rufas, J S; Suja, J A

2001-12-01

In somatic cells colchicine promotes the arrest of cell division at prometaphase, and chromosomes show a sequential loss of sister chromatid arm and centromere cohesion. In this study we used colchicine to analyse possible changes in chromosome structure and sister chromatid cohesion in prometaphase I-arrested bivalents of the katydid Pycnogaster cucullata. After silver staining we observed that in colchicine-arrested prometaphase I bivalents, and in contrast to what was found in control bivalents, sister kinetochores appeared individualised and sister chromatid axes were completely separated all along their length. However, this change in chromosome structure occurred without loss of sister chromatid arm cohesion. We also employed the MPM-2 monoclonal antibody against mitotic phosphoproteins on control and colchicine-treated spermatocytes. In control metaphase I bivalents this antibody labelled the tightly associated sister kinetochores and the interchromatid domain. By contrast, in colchicine-treated prometaphase I bivalents individualised sister kinetochores appeared labelled, but the interchromatid domain did not show labelling. These results support the notion that MPM-2 phosphoproteins, probably DNA topoisomerase IIalpha, located in the interchromatid domain act as "chromosomal staples" associating sister chromatid axes in metaphase I bivalents. The disappearance of these chromosomal staples would induce a change in chromosome structure, as reflected by the separation of sister kinetochores and sister axes, but without a concomitant loss of sister chromatid cohesion.

SU-E-T-133: Dosimetric Impact of Scan Orientation Relative to Target Motion During Spot Scanning Proton Therapy

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

Stoker, J; Summers, P; Li, X

2014-06-01

Purpose: This study seeks to evaluate the dosimetric effects of intra-fraction motion during spot scanning proton beam therapy as a function of beam-scan orientation and target motion amplitude. Method: Multiple 4DCT scans were collected of a dynamic anthropomorphic phantom mimicking respiration amplitudes of 0 (static), 0.5, 1.0, and 1.5 cm. A spot-scanning treatment plan was developed on the maximum intensity projection image set, using an inverse-planning approach. Dynamic phantom motion was continuous throughout treatment plan delivery.The target nodule was designed to accommodate film and thermoluminescent dosimeters (TLD). Film and TLDs were uniquely labeled by location within the target. The phantommore » was localized on the treatment table using the clinically available orthogonal kV on-board imaging device. Film inserts provided data for dose uniformity; TLDs provided a 3% precision estimate of absolute dose. An inhouse script was developed to modify the delivery order of the beam spots, to orient the scanning direction parallel or perpendicular to target motion.TLD detector characterization and analysis was performed by the Imaging and Radiation Oncology Core group (IROC)-Houston. Film inserts, exhibiting a spatial resolution of 1mm, were analyzed to determine dose homogeneity within the radiation target. Results: Parallel scanning and target motions exhibited reduced target dose heterogeneity, relative to perpendicular scanning orientation. The average percent deviation in absolute dose for the motion deliveries relative to the static delivery was 4.9±1.1% for parallel scanning, and 11.7±3.5% (p<<0.05) for perpendicularly oriented scanning. Individual delivery dose deviations were not necessarily correlated to amplitude of motion for either scan orientation. Conclusions: Results demonstrate a quantifiable difference in dose heterogeneity as a function of scan orientation, more so than target amplitude. Comparison to the analyzed planar dose of a single field hint that multiple-field delivery alters intra-fraction beam-target motion synchronization and may mitigate heterogeneity, though further study is warranted.« less

A survey of the assessment and management of gout in general practitioners and medical officers within the Illawarra Network, Australia.

PubMed

Terrill, Matthew; Riordan, John

2017-08-01

To review the assessment and management of gout by general practitioners (GPs) and medical officers (MOs) within the Illawarra Network, Australia. A survey was sent to GPs and MOs within the Illawarra Network. Of 110 GPs, 45 responded. Of 129 MOs, 42 responded. The overall response was 32.6%. On analysis, 65.1% felt their knowledge of gout to be adequate and 61.6% thought they had been educated well. In acute assessment, 59.1% of GPs responded that the diagnosis of gout best be confirmed with a joint aspiration and 36.4% clinical suspicion. Differing, 85.7% of MOs chose a joint aspiration. In acute management, if colchicine were used, 59.1% of GPs would give 1 mg followed by 0.5 mg an hour later, then 0.5 mg twice daily, compared to 9.5% of MOs, while 20.5% of GPs would use 1 mg twice daily. Chronic management was answered poorly. After an acute attack, urate lowering therapy (ULT) would be started 14 days after by 47.7% of GPs, compared to 69.0% of MOs. GPs were more likely to start ULT within 7 days (52.3% vs. 31.0%). With dosing of ULT, 45.3% would treat to target, while 46.5% would dose to the creatinine clearance. Prophylactic therapy with ULT would be started by 81.8%, although only 17.4% would continue it for 3-6 months. There is poor adherence to recommended practice for dosing of colchicine in acute gout. Also in the management of chronic gout, in particular, the timing of starting ULT and the use of prophylaxis when initiating ULT. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Enantiomeric separation of the antiuremic drug colchicine by electrokinetic chromatography. Method development and quantitative analysis.

PubMed

Menéndez-López, Nuria; Valimaña-Traverso, Jesús; Castro-Puyana, María; Salgado, Antonio; García, María Ángeles; Marina, María Luisa

2017-05-10

Two analytical methodologies were developed by CE enabling the enantiomeric separation of colchicine, an antiuremic drug commercialized as pure enantiomer. Succinyl-γ-CD and Sulfated-γ-CD were selected as chiral selectors after a screening with different anionic CDs. Under the optimized conditions, chiral resolutions of 5.6 in 12min and 3.2 in 8min were obtained for colchicine with Succinyl-γ-CD and Sulfated-γ-CD, respectively. An opposite enantiomeric migration order was observed with these two CDs being S-colchicine the first-migrating enantiomer with Succinyl-γ-CD and the second-migrating enantiomer with Sulfated-γ-CD. H NMR experiments showed a 1:1 stoichiometry for the enantiomer-CD complexes in both cases. However, the apparent and averaged equilibrium constants for the enantiomer-CD complexes could be calculated only for Succinyl-γ-CD. The developed methods were applied to the analysis of pharmaceutical formulations but only the use of Succinyl-γ-CD enabled to detect a 0.1% of enantiomeric impurity in colchicine formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Low-dose combined oral contraceptive use is associated with lower bone mineral content variation in adolescents over a 1-year period.

PubMed

Biason, Talita Poli; Goldberg, Tamara Beres Lederer; Kurokawa, Cilmery Suemi; Moretto, Maria Regina; Teixeira, Altamir Santos; Nunes, Hélio Rubens de Carvalho

2015-04-03

Low-dose combined oral contraceptives (COCs) can interfere with bone mass acquisition during adolescence. This study aimed to evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low-dose COC (ethinylestradiol 20 μg/desogestrel 150 μg) over a 1-year period and to compare their data with those of healthy adolescents from the same age group not taking COCs. This was a non-randomized parallel-control study with a 1-year follow-up. Sixty-seven adolescents aged from 12 to 19 years, divided into COC users (n = 41) taking 20 μg ethinylestradiol/150 μg desogestrel and COC non-user controls (n = 26), were evaluated by bone densitometry examinations at baseline and after 12 months. Comparisons between the groups at the study onset were performed using the Mann-Whitney test with the significance level fixed at 5% or p < 0.05. Comparisons between the groups at the study onset and after 12 months were based on variations in the median percentages for bone mass variables. The COC users presented with low bone mass acquisition in the lumbar spine, and had BMD and BMC median variations of 2.07% and +1.57%, respectively, between the measurements at baseline and 12 months. The control group had median variations of +12.16% and +16.84% for BMD and BMC, respectively, over the same period. The total body BMD and BMC showed similar evolutions during the study in both groups. Statistical significance (p < 0.05) was seen for the BMC percentage variation between COC users and non-users. Use of a low-dose COC (ethinylestradiol 20 μg/desogestrel 150 μg) was associated with lower bone mass acquisition in adolescents during the study period. Registry Number, RBR-5h9b3c.

Dose-dependent efficacy of the Vitex agnus castus extract Ze 440 in patients suffering from premenstrual syndrome.

PubMed

Schellenberg, Ruediger; Zimmermann, Christian; Drewe, Jürgen; Hoexter, Godehard; Zahner, Catherine

2012-11-15

Preparations of Vitex agnus castus L. (VAC) have been shown to be effective to treat irregular menstrual cycles, cyclical mastalgia and symptoms of the premenstrual syndrome (PMS). However, the dose-effect relationship for the treatment of PMS has not yet been established. This study aimed to investigate the clinical effects of three different doses of the VAC extract Ze 440 in comparison to placebo in patients suffering from PMS. In a multicenter, double-blind, placebo-controlled, parallel-group study, 162 female patients with PMS (18-45 years) were randomized to either placebo or different doses of Ze 440 (8, 20 and 30 mg) over three menstrual cycles. PMS symptoms' severity was assessed by patients using visual analog scales (VAS) for the symptoms irritability, mood alteration, anger, headache, bloating and breast fullness. Each of the treatments was well tolerated. Improvement in the total symptom score (TSS) in the 20mg group was significantly higher than in the placebo and 8 mg treatment group. The higher dose of 30 mg, on the other hand, did not significantly decrease symptom severity compared to the 20mg treatment, providing a rational for the usage of 20mg. Corresponding results were observed with the single PMS symptom scores. This study demonstrated that the VAC extract Ze 440 was effective in relieving symptoms of PMS, when applied in a dose of 20mg. Therefore, for patients suffering from PMS, 20mg Ze 440 should be the preferred daily dose. Copyright © 2012 Elsevier GmbH. All rights reserved.

A Comparison of Dose-Response Models for the Parotid Gland in a Large Group of Head-and-Neck Cancer Patients

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

Houweling, Antonetta C., E-mail: A.Houweling@umcutrecht.n; Philippens, Marielle E.P.; Dijkema, Tim

2010-03-15

Purpose: The dose-response relationship of the parotid gland has been described most frequently using the Lyman-Kutcher-Burman model. However, various other normal tissue complication probability (NTCP) models exist. We evaluated in a large group of patients the value of six NTCP models that describe the parotid gland dose response 1 year after radiotherapy. Methods and Materials: A total of 347 patients with head-and-neck tumors were included in this prospective parotid gland dose-response study. The patients were treated with either conventional radiotherapy or intensity-modulated radiotherapy. Dose-volume histograms for the parotid glands were derived from three-dimensional dose calculations using computed tomography scans. Stimulatedmore » salivary flow rates were measured before and 1 year after radiotherapy. A threshold of 25% of the pretreatment flow rate was used to define a complication. The evaluated models included the Lyman-Kutcher-Burman model, the mean dose model, the relative seriality model, the critical volume model, the parallel functional subunit model, and the dose-threshold model. The goodness of fit (GOF) was determined by the deviance and a Monte Carlo hypothesis test. Ranking of the models was based on Akaike's information criterion (AIC). Results: None of the models was rejected based on the evaluation of the GOF. The mean dose model was ranked as the best model based on the AIC. The TD{sub 50} in these models was approximately 39 Gy. Conclusions: The mean dose model was preferred for describing the dose-response relationship of the parotid gland.« less

Mutagenic influences of colchicine on phenological and molecular diversity of Calendula officinalis L.

PubMed

El-Nashar, Y I; Ammar, M H

2016-04-26

Six different colchicine concentrations: 0, 400, 800, 1200, 1600, and 2000 ppm, in combination with four soaking time treatments (1, 2, 3, and 4 h), were selected to assess the effects on germination, vegetative growth, and flower yield components in calendula plants. The molecular diversity among the treatments was assessed using ten SRAP marker combinations. Seed soaking in colchicine significantly enhanced both the fresh and the dry shoot and root masses, flowering date, number of flowers per plant, and flower diameter. At 1200-ppm colchicine combined with a 4-h soaking time, a superior effect on seed germination was observed, whereas 800 ppm for 4 h produced the highest number of flowers and the largest flower diameter. The earliest flowering time was found at 800 ppm combined with a short soaking time (1 h), while the 4-h soaking time with 800 ppm, is recommended for growing calendula outdoors, since it enhances flower development. At the molecular level, 752 fragments were successfully amplified using the SRAP primers, with 280 genetic loci found throughout the calendula genome. The polymorphism percentage ranged from 79 to 100% and the polymorphic information content (PIC) values ranged between 0.85 and 0.97. The high number of detected loci and PIC values suggests a great power of SRAP markers in detecting mutant molecular diversity. Our results clearly show the existence of genetic variation among colchicine treated calendula plants and the clustering of the studied mutants was concordant with the colchicine concentration used.

Fenoterol hydrobromide delivered via HFA-MDI or CFC-MDI in patients with asthma: a safety and efficacy comparison.

PubMed

Goldberg, J; Böhning, W; Schmidt, P; Freund, E

2000-10-01

The main objective of the study was to compare the long-term safety and tolerability of fenoterol hydrobromide delivered using a metered-dose inhaler formulated with the alternative propellant, hydrofluoroalkane 134a (HFA-MDI), with delivery using the currently available chlorofluorocarbon MDI (CFC-MDI; Berotec 100). A further objective was to compare the efficacy of fenoterol HFA-MDI with fenoterol CFC-MDI, using the pulmonary function parameters of forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). Following a 2-week run-in phase, a 12-week, double-blind parallel group comparison was undertaken in 290 patients randomized on a 2:1 basis to two puffs of 100 microg fenoterol four times a day (HFA-MDI=197 patients; CFC-MDI=93 patients). A total of 236 patients in this multi-centre study completed the trial as planned. The overall incidence of adverse events (AEs) was similar in both groups (29.9% of HFA-MDI patients and 28% of CFC-MDI patients). Reports of respiratory disorder AEs were also comparable (21.8% HFA-MDI; 22.6% CFCMDI). End of study laboratory tests, ECG, pulse, blood pressure and physical examination showed no significant differences from pre-study baselines in either group and both treatments appeared to be well tolerated. Pre-dose FEV1 measurements taken at the three clinic visits were constant and increase in FEV1 at 5 and 30 min post-dose demonstrated equivalent efficacy for the two formulations. No difference between the two groups was observed in PEF or in the use of rescue medication. We conclude from these findings that the long-term safety and efficacy profile of fenoterol HFA-MDI is comparable to that of the fenoterol CFC-MDI.

Lipid modifying action of atorvastatin in comparison to combination of atorvastatin and nicotinic acid in patients with ischaemic heart disease.

PubMed

Santanu, Guha; Suhrita, Paul; Mookerjee, Soura; Tania, Kundu; Mita, Saha; Pramit, Ghosh; Sharmila, Guha; Miraj, Mandal; Debdutta, Majumder

2011-01-01

The current study is a prospective, randomized controlled study with two parallel treatment groups done to assess the tolerability and efficacy of a combination of atorvastatin (10 mg) and extended release nicotinic acid (1G) in comparison to atorvastatin (20 mg) alone in modulating the lipid profile in patients of Ischemic Heart Disease in our population. Patients were randomly allocated into two equal groups (n = 216) as per selection criteria. Group A received Atorvastatin 20 mg while Group B received combination of Atorvastatin -10 mg and extended release nicotinic acid (1G), both once daily at bed time, for a period of 24 weeks. Final end-of-study assessment and evaluation of tolerability and efficacy was done after 24 weeks. Comparison between the groups was performed with paired t-test. A p value < 0.05 was considered to be statistically significant. There was significant reduction in cholesterol, LDL & triglycerides in both the groups. Mean values of cholesterol and LDL were comparable in both groups where as there was increased reduction of triglycerides in Group B. Mean value of HDL cholesterol significantly increased only in group B thus the total cholesterol: HDL ratio was decreased more favorably. SGPT level was not significantly altered in either of the groups. In the Indian perspective, where HDL is low and the LDL values are not very high, a combination of low dose atorvastatin with nicotinic acid may influence the lipid profile more favorably and reduce the cholesterol/HDL ratio in comparison to atorvastatin alone and is also fairly well tolerated.

The natural naphthoquinone plumbagin exhibits antiproliferative activity and disrupts the microtubule network through tubulin binding.

PubMed

Acharya, Bipul R; Bhattacharyya, Bhabatarak; Chakrabarti, Gopal

2008-07-29

Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone), a naphthoquinone isolated from the roots of Plumbaginaceae plants, has potential antiproliferative activity against several tumor types. We have examined the effects of plumbagin on cellular microtubules ex vivo as well as its binding with purified tubulin and microtubules in vitro. Cell viability experiments using human non-small lung epithelium carcinoma cells (A549) indicated that the IC 50 value for plumbagin is 14.6 microM. Immunofluorescence studies using an antitubulin FITC conjugated antibody showed a significant perturbation of the interphase microtubule network in a dose dependent manner. In vitro polymerization of purified tubulin into microtubules is inhibited by plumbagin with an IC 50 value of 38 +/- 0.5 microM. Its binding to tubulin quenches protein tryptophan fluorescence in a time and concentration dependent manner. Binding of plumbagin to tubulin is slow, taking 60 min for equilibration at 25 degrees C. The association reaction kinetics is biphasic in nature, and the association rate constants for fast and slow phases are 235.12 +/- 36 M (-1) s (-1) and 11.63 +/- 11 M (-1) s (-1) at 25 degrees C respectively. The stoichiometry of plumbagin binding to tubulin is 1:1 (mole:mole) with a dissociation constant of 0.936 +/- 0.71 microM at 25 degrees C. Plumbagin competes for the colchicine binding site with a K i of 7.5 microM as determined from a modified Dixon plot. Based on these data we conclude that plumbagin recognizes the colchicine binding site to tubulin. Further study is necessary to locate the pharmacophoric point of attachment of the inhibitor to the colchicine binding site of tubulin.

Recurrent pericarditis.

PubMed

Imazio, M; Battaglia, A; Gaido, L; Gaita, F

2017-05-01

Recurrent pericarditis is the most troublesome complication of pericarditis occurring in 15 to 30% of cases. The pathogenesis is often presumed to be immune-mediated although a specific rheumatologic diagnosis is commonly difficult to find. The clinical diagnosis is based on recurrent pericarditis chest pain and additional objective evidence of disease activity (e.g. pericardial rub, ECG changes, pericardial effusion, elevation of markers of inflammation, and/or imaging evidence of pericardial inflammation by CT or cardiac MR). The mainstay of medical therapy for recurrent pericarditis is aspirin or a non-steroidal anti-inflammatory drug (NSAID) plus colchicine. Second-line therapy is considered after failure of such treatments and it is generally based on low to moderate doses of corticosteroids (e.g. prednisone 0.2 to 0.5 mg/kg/day or equivalent) plus colchicine. More difficult cases are treated with combination of aspirin or NSAID, colchicine and corticosteroids. Refractory cases are managed by alternative medical options, including azathioprine, or intravenous human immunoglobulins or biological agents (e.g. anakinra). When all medical therapies fail, the last option may be surgical by pericardiectomy to be recommended in well-experienced centres. Despite a significant impairment of the quality of life, the most common forms of recurrent pericarditis (usually named as "idiopathic recurrent pericarditis" since without a well-defined etiological diagnosis) have good long-term outcomes with a negligible risk of developing constriction and rarely cardiac tamponade during follow-up. The present article reviews current knowledge on the definition, diagnosis, aetiology, therapy and prognosis of recurrent pericarditis with a focus on the more recent available literature. Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Interaction of pseudolaric acid B with the colchicine site of tubulin.

PubMed

Sarkar, Taradas; Nguyen, Tam Luong; Su, Zhi-Wei; Hao, Jun; Bai, Ruoli; Gussio, Rick; Qiu, Samuel X; Hamel, Ernest

2012-08-15

We purified pseudolaric acid B (PAB) from the root and stem bark of Pseudolarix kaempferi (Lindl.) Gorden. Confirming previous findings, we found that the compound had high nanomolar IC₅₀ antiproliferative effects in several cultured cell lines, causing mitotic arrest and the disappearance of intracellular microtubules. PAB strongly inhibited tubulin assembly (IC₅₀, 1.1 μM) but weakly inhibited the binding of colchicine to tubulin, as demonstrated by fluorescence and with [³H]colchicine. Kinetic analysis demonstrated that the mechanism of inhibition was competitive, with an apparent K(i) of 12-15 μM. Indirect studies demonstrated that PAB bound rapidly to tubulin and dissociated more rapidly from tubulin than the colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, whose complex with tubulin is known to have a half-life of 17s at 37 °C. We modeled PAB into the colchicine site of tubulin, using the crystal structure 1SA0 that contains two αβ-tubulin heterodimers, both bound to a colchicinoid and to a stathmin fragment. The binding model of PAB revealed common pharmacophoric features between PAB and colchicinoids, not readily apparent from their chemical structures. Published by Elsevier Inc.

Exploration of interaction zones of β-tubulin colchicine binding domain of helminths and binding mechanism of anthelmintics.

PubMed

Ranjan, Prabodh; Kumar, Sivakumar Prasanth; Kari, Vijayakrishna; Jha, Prakash Chandra

2017-06-01

Numerous studies postulated the possible modes of anthelmintic activity by targeting alternate or extended regions of colchicine binding domain of helminth β-tubulin. We present three interaction zones (zones vide -1 to -3) in the colchicine binding domain of Haemonchus contortus (a helminth) β-tubulin homology model and developed zone-wise structure-based pharmacophore models coupled with molecular docking technique to unveil the binding hypotheses. The resulted ten structure-based hypotheses were then refined to essential three point pharmacophore features that captured recurring and crucial non-covalent receptor contacts and proposed three characteristics necessary for optimal zone-2 binding: a conserved pair of H bond acceptor (HBA to form H bond with Asn226 residue) and an aliphatic moiety of molecule separated by 3.75±0.44Å. Further, an aliphatic or a heterocyclic group distant (11.75±1.14Å) to the conserved aliphatic site formed the third feature component in the zone-2 specific anthelmintic pharmacophore model. Alternatively, an additional HBA can be substituted as a third component to establish H bonding with Asn204. We discern that selective zone-2 anthelmintics can be designed effectively by closely adapting the pharmacophore feature patterns and its geometrical constraints. Copyright © 2017 Elsevier Ltd. All rights reserved.

Canakinumab relieves symptoms of acute flares and improves health-related quality of life in patients with difficult-to-treat Gouty Arthritis by suppressing inflammation: results of a randomized, dose-ranging study

PubMed Central

2011-01-01

Introduction We report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis. Methods In this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to - or had contraindications for - non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version). Results At baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose. Conclusions Canakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg. Trial registration clinicaltrials.gov: NCT00798369. PMID:21439048

Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine.

PubMed

Pareek, Anil; Chandurkar, Nitin B; Sharma, Ravishankar; Tiwari, Dharmendra; Gupta, Bhagwan S

2010-01-01

Epidemiological studies and clinical trials have shown that prevention of cardiovascular disease, the ultimate goal of hypertension treatment, requires a sufficient reduction in blood pressure. The primary objective of this study was to compare the mean decrease in systolic (SBP) and diastolic (DBP) blood pressure between metoprolol extended release (XL)/amlodipine fixed-dose combination and losartan plus amlodipine combination in patients with mild-to-moderate essential hypertension. The secondary objectives of this study were to compare the proportion of responders in the two treatment groups and to evaluate the tolerability of the study medications. This was a randomized, parallel-group, multicentre comparative study conducted at the outpatient departments of three teaching hospitals in India. Patients with mild-to-moderate hypertension (defined as DBP 90-109 mmHg) aged between 18 and 75 years were enrolled in this study and followed up for 12 weeks. Response to study treatments was evaluated in terms of mean decrease in SBP and DBP and the response rate (reduction to SBP <140 mmHg and DBP <90 mmHg). Out of 152 patients who underwent a 1-week placebo washout, 148 eligible patients were randomized to receive either metoprolol XL 25 mg/amlodipine 2.5 mg fixed-dose combination (76 patients) or losartan 25 mg plus amlodipine 2.5 mg (72 patients). The two treatment groups were similar with respect to demographic and baseline characteristics. Non-responders after 4 weeks of therapy were escalated to metoprolol XL 50 mg/amlodipine 5 mg fixed-dose combination or losartan 50 mg plus amlodipine 5 mg, respectively. The study was completed by 66 patients in each group, of whom 43 patients in each group responded to the starting doses. After 4 weeks' therapy, both treatments were associated with significant decreases in SBP and DBP from baseline (p < 0.001) and were comparable with respect to mean decrease in SBP (p = 0.304), mean decrease in DBP (p = 0.630) and response rate (p = 1.0). Also, both the step-up therapies were comparable with respect to mean decrease in SBP (p = 0.484), mean decrease in DBP (p = 0.650) and response rate (p = 0.134) at week 12. Both treatments were well tolerated in the studied population. Metoprolol XL/amlodipine fixed-dose combination was found to be as effective and well tolerated as losartan plus amlodipine in the treatment of essential hypertension.

Sterile osteitis and suppurative arthritis associated with pannus responding to colchicine.

PubMed

Tezcan, Mehmet Engin; Ekinci, Ozgür; Uçar, Murat; Göker, Berna

2013-01-01

Sterile suppurative arthritis is characterized by neutrophilic infiltration of joints without any causative pathogen. Here, we present a 32-year-old man with refractory osteitis and erosive suppurative oligoarthritis with pannus. Treatments with multiple disease modifying antirheumatic drugs were all unsuccessful. However, he had clinical response to colchicine and the synovial hypertrophy and the pannus in the MRI of his left shoulder resolved. In this case, the effects of colchicine on neutrophils might have played a role in treating neutrophilic sterile suppurative arthritis, which, in adults, might be a distinct oligoarticular disease.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study.

PubMed

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed.

Efficacy and safety of guaifenesin for upper back, neck, and shoulder pain: a Phase II proof-of-concept, multicenter, placebo-controlled, repeat-dose, parallel-group study

PubMed Central

Collaku, Agron; Yue, Yong; Reed, Kenneth

2017-01-01

Background/objective Guaifenesin, an over-the-counter (OTC) expectorant, has exhibited muscle relaxant effects preclinically and clinically. This proof-of-principle study explored whether OTC doses of guaifenesin can provide relief from acute upper back, neck, or shoulder muscle spasm and pain. Methods This multicenter, placebo-controlled, repeat-dose, parallel study randomly assigned adults experiencing acute pain and muscle spasm in their upper back, neck, or shoulder to guaifenesin 600 or 1200 mg or matched placebo twice daily (BID) in a 2:2:1:1 ratio for 7 days. The primary end point was the change from baseline in muscle spasm relief, measured using an 11-point numeric rating scale (0=not present to 10=unbearable) recorded twice daily and averaged over the 7-day treatment period. Analyses were performed using a linear mixed model that included treatment as a fixed effect and site as a random effect. Results A total of 77 subjects were included in the 4 treatment groups. Least squares mean muscle spasm score over 7 days was 1.77 with guaifenesin 1200 mg, 1.42 with its matched placebo, 1.53 with guaifenesin 600 mg, and 1.74 with its matched placebo. Treatment with guaifenesin 1200 mg BID provided 25% greater reduction in mean muscle spasm over its matched placebo and 16% greater reduction than guaifenesin 600 mg BID. These differences were not statistically significant. Based on comparisons of absolute mean values, a consistent directional change in effect was observed, suggesting some benefit from placebo to lower-to-upper doses of guaifenesin with regard to muscle spasm, tension, pain, discomfort, and relaxation. No severe or serious adverse events were reported. Conclusion Results suggest the potential for OTC dose of guaifenesin 1200 mg BID to provide symptomatic relief of upper back musculoskeletal pain and spasm. Confirmation of this preliminary result in a larger, adequately powered study is needed. PMID:28356767

Comparison of the pharmacokinetics of a new 30 mg modified-release tablet formulation of metoclopramide for once-a-day administration versus 10 mg immediate-release tablets: a single and multiple-dose, randomized, open-label, parallel study in healthy male subjects.

PubMed

Bernardo-Escudero, Roberto; Alonso-Campero, Rosalba; Francisco-Doce, María Teresa de Jesús; Cortés-Fuentes, Myriam; Villa-Vargas, Miriam; Angeles-Uribe, Juan

2012-12-01

The study aimed to assess the pharmacokinetics of a new, modified-release metoclopramide tablet, and compare it to an immediate-release tablet. A single and multiple-dose, randomized, open-label, parallel, pharmacokinetic study was conducted. Investigational products were administered to 26 healthy Hispanic Mexican male volunteers for two consecutive days: either one 30 mg modified-release tablet every 24 h, or one 10 mg immediate-release tablet every 8 h. Blood samples were collected after the first and last doses of metoclopramide. Plasma metoclopramide concentrations were determined by high-performance liquid chromatography. Safety and tolerability were assessed through vital signs measurements, clinical evaluations, and spontaneous reports from study subjects. All 26 subjects were included in the analyses [mean (SD) age: 27 (8) years, range 18-50; BMI: 23.65 (2.22) kg/m², range 18.01-27.47)]. Peak plasmatic concentrations were not statistically different with both formulations, but occurred significantly later (p < 0.05) with the modified-release form [tmax: 3.15 (1.28) vs. 0.85 (0.32) h and tmax-ss: 2.92 (1.19) vs. 1.04 (0.43) h]. There was no difference noted in the average plasma concentrations [Cavgτ: 23.90 (7.90) vs. 20.64 (7.43) ng/mL after the first dose; and Cavg-ss: 31.14 (9.64) vs. 35.59 (12.29) ng/mL after the last dose, (p > 0.05)]. One adverse event was reported in the test group (diarrhea), and one in the reference group (headache). This study suggests that the 30 mg modified-release metoclopramide tablets show features compatible with slow-release formulations when compared to immediate-release tablets, and is suitable for once-a-day administration.

Analysis of the data on pregnancy and lactation provided by patient information leaflets of anti-rheumatic drugs in Argentina.

PubMed

Sabando, Miguel Ormaza; Saavedra, Maira Arias; Sequeira, Gabriel; Kerzberg, Eduardo

2018-04-01

To analyse the level of consistency and updating of the information on pregnancy and lactation provided by patient information leaflets (PILs) of the antirheumatic drugs approved in Argentina. Inconsistencies between the 2016 EULAR Task Force recommendations on the use of anti-rheumatic drugs during pregnancy and lactation and the information provided by PILs of the same drugs approved in Argentina were analysed along with inconsistencies within the PILs of different registered trademarks of these drugs. Eighty-eight PILs of 32 drugs were analysed. Out of the 88 PILs, 50% presented information inconsistencies as to pregnancy. Medications comprised in this group were: hydroxychloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs (during the first two trimesters), celecoxib, some glucocorticoids, colchicine, and some anti-TNF drugs (etanercept, adalimumab and infliximab) during part of the pregnancy. As for lactation, 56% had information inconsistencies. Medications encompassed in this group were: hydroxychloroquine, chloroquine, sulfasalazine, azathioprine, tacrolimus, cyclosporine, NSAIDs, celecoxib, meprednisone, prednisone, colchicine, and anti-TNF drugs. Out of 17 drugs that had more than one registered trademark, information inconsistencies on pregnancy were found in the PILs of sulfasalazine, diclofenac, ibuprofen and methylprednisolone. Concerning lactation, inconsistencies were present in the PILs of hydroxychloroquine, sulfasalazine, diclofenac, ibuprofen, meprednisone, and colchicine. At least half of the PILs of anti-rheumatic drugs analysed in this study had information inconsistencies on pregnancy and lactation. This is a serious state of affairs because the consensual decision-making process between patient and professional may be compromised, which, in turn, may give rise to medical-legal issues.

Prolonged cytotoxic effect of colchicine released from biodegradable microspheres.

PubMed

Muvaffak, Asli; Gurhan, Ismet; Hasirci, Nesrin

2004-11-15

One the main problems of cancer chemotherapy is the unwanted damage to normal cells caused by the high toxicities of anticancer drugs. Any system of controlled drug delivery that would reduce the total amount of drug required, and thus reduce the side effects, would potentially help to improve chemotherapy. In this respect, biodegradable gelatin microspheres were prepared by water/oil emulsion polymerization and by crosslinking with glutaraldehyde (GTA) as the drug-carrier system. Microspheres were loaded with colchicine, a model antimitotic drug, which was frequently used as an antimitotic agent in cancer research involving cell cultures. Microsphere sizes, swelling and degradation properties, drug-release kinetics, and cytotoxities were studied. Swelling characteristics of microspheres changed upon changing GTA concentration. A decrease in swelling values was recorded as GTA crosslink density was increased. In vitro drug release in PBS (0.01M, pH 7.4) showed rapid colchicine release up to approximately 83% (at t = 92 h) for microspheres with low GTA (0.05% v/v), whereas a slower release profile (only approximately 39%) was obtained for microspheres with high GTA (0.50% v/v) content, for the same period. Cytotoxicity tests with MCF-7, HeLa and H-82 cancer cell lines showed that free colchicine was very toxic, showing an approximately 100% lethal effect in both HeLa and H-82 cell lines and more than 50% decrease in viability in MCF-7 cells in 4 days. Indeed, entrapped colchicine indicated similar initial high toxic effect on cell viability in MCF-7 cell line and this effect became more dominant as colchicine continued to be released from microspheres in the same period. In conclusion, the control of the release rate of colchicine from gelatin microspheres was achieved under in vitro conditions by gelatin through the alteration of crosslinking conditions. Indeed, the results suggested the potential application of gelatin microspheres crosslinked with GTA as a sustained drug-delivery system for anticancer drugs for local chemotherapy administrations. (c) 2004 Wiley Periodicals, Inc.

[Intoxications with plants].

PubMed

Kupper, Jacqueline; Reichert, Cornelia

2009-05-01

Ingestions of plants rarely lead to life-threatening intoxications. Highly toxic plants, which can cause death, are monkshood (Aconitum sp.), yew (Taxus sp.) and autumn crocus (Colchicum autumnale). Lethal ingestions of monkshood and yew are usually suicides, intoxications with autumn crocus are mostly accidental ingestions of the leaves mistaken for wild garlic (Allium ursinum). Severe intoxications can occur with plants of the nightshade family like deadly nightshade (Atropa belladonna), angel's trumpet (Datura suaveolens) or jimsonweed (Datura stramonium). These plants are ingested for their psychoactive effects. Ingestion of plant material by children most often only causes minor symptoms or no symptoms at all, as children usually do not eat great quantities of the plants. They are especially attracted by the colorful berries. There are plants with mostly cardiovascular effects like monkshood, yew and Digitalis sp. Some of the most dangerous plants belong to this group. Plants of the nightshade family cause an anticholinergic syndrome. With golden chain (Laburnum anagyroides), castor bean (Ricinus communis) and raw beans (Phaseolus vulgaris) we see severe gastrointestinal effects. Autumn crocus contains a cell toxin, colchicine, which leads to multiorgan failure. Different plants are irritative or even caustic to the skin. Treatment is usually symptomatic. Activated charcoal is administered within one hour after ingestion (1 g/kg). Endoscopic removal of plant material can be considered with ingestions of great quantities of highly toxic plants. Administration of repeated doses of charcoal (1-2 g/h every 2-4 hours) may be effective in case of oleander poisoning. There exist only two antidotes: Anti-digoxin Fab fragments can be used with cardenolide glycoside-containing plants (Digitalis sp., Oleander). Physostigmine is the antidote for severe anticholinergic symptoms of the CNS. Antibodies against colchicine, having been developed in France, are not available at the moment.

New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation.

PubMed

Chen, Zecheng; Maderna, Andreas; Sukuru, Sai Chetan K; Wagenaar, Melissa; O'Donnell, Christopher J; Lam, My-Hanh; Musto, Sylvia; Loganzo, Frank

2013-12-15

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results. Copyright © 2013 Elsevier Ltd. All rights reserved.

COMPENSATORY CHANGES IN THE HIPPOCAMPUS FOLLOWING INTRADENTATE INFUSION OF COLCHICINE

EPA Science Inventory

Direct infusion of colchicine into the dentate gyrus of the hippocampus kills granule cells and elicits compensatory behavioral, neurochemical and neuroanatomical changes. olchicine-treated rats are less sensitive to the behavioral effects of cholinergic muscarinic receptor antag...

High-performance Thin-layer Chromatographic-densitometric Quantification and Recovery of Bioactive Compounds for Identification of Elite Chemotypes of Gloriosa superba L. Collected from Sikkim Himalayas (India)

PubMed Central

Misra, Ankita; Shukla, Pushpendra Kumar; Kumar, Bhanu; Chand, Jai; Kushwaha, Poonam; Khalid, Md.; Singh Rawat, Ajay Kumar; Srivastava, Sharad

2017-01-01

Background: Gloriosa superba L. (Colchicaceae) is used as adjuvant therapy in gout for its potential antimitotic activity due to high colchicine(s) alkaloids. Objective: This study aimed to develop an easy, cheap, precise, and accurate high-performance thin-layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L. and to identify its elite chemotype(s) from Sikkim Himalayas (India). Methods: The HPTLC chromatographic method was developed using mobile phase of chloroform: acetone: diethyl amine (5:4:1) at λmax of 350 nm. Results: Five germplasms were collected from targeted region, and on morpho-anatomical inspection, no significant variation was observed among them. Quantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%–0.150% to 0.006%–0.032% (dry wt. basis). Linearity of method was obtained in the concentration range of 100–400 ng/spot of marker(s), exhibiting regression coefficient of 0.9987 (colchicine) and 0.9983 (gloriosine) with optimum recovery of 97.79 ± 3.86 and 100.023% ± 0.01%, respectively. Limit of detection and limit of quantification were analyzed, respectively, as 6.245, 18.926 and 8.024, 24.316 (ng). Two germplasms, namely NBG-27 and NBG-26, were found to be elite chemotype of both the markers. Conclusion: The developed method is validated in terms of accuracy, recovery, and precision studies as per the ICH guidelines (2005) and can be adopted for the simultaneous quantification of colchicine and gloriosine in phytopharmaceuticals. In addition, this study is relevant to explore the chemotypic variability in metabolite content for commercial and medicinal purposes. SUMMARY An easy, cheap, precise, and accurate high performance thin layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L.Five germplasms were collected from targeted region, and on morpho anatomical inspection, no significant variation was observed among themQuantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%–0.150% to 0.006%–0.032% (dry wt. basis)Two germplasms, namely NBG 27 and NBG 26, were found to be elite chemotype of both the markers. PMID:29142436

High-performance Thin-layer Chromatographic-densitometric Quantification and Recovery of Bioactive Compounds for Identification of Elite Chemotypes of Gloriosa superba L. Collected from Sikkim Himalayas (India).

PubMed

Misra, Ankita; Shukla, Pushpendra Kumar; Kumar, Bhanu; Chand, Jai; Kushwaha, Poonam; Khalid, Md; Singh Rawat, Ajay Kumar; Srivastava, Sharad

2017-10-01

Gloriosa superba L. (Colchicaceae) is used as adjuvant therapy in gout for its potential antimitotic activity due to high colchicine(s) alkaloids. This study aimed to develop an easy, cheap, precise, and accurate high-performance thin-layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L. and to identify its elite chemotype(s) from Sikkim Himalayas (India). The HPTLC chromatographic method was developed using mobile phase of chloroform: acetone: diethyl amine (5:4:1) at λ max of 350 nm. Five germplasms were collected from targeted region, and on morpho-anatomical inspection, no significant variation was observed among them. Quantification data reveal that content of colchicine ( R f : 0.72) and gloriosine ( R f : 0.61) varies from 0.035%-0.150% to 0.006%-0.032% (dry wt. basis). Linearity of method was obtained in the concentration range of 100-400 ng/spot of marker(s), exhibiting regression coefficient of 0.9987 (colchicine) and 0.9983 (gloriosine) with optimum recovery of 97.79 ± 3.86 and 100.023% ± 0.01%, respectively. Limit of detection and limit of quantification were analyzed, respectively, as 6.245, 18.926 and 8.024, 24.316 (ng). Two germplasms, namely NBG-27 and NBG-26, were found to be elite chemotype of both the markers. The developed method is validated in terms of accuracy, recovery, and precision studies as per the ICH guidelines (2005) and can be adopted for the simultaneous quantification of colchicine and gloriosine in phytopharmaceuticals. In addition, this study is relevant to explore the chemotypic variability in metabolite content for commercial and medicinal purposes. An easy, cheap, precise, and accurate high performance thin layer chromatographic (HPTLC) validated method for simultaneous quantification of bioactive alkaloids (colchicine and gloriosine) in G. superba L.Five germplasms were collected from targeted region, and on morpho anatomical inspection, no significant variation was observed among themQuantification data reveal that content of colchicine (Rf: 0.72) and gloriosine (Rf: 0.61) varies from 0.035%-0.150% to 0.006%-0.032% (dry wt. basis)Two germplasms, namely NBG 27 and NBG 26, were found to be elite chemotype of both the markers.

Colchicine triggered severe rhabdomyolysis after long-term low-dose simvastatin therapy: a case report.

PubMed

Frydrychowicz, Clara; Pasieka, Bastian; Pierer, Matthias; Mueller, Wolf; Petros, Sirak; Weidhase, Lorenz

2017-01-04

Rhabdomyolysis is a widely recognized yet rare complication in statin use. Rhabdomyolysis might be triggered by the prescription of high doses of statins or by statin accumulation due to interactions with concomitant medication. Muscle cell destruction as evidenced by myoglobin elevation can induce potentially life-threatening acute renal failure. We report a case of a 70-year-old obese white man with sudden onset of severe rhabdomyolysis with consecutive renal failure. His medication included low-dose simvastatin, which he had taken for 6 years up until the event. The statin was withdrawn immediately. After 3 days of veno-venous hemofiltration his renal function was completely restored. Clinicians in both primary and special care might be unaware that side effects of statins do occur even after a long uneventful statin medication; they should be advised not to exclude that possibility upfront, even if a patient has tolerated the medication for years.

Comparison of Fucithalmic viscous eye drops and Chloramphenicol eye ointment as a single treatment in corneal abrasion.

PubMed

Boberg-Ans, G; Nissen, K R

1998-02-01

To compare the healing of the cornea and the incidence of infection after traumatic corneal epithelial defect after single treatment with double bandage combined with either Fucithalmic single unit dose eye drops or chloramphenicol eye ointment. This is a single-centre, randomised, single-blind, parallel-group study of 144 patients with accidental corneal abrasion or corpus alieni cornea who were referred to the Eye Department at Gentofte Hospital. The injured eye was examined with a photo slit-lamp before and 24 hours after treatment. The size of the abrasion was recorded and calculated on a PCX computerized video system and by slit-lamp photography. The Fucithalmic and chloramphenicol ointment treated groups showed no significant difference in corneal healing, local side effects, or signs of local infection.

Sterile Osteitis and Suppurative Arthritis Associated with Pannus Responding to Colchicine

PubMed Central

Tezcan, Mehmet Engin; Ekinci, Özgür; Uçar, Murat; Göker, Berna

2013-01-01

Sterile suppurative arthritis is characterized by neutrophilic infiltration of joints without any causative pathogen. Here, we present a 32-year-old man with refractory osteitis and erosive suppurative oligoarthritis with pannus. Treatments with multiple disease modifying antirheumatic drugs were all unsuccessful. However, he had clinical response to colchicine and the synovial hypertrophy and the pannus in the MRI of his left shoulder resolved. In this case, the effects of colchicine on neutrophils might have played a role in treating neutrophilic sterile suppurative arthritis, which, in adults, might be a distinct oligoarticular disease. PMID:23984159

Colchicine in therapy. State of the art and new perspectives for an old drug.

PubMed

Famaey, J P

1988-01-01

Colchicine is the most specific treatment in acute gouty attacks. In several European countries, oral colchicine is still used for routine treatment of acute gout. Its selectivity is used as a diagnostic tool. It is also active in the treatment of acute crises of chondrocalcinosis and more occasionally of other arthritic crises (e.g. sarcoidosis). Colchicine appears to be the necessary adjuvant prophylactic drug when starting a hypouricemic treatment with uricosuric or uricolytic drugs for avoiding acute gouty crisis due to sudden mobilisation of the uric acid pool. Besides gout, colchicine is the drug of choice for treating familial mediterranean fever. It appears to be helpful in the treatment of Behçet's disease. It seems also useful for treating fibrosing conditions such as liver cirrhosis and scleroderma. As an adjuvant therapy, it helps treating dermatological disorders which are associated with leucocyte migration as an essential pathogenic factor (e.g. psoriasis, dermatitis herpetiformis, necrotising vasculitis ...). It has been advocated as an adjuvant therapy in malignant diseases as a support in radiotherapy and as an useful drug in various other diseases where it has been tried occasionally (e.g. Paget's disease of the bone, idiopathic thrombocytopenic purpura, disc syndrome). This very old drug remains a modern therapeutic agent.

Quantum-chemical, NMR, FT IR, and ESI MS studies of complexes of colchicine with Zn(II).

PubMed

Jankowski, Wojciech; Kurek, Joanna; Barczyński, Piotr; Hoffmann, Marcin

2017-04-01

Colchicine is a tropolone alkaloid from Colchicinum autumnale. It shows antifibrotic, antimitotic, and anti-inflammatory activities, and is used to treat gout and Mediterranean fever. In this work, complexes of colchicine with zinc(II) nitrate were synthesized and investigated using DFT, 1 H and 13 C NMR, FT IR, and ESI MS. The counterpoise-corrected and uncorrected interaction energies of these complexes were calculated. We also calculated their 1 H, 13 C NMR, and IR spectra and compared them with the corresponding experimentally obtained data. According to the ESI MS mass spectra, colchicine forms stable complexes with zinc(II) nitrate that have various stoichiometries: 2:1, 1:1:1, and 2:1:1 with respect to colchichine, Zn(II), and nitrate ion. All of the complexes were investigated using the quantum theory of atoms in molecules (QTAIM). The calculated and the measured spectra showed differences before and after the complexation process. Calculated electron densities and bond critical points indicated the presence of bonds between the ligands and the central cation in the investigated complexes that satisfied the quantum theory of atoms in molecules. Graphical Abstract DFT, NMR, FT IR, ESI MS, QTAIM and puckering studies of complexes of colchicine with Zn(II).

Experimental eczema. 12 effects of x-rays in experimental eczema (combined injury) (in French)

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

Adatto, R.

1961-01-01

Contact dermatitis was induced in guinea pig nipples by local application of 2,4-dinitrochlorobenzene after previous sensitization. No effect of x irradiation on the histologic aspects of the developing dermatitis could be detected when doses of 800 or 1600 r were given 2 to 16 days after sensitization or repeated 100-r doses were given. Although a 800-r dose had no detectable effect on epithelium, it was found to alter the eczematous reaction when given 72 hr before the eliciting application of dinitrocitlorobenzene in sensitized animals. Eczematous epithelium in irradiated skin showed swelling of cells, indistinct cell boundaries, diminished numbers of nuclei,more » and fewer mitoses blocked by colchicine; none of these changes was produced by eczema alone. The changes in epidermis induced by irradiation with 800 r before eliciting eczema resembled those produced by much higher x-ray doses (2400 r), indicating that eczema augments the cellular changes induced by irradiation.« less

Parent-Child Parallel-Group Intervention for Childhood Aggression in Hong Kong

ERIC Educational Resources Information Center

Fung, Annis L. C.; Tsang, Sandra H. K. M.

2006-01-01

This article reports the original evidence-based outcome study on parent-child parallel group-designed Anger Coping Training (ACT) program for children aged 8-10 with reactive aggression and their parents in Hong Kong. This research program involved experimental and control groups with pre- and post-comparison. Quantitative data collection…

LONG-TERM BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF INTRADENTATE ADMINISTRATION OF COLCHICINE IN RATS

EPA Science Inventory

Previous work has shown that the intradentate administration of colchicine produces time-dependent behavioral and neurochemical changes. eficits in learning and memory and alterations In the signal transduction process for the cholinergic muscarinic receptor have been observed up...

COLCHICINE DECREASES AIRWAY HYPERACTIVITY AFTER PHOSGENE EXPOSURE

EPA Science Inventory

Phosgene (COCl(2)) exposure affects an influx of inflammatory cells into the lung, which can be reduced in an animal model by pretreatment with colchicine. Inflammation in the respiratory tract can be associated with an increase in airway hyperreactivity. We tested the hypotheses...

A behavioural analysis of spatial localization following electrolytic, kainate- or colchicine-induced damage to the hippocampal formation in the rat.

PubMed

Sutherland, R J; Whishaw, I Q; Kolb, B

1983-02-01

This experiment examines the notion that in the rat the hippocampal formation is an essential structure in the neurological representation of spatial abilities. Spatial localization by rats with different types of hippocampal damage, including bilateral electrolytic lesions, unilateral and bilateral kainic acid-induced CA3-CA4 lesions, and unilateral and bilateral colchicine-induced dentate gyrus lesions, was compared with vehicle-injected and normal control groups in the Morris water task. The task required the rats to escape from cold water by finding a submerged and hidden platform located at a fixed place within the room. The start point was varied randomly from trial to trial and there were no local cues available to indicate the position of the hidden platform. After training, the platform was moved. Escape latencies and the initial swimming headings revealed that all lesion groups, except the unilateral CA3-damaged group, were impaired at finding the platform: the dentate-damaged rats exhibited the greatest deficit. When the platform was moved the control rats swam mainly in the part of the pool that had previously contained the platform and, on finding it in the new location, they showed a marked dishabituation of rearing. None of the bilateral lesion groups showed these effects.

A comparison of the effects of 2 doses of soy protein or casein on serum lipids, serum lipoproteins, and plasma total homocysteine in hypercholesterolemic subjects.

PubMed

Tonstad, Serena; Smerud, Knut; Høie, Lars

2002-07-01

Studies have shown that soy protein reduces some atherogenic lipid and lipoprotein concentrations, although lipoprotein(a) concentrations may be increased. The dose response of soy protein has not been established; neither has its effect on plasma total homocysteine. Our objective was to evaluate the effect of 2 doses of soy protein on lipid, lipoprotein, and homocysteine concentrations. Four to 24 wk after being instructed to consume a lipid-lowering diet, 130 men and women with LDL-cholesterol concentrations > or = 4 mmol/L were studied during a parallel group trial in which 4 interventions were assigned randomly. Thirty grams isolated soy protein (ISP) and 10 g cotyledon fiber or 50 g ISP and 16.6 g cotyledon fiber or equivalent doses of casein and cellulose were consumed daily as a beverage for 16 wk. When the 2 groups who consumed ISP were compared with the 2 groups who consumed casein, the differences in the net changes from baseline to week 16 in the concentrations of LDL cholesterol and plasma total homocysteine were -0.26 mmol/L (95% CI: -0.43, -0.09 mmol/L; P = 0.01) and -0.8 micromol/L (-1.4, -0.2 micromol/L; P = 0.005), respectively. The effect of the ISP dose was not significant. There were no significant differences between the 2 ISP and the 2 casein groups in changes in lipoprotein(a), HDL-cholesterol, or triacylglycerol concentrations. Adding 30-50 g soy protein/d to a lipid-lowering diet significantly reduced LDL-cholesterol concentrations without increasing lipoprotein(a) concentrations. Plasma total homocysteine concentrations also decreased, suggesting a novel, possibly antiatherosclerotic effect.

Concise Synthesis and Biological Evaluation of 2-Aroyl-5-Amino Benzo[b]thiophene Derivatives As a Novel Class of Potent Antimitotic Agents

PubMed Central

Romagnoli, Romeo; Baraldi, Pier Giovanni; Lopez-Cara, Carlota; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Balzarini, Jan; Bassetto, Marcella; Brancale, Andrea; Fu, Xian-Hua; Gao, Yang; Li, Jun; Zhang, Su-Zhan; Hamel, Ernest; Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro

2014-01-01

The biological importance of microtubules make them an interesting target for the synthesis of antitumor agents. The 2-(3′,4′,5′-trimethoxybenzoyl)-5-aminobenzo[b]thiophene moiety was identified as a novel scaffold for the preparation of potent inhibitors of microtubule polymerization acting through the colchicine site of tubulin. The position of the methoxy group on the benzo[b]thiophene was important for maximal antiproliferative activity. Structure–activity relationship analysis established that the best activities were obtained with amino and methoxy groups placed at the C-5 and C-7 positions, respectively. Compounds 3c–e showed more potent inhibition of tubulin polymerization than combretastatin A-4 and strong binding to the colchicine site. These compounds also demonstrated substantial antiproliferative activity, with IC50 values ranging from 2.6 to 18 nM in a variety of cancer cell lines. Importantly, compound 3c (50 mg/kg), significantly inhibited the growth of the human osteosarcoma MNNG/HOS xenograft in nude mice. PMID:24164557

Lack of significant anti-inflammatory activity with clindamycin in the treatment of rosacea: results of 2 randomized, vehicle-controlled trials.

PubMed

Martel, Philippe; Jarratt, Michael; Weiss, Jonathan; Carlavan, Isabelle

2017-07-01

Rosacea is a chronic inflammatory skin disease of the face. The objective of the studies described here was to evaluate the efficacy of clindamycin in the treatment of rosacea. Two multicenter, randomized, vehicle-controlled, phase 2 studies were conducted in participants with moderate to severe rosacea. Study A was a 12-week dose-comparison, 5-arm, parallel group comparison of clindamycin cream 1% or vehicle once or twice daily and clindamycin cream 0.3% once daily. Study B was a 2-arm comparison of twice daily clindamycin gel 1% versus vehicle gel. A total of 629 participants (study A, N=416; study B, N=213) were randomized. The results of these studies indicated that clindamycin cream 0.3% and 1% and clindamycin gel 1% were no more effective than the vehicle in the treatment of moderate to severe rosacea, suggesting clindamycin has no intrinsic anti-inflammatory activity in rosacea.

75 FR 60768 - Single-Ingredient Oral Colchicine Products; Enforcement Action Dates

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-01

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-N-0257] Single-Ingredient Oral Colchicine Products; Enforcement Action Dates AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA or agency) is announcing its...

Dose Response Effects of Lisdexamfetamine Dimesylate Treatment in Adults with ADHD: An Exploratory Study

ERIC Educational Resources Information Center

Faraone, Stephen V.; Spencer, Thomas J.; Kollins, Scott H.; Glatt, Stephen J.; Goodman, David

2012-01-01

Objective: To explore dose-response effects of lisdexamfetamine dimesylate (LDX) treatment for ADHD. Method: This was a 4-week, randomized, double-blinded, placebo-controlled, parallel-group, forced-dose titration study in adult participants, aged 18 to 55 years, meeting "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.)…

Saccadic eye movements as a measure of residual effects: temazepam compared with other hypnotics.

PubMed

Hofferberth, B; Hirschberg; Grotemeyer

1986-01-01

Eye movements are classified into two categories: quickly running saccades and smooth pursuit movements. Saccades are fast conjugate eye movements with a preprogrammed direction, amplitude, and speed course; their purpose is to register new objects in the visual field. The duration and velocity of saccadic eye movements are very much dependent on vigilance. Comparisons were made with a number of psychometric tests [d 2 Durchstreichtest (cross out test), Viennese determination apparatus, and flicker fusion frequency] and the velocity of fast eye movements. The results of three separate investigations are presented. Standardization was undertaken in 100 healthy volunteers, 50 male and 50 female subjects aged between 20 and more than 50 years were included. In an open parallel group study, comparisons were made between various hypnotics with different half-lives (temazepam, flunitrazepam, flurazepam, and phenobarbital). There were 10 healthy volunteers in each group, and medication was taken as a single night-time dose for 7 nights. In a double-blind study, temazepam (20 mg/day) was tested against flunitrazepam (2 mg/day). Dosing lasted 7 days. A marked impairment of the saccadic eye movements was observed with flunitrazepam but not with temazepam. Of all the benzodiazepines tested, only temazepam had no influence on the parameters of the saccade test. These results can be explained by temazepam's short half-life and also by the fact that no active metabolites are formed.

MO-C-17A-10: Comparison of Dose Deformable Accumulation by Using Parallel and Serial Approaches

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

Gao, Z; Li, M; Wong, J

Purpose: The uncertainty of dose accumulation over multiple CT datasets with deformable fusion may have significant impact on clinical decisions. In this study, we investigate the difference of two dose summation approaches involving deformable fusion. Methods: Five patients, four external beam and one brachytherapy(BT), were chosen for the study. The BT patient was treated with CT-based HDR. The CT image sets acquired in the imageguidance process (8-11 CTs/patient) were used to determine the dose delivered to the four external beam patients. (prostate, pelvis, lung and head and neck). For the HDR patient (cervix), five CT image sets and the correspondingmore » BT plans were used. In total 44 CT datasets and RT dose/plans were imported into the image fusion software MiM (6.0.4) for analysis.For each of the five clinical cases, the dose from each fraction was accumulated into the primary CT dataset by using both Parallel and Serial approaches. The dose-volume histogram (DVH) for CTV and selected organs-at-risks (OAR) were generated. The D95(CTV), OAR(mean) and OAR(max) for the four external beam cases the D90(CTV), and the max dose to bladder and rectum for the BT case were compared. Results: For the four external beam patients, the difference in D95(CTV) were <1.2% PD between the parallel and the serial approaches. The differences of the OAR(mean) and the OAR(max ) range from 0 to 3.7% and <1% PD respectively. For the HDR patient, the dose difference for D90 is 11% PD while that of the max dose to bladder and rectum were 11.5% and 23.3% respectively. Conclusion: For external beam treatments, the parallel and serial approaches have <5% difference probably because tumor volume and OAR have less changes from fraction to fraction. For the brachytherapy case, >10% dose difference between the two approaches was observed as significant volume changes of tumor and OAR were observed among treatment fractions.« less

[Effect of urapidil combined with phentolamine on hypertension during extracorporeal circulation].

PubMed

Wang, Fangjun; Chen, Bin; Liu, Yang; Tu, Faping

2014-08-01

To study the effect of urapidil combined with phentolamine in the management of hypertension during extracorporeal circulation. Ninety patients undergoing aortic and mitral valve replacement were randomly divided into 3 equal groups to receive treatment with phentolamine (group A), urapidil (group B), or both (group C) during extracorporeal circulation. The mean arterial pressure (MAP) before and after drug administration, time interval of two administrations, spontaneous recovery of heart beat after aorta unclamping, ventricular arrhythmia, changes of ST-segment 1 min after the recovery of heart beat, ante-parallel cycle time, aorta clamping time, post-parallel cycle time, dopamine dose after cardiac resuscitation, and perioperative changes of plasma TNF-α and IL-6 levels were recorded. There was no significant difference in MAP between the 3 groups before or after hypotensive drug administration (P>0.05). The time interval of two hypotensive drug administrations was longer in group C than in groups A and B (P<0.05). The incidence of spontaneous recovery of heart beat after aorta unclamping, incidence of ventricular arrhythmia, changes of ST-segment 1 min after the recovery of heart beat, ante-parallel cycle time, aorta clamping time, and post-parallel cycle time were all comparable between the 3 groups. The dose of dopamine administered after cardiac resuscitation was significantly larger in group B than in groups A or group C (P<0.05). The plasma levels of TNF-α and IL-6 were significantly increased after CPB and after the operation in all the groups, but were lowed in group C than in groups A and B at the end of CPB and at 2 h and 12 after the operation. Urapidil combined with phentolamine can control hypertension during extracorporeal circulation without causing hypotension.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

PubMed

Sun, Bing; Xie, Yuan; Jiang, Jinfa; Wang, Yiping; Xu, Xiaolin; Zhao, Cuimei; Huang, Feifei

2015-04-14

Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

Radioimmunoassay for colchicine: synthesis and properties of three haptens.

PubMed

Pontikis, R; Scherrmann, J M; Nguyen, H N; Boudet, L; Pichat, L

1980-01-01

For the development of radioimmunoassay procedures for colchicine, three haptens, N-ethylamino-colchiceinamide, 4-formylchochicine - (O-carboxymethyl) oxime and 4-hydroxymethylcolchicine O-hemisuccinic acid were synthetized and characterized by mass and proton magnetic resonance spectrometries. The conjugates obtained by coupling the haptens to bovine serum albumin were employed to immunize rabbits and goats.

Antagonistic effects of pemoline to colchicine and caffeine.

PubMed

Röper, W

1975-10-15

Pemoline, the constituent of Tradon, is able to slow down the decrease of the mitotic index caused by 0.1% caffeine in roots of Vicia faba, and mitotic aberrations are reduced. With 0.005% colchicine and 3 x 10(-4) g/ml pemoline, no metaphase-accumulation can be observed, and anaphase-disorder is delayed.

Induced Polyploidy in Diploid Ornamental Ginger (Hedychium muluense) Using Colchicine and Oryzalin

USDA-ARS?s Scientific Manuscript database

The ploidy level of H. muluense, a diploid (2n = 2x = 34) and dwarf ornamental ginger species, has been determined and is reported for the first time. Oryzalin and colchicine were successfully used to induce polyploidy in Hedychium muluense in vitro. Embryogenic cell lines were treated with oryzalin...

Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril.

PubMed

Susalit, Endang; Agus, Nafrialdi; Effendi, Imam; Tjandrawinata, Raymond R; Nofiarny, Dwi; Perrinjaquet-Moccetti, Tania; Verbruggen, Marian

2011-02-15

A double-blind, randomized, parallel and active-controlled clinical study was conducted to evaluate the anti-hypertensive effect as well as the tolerability of Olive leaf extract in comparison with Captopril in patients with stage-1 hypertension. Additionally, this study also investigated the hypolipidemic effects of Olive leaf extract in such patients. It consisted of a run-in period of 4 weeks continued subsequently by an 8-week treatment period. Olive (Olea europaea L.) leaf extract (EFLA(®)943) was given orally at the dose of 500 mg twice daily in a flat-dose manner throughout the 8 weeks. Captopril was given at the dosage regimen of 12.5 mg twice daily at start. After 2 weeks, if necessary, the dose of Captopril would be titrated to 25 mg twice daily, based on subject's response to treatment. The primary efficacy endpoint was reduction in systolic blood pressure (SBP) from baseline to week-8 of treatment. The secondary efficacy endpoints were SBP as well as diastolic blood pressure (DBP) changes at every time-point evaluation and lipid profile improvement. Evaluation of BP was performed every week for 8 weeks of treatment; while of lipid profile at a 4-week interval. Mean SBP at baseline was 149.3±5.58 mmHg in Olive group and 148.4±5.56 mmHg in Captopril group; and mean DBPs were 93.9±4.51 and 93.8±4.88 mmHg, respectively. After 8 weeks of treatment, both groups experienced a significant reduction of SBP as well as DBP from baseline; while such reductions were not significantly different between groups. Means of SBP reduction from baseline to the end of study were -11.5±8.5 and -13.7±7.6 mmHg in Olive and Captopril groups, respectively; and those of DBP were -4.8±5.5 and -6.4±5.2 mmHg, respectively. A significant reduction of triglyceride level was observed in Olive group, but not in Captopril group. In conclusion, Olive (Olea europaea) leaf extract, at the dosage regimen of 500 mg twice daily, was similarly effective in lowering systolic and diastolic blood pressures in subjects with stage-1 hypertension as Captopril, given at its effective dose of 12.5-25 mg twice daily. Copyright © 2010 Elsevier GmbH. All rights reserved.

Design, Synthesis, in Vitro, and in Vivo Anticancer and Antiangiogenic Activity of Novel 3-Arylaminobenzofuran Derivatives Targeting the Colchicine Site on Tubulin

PubMed Central

Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Prencipe, Filippo; Lopez-Cara, Carlota; Ortega, Santiago Schiaffino; Brancale, Andrea; Hamel, Ernest; Castagliuolo, Ignazio; Mitola, Stefania; Ronca, Roberto; Bortolozzi, Roberta; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

2015-01-01

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3′,4′,5′-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-6-methoxybenzo-[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3–27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate. PMID:25785605

A survey on the beliefs and knowledge of gout management in new medical graduates - New South Wales, Australia.

PubMed

Terrill, Matthew; Riordan, John

2018-02-01

To assess the beliefs and knowledge of gout management in new medical graduates. A survey on gout management was sent to new medical graduates during their orientation week, New South Wales, Australia. Of 15 hospital networks, 11 agreed to participate. From these, 168 graduates responded (23.7% response rate). Most (81.1%) felt that gout was a serious disease, 51.2% answered that they had been taught adequately to manage acute gout, only 37.2% for chronic gout. In an acute gout flare, 63.4% answered they would continue urate lowering therapy and 67.2% were aware of first-line pharmacological management options; 28% answered the correct dosing regimen for colchicine. Chronic management was answered poorly. Only 42.0% stated they would titrate allopurinol dosing to a target urate level; 23.5% would check the urate level monthly. More than half, 56.8%, were aware that medical prophylaxis is indicated when initiating urate lowering therapy. Of this subgroup, 46.7% (25.9% overall) knew that non-steroidal anti-inflammatory drugs and colchicine were recommended and 28.4% (15.4% overall) answered the correct timeframe of use. Close to one-third (35.0%), were aware of febuxostat, probenecid and benzbromarone as second-line urate lowering therapy. The findings of this study suggest that new graduates' knowledge of gout management, especially chronic management, is suboptimal. Many felt their teaching on gout management inadequate; this is a potential target for intervention. Up to date university education which covers chronic management may lead to better clinical outcomes for this burdensome disease. © 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Comparison of original and generic clopidogrel 600 mg loading dose in the patients who planned undergoing coronary angiography.

PubMed

Srimahachota, Suphot; Rojnuckarin, Ponlapat; Udayachalerm, Wasan; Buddhari, Wacin; Chaipromprasit, Jarkarpun; Lertsuwunseri, Vorarit; Akkawat, Benjaporn; Jirapattrathamrong, Somboon

2012-12-01

To compare the efficacy and safety of original (Plavix) and generic (Apolets) clopidogrel 600 mg loading in patients planning to undergo coronary angiography. This is an experimental design, parallel, randomized-controlled study. Coronary artery disease patients planned for cardiac catheterization were recruited Patients were randomized to receive either original or generic clopidogrel 600 mg loading dose. Platelet aggregation induced by 5 micromol/L and 20 micromol/L adenosine diphosphate (ADP) was measured by light transmission aggregometry (LTA) at baseline and 6 hours after clopidogrel 600 mg administration. Forty-nine patients were enrolled, 24 patients received original clopidogrel, and 25 patients received generic clopidogrel. After six hours of loading, there was significantly reduction in platelet aggregation induced by adenosine 5 micromol/L from 41.08 +/- 3.04% to 19.50 +/- 1.68% (p < 0.001) in original group compared to 36.76 +/- 2.66% to 21.32 +/- 2.60% (p < 0.001) in generic group. When induced by 20 micromol/L, the platelet aggregation was reduced from 58.50 +/- 2.09% to 32.25 +/- 2.30% (p < 0.001) in original group and from 61.12 +/- 2.54% to 30.04 +/- 3.14% (p < 0.001) in generic group. There was no significant difference between original and generic clopidogrel in reducing platelet aggregation induced by both adenosine 5 and 20 micromol/L. Groin hematoma was found in one case (4.2%) in the original clopidogrel group. Generic clopidogrel (Apolets) 600 mg loading dose is as effective as original clopidogrel (Plavix) in term of platelet aggregation inhibition.

Iron-Magnesium Hydroxycarbonate (Fermagate): A Novel Non-Calcium-Containing Phosphate Binder for the Treatment of Hyperphosphatemia in Chronic Hemodialysis Patients

PubMed Central

McIntyre, Christopher W.; Pai, Pearl; Warwick, Graham; Wilkie, Martin; Toft, Alex J.; Hutchison, Alastair J.

2009-01-01

Background and objectives: This phase II study tested the safety and efficacy of fermagate, a calcium-free iron and magnesium hydroxycarbonate binder, for treating hyperphosphatemia in hemodialysis patients. Design, setting, participants, & measurements: A randomized, double-blind, three-arm, parallel-group study compared two doses of fermagate (1 g three times daily or 2 g three times daily with placebo). Sixty-three patients who had been on a stable hemodialysis regimen for ≥3 mo were randomized to the treatment phase. Study medication was administered three times daily just before meals for 21 d. The primary endpoint was reduction in serum phosphate over this period. Results: In the intention-to-treat analysis, mean baseline serum phosphate was 2.16 mmol/L. The fermagate 1- and 2-g three-times-daily treatment arms were associated with statistical reductions in mean serum phosphate to 1.71 and 1.47 mmol/L, respectively. Adverse event (AE) incidence in the 1-g fermagate arm was statistically comparable to the placebo group. The 2-g arm was associated with a statistically higher number of patients reporting AEs than the 1-g arm, particularly gastrointestinal AEs, as well as a higher number of discontinuations, complicating interpretation of this dose's efficacy. Both doses were associated with elevations of prehemodialysis serum magnesium levels. Conclusions: The efficacy and tolerability of fermagate were dose dependent. Fermagate showed promising efficacy in the treatment of hyperphosphatemia in chronic hemodialysis patients as compared with placebo in this initial phase II study. The optimal balance between efficacy and tolerability needs to be determined from future dose-titration studies, or fixed-dose comparisons of more doses. PMID:19158369

SU-E-T-765: Treatment Planning Comparison of SFUD Proton and 4Ï€ Radiotherapy for Prostate Cases

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

Tran, A; Woods, K; Yu, V

2015-06-15

Purpose: Single-Field Uniform Dose (SFUD) proton scanning beams and non-coplanar 4π intensity-modulated radiation therapy (IMRT) represent the most advanced treatment methods based on heavy ion and X-rays, respectively. Here we compare their performance for prostate treatment. Methods: Five prostate patients were planned using 4π radiotherapy and SFUD to an initial dose of 54Gy to a planning target volume (PTV) that encompassed the prostate and seminal vesicles, then a boost prescription dose of 25.2Gy to the prostate for a total dose of 79.2 Gy. 4π plans were created by inversely selecting and optimizing 30 beams from 1162 candidate non-coplanar beams usingmore » a greedy column generation algorithm. The SFUD plans utilized two coplanar, parallel-opposing lateral scanning beams. The SFUD plan PTV was modified to account for range uncertainties while keeping an evaluation PTV identical to that of the X-ray plans for comparison. PTV doses, bladder and rectum dose volumes (V40, V45, V60, V70, V75.6, and V80), R50, and PTV homogeneity index (D95/D5) were evaluated. Results: Compared to SFUD, 4π resulted in 6.8% lower high dose spillage as indicated by R50. Bladder and rectum mean doses were 38.3% and 28.2% lower for SFUD, respectively. However, bladder and rectum volumes receiving >70Gy were 13.1% and 12% greater using proton SFUD. Due to the parallel-opposing beam arrangement, SFUD resulted in greater femoral head (87.8%) and penile bulb doses (43.7%). 4π PTV doses were slightly more homogeneous (HI 0.99 vs. 0.98) than the SFUD dose. Conclusion: Proton is physically advantageous to reduce the irradiated normal volume and mean doses to the rectum and bladder but it is also limited in the beam orientations and entrance dose, which resulted in greater doses to the femoral heads and penile bulb, and larger volumes of rectum and bladder exposed to high dose due to the required robust PTV definition. This project is supported by Varian Medical Systems.« less

The mechanism of tubulin-colchicine recognition--a kinetic study of the binding of a bicyclic colchicine analogue with a minor modification of the A ring.

PubMed

Dumortier, C; Potenziano, J L; Bane, S; Engelborghs, Y

1997-10-01

2-Methoxy-5-(2',3',4'-trimethoxy)-2,4,6-cycloheptatrien-1-one (MTC) is a colchicine analogue that lacks the B ring. 2-Methoxy-5-(2',4'-dimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MD) is an A-ring analogue of MTC, in which one methoxy group is replaced by a hydrogen atom. This paper describes the kinetic features of MDC binding to tubulin, and compares its behaviour with MTC to analyse the effect of the A-ring modification on the recognition process by tubulin. Binding is accompanied by a strong enhancement of MDC fluorescence and quenching of protein fluorescence. The kinetic and thermodynamic parameters were obtained from fluorescence stopped-flow measurements. The kinetics are described by a single exponential, indicating that this drug does not discriminate between the different tubulin isotypes. The observed pseudo-first-order rate constant of the fluorescence increase upon binding increases in a non-linear way, indicating that this ligand binds with a similar overall mechanism as colchicine and MTC, consisting of a fast initial binding of low affinity followed by a slower isomerisation step leading to full affinity. The K1 and k2 values for MDC at 25 degrees C were 540 +/- 65 M(-1) and 70 +/- 6 s(-1) respectively. From the temperature dependence, a reaction enthalpy change (deltaH(o)1) of the initial binding of 49 +/- 11 kJ/mol(-1) and an activation energy for the second step of 28 +/- 9 kJ/mol(-1) were calculated. Displacement experiments of bound MDC by MTC allowed the determination of a rate constant of reverse isomerisation of 0.60 +/- 0.07 s(-1) at 25 degrees C and the activation energy of 81 +/- 6 kJ/mol(-1). The overall binding constant was (6.3 +/- 0.2) x 10(4) M(-1) at 25 degrees C. Combination of these results with the kinetic parameters for association gives a full characterisation of the enthalpy pathway for the binding of MDC. The pathway of MDC is shown to differ considerably from that of MTC binding. Since its structural difference is located in ring A, this result indicates the use of ring A in the first step. The kinetics of the binding of MDC in the presence of some A-ring colchicine analogues (podophyllotoxin, 3',4',5'-trimethoxyacetophenone and N-acetylmescaline) and a C-ring analogue (tropolone methyl ether) suggest that the A and C rings are involved in the binding of MDC.

Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma.

PubMed

Holló, Gábor; Ropo, Auli

2015-01-01

We investigated the intraocular pressure (IOP) lowering efficacy of preservative-free fixed and non-fixed combination of tafluprost 0.0015% and timolol 0.5% in pseudoexfoliative glaucoma (XFG). A per protocol worse eye analysis was made on all XFG patients who participated in a recent 6 month, prospective, randomized, double-masked, parallel group, multicenter phase III study. The mean time-wise IOP decreased by 8.62 to 10.25 mmHg (31.8 to 36.7%) in the fixed dose combination arm (15 patients) and by 5.38 to 11.35 mmHg (21.3 to 41.2%) in the non-fixed combination arm (13 patients), respectively (p < 0.001 for all comparisons). The results show that a preservative-free fixed dose combination of tafluprost and timolol provides a clinically significant IOP reduction in XFG, and may offer an advantage for the XFG patients with dry eye, due to its preservative-free nature.

Novel quinolone chalcones targeting colchicine-binding pocket kill multidrug-resistant cancer cells by inhibiting tubulin activity and MRP1 function.

PubMed

Lindamulage, I Kalhari; Vu, Hai-Yen; Karthikeyan, Chandrabose; Knockleby, James; Lee, Yi-Fang; Trivedi, Piyush; Lee, Hoyun

2017-08-31

Agents targeting colchicine-binding pocket usually show a minimal drug-resistance issue, albeit often associated with high toxicity. Chalcone-based compounds, which may bind to colchicine-binding site, are found in many edible fruits, suggesting that they can be effective drugs with less toxicity. Therefore, we synthesized and examined 24 quinolone chalcone compounds, from which we identified ((E)-3-(3-(2-Methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-17) and ((E)-6-Methoxy-3-(3-(2-methoxyphenyl)-3-oxoprop-1-enyl) quinolin-2(1H)-one) (CTR-20) as promising leads. In particular, CTR-20 was effective against 65 different cancer cell lines originated from 12 different tissues, largely in a cancer cell-specific manner. We found that both CTR-17 and CTR-20 reversibly bind to the colchicine-binding pocket on β-tubulin. Interestingly however, both the CTRs were highly effective against multidrug-resistant cancer cells while colchicine, paclitaxel and vinblastine were not. Our study with CTR-20 showed that it overcomes multidrug-resistance through its ability to impede MRP1 function while maintaining strong inhibition against microtubule activity. Data from mice engrafted with the MDA-MB-231 triple-negative breast cancer cells showed that both CTR-17 and CTR-20 possess strong anticancer activity, alone or in combination with paclitaxel, without causing any notable side effects. Together, our data demonstrates that both the CTRs can be effective and safe drugs against many different cancers, especially against multidrug-resistant tumors.

Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea.

PubMed

Carley, David W; Prasad, Bharati; Reid, Kathryn J; Malkani, Roneil; Attarian, Hryar; Abbott, Sabra M; Vern, Boris; Xie, Hui; Yuan, Chengbo; Zee, Phyllis C

2018-01-01

There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study. Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully blinded parallel groups, placebo-controlled randomized trial of dronabinol in people with moderate or severe OSA. By random assignment, 73 adults with moderate or severe OSA received either placebo (N = 25), 2.5 mg dronabinol (N = 21), or 10 mg dronabinol (N = 27) daily, 1 hour before bedtime for up to 6 weeks. At baseline, overall apnea-hypopnea index (AHI) was 25.9 ± 11.3, Epworth Sleepiness Scale (ESS) score was 11.45 ± 3.8, maintenance of wakefulness test (MWT) mean latency was 19.2 ± 11.8 minutes, body mass index was 33.4 ± 5.4 kg/m2, and age was 53.6 ± 9.0 years. The number and severity of adverse events, and treatment adherence (0.3 ± 0.6 missed doses/week) were equivalent among all treatment groups. Participants receiving 10 mg/day of dronabinol expressed the highest overall satisfaction with treatment (p = .04). In comparison to placebo, dronabinol dose-dependently reduced AHI by 10.7 ± 4.4 (p = .02) and 12.9 ± 4.3 (p = .003) events/hour at doses of 2.5 and 10 mg/day, respectively. Dronabinol at 10 mg/day reduced ESS score by -3.8 ± 0.8 points from baseline (p < .0001) and by -2.3 ± 1.2 points in comparison to placebo (p = .05). MWT sleep latencies, gross sleep architecture, and overnight oxygenation parameters were unchanged from baseline in any treatment group. These findings support the therapeutic potential of cannabinoids in people with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved self-reported sleepiness, and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

In vitro induction of tetraploid plants from diploid Zizyphus jujuba Mill. cv. Zhanhua.

PubMed

Gu, X F; Yang, A F; Meng, H; Zhang, J R

2005-12-01

Tetraploid plants of Zizyphus jujuba Mill. cv. Zhanhua were obtained with in vitro colchicine treatment. Shoot tips from in vitro-grown plants were treated with five different concentrations of colchicine (0.01, 0.03, 0.05, 0.1, 0.3%) in liquid MS medium (Murashige and Skoog 1962), and shaken (100 rpm) at 25 degrees C in darkness for 24, 48, 72 or 96 h, respectively. Tetraploids were obtained at a frequency of over 3% by using 0.05% colchicine (48 h, 72 h) and 0.1% colchicine (24 h, 48 h) treatment as determined by flow cytometry. Cytological and morphological evidence confirmed the results of flow cytometric analysis. The chromosome number of diploid plants was 24 and that of tetraploid plants was 48. The stomata sizes of tetraploid plants were significantly larger than those of diploid plants, while the frequency of stomata were reduced significantly. Similarly, the chloroplast number of guard cells of tetraploid plants increased significantly. The selected tetraploid plants were grafted onto mature trees of Z. jujuba Mill. cv. Zhanhua in the field, resulted in thicker stems, rounder and succulent leaves, larger flowers and a delay in florescence time (3-4 days later) than diploid plants.

Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study

PubMed Central

Sandrini, G; Cerbo, R; Del Bene, E; Ferrari, A; Genco, S; Grazioli, I; Martelletti, P; Nappi, G; Pinessi, L; Sarchielli, P; Tamburro, P; Uslenghi, C; Zanchin, G

2007-01-01

Aims and methods: In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. Results: Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57–1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82–1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. Conclusion: The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf. PMID:17627707

Impact evaluation of a healthy lifestyle intervention to reduce cardiovascular disease risk in health centers in San José, Costa Rica and Chiapas, Mexico.

PubMed

Fort, Meredith P; Murillo, Sandra; López, Erika; Dengo, Ana Laura; Alvarado-Molina, Nadia; de Beausset, Indira; Castro, Maricruz; Peña, Liz; Ramírez-Zea, Manuel; Martínez, Homero

2015-12-28

Previous healthy lifestyle interventions based on the Salud para Su Corazón curriculum for Latinos in the United States, and a pilot study in Guatemala, demonstrated improvements in patient knowledge, behavior, and clinical outcomes for adults with hypertension. This article describes the implementation of a healthy lifestyle group education intervention at the primary care health center level in the capital cities of Costa Rica and Chiapas, Mexico for patients with hypertension and/or type 2 diabetes and presents impact evaluation results. Six group education sessions were offered to participants at intervention health centers from November 2011 to December 2012 and participants were followed up for 8 months. The study used a prospective, longitudinal, nonequivalent pretest-posttest comparison group design, and was conducted in parallel in the two countries. Cognitive and behavioral outcome measures were knowledge, self-efficacy, stage-of-change, dietary behavior and physical activity. Clinical outcomes were: body mass index, systolic and diastolic blood pressure, and fasting blood glucose. Group by time differences were assessed using generalized estimating equation models, and a dose-response analysis was conducted for the intervention group. The average number of group education sessions attended in Chiapas was 4 (SD: 2.2) and in Costa Rica, 1.8 (SD: 2.0). In both settings, participation in the study declined by 8-month follow-up. In Costa Rica, intervention group participants showed significant improvements in systolic and diastolic blood pressure and borderline significant improvement for fasting glucose, and significant improvement in the stages-of-change measure vs. the comparison group. In Chiapas, the intervention group showed significant improvement in the stages-of-change measure in relation to the comparison group. Significant improvements were not observed for knowledge, self-efficacy, dietary behavior or physical activity. In Chiapas only, a significant dose-response relationship was observed for systolic and diastolic blood pressure. Group education interventions at health centers have the potential to improve stage-of-change activation, and may also improve clinical outcomes. In the future, it will be essential to dedicate resources to understand ways to reach a representative group of the patient population, tailor the intervention so that patients are engaged to participate, and consider the broader family and community context that influences patients' capacity to manage their condition.

Allopurinol treatment and its effect on renal function in gout: a controlled study.

PubMed Central

Gibson, T; Rodgers, V; Potter, C; Simmonds, H A

1982-01-01

Fifty-nine patients with primary gout were treated with either a combination of colchicine and allopurinol or colchicine alone. Assessments of renal function over 2 years revealed a statistically significant fall of glomerular filtration rate an urine concentrating ability in those receiving only colchicine. The renal function of patients given allopurinol did not change. Treatment with allopurinol resulted ina significant reduction of ammonium excretion, a phenomenon which could not be readily explained. Urate clearance also declined during allopurinol treatment, and the impaired urate clearance associated with gout became more evident. The most important observation was that allopurinol retarded an apparent decline of renal function. Presumably this was achieved through its hypouricaemic effect and implies that the hyperuricaemia of gouty patients is deleterious to the kidneys. PMID:7039523

Tofacitinib suppresses disease activity and febrile attacks in a patient with coexisting rheumatoid arthritis and familial Mediterranean fever.

PubMed

Gök, Kevser; Cengiz, Gizem; Erol, Kemal; Ozgocmen, Salih

2017-01-01

Familial Mediterranean fever (FMF) is the most common hereditary auto-inflammatory (periodic fever) syndrome, and usually successfully treated with colchicine. However, nearly 5-10% of FMF cases are resistant or intolerant to colchicine and treatment options are highly restricted in these cases. Biologics including anakinra, canakinumab, rilonacept, etanercept, infliximab, interferon-alpha, and tocilizumab are shown to have efficacy to control FMF attacks. Tofacitinib, a Janus kinase (JAK) inhibitor, is an orally administered non-biologic disease modifying anti-rheumatic drug for the treatment of rheumatoid arthritis (RA). Herein we report a female patient with coexisting RA and colchicine resistant FMF whose FMF attacks and disease activity were completely controlled after treatment with tofacitinib, a small-molecule JAK3 inhibitor.

Polymerization of the tubulin-colchicine complex: relation to microtubule assembly.

PubMed

Andreu, J M; Wagenknecht, T; Timasheff, S N

1983-03-29

The polymerization of purified tubulin-colchicine complex, which results in polymers different from microtubules under microtubule-promoting conditions, has been characterized. It proceeds as a nucleated condensation polymerization, requires Mg2+, and is inhibited by small concentrations of Ca2+. Polymerization requires GTP binding, but GDP is inhibitory. The GTPase activity proceeds, but it is unlinked to polymerization. The thermodynamic characteristics of the growth reaction, namely, the apparent changes of free energy, enthalpy, entropy, heat capacity, and preferential interaction with H+ and Mg2+, are very similar to those of microtubule assembly. It is proposed that the interactions responsible for the two types of polymerization are very similar and that the molecular mechanism of microtubule inhibition by colchicine may consist in a drug-induced distortion of the normal protomer bonding geometry.

Dose-response comparisons of five lung surfactant factor (LSF) preparations in an animal model of adult respiratory distress syndrome (ARDS).

PubMed Central

Häfner, D.; Beume, R.; Kilian, U.; Krasznai, G.; Lachmann, B.

1995-01-01

1. We have examined the effects of five different lung surfactant factor (LSF) preparations in the rat lung lavage model. In this model repetitive lung lavage leads to lung injury with some similarities to adult respiratory distress syndrome with poor gas exchange and protein leakage into the alveolar spaces. These pathological sequelae can be reversed by LSF instillation soon after lavage. 2. The tested LSF preparations were: two bovine: Survanta and Alveofact: two synthetic: Exosurf and a protein-free phospholipid based LSF (PL-LSF) and one Recombinant LSF at doses of 25, 50 and 100 mg kg-1 body weight and an untreated control group. 3. Tracheotomized rats (10-12 per dose) were pressure-controlled ventilated (Siemens Servo Ventilator 900C) with 100% oxygen at a respiratory rate of 30 breaths min-1, inspiration expiration ratio of 1:2, peak inspiratory pressure (PIP) of 28 cmH2O at positive end-expiratory pressure (PEEP) of 8 cmH2O. Two hours after LSF administration, PEEP and in parallel PIP was reduced from 8 to 6 (1st reduction), from 6 to 3 (2nd reduction) and from 3 to 0 cmH2O (3rd reduction). 4. Partial arterial oxygen pressure (PaO2, mmHg) at 5 min and 120 min after LSF administration and during the 2nd PEEP reduction (PaO2(PEEP23/3)) were used for statistical comparison. All LSF preparations caused a dose-dependent increase for the PaO2(120'), whereas during the 2nd PEEP reduction only bovine and recombinant LSF exhibited dose-dependency. Exosurf did not increase PaO2 after administration of the highest dose. At the highest dose Exosurf exerted no further improvement but rather a tendency to relapse.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 2 Figure 3 Figure 4 PMID:7582456

Bio-inspired synthesis and biological evaluation of a colchicine-related compound library.

PubMed

Nicolaou, K C; Valiulin, Roman A; Pokorski, Jonathan K; Chang, Vicki; Chen, Jason S

2012-06-01

A bio-inspired investigation of the reactions of substrates of type 1 with VOF(3) and PIFA [phenyliodine(III) bis(trifluoroacetate)] led to a collection of colchicine-like compounds 2-5 and related systems. Biological evaluation revealed that some of the synthesized products had significant cytotoxic properties against the colon cancer cell line HT-29. Copyright © 2012 Elsevier Ltd. All rights reserved.

The efficacy and safety of palonosetron compared with granisetron in preventing highly emetogenic chemotherapy-induced vomiting in the Chinese cancer patients: a phase II, multicenter, randomized, double-blind, parallel, comparative clinical trial.

PubMed

Yu, Zhaocai; Liu, Wenchao; Wang, Ling; Liang, Houjie; Huang, Ying; Si, Xiaoming; Zhang, Helong; Liu, Duhu; Zhang, Hongmei

2009-01-01

This clinical trial was conducted to evaluate the efficacy and safety of Palonosetron in preventing chemotherapy-induced vomiting (CIV) among the Chinese cancer patients. Two hundred and forty patients were scheduled to be enrolled and randomized to receive a single intravenous dose of palonosetron 0.25 mg, or granisetron 3 mg, 30 min before receiving highly emetogenic chemotherapy. The primary efficacy endpoint was the complete response (CR) rate for acute CIV (during the 0-24-h interval after chemotherapy). Secondary endpoints included the CR rates for delayed CIV (more than 24 h after chemotherapy). Two hundred and eight patients were accrued and received study medication. CR rates for acute CIV were 82.69% for palonosetron and 72.12% for granisetron, which demonstrated that palonosetron was not inferior to granisetron in preventing acute CIV. Comparisons of CR rates for delayed CIV yielded no statistical difference between palonosetron and granisetron groups and did not reveal non-inferiority of palonosetron to granisetron. Adverse events were mostly mild to moderate, with quite low rates among the two groups. A single dose (0.25 mg) of palonosetron is not inferior to a single dose (3 mg) of granisetron in preventing CIV and possesses an acceptable safety profile in the Chinese population.

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

PubMed

Ranganath, Lakshminarayan R; Milan, Anna M; Hughes, Andrew T; Dutton, John J; Fitzgerald, Richard; Briggs, Michael C; Bygott, Helen; Psarelli, Eftychia E; Cox, Trevor F; Gallagher, James A; Jarvis, Jonathan C; van Kan, Christa; Hall, Anthony K; Laan, Dinny; Olsson, Birgitta; Szamosi, Johan; Rudebeck, Mattias; Kullenberg, Torbjörn; Cronlund, Arvid; Svensson, Lennart; Junestrand, Carin; Ayoob, Hana; Timmis, Oliver G; Sireau, Nicolas; Le Quan Sang, Kim-Hanh; Genovese, Federica; Braconi, Daniela; Santucci, Annalisa; Nemethova, Martina; Zatkova, Andrea; McCaffrey, Judith; Christensen, Peter; Ross, Gordon; Imrich, Richard; Rovensky, Jozef

2016-02-01

Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells

PubMed Central

Larocque, Kristen; Ovadje, Pamela; Djurdjevic, Sinisa; Mehdi, Mariam; Green, James; Pandey, Siyaram

2014-01-01

Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy. PMID:24466327

SKLB060 Reversibly Binds to Colchicine Site of Tubulin and Possesses Efficacy in Multidrug-Resistant Cell Lines.

PubMed

Yan, Wei; Yang, Tao; Yang, Jianhong; Wang, Taijin; Yu, Yamei; Wang, Yuxi; Chen, Qiang; Bai, Peng; Li, Dan; Ye, Haoyu; Qiu, Qiang; Zhou, Yongzhao; Hu, Yiguo; Yang, Shengyong; Wei, Yuquan; Li, Weimin; Chen, Lijuan

2018-05-22

Many tubulin inhibitors are in clinical use as anti-cancer drugs. In our previous study, a novel series of 4-substituted coumarins derivatives were identified as novel tubulin inhibitors. Here, we report the anti-cancer activity and underlying mechanism of one of the 4-substituted coumarins derivatives (SKLB060). The anti-cancer activity of SKLB060 was tested on 13 different cancer cell lines and four xenograft cancer models. Immunofluorescence staining, cell cycle analysis, and tubulin polymerization assay were employed to study the inhibition of tubulin. N, N '-Ethylenebis(iodoacetamide) assay was used to measure binding to the colchicine site. Wound-healing migration and tube formation assays were performed on human umbilical vascular endothelial cells to study anti-vascular activity (the ability to inhibit blood vessel growth). Mitotic block reversibility and structural biology assays were used to investigate the SKLB060-tubulin bound model. SKLB060 inhibited tubulin polymerization and subsequently induced G2/M cell cycle arrest and apoptosis in cancer cells. SKLB060 bound to the colchicine site of β-tubulin and showed antivascular activity in vitro. Moreover, SKLB060 induced reversible cell cycle arrest and reversible inhibition of tubulin polymerization. A mitotic block reversibility assay showed that the effects of SKLB060 have greater reversibility than those of colcemid (a reversible tubulin inhibitor), indicating that SKLB060 binds to tubulin in a totally reversible manner. The crystal structures of SKLB060-tubulin complexes confirmed that SKLB060 binds to the colchicine site, and the natural coumarin ring in SKLB060 enables reversible binding. These results reveal that SKLB060 is a powerful and reversible microtubule inhibitor that binds to the colchicine site and is effective in multidrug-resistant cell lines. © 2018 The Author(s). Published by S. Karger AG, Basel.

The small molecule CS1 inhibits mitosis and sister chromatid resolution in HeLa cells.

PubMed

Wu, Xingkang; Li, Zhenyu; Shen, Yuemao

2018-05-01

Mitosis, the most dramatic event in the cell cycle, involves the reorganization of virtually all cellular components. Antimitotic agents are useful for dissecting the mechanism of this reorganization. Previously, we found that the small molecule CS1 accumulates cells in G2/M phase [1], but the mechanism of its action remains unknown. Cell cycle analysis, live cell imaging and nuclear staining were used. Chromosomal morphology was detected by chromosome spreading. The effects of CS1 on microtubules were confirmed by tubulin polymerization, colchicine tubulin-binding, cellular tubulin polymerization and immunofluorescence assays and by analysis of microtubule dynamics and molecular modeling. Histone phosphoproteomics was performed using mass spectrometry. Cell signaling cascades were analyzed using immunofluorescence, immunoprecipitation, immunoblotting, siRNA knockdown and chemical inhibition of specific proteins. The small molecule CS1 was shown to be an antimitotic agent. CS1 potently inhibited microtubule polymerization via interaction with the colchicine-binding pocket of tubulin in vitro and inhibited the formation of the spindle apparatus by reducing the bulk of growing microtubules in HeLa cells, which led to activation of the spindle assembly checkpoint (SAC) and mitotic arrest of HeLa cells. Compared with colchicine, CS1 impaired the progression of sister chromatid resolution independent of cohesin dissociation, and this was reversed by the removal of CS1. Additionally, CS1 induced unique histone phosphorylation patterns distinct from those induced by colchicine. CS1 is a unique antimitotic small molecule and a powerful tool with unprecedented value over colchicine that makes it possible to specifically and conditionally perturb mitotic progression. Copyright © 2018 Elsevier B.V. All rights reserved.

Absolute dose determination in high-energy electron beams: Comparison of IAEA dosimetry protocols

PubMed Central

Sathiyan, S.; Ravikumar, M.

2008-01-01

In this study, absorbed doses were measured and compared for high-energy electrons (6, 9, 12, 16, and 20 MeV) using International Atomic Energy Agency (IAEA), Technical Reports Series No. 277 (TRS), TRS 381, and TRS 398 dosimetry protocols. Absolute dose measurements were carried out using FC65-G Farmer chamber and Nordic Association of Clinical Physicists (NACP) parallel plate chamber with DOSE1 electrometer in WP1-D water phantom for reference field size of 15 × 15 cm2 at 100 cm source-to-surface distance. The results show that the difference between TRS 398 and TRS 381 was about 0.24% to 1.3% depending upon the energy, and the maximum difference between TRS 398 and TRS 277 was 1.5%. The use of cylindrical chamber in electron beam gives the maximum dose difference between the TRS 398 and TRS 277 in the order of 1.4% for energies above 10 MeV (R50 > 4 g/cm2). It was observed that the accuracy of dose estimation was better with the protocols based on the water calibration procedures, as no conversion quantities are involved for conversion of dose from air to water. The cross-calibration procedure of parallel plate chamber with high-energy electron beams is recommended as it avoids pwall correction factor entering into the determination of kQ,Qo. PMID:19893700

First-in-man study with a novel PEGylated recombinant human insulin-like growth factor-I.

PubMed

Kletzl, H; Guenther, A; Höflich, A; Höflich, C; Frystyk, J; Staack, R F; Schick, E; Wandel, C; Bleich, N; Metzger, F

2017-04-01

This study is a first time assessment of safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 in human, in comparison with unmodified rhIGF-I. The study was conducted as a single-center, randomized, double-blinded, placebo-controlled, single ascending dose, parallel group study in a clinical research unit in France. A total of 62 healthy volunteers participated in this clinical trial. RO5046013 was given as single subcutaneous injection, or as intravenous infusion over 48h, at ascending dose levels. The active comparator rhIGF-I was administered at 50μg/kg subcutaneously twice daily for 4days. Safety and tolerability, pharmacokinetics, and pharmacodynamics of RO5046013 were evaluated. PEGylation resulted in long exposure to RO5046013 with a half-life of 140-200h. Exposure to RO5046013 increased approximately dose proportionally. RO5046013 was safe and well tolerated at all doses, injection site erythema after SC administration was the most frequent observed AE. No hypoglycemia occurred. Growth hormone (GH) secretion was almost completely suppressed with rhIGF-I administration, whereas RO5046013 caused only a modest decrease in GH at the highest dose given IV. PEGylation of IGF-I strongly enhances half-life, reduces the negative GH feedback and hypoglycemia potential, and therefore offers a valuable alternative to rhIGF-I in treatment of relevant diseases. Copyright © 2017 Elsevier Ltd. All rights reserved.

Alterations of rings B and C of colchicine are cumulative in overall binding to tubulin but modify each kinetic step.

PubMed

Dumortier, C; Gorbunoff, M J; Andreu, J M; Engelborghs, Y

1996-12-10

The role of the elimination of ring B and/or the modification of ring C of colchicine in tubulin binding kinetics and thermodynamics has been characterized, using four different molecules. These ligands are colchicine (COL); 2-methoxy-5-(2',3',4'-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-on e (MTC), in which the central ring B has been reduced to one bond; allocolchicine (ALLO), in which ring C has been replaced by a six-membered ring; and 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB), where the same two modifications are made simultaneously. This paper describes the kinetics of association of ALLO with tubulin. The binding is accompanied by a fluorescence increase with slow biphasic kinetics, indicating binding to fast and slow tubulin isotypes. Binding to each of these isotypes occurs in two steps: a fast initial binding followed by a slower isomerization step. The K1 and k2 values for ALLO at 25 degrees C are 14,000 +/- 2,000 and 25,000 +/- 6,000 M-1 (fast and slow isotypes) and 0.055 +/- 0.003 s-1 and 0.013 +/- 0.001 s-1 (fast and slow isotype), respectively. For ALLO the reaction standard enthalpy change of the initial binding is 68 +/- 5 kJ.mol-1 (fast isotype) and 45 +/- 33 kJ.mol-1 (slow isotype) and the activation energy for the second forward step is 58 +/- 14 kJ.mol-1 (fast isotype) and 81 +/- 17 kJ.mol-1 (slow isotype). Displacement kinetics of bound ALLO by podophyllotoxin was monoexponential. The activation energy for the isomerization in the off direction is 107 +/- 7 kJ.mol-1. Comparison of the thermodynamic parameters for all four compounds shows that the modifications of both rings are cumulative with respect to overall binding. For the intermediate state there is a mutual influence of both modifications, suggesting an alteration of the reaction pathway.

Multifocal recurrent periostitis responsive to colchicine.

PubMed

Festen, J J; Kuipers, F C; Schaars, A H

1985-01-01

A brother and sister with multifocal recurrent periostitis are presented. Their disease started at an early age and manifested itself as an episodic migrating arthropathy. At roentgenography, reversible solid periosteal reactions were visible along large tubular bones. Scintigraphic and histological investigations revealed a sterile osteitis and thickened periosteum, but there was no indication of a viral infection. The girl experienced spontaneous amelioration after puberty; the boy improved markedly on colchicine.

Effects of Melatonin on Colchicine-Treated PLBs of Dendrobium sonia-28 Orchid.

PubMed

Lim, M S; Antony, J J J; Islam, S M Shahinul; Suhana, Z; Sreeramanan, S

2017-01-01

Dendrobium hybrid orchid is popular in orchid commercial industry due to its short life cycle and ability to produce various types of flower colours. This study was conducted to identify the morphological, biochemical and scanning electron microscopy (SEM) analysis in the Dendrobium sonia-28 orchid plants. In this study, 0.05 and 0.075 % of colchicine-treated Dendrobium sonia-28 (4-week-old culture) protocorm-like bodies (PLBs) were treated in different concentrations of melatonin (MEL) posttreatments (0, 0.05, 0.1, 0.5, 1, 5 and 10 μM). Morphological parameters such as number of shoots, growth index and number of PLBs were determined. In the 0.05 and 0.075 % of colchicine-treated PLBs which were posttreated with 0.05 μM MEL resulted in the highest value of the morphological parameters tested based on the number of shoots (84.5 and 96.67), growth index (16.94 and 12.15) and number of PLBs (126.5 and 162.33), respectively. SEM analysis of the 0.05 μM MEL posttreatment on both the colchicine-treated regenerated PLBs showed irregular cell lineages, and some damages occurred on the stomata. This condition might be due to the effect of plasmolyzing occurred in the cell causing irregular cell lineages.

Comparison of the effects of treatment with celecoxib, loxoprofen, and acetaminophen on postoperative acute pain after arthroscopic knee surgery: A randomized, parallel-group trial.

PubMed

Onda, Akira; Ogoshi, Atsuko; Itoh, Mieko; Nakagawa, Tomoyuki; Kimura, Masashi

2016-03-01

Selective cyclooxygenase-2 (COX-2) inhibitors, conventional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen have been adopted for the relief of mild to moderate acute and chronic pain. However, it remains unclarified whether the therapeutic differences in pain sensation exist among these agents. The aim of this study was to compare the efficacy of different types of analgesic agents for postoperative acute pain management. A single-center, randomized, controlled study was performed in consecutive patients who underwent the second-look procedure with removal of internal fixation after anterior cruciate ligament reconstruction or arthroscopic meniscal repair/meniscectomy. Celecoxib (400 mg for the first dose and then 200 mg), loxoprofen (60 mg), or acetaminophen (600 mg) was orally administered from postoperative 3 h. The pain intensity on a 100-mm VAS scale and subjective assessment of therapeutic pain-relief were compared among these three treatment groups until postoperative 2 days. The acquired data were analyzed according to the per-protocol analysis principle. A total of 432 patients were screened, and 160 were enrolled. The VAS score tended to decrease over time in all groups. There was a significant improvement in the pain score both at rest and on movement, and subjective impression in the celecoxib-treated group compared with acetaminophen at postoperative 2 days. On the other hand, loxoprofen resulted in the benefit only in the pain score at rest in comparison with acetaminophen. Any comparisons between celecoxib and loxoprofen showed insignificant differences throughout observations. No adverse effects were confirmed in each group. These obtained findings in our dose setting conditions suggest that celecoxib and loxoprofen treatments were superior to acetaminophen in pain-relief, though the superiority of loxoprofen over acetaminophen was modest. Overall, selective COX-2 inhibitors including conventional NSAIDs seem to have a possible advantage in acute pain management of relatively less invasive surgery. Copyright © 2015 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.

Arylthioindole inhibitors of tubulin polymerization. 3. Biological evaluation, structure-activity relationships and molecular modeling studies.

PubMed

La Regina, Giuseppe; Edler, Michael C; Brancale, Andrea; Kandil, Sahar; Coluccia, Antonio; Piscitelli, Francesco; Hamel, Ernest; De Martino, Gabriella; Matesanz, Ruth; Díaz, José Fernando; Scovassi, Anna Ivana; Prosperi, Ennio; Lavecchia, Antonio; Novellino, Ettore; Artico, Marino; Silvestri, Romano

2007-06-14

The new arylthioindole (ATI) derivatives 10, 14-18, and 21-24, which bear a halogen atom or a small size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21-24 inhibited MCF-7 cell growth with IC50 values <50 nM. A halogen atom (14-17) at position 5 caused a significant reduction in the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast, methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16, the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine site in the same orientation as the previously studied ATIs. Binding to beta-tubulin involved formation of a hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a hydrophobic pocket near Cys241.

Venlafaxine versus methylphenidate in pediatric outpatients with attention deficit hyperactivity disorder: a randomized, double-blind comparison trial.

PubMed

Zarinara, Ali-Reza; Mohammadi, Mohammad-Reza; Hazrati, Nazanin; Tabrizi, Mina; Rezazadeh, Shams-Ali; Rezaie, Farzin; Akhondzadeh, Shahin

2010-11-01

The present report aimed to investigate the efficacy and tolerability of venlafaxine compared to methylphenidate in children and adolescents with Attention Deficit/Hyperactivity Disorder (ADHD). This was a 6-week, parallel group, randomized clinical trial. Thirty-eight patients (27 boys and 11 girls) with a DSM-IV-TR diagnosis of ADHD were the study population of this trial. All study subjects were randomly assigned to receive treatment using capsules of venlafaxine at doses of 50-75 mg/day depending on weight (50 mg/day for <30 kg and 75 mg/day for >30 kg (group 1) or methylphenidate at a dose of 20-30 mg/day depending on weight (group 2) for a 6-week double blind, randomized clinical trial. The principal measure of outcome was the Teacher and Parent Attention Deficit/Hyperactivity Disorder Rating Scale-IV. No significant differences were observed between the two groups on the Parent and Teacher Rating Scale scores (df = 1; F = 1.77; p = 0.19 and df = 1; F = 1.64; p = 0.20, respectively). Side effects of headaches and insomnia were observed more frequently in the methylphenidate group. The results suggest that venlafaxine may be useful for the treatment of ADHD. In addition, a tolerable side-effect profile is one of the advantages of venlafaxine in the treatment of ADHD. Copyright © 2010 John Wiley & Sons, Ltd.

Nasal budesonide offers superior symptom relief in perennial allergic rhinitis in comparison to nasal azelastine.

PubMed

Stern, M A; Wade, A G; Ridout, S M; Cambell, L M

1998-10-01

Allergic rhinitis is usually treated with oral antihistamines or nasal steroids. Topically active nasal antihistamine is a new treatment modality for allergic rhinitis. The efficacy in comparison to well established topical treatment alternatives is not fully known. To compare the efficacy of intranasally administered azelastine to budesonide, at their respectively recommended dosage, on the symptoms of perennial rhinitis patients. A placebo-controlled, randomized, parallel group study was conducted to compare the efficacy and tolerability of intranasal budesonide aqueous suspension (256 microg once daily) with azelastine hydrochloride nasal spray (280 microg twice daily (560 microg/day)) and with placebo in the treatment of perennial allergic rhinitis. The 195 patients (with at least a 2-year history of perennial allergic rhinitis) recorded individual nasal symptom scores, the degree of symptom control achieved and any adverse events experienced over a 2-week baseline period and a 6-week treatment period. Following treatment, the reductions in mean combined and individual nasal symptom scores from baseline values were significantly greater in the budesonide group compared with the placebo group (P < .0001 for all variables except runny nose P = .01). In patients treated with budesonide, there were also significantly larger reductions from baseline values in combined nasal symptom scores (P < .01) and in scores for all individual nasal symptoms (P < or = .05) compared with those treated with azelastine. The reductions from baseline in both combined and individual nasal symptom scores did not differ between azelastine and placebo. The study medications were well tolerated, producing no unexpected or serious treatment-related adverse events. A once-daily dose of 256 microg of intranasal budesonide aqueous suspension is significantly more effective at relieving the symptoms of perennial allergic rhinitis compared with a twice daily dose of 280 microg of azelastine nasal spray.

Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCath (registered) technique

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

Fransson, Per; Bergstroem, Per; Loefroth, Per-Olov

2006-10-01

Purpose: Late side effects were prospectively evaluated up to 5 years after dose-escalated external beam radiotherapy (EBRT) and were compared with a previously treated series with conventional conformal technique. Methods and Materials: Bladder and bowel symptoms were prospectively evaluated with the Prostate Cancer Symptom Scale (PCSS) questionnaire up to 5 years posttreatment. In all, 257 patients completed the questionnaire 5 years posttreatment. A total of 168 patients were treated with the conformal technique at doses <71 Gy, and 195 were treated with the dose-escalated stereotactic BeamCath (registered) technique comprising three dose levels: 74 Gy (n = 68), 76 Gy (nmore » = 74), and 78 Gy (n = 53). Results: For all dose groups analyzed together, 5 years after treatment, urinary starting problems decreased and urinary incontinence increased in comparison to baseline values. No increase in other bladder symptoms or frequency was detected. When comparing dose groups after 5 years, both the 74-Gy and 78-Gy groups reported increased urinary starting problems compared with patients given the conventional dose (<71 Gy). No increased incontinence was seen in the 76-Gy or the 78-Gy groups. Bowel symptoms were slightly increased during the follow-up period in comparison to baseline. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal late side effects after 5 years in comparison to doses <71 Gy. Conclusion: Dose-escalated EBRT with the BeamCath (registered) technique with doses up to 78 Gy is tolerable, and the toxicity profile is similar to that observed with conventional doses <71 Gy.« less

GPU-based ultra-fast dose calculation using a finite size pencil beam model.

PubMed

Gu, Xuejun; Choi, Dongju; Men, Chunhua; Pan, Hubert; Majumdar, Amitava; Jiang, Steve B

2009-10-21

Online adaptive radiation therapy (ART) is an attractive concept that promises the ability to deliver an optimal treatment in response to the inter-fraction variability in patient anatomy. However, it has yet to be realized due to technical limitations. Fast dose deposit coefficient calculation is a critical component of the online planning process that is required for plan optimization of intensity-modulated radiation therapy (IMRT). Computer graphics processing units (GPUs) are well suited to provide the requisite fast performance for the data-parallel nature of dose calculation. In this work, we develop a dose calculation engine based on a finite-size pencil beam (FSPB) algorithm and a GPU parallel computing framework. The developed framework can accommodate any FSPB model. We test our implementation in the case of a water phantom and the case of a prostate cancer patient with varying beamlet and voxel sizes. All testing scenarios achieved speedup ranging from 200 to 400 times when using a NVIDIA Tesla C1060 card in comparison with a 2.27 GHz Intel Xeon CPU. The computational time for calculating dose deposition coefficients for a nine-field prostate IMRT plan with this new framework is less than 1 s. This indicates that the GPU-based FSPB algorithm is well suited for online re-planning for adaptive radiotherapy.

SU-E-T-37: A GPU-Based Pencil Beam Algorithm for Dose Calculations in Proton Radiation Therapy

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

Kalantzis, G; Leventouri, T; Tachibana, H

Purpose: Recent developments in radiation therapy have been focused on applications of charged particles, especially protons. Over the years several dose calculation methods have been proposed in proton therapy. A common characteristic of all these methods is their extensive computational burden. In the current study we present for the first time, to our best knowledge, a GPU-based PBA for proton dose calculations in Matlab. Methods: In the current study we employed an analytical expression for the protons depth dose distribution. The central-axis term is taken from the broad-beam central-axis depth dose in water modified by an inverse square correction whilemore » the distribution of the off-axis term was considered Gaussian. The serial code was implemented in MATLAB and was launched on a desktop with a quad core Intel Xeon X5550 at 2.67GHz with 8 GB of RAM. For the parallelization on the GPU, the parallel computing toolbox was employed and the code was launched on a GTX 770 with Kepler architecture. The performance comparison was established on the speedup factors. Results: The performance of the GPU code was evaluated for three different energies: low (50 MeV), medium (100 MeV) and high (150 MeV). Four square fields were selected for each energy, and the dose calculations were performed with both the serial and parallel codes for a homogeneous water phantom with size 300×300×300 mm3. The resolution of the PBs was set to 1.0 mm. The maximum speedup of ∼127 was achieved for the highest energy and the largest field size. Conclusion: A GPU-based PB algorithm for proton dose calculations in Matlab was presented. A maximum speedup of ∼127 was achieved. Future directions of the current work include extension of our method for dose calculation in heterogeneous phantoms.« less

[Immunohistochemical observation on keratin filaments of cultured tumor cells by ABC staining].

PubMed

Wang, J; Yang, F

1991-06-01

Avidin-Biotin Peroxidase complex technique, ABV staining, was employed by using monoclonal anti-keratin antibody HK2 in this study. The organization and dynamics of keratins in both interphase and mitotic T56 and HeLa cells were analysed. We also observed the effects of microtubule (MT) and microfilament (MF) inhibitors, colchicine and cytochalasin B, on the organization of keratin filaments in T56 and HeLa cells. The results showed that a significant alteration in the structural organization and distribution of keratin filaments occurred during mitosis, and an extensive rearrangement of keratin networks of the two cell lines was induced in interphase after the MT and MF were disrupted by combined treatment with the two drugs, colchicine and cytochalasin B; the keratin networks turned into a star-like lattice rapidly within 1-2h. Neither colchicine nor cytochalasin B alone elicited significant organizational change in the keratin networks of the two cell lines.

A Comparison of Automatic Parallelization Tools/Compilers on the SGI Origin 2000 Using the NAS Benchmarks

NASA Technical Reports Server (NTRS)

Saini, Subhash; Frumkin, Michael; Hribar, Michelle; Jin, Hao-Qiang; Waheed, Abdul; Yan, Jerry

1998-01-01

Porting applications to new high performance parallel and distributed computing platforms is a challenging task. Since writing parallel code by hand is extremely time consuming and costly, porting codes would ideally be automated by using some parallelization tools and compilers. In this paper, we compare the performance of the hand written NAB Parallel Benchmarks against three parallel versions generated with the help of tools and compilers: 1) CAPTools: an interactive computer aided parallelization too] that generates message passing code, 2) the Portland Group's HPF compiler and 3) using compiler directives with the native FORTAN77 compiler on the SGI Origin2000.

Quantitative analysis of microtubule orientation in interdigitated leaf pavement cells.

PubMed

Akita, Kae; Higaki, Takumi; Kutsuna, Natsumaro; Hasezawa, Seiichiro

2015-01-01

Leaf pavement cells are shaped like a jigsaw puzzle in most dicotyledon species. Molecular genetic studies have identified several genes required for pavement cells morphogenesis and proposed that microtubules play crucial roles in the interdigitation of pavement cells. In this study, we performed quantitative analysis of cortical microtubule orientation in leaf pavement cells in Arabidopsis thaliana. We captured confocal images of cortical microtubules in cotyledon leaf epidermis expressing GFP-tubulinβ and quantitatively evaluated the microtubule orientations relative to the pavement cell growth axis using original image processing techniques. Our results showed that microtubules kept parallel orientations to the growth axis during pavement cell growth. In addition, we showed that immersion treatment of seed cotyledons in solutions containing tubulin polymerization and depolymerization inhibitors decreased pavement cell complexity. Treatment with oryzalin and colchicine inhibited the symmetric division of guard mother cells.

Effects of Different Doses of Irbesartan Combined With Spironolactone on Urinary Albumin Excretion Rate in Elderly Patients With Early Type 2 Diabetic Nephropathy.

PubMed

Chen, Yingying; Liu, Peng; Chen, Xia; Li, Yanan; Zhang, Fengmei; Wang, Yangang

2018-05-01

There is a lack of research on the effect of low dose of angiotensin receptor blockers combined with spironolactone, and the effect of high dose of angiotensin receptor blockers alone on the urinary albumin excretion rate (UAER) in elderly patients with early type 2 diabetic nephropathy (DN). We conducted a prospective, randomized, open-label, parallel-controlled study that included 244 elderly patients with early DN and mild-to-moderate essential hypertension. Patients were randomly divided into 4 groups: low-dose irbesartan (group A), high-dose irbesartan (group B), low-dose irbesartan combined with spironolactone (group C) and high-dose irbesartan combined with spironolactone (group D). Changes in UAER, serum potassium and blood pressure were compared. There were no statistical differences in the baseline characteristics among groups. Furthermore, no significant difference in blood pressure before and after treatment was found among different groups. After 72-week treatment, UAER in group D was lower compared to group A and B (P < 0.05). Meanwhile, compared with group B, UAER in group C decreased significantly (P < 0.05). Additionally, significantly higher serum potassium was found in group D compared to other groups (P < 0.05). Also, group D had the highest count of patients who withdrew from the study due to hyperkalemia compared to other groups (P < 0.05). Our results indicate high-dose irbesartan combined with spironolactone may be more efficient in reducing UAER in elderly patients with early DN, but this treatment could cause hyperkalemia. Low-dose irbesartan combined with spironolactone was shown to be safer and more effective in decreasing UAER compared to high-dose irbesartan. Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

Efficacy and Safety of Pemafibrate Versus Fenofibrate in Patients with High Triglyceride and Low HDL Cholesterol Levels: A Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial.

PubMed

Arai, Hidenori; Yamashita, Shizuya; Yokote, Koutaro; Araki, Eiichi; Suganami, Hideki; Ishibashi, Shun

2018-06-01

To verify the superiority of pemafibrate over placebo and the non-inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs). This phase III, placebo/active drug-controlled, randomized, double-blind, parallel group comparison study enrolled patients with high TG and low high-density lipoprotein cholesterol levels. Patients were randomly assigned to receive placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, or 0.4 mg/day; or fenofibrate 100 mg/day or 200 mg/day for 12 weeks. Among 526 randomized patients, 489 completed the study, with drop-out rates of 0%, 6.7%, 5.5%, 5.9%, 8.2%, and 10.7% in the placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, and 0.4 mg/day; and fenofibrate 100 mg/day and 200 mg/day groups. The study showed the non-inferiority of pemafibrate 0.4 mg/day and 0.2 mg/day to fenofibrate 200 mg/day as well the non-inferiority and superiority of all pemafibrate doses to fenofibrate 100 mg/day for reducing TG levels. No dose-dependent increase in the incidence of AEs or ADRs was observed among the pemafibrate dose groups. The incidence of AEs and ADRs for all pemafibrate doses was similar to that for placebo and fenofibrate 100 mg/day and significantly lower than that for fenofibrate 200 mg/day (P＜0.05). The favorable safety profile of pemafibrate, with fewer adverse effects on kidney/liver-related laboratory tests and fewer AEs/ADRs, including those leading to treatment discontinuation, over fenofibrate 200 mg/day may justify the use of this novel and potent treatment option for reducing TG levels in a broader range of patients.

Dosimetric Comparison in Breast Radiotherapy of 4 MV and 6 MV on Physical Chest Simulator

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

Donato da Silva, Sabrina; Passos Ribeiro Campos, Tarcisio; Batista Nogueira, Luciana

2015-07-01

According to the World Health Organization (2014) breast cancer is the main cause of death by cancer in women worldwide. The biggest challenge of radiotherapy in the treatment of cancer is to deposit the entire prescribed dose homogeneously in the breast, sparing the surrounding tissue. In this context, this paper aimed at evaluating and comparing internal dose distribution in the mammary gland based on experimental procedures submitted to two distinct energy spectra produced in breast cancer radiotherapy. The methodology consisted of reproducing opposite parallel fields used in the treatment of breast tumors in a chest phantom. This simulator with syntheticmore » breast, composed of equivalent tissue material (TE), was previously developed by the NRI Research Group (UFMG). The computer tomography (CT) scan of the simulator was obtained antecedently. The radiotherapy planning systems (TPS) in the chest phantom were performed in the ECLIPSE system from Varian Medical Systems and CAT 3D system from MEVIS. The irradiations were reproduced in the Varian linear accelerator, model SL- 20 Precise, 6 MV energy and Varian linear accelerator, 4 MV Clinac 6x SN11 model. Calibrations of the absorbed dose versus optical density from radiochromic films were generated in order to obtain experimental dosimetric distribution at the films positioned within the glandular and skin equivalent tissues of the chest phantom. The spatial dose distribution showed equivalence with the TPS on measurement data performed in the 6 MV spectrum. The average dose found in radiochromic films placed on the skin ranged from 49 to 79%, and from 39 to 49% in the mammary areola, for the prescribed dose. Dosimetric comparisons between the spectra of 4 and 6 MV, keeping the constant geometry of the fields applied in the same phantom, will be presented showing their equivalence in breast radiotherapy, as well as the variations will be discussed. To sum up, the dose distribution has reached the value expected in the breast dose of the 180 cGy in a wide range of the film in the glandular TE in both spectra. (authors)« less

Evaluation of Preclinical Assays to Investigate an Anthroposophic Pharmaceutical Process Applied to Mistletoe (Viscum album L.) Extracts

PubMed Central

Flückiger, Heidi

2014-01-01

Extracts from European mistletoe (Viscum album L.) developed in anthroposophic medicine are based on specific pharmaceutical procedures to enhance remedy efficacy. One such anthroposophic pharmaceutical process was evaluated regarding effects on cancer cell toxicity in vitro and on colchicine tumor formation in Lepidium sativum. Anthroposophically processed Viscum album extract (APVAE) was produced by mixing winter and summer mistletoe extracts in the edge of a high-speed rotating disk and was compared with manually mixed Viscum album extract (VAE). The antiproliferative effect of VAE/APVAE was determined in five cell lines (NCI-H460, DU-145, HCC1143, MV3, and PA-TU-8902) by WST-1 assay in vitro; no difference was found between VAE and APVAE in any cell line tested (P > 0.14). Incidence of colchicine tumor formation was assessed by measurement of the root/shoot-ratio of seedlings of Lepidium sativum treated with colchicine as well as VAE, APVAE, or water. Colchicine tumor formation decreased after application of VAE (−5.4% compared to water, P < 0.001) and was even stronger by APVAE (−8.8% compared to water, P < 0.001). The high-speed mistletoe extract mixing process investigated thus did not influence toxicity against cancer cells but seemed to sustain morphostasis and to enhance resistance against external noxious influences leading to phenomenological malformations. PMID:24876872

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

PubMed

Mease, Philip; Hall, Stephen; FitzGerald, Oliver; van der Heijde, Désirée; Merola, Joseph F; Avila-Zapata, Francisco; Cieślak, Dorota; Graham, Daniela; Wang, Cunshan; Menon, Sujatha; Hendrikx, Thijs; Kanik, Keith S

2017-10-19

Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs). In this 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group (P=0.006 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668 .).

Exploring asynchronous brainstorming in large groups: a field comparison of serial and parallel subgroups.

PubMed

de Vreede, Gert-Jan; Briggs, Robert O; Reiter-Palmon, Roni

2010-04-01

The aim of this study was to compare the results of two different modes of using multiple groups (instead of one large group) to identify problems and develop solutions. Many of the complex problems facing organizations today require the use of very large groups or collaborations of groups from multiple organizations. There are many logistical problems associated with the use of such large groups, including the ability to bring everyone together at the same time and location. A field study involved two different organizations and compared productivity and satisfaction of group. The approaches included (a) multiple small groups, each completing the entire process from start to end and combining the results at the end (parallel mode); and (b) multiple subgroups, each building on the work provided by previous subgroups (serial mode). Groups using the serial mode produced more elaborations compared with parallel groups, whereas parallel groups produced more unique ideas compared with serial groups. No significant differences were found related to satisfaction with process and outcomes between the two modes. Preferred mode depends on the type of task facing the group. Parallel groups are more suited for tasks for which a variety of new ideas are needed, whereas serial groups are best suited when elaboration and in-depth thinking on the solution are required. Results of this research can guide the development of facilitated sessions of large groups or "teams of teams."

Dose Comparisons for a Site-specific Representative Person Using the Age-dependent Dose Coefficients in CAP88-PC Version 4.

PubMed

Stagich, Brooke H; Moore, Kelsey R; Newton, Joseph R; Dixon, Kenneth L; Jannik, G Timothy

2017-04-01

Most U.S. Department of Energy (DOE) facilities with radiological airborne releases use the U.S. Environmental Protection Agency's (EPA) environmental dosimetry code CAP88-PC to demonstrate compliance with regulations in 40CFR61, subpart H [National Emission Standards for Hazardous Air Pollutants: Radiological (NESHAP)]. In 2015, EPA released Version 4 of CAP88-PC, which included significant modifications that improved usability and age-dependent dose coefficients and usage factors for six age groups (infant, 1 y, 5 y, 10 y, 15 y, and adult). However, EPA has not yet provided specific guidance on how to use these age-dependent factors. For demonstrating compliance with DOE public dose regulations, the Savannah River Site (SRS) recently changed from using the maximally exposed individual (MEI) concept (adult male) to the representative person concept (age- and gender-averaged reference person). In this study, dose comparisons are provided between the MEI and a SRS-specific representative person using the age-specific dose coefficients and usage factors in CAP88-PC V.4. Dose comparisons also are provided for each of the six age groups using five radionuclides of interest at SRS (tritium oxide, Cs, Sr, Pu, and I). In general, the total effective dose increases about 11% for the representative person as compared to the current NESHAP MEI because of the inclusion of the more radiosensitive age groups.

MOF-5(Zn)-Fe2O4 nanocomposite based magnetic solid-phase microextraction followed by HPLC-UV for efficient enrichment of colchicine in root of colchicium extracts and plasma samples.

PubMed

Bahrani, Sonia; Ghaedi, Mehrorang; Dashtian, Kheibar; Ostovan, Abbas; Mansoorkhani, Mohammad Javad Khoshnood; Salehi, Amin

2017-11-01

In present work, facile method is developed for determination of colchicine in human plasma sample, autumn and spring root of colchicium extracts by ultrasound assisted dispersive magnetic solid phase microextraction followed by HPLC-UV method (UAD-MSPME-HPLC-UV). Magnetic (Fe 2 O 4 -nanoparticles) metal organic framework-5, (MOF-5(Zn)-Fe 2 O 4 NPs) was synthesized by dispersing MOF-5 and Fe(NO 3 ) 3 .9H 2 O in ethylene glycol (as capping agent) and NaOH (pH adjustment agent) by hydrothermal method. The prepared sorbent was characterized via XRD and SEM analysis and applied as magnetic solid phase in UAD-MSPME-HPLC-UV method. In this method, colchicine molecules were sorbed on MOF-5(Zn)-Fe 2 O 4 NPs sorbent by various mechanisms like ion exchange, hydrogen bonding and electrostatic, ᴨ-ᴨ, hard-hard and dipole-ion interaction followed by exposing sonication waves as incremental mass transfer agent and then the sorbent was separated from the sample matrix by an external magnetic fields. Subsequently, accumulated colchicine were eluted by small volume of desorption organic solvent. Influence of operational variables such as MOF-5(Zn)-Fe 2 O 4 NPs mass, volume of extracting solvent and sonication time on response property (recovery) were studied and optimized by central composite design (CCD) combined with desirability function (DF) approach. Under optimum condition, the method has wide linear calibration rang (0.5-1700ngmL -1 ) with reasonable detection limit (0.13ngmL -1 ) and R 2 =0.9971. Finally, the UAD-MSPME-HPLC-UV method was successfully applied for determination of colchicine autumn and spring root of colchicium extracts and plasma samples. Copyright © 2017 Elsevier B.V. All rights reserved.

Interferon alfa-2b, colchicine, and benzathine penicillin versus colchicine and benzathine penicillin in Behçet's disease: a randomised trial.

PubMed

Demiroglu, H; Ozcebe, O I; Barista, I; Dündar, S; Eldem, B

2000-02-19

Sight-threatening eye involvement is a serious complication of Behçet's disease. Extraocular complications such as arthritis, vascular occlusive disorders, mucocutaneous lesions, and central-nervous-system disease may lead to morbidity and even death. We designed a prospective study in newly diagnosed patients without previous eye disease to assess whether prevention of eye involvement and extraocular manifestations, and preservation of visual acuity are possible with combination treatments with and without interferon alfa-2b. Patients were randomly assigned 3 million units interferon alfa-2b subcutaneously every other day for the first 6 months plus 1.5 mg colchicine orally daily and 1.2 million units benzathine penicillin intramuscularly every 3 weeks (n=67), or colchicine and benzathine penicillin alone (n=68). The primary endpoint was visual-acuity loss. Analysis was by intention to treat. Significantly fewer patients who were treated with interferon had eye involvement than did patients who did not receive interferon (eight vs 27, relative risk 0.21 [95% CI 0.09-0.50], p<0.001). Ocular attack rate was 0.2 (SD 0.62) per year with interferon therapy and 1.02 (1.13) without interferon therapy (p=0.0001). Visual-acuity loss was significantly lower among patients treated with interferon than in those without interferon (two vs 13, relative risk 0.13 [95% CI 0.03-0.60], p=0.003). Arthritis episodes, vascular events, and mucocutaneous lesions were also less frequent in patients treated with interferon than in those not receiving interferon. No serious side-effects were reported. Therapy with interferon alfa-2b, colchicine, and benzathine penicillin seems to be an effective regimen in Behçet's disease for the prevention of recurrent eye attacks and extraocular complications, and for the protection of vision.

Chromosome Doubling of Microspore-Derived Plants from Cabbage (Brassica oleracea var. capitata L.) and Broccoli (Brassica oleracea var. italica L.)

PubMed Central

Yuan, Suxia; Su, Yanbin; Liu, Yumei; Li, Zhansheng; Fang, Zhiyuan; Yang, Limei; Zhuang, Mu; Zhang, Yangyong; Lv, Honghao; Sun, Peitian

2015-01-01

Chromosome doubling of microspore-derived plants is an important factor in the practical application of microspore culture technology because breeding programs require a large number of genetically stable, homozygous doubled haploid plants with a high level of fertility. In the present paper, 29 populations of microspore-derived plantlets from cabbage (Brassica oleracea var. capitata) and broccoli (Brassica oleracea var. italica) were used to study the ploidy level and spontaneous chromosome doubling of these populations, the artificial chromosome doubling induced by colchicine, and the influence of tissue culture duration on the chromosomal ploidy of the microspore-derived regenerants. Spontaneous chromosome doubling occurred randomly and was genotype dependent. In the plant populations derived from microspores, there were haploids, diploids, and even a low frequency of polyploids and mixed-ploidy plantlets. The total spontaneous doubling in the 14 cabbage populations ranged from 0 to 76.9%, compared with 52.2 to 100% in the 15 broccoli populations. To improve the rate of chromosome doubling, an efficient and reliable artificial chromosome doubling protocol (i.e., the immersion of haploid plantlet roots in a colchicine solution) was developed for cabbage and broccoli microspore-derived haploids. The optimal chromosome doubling of the haploids was obtained with a solution of 0.2% colchicine for 9–12 h or 0.4% colchicine for 3–9 h for cabbage and 0.05% colchicine for 6–12 h for broccoli. This protocol produced chromosome doubling in over 50% of the haploid genotypes for most of the populations derived from cabbage and broccoli. Notably, after 1 or more years in tissue culture, the chromosomes of the haploids were doubled, and most of the haploids turned into doubled haploid or mixed-ploidy plants. This is the first report indicating that tissue culture duration can change the chromosomal ploidy of microspore-derived regenerants. PMID:26734028

Chromosome Doubling of Microspore-Derived Plants from Cabbage (Brassica oleracea var. capitata L.) and Broccoli (Brassica oleracea var. italica L.).

PubMed

Yuan, Suxia; Su, Yanbin; Liu, Yumei; Li, Zhansheng; Fang, Zhiyuan; Yang, Limei; Zhuang, Mu; Zhang, Yangyong; Lv, Honghao; Sun, Peitian

2015-01-01

Chromosome doubling of microspore-derived plants is an important factor in the practical application of microspore culture technology because breeding programs require a large number of genetically stable, homozygous doubled haploid plants with a high level of fertility. In the present paper, 29 populations of microspore-derived plantlets from cabbage (Brassica oleracea var. capitata) and broccoli (Brassica oleracea var. italica) were used to study the ploidy level and spontaneous chromosome doubling of these populations, the artificial chromosome doubling induced by colchicine, and the influence of tissue culture duration on the chromosomal ploidy of the microspore-derived regenerants. Spontaneous chromosome doubling occurred randomly and was genotype dependent. In the plant populations derived from microspores, there were haploids, diploids, and even a low frequency of polyploids and mixed-ploidy plantlets. The total spontaneous doubling in the 14 cabbage populations ranged from 0 to 76.9%, compared with 52.2 to 100% in the 15 broccoli populations. To improve the rate of chromosome doubling, an efficient and reliable artificial chromosome doubling protocol (i.e., the immersion of haploid plantlet roots in a colchicine solution) was developed for cabbage and broccoli microspore-derived haploids. The optimal chromosome doubling of the haploids was obtained with a solution of 0.2% colchicine for 9-12 h or 0.4% colchicine for 3-9 h for cabbage and 0.05% colchicine for 6-12 h for broccoli. This protocol produced chromosome doubling in over 50% of the haploid genotypes for most of the populations derived from cabbage and broccoli. Notably, after 1 or more years in tissue culture, the chromosomes of the haploids were doubled, and most of the haploids turned into doubled haploid or mixed-ploidy plants. This is the first report indicating that tissue culture duration can change the chromosomal ploidy of microspore-derived regenerants.

Influence of the antiseptic agents polyhexanide and octenidine on FL cells and on healing of experimental superficial aseptic wounds in piglets. A double-blind, randomised, stratified, controlled, parallel-group study.

PubMed

Kramer, A; Roth, B; Müller, G; Rudolph, P; Klöcker, N

2004-01-01

The main target of the combination of octenidine with phenoxyethanol (Octenisept) is the antisepsis of acute wounds, whereas polyhexanide combined with polyethylene glycol in Ringer solution (Lavasept) is the agent of choice for antisepsis of chronic wounds and burns. Because comparative data for both agents on the effects on wound healing are lacking, we investigated the influence of preparations based on polyhexanide and octenidine versus placebo (Ringer solution) in experimental superficial aseptic skin wounds (n = 108) of 20 mm diameter, using a double-blind, randomised, stratified, controlled, parallel-group design in piglets. Computerised planimetry and histopathological methods were used for the assessment of wound healing. Histologically, no significant differences could be verified at any time between the 3 groups. However, in the early phase (day 9 after wounding), the octenidine-based product retarded wound contraction to a significantly greater extent than placebo and polyhexanide, whereas in the later phase (days 18 and 28), polyhexanide promoted contraction significantly more than did placebo and octenidine. The consequence is complete wound closure after 22.9 days using polyhexanide, in comparison to the placebo after 24.1 days (p < 0.05) and octenidine after 28.3 days (no statistical difference to placebo). This may be explained by the better tolerance of polyhexanide in vitro, which was demonstrated with dose and time dependence in cytotoxicity tests on human amnion cells. Copyright 2004 S. Karger AG, Basel

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials.

PubMed

Holmskov, Mathilde; Storebø, Ole Jakob; Moreira-Maia, Carlos R; Ramstad, Erica; Magnusson, Frederik Løgstrup; Krogh, Helle B; Groth, Camilla; Gillies, Donna; Zwi, Morris; Skoog, Maria; Gluud, Christian; Simonsen, Erik

2017-01-01

To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found.

In-flight measured and predicted ambient dose equivalent and latitude differences on effective dose estimates.

PubMed

Saez Vergara, J C; Romero Gutiérrez, A M; Rodriguez Jiménez, R; Dominguez-Mompell Román, R

2004-01-01

The results from 2 years (2001-2002) of experimental measurements of in-board radiation doses received at IBERIA commercial flights are presented. The routes studied cover the most significant destinations and provide a good estimate of the route doses as required by the new Spanish regulations on air crew radiation protection. Details on the experimental procedures and calibration methods are given. The experimental measurements from the different instruments (Tissue Equivalent Proportional Counter and the combination of a high pressure ion chamber and a high-energy neutron compensated rem-counter) and their comparison with the predictions from some route-dose codes (CARI-6, EPCARD 3.2) are discussed. In contrast with the already published data, which are mainly focused on North latitudes over parallel 50, many of the data presented in this work have been obtained for routes from Spain to Central and South America.

Losartan/hydrochlorothiazide combination vs. high-dose losartan in patients with morning hypertension--a prospective, randomized, open-labeled, parallel-group, multicenter trial.

PubMed

Ueda, Tamenobu; Kai, Hisashi; Imaizumi, Tsutomu

2012-07-01

The treatment of morning hypertension has not been established. We compared the efficacy and safety of a losartan/hydrochlorothiazide (HCTZ) combination and high-dose losartan in patients with morning hypertension. A prospective, randomized, open-labeled, parallel-group, multicenter trial enrolled 216 treated outpatients with morning hypertension evaluated by home blood pressure (BP) self-measurement. Patients were randomly assigned to receive a combination therapy of 50 mg losartan and 12.5 mg HCTZ (n=109) or a high-dose therapy with 100 mg losartan (n=107), each of which were administered once every morning. Primary efficacy end points were morning systolic BP (SBP) level and target BP achievement rate after 3 months of treatment. At baseline, BP levels were similar between the two therapy groups. Morning SBP was reduced from 150.3±10.1 to 131.5±11.5 mm Hg by combination therapy (P<0.001) and from 151.0±9.3 to 142.5±13.6 mm Hg by high-dose therapy (P<0.001). The morning SBP reduction was greater in the combination therapy group than in the high-dose therapy group (P<0.001). Combination therapy decreased evening SBP from 141.6±13.3 to 125.3±13.1 mm Hg (P<0.001), and high-dose therapy decreased evening SBP from 138.9±9.9 to 131.4±13.2 mm Hg (P<0.01). Although both therapies improved target BP achievement rates in the morning and evening (P<0.001 for both), combination therapy increased the achievement rates more than high-dose therapy (P<0.001 and P<0.05, respectively). In clinic measurements, combination therapy was superior to high-dose therapy in reducing SBP and improving the achievement rate (P<0.001 and P<0.01, respectively). Combination therapy decreased urine albumin excretion (P<0.05) whereas high-dose therapy reduced serum uric acid. Both therapies indicated strong adherence and few adverse effects (P<0.001). In conclusion, losartan/HCTZ combination therapy was more effective for controlling morning hypertension and reducing urine albumin than high-dose losartan.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles.

PubMed

Jin, Yan; Smith, Claire; Hu, Leijun; Coutant, David E; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2018-01-01

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

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.

A phase 2a randomized, parallel group, dose-ranging study of molindone in children with attention-deficit/hyperactivity disorder and persistent, serious conduct problems.

PubMed

Stocks, Jennifer Dugan; Taneja, Baldeo K; Baroldi, Paolo; Findling, Robert L

2012-04-01

To evaluate safety and tolerability of four doses of immediate-release molindone hydrochloride in children with attention-deficit/hyperactivity disorder (ADHD) and serious conduct problems. This open-label, parallel-group, dose-ranging, multicenter trial randomized children, aged 6-12 years, with ADHD and persistent, serious conduct problems to receive oral molindone thrice daily for 9-12 weeks in four treatment groups: Group 1-10 mg (5 mg if weight <30 kg), group 2-20 mg (10 mg if <30 kg), group 3-30 mg (15 mg if <30 kg), and group 4-40 mg (20 mg if <30 kg). The primary outcome measure was to evaluate safety and tolerability of molindone in children with ADHD and serious conduct problems. Secondary outcome measures included change in Nisonger Child Behavior Rating Form-Typical Intelligence Quotient (NCBRF-TIQ) Conduct Problem subscale scores, change in Clinical Global Impressions-Severity (CGI-S) and -Improvement (CGI-I) subscale scores from baseline to end point, and Swanson, Nolan, and Pelham rating scale-revised (SNAP-IV) ADHD-related subscale scores. The study randomized 78 children; 55 completed the study. Treatment with molindone was generally well tolerated, with no clinically meaningful changes in laboratory or physical examination findings. The most common treatment-related adverse events (AEs) included somnolence (n=9), weight increase (n=8), akathisia (n=4), sedation (n=4), and abdominal pain (n=4). Mean weight increased by 0.54 kg, and mean body mass index by 0.24 kg/m(2). The incidence of AEs and treatment-related AEs increased with increasing dose. NCBRF-TIQ subscale scores improved in all four treatment groups, with 34%, 34%, 32%, and 55% decreases from baseline in groups 1, 2, 3, and 4, respectively. CGI-S and SNAP-IV scores improved over time in all treatment groups, and CGI-I scores improved to the greatest degree in group 4. Molindone at doses of 5-20 mg/day (children weighing <30 kg) and 20-40 mg (≥ 30 kg) was well tolerated, and preliminary efficacy results suggest that molindone produces dose-related behavioral improvements over 9-12 weeks. Additional double-blind, placebo-controlled trials are needed to further investigate molindone in this pediatric population.

Oral sumatriptan for migraine in children and adolescents: a randomized, multicenter, placebo-controlled, parallel group study.

PubMed

Fujita, Mitsue; Sato, Katsuaki; Nishioka, Hiroshi; Sakai, Fumihiko

2014-04-01

The objective of this article is to evaluate the efficacy and tolerability of two doses of oral sumatriptan vs placebo in the acute treatment of migraine in children and adolescents. Currently, there is no approved prescription medication in Japan for the treatment of migraine in children and adolescents. This was a multicenter, outpatient, single-attack, double-blind, randomized, placebo-controlled, parallel-group study. Eligible patients were children and adolescents aged 10 to 17 years diagnosed with migraine with or without aura (ICHD-II criteria 1.1 or 1.2) from 17 centers. They were randomized to receive sumatriptan 25 mg, 50 mg or placebo (1:1:2). The primary efficacy endpoint was headache relief by two grades on a five-grade scale at two hours post-dose. A total of 178 patients from 17 centers in Japan were enrolled and randomized to an investigational product in double-blind fashion. Of these, 144 patients self-treated a single migraine attack, and all provided a post-dose efficacy assessment and completed the study. The percentage of patients in the full analysis set (FAS) population who report pain relief at two hours post-treatment for the primary endpoint was higher in the placebo group than in the pooled sumatriptan group (38.6% vs 31.1%, 95% CI: -23.02 to 8.04, P  = 0.345). The percentage of patients in the FAS population who reported pain relief at four hours post-dose was higher in the pooled sumatriptan group (63.5%) than in the placebo group (51.4%) but failed to achieve statistical significance ( P  = 0.142). At four hours post-dose, percentages of patients who were pain free or had complete relief of photophobia or phonophobia were numerically higher in the sumatriptan pooled group compared to placebo. Both doses of oral sumatriptan were well tolerated. No adverse events (AEs) were serious or led to study withdrawal. The most common AEs were somnolence in 6% (two patients) in the sumatriptan 25 mg treatment group and chest discomfort in 7% (three patients) in the sumatriptan 50 mg treatment group. There was no statistically significant improvement between the sumatriptan pooled group and the placebo group for pain relief at two hours. Oral sumatriptan was well tolerated.

Optimizing radiofrequency ablation of paroxysmal and persistent atrial fibrillation by direct catheter force measurement-a case-matched comparison in 198 patients.

PubMed

Sigmund, Elisabeth; Puererfellner, Helmut; Derndorfer, Michael; Kollias, Georgios; Winter, Siegmund; Aichinger, Josef; Nesser, Hans-Joachim; Martinek, Martin

2015-02-01

Sufficient electrode-tissue contact is crucial for adequate lesion formation in radiofrequency catheter ablation (RFCA). We assessed the impact of direct catheter force measurement on acute procedural parameters and outcome of RFCA for paroxysmal and persistent atrial fibrillation (AF). Ninety-nine consecutive patients (70% men) with paroxysmal (63.6%) or persistent AF underwent left atrial RFCA using a 3.5-mm open-irrigated-tip (OIT) catheter with contact force measurement capabilities (group 1). For comparison a case-matched cohort with standard OIT catheters was used (99 patients; group 2). Case matching included gender, type of AF, number or RFCA procedures, and type of procedure. Procedural data showed a significant decline in radiofrequency ablation time from 52 ± 20 to 44 ± 16 minutes (P = 0.003) with a remarkable mean reduction in overall procedure time of 34 minutes (P = 0.0001; 225.8 ± 53.1 vs 191.9 ± 53.3 minutes). In parallel, the total fluoroscopy time could be significantly reduced from 28.5 ± 11.0 to 19.9 ± 9.3 minutes (P = 0.0001) as well as fluoroscopy dose from 74.1 ± 58.0 to 56.7 ± 38.9 Gy/cm(2) (P = 0.016). Periprocedural complications were similar in both groups. The use of contact force sensing technology is able to significantly reduce ablation, procedure, and fluoroscopy times as well as dose in RFCA of AF in a mixed case-matched group of paroxysmal and persistent AF. Energy delivery is substantially reduced by avoiding radiofrequency ablation in positions with insufficient surface contact. Additionally 12-month outcome data showed increased efficacy. Such time saving and equally safe technology may have a relevant impact on laboratory management and increased cost effectiveness. © 2014 Wiley Periodicals, Inc.

Evaluation of a 99mTc-tricine Vascular Disrupting Agent as an In-vivo Imaging in 4T1 Mouse Breast Tumor Model

PubMed Central

Erfani, Mostafa; Shirmardi, Seyed Pezhman; Shafiei, Mohammad

2017-01-01

Colchicine as a vascular disrupting agent creates microtubule destabilization which induces vessel blockage and consequently cell death. Accordingly, colchicines and its analogues radiolabeled with 99mTc may have potential for visualization of tumor. In this work, deacetylcolchicine a colchicine analogue was labeled with 99mTc via tricine as a coligand and characterized for its tumor targeting properties. The in-vitro radiochemical stability and the biodistribution were studied in 4T1 breast tumor model bearing mice. Labeling yield of more than 90% was obtained corresponding to a specific activity of 46 MBq/µmol. In-vivo biodistribution studies demonstrated that radiocomplex had high tumor to muscle and tumor to blood ratios at early time points. Planer gamma imaging of tumor bearing mice showed that this radioconjugate was able to clearly visualize tumors. According to high tumor uptake, presented radiocomplex may have a potential for targeted imaging studies. PMID:29201088

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

Hahne, G.; Hoffmann, F.

A serious problem in the technology of plant cell culture is that isolated protoplasts from many species are reluctant to divide. We have succeeded in inducing consecutive divisions in a naturally arrested system i.e., protoplasts from a hibiscus cell line, which do not divide under standard conditions and in an artificially arrested system i.e., colchicine-inhibited callus protoplasts of Nicotiana glutinosa, which do readily divide in the absence of colchicine. In both cases, the reinstallation of a net of cortical microtubules, which had been affected either by colchicine or by the protoplast isolation procedure, resulted in continuous divisions of the formerlymore » arrested protoplasts. Several compounds known to support microtubule assembly in vitro were tested for their ability to promote microtubule assembly in vivo. Best results were obtained by addition of dimethyl sulfoxide to the culture medium. Unlimited amounts of callus could be produced with the dimethyl sulfoxide method from protoplasts which never developed a single callus in control experiments. 30 references, 3 figures.« less

Guidelines for the management and treatment of periodic fever syndromes familial Mediterranean fever.

PubMed

Terreri, Maria Teresa R A; Bernardo, Wanderley Marques; Len, Claudio Arnaldo; da Silva, Clovis Artur Almeida; de Magalhães, Cristina Medeiros Ribeiro; Sacchetti, Silvana B; Ferriani, Virgínia Paes Leme; Piotto, Daniela Gerent Petry; de Souza Cavalcanti, André; de Moraes, Ana Júlia Pantoja; Sztajnbok, Flavio Roberto; de Oliveira, Sheila Knupp Feitosa; Campos, Lucia Maria Arruda; Bandeira, Marcia; Santos, Flávia Patricia Sena Teixeira; Magalhães, Claudia Saad

2016-01-01

To establish guidelines based on scientific evidence for the management of familial Mediterranean fever. The Guideline was prepared from 5 clinical questions that were structured through PICO (Patient, Intervention or indicator, Comparison and Outcome), to search key primary scientific information databases. After defining the potential studies to support the recommendations, these were graduated considering their strength of evidence and grade of recommendation. 10,341 articles were retrieved and evaluated by title and abstract; from these, 46 articles were selected to support the recommendations. 1. The diagnosis of FMF is based on clinical manifestations, characterized by recurrent febrile episodes associated with abdominal pain, chest or arthritis of large joints. 2. FMF is a genetic disease presenting an autosomal recessive trait, caused by mutation in the MEFV gene. 3. Laboratory tests are not specific, demonstrating high serum levels of inflammatory proteins in the acute phase of the disease, but also often showing high levels even between attacks. SAA serum levels may be especially useful in monitoring the effectiveness of treatment. 4. The therapy of choice is colchicine; this drug has proven its effectiveness in preventing acute inflammatory episodes and progression toward amyloidosis in adults. 5. Based on the available information, the use of biological drugs appears to be an alternative for patients with FMF who do not respond or are intolerant to therapy with colchicine. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Quantitative analysis of microtubule orientation in interdigitated leaf pavement cells

PubMed Central

Akita, Kae; Higaki, Takumi; Kutsuna, Natsumaro; Hasezawa, Seiichiro

2015-01-01

Leaf pavement cells are shaped like a jigsaw puzzle in most dicotyledon species. Molecular genetic studies have identified several genes required for pavement cells morphogenesis and proposed that microtubules play crucial roles in the interdigitation of pavement cells. In this study, we performed quantitative analysis of cortical microtubule orientation in leaf pavement cells in Arabidopsis thaliana. We captured confocal images of cortical microtubules in cotyledon leaf epidermis expressing GFP-tubulinβ and quantitatively evaluated the microtubule orientations relative to the pavement cell growth axis using original image processing techniques. Our results showed that microtubules kept parallel orientations to the growth axis during pavement cell growth. In addition, we showed that immersion treatment of seed cotyledons in solutions containing tubulin polymerization and depolymerization inhibitors decreased pavement cell complexity. Treatment with oryzalin and colchicine inhibited the symmetric division of guard mother cells. PMID:26039484

Zampanolide Binding to Tubulin Indicates Cross-Talk of Taxane Site with Colchicine and Nucleotide Sites.

PubMed

Field, Jessica J; Pera, Benet; Gallego, Juan Estévez; Calvo, Enrique; Rodríguez-Salarichs, Javier; Sáez-Calvo, Gonzalo; Zuwerra, Didier; Jordi, Michel; Andreu, José M; Prota, Andrea E; Ménchon, Grégory; Miller, John H; Altmann, Karl-Heinz; Díaz, J Fernando

2018-03-23

The marine natural product zampanolide and analogues thereof constitute a new chemotype of taxoid site microtubule-stabilizing agents with a covalent mechanism of action. Zampanolide-ligated tubulin has the switch-activation loop (M-loop) in the assembly prone form and, thus, represents an assembly activated state of the protein. In this study, we have characterized the biochemical properties of the covalently modified, activated tubulin dimer, and we have determined the effect of zampanolide on tubulin association and the binding of tubulin ligands at other binding sites. Tubulin activation by zampanolide does not affect its longitudinal oligomerization but does alter its lateral association properties. The covalent binding of zampanolide to β-tubulin affects both the colchicine site, causing a change of the quantum yield of the bound ligand, and the exchangeable nucleotide binding site, reducing the affinity for the nucleotide. While these global effects do not change the binding affinity of 2-methoxy-5-(2,3,4-trimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MTC) (a reversible binder of the colchicine site), the binding affinity of a fluorescent analogue of GTP (Mant-GTP) at the nucleotide E-site is reduced from 12 ± 2 × 10 5 M -1 in the case of unmodified tubulin to 1.4 ± 0.3 × 10 5 M -1 in the case of the zampanolide tubulin adduct, indicating signal transmission between the taxane site and the colchicine and nucleotide sites of β-tubulin.

MRP1 and glucosylceramide are coordinately over expressed and enriched in rafts during multidrug resistance acquisition in colon cancer cells.

PubMed

Klappe, Karin; Hinrichs, John W J; Kroesen, Bart-Jan; Sietsma, Hannie; Kok, Jan Willem

2004-07-01

Previously we have described a novel multidrug-resistant cell line, HT29(col), which displayed over expression of the multidrug-resistance protein 1 (MRP1) and an altered sphingolipid composition, including enhanced levels of glucosylceramide (GlcCer; Kok JW, Veldman RJ, Klappe K, Koning H, Filipeanu C, Muller M. Int J Cancer 2000;87:172-8). In our study, long-term screening revealed that, during colchicine-induced acquisition of multidrug resistance in a new HT29(col) cell line, increases in GlcCer occurred concomitantly with upregulation of MRP1 expression. Both MRP1 and GlcCer were found enriched in Lubrol-insoluble membrane domains. The expression of MRP1 and GlcCer were tightly correlated, as indicated also by a reversal of both at the later stage of colchicine consolidation. Resistance to colchicine was determined by MRP1, while glucosylceramide synthase (GCS) did not contribute: 1). Resistance was fully inhibited by MK571. 2). GCS expression and activity were not upregulated in HT29(col) cells. 3). Inhibition of GCS did not affect MRP1-mediated efflux function or sensitivity to colchicine. Instead, overall sphingolipid metabolism was upregulated through an increased rate of ceramide biosynthesis. In conclusion, upregulation of MRP1 occurs in concert with upregulation of GlcCer during multidrug-resistance acquisition, and both are enriched in rafts. The increased GlcCer pool does not directly modulate MRP1 function and cell survival. Copyright 2004 Wiley-Liss, Inc.

Microtubule-dependent relocation of branchial V-H+-ATPase to the basolateral membrane in the Pacific spiny dogfish (Squalus acanthias): a role in base secretion.

PubMed

Tresguerres, Martin; Parks, Scott K; Katoh, Fumi; Goss, Greg G

2006-02-01

We have previously shown that continuous intravenous infusion of NaHCO3 for 24 h ( approximately 1000 micromol kg(-1) h(-1)) results in the relocation of V-H+-ATPase from the cytoplasm to the basolateral membrane in the gills of the Pacific dogfish. To further investigate this putative base-secretive process we performed similar experiments with the addition of colchicine, an inhibitor of cytoskeleton-dependent cellular trafficking processes. Blood pH and plasma total CO2 were significantly higher in the colchicines-treated, HCO3- -infused fish compared with fish infused with HCO3- alone. The effect of colchicine was highest after 24 h of infusion (8.33+/-0.06 vs 8.02+/-0.03 pH units, 15.72+/-3.29 vs 6.74+/-1.34 mmol CO2 l(-1), N=5). Immunohistochemistry and western blotting confirmed that colchicine blocked the transit of V-H+-ATPase to the basolateral membrane. Furthermore, western blotting analyses from whole gill and cell membrane samples suggest that the short-term (6 h) response to alkaline stress consists of relocation of V-H+-ATPases already present in the cell to the basolateral membrane, while in the longer term (24 h) there is both relocation of preexistent enzyme and upregulation in the synthesis of new units. Our results strongly suggest that cellular relocation of V-H+-ATPase is necessary for enhanced HCO3- secretion across the gills of the Pacific dogfish.

Surface dose measurements for highly oblique electron beams.

PubMed

Ostwald, P M; Kron, T

1996-08-01

Clinical applications of electrons may involve oblique incidence of beams, and although dose variations for angles up to 60 degrees from normal incidence are well documented, no results are available for highly oblique beams. Surface dose measurements in highly oblique beams were made using parallel-plate ion chambers and both standard LiF:Mg, Ti and carbon-loaded LiF Thermoluminescent Dosimeters (TLD). Obliquity factors (OBF) or surface dose at an oblique angle divided by the surface dose at perpendicular incidence, were obtained for electron energies between 4 and 20 MeV. Measurements were performed on a flat solid water phantom without a collimator at 100 cm SSD. Comparisons were also made to collimated beams. The OBFs of surface doses plotted against the angle of incidence increased to a maximum dose followed by a rapid dropoff in dose. The increase in OBF was more rapid for higher energies. The maximum OBF occurred at larger angles for higher-energy beams and ranged from 73 degrees for 4 MeV to 84 degrees for 20 MeV. At the dose maximum, OBFs were between 130% and 160% of direct beam doses, yielding surface doses of up to 150% of Dmax for the 20 MeV beam. At 2 mm depth the dose ratio was found to increase initially with angle and then decrease as Dmax moved closer to the surface. A higher maximum dose was measured at 2 mm depth than at the surface. A comparison of ion chamber types showed that a chamber with a small electrode spacing and large guard ring is required for oblique dose measurement. A semiempirical equation was used to model the dose increase at the surface with different energy electron beams.

Exercise as an augmentation treatment for nonremitted major depressive disorder: a randomized, parallel dose comparison.

PubMed

Trivedi, Madhukar H; Greer, Tracy L; Church, Timothy S; Carmody, Thomas J; Grannemann, Bruce D; Galper, Daniel I; Dunn, Andrea L; Earnest, Conrad P; Sunderajan, Prabha; Henley, Steven S; Blair, Steven N

2011-05-01

Most patients with major depressive disorder (MDD) require second-step treatments to achieve remission. The Treatment with Exercise Augmentation for Depression (TREAD) study was designed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment. Eligible participants in this randomized controlled trial were sedentary individuals (men and women aged 18-70 years) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor (SSRI) treatment. Participants were recruited through physician referrals and advertisements. A total of 126 participants were randomized to augmentation treatment with either 16 kcal per kg per week (KKW) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant. Supervised sessions were conducted at The Cooper Institute, Dallas, Texas, with additional home-based sessions as needed to fulfill the weekly exercise prescription. The primary outcome was remission (as determined by a score ≤ 12 on the Inventory of Depressive Symptomatology, Clinician-Rated). The study took place between August 2003 and August 2007. There were significant improvements over time for both groups combined (F₁,₁₂₁ = 39.9, P < .0001), without differential group effect (group effect: F₁,₁₃₄ = 3.2, P = .07; group-by-time effect: F₁,₁₁₉ = 3.8, P = .06). Adjusted remission rates at week 12 were 28.3% versus 15.5% for the 16-KKW and 4-KKW groups, respectively, leading to a number needed to treat (NNT) of 7.8 for 16 KKW versus 4 KKW. Men, regardless of family history of mental illness, and women without a family history of mental illness had higher remission rates by week 12 with higher-dose (women, 39.0%; men, 85.4%) than with lower-dose exercise (women, 5.6%; men, 0.1%) (women: t₉₅ = 2.1, P = .04; men: t₈₈ = 5.4, P < .0001) (NNT: women, 3.0; men, 1.2). There was a trend for higher remission rates in the higher-dose exercise group (P < .06), with a clinically meaningful NNT of 7.8 in favor of the high exercise dose. Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness. clinicaltrials.gov Identifier: NCT00076258. © Copyright 2011 Physicians Postgraduate Press, Inc.

Evaluation of growth hormone treatment efficacy in short Japanese children born small for gestational age: Five-year treatment outcome and impact on puberty

PubMed Central

Horikawa, Reiko; Tanaka, Toshiaki; Nishinaga, Hiromi; Ogawa, Yoshihisa; Yokoya, Susumu

2017-01-01

Abstract. Some children born small for gestational age (SGA) have short stature and are at an increased risk of developing psychosocial or behavioral problems. Here we evaluated the efficacy of GH and its effects on the timing of pubertal onset in a 3-yr extension of our previous 2-yr (total 5 yr) multicenter, randomized, double-blind, parallel-group clinical trial of 65 short Japanese children born SGA. Patients received low or high doses of GH (0.033 or 0.067 mg/kg/day, respectively). Age at onset of puberty was not statistically different for male and female patients receiving high- or low-dose GH. After the onset of puberty, no difference in height gain was observed between the two GH dose groups. At the onset of puberty, height standard deviation scores for chronological age of boys and girls improved significantly in both dose groups with evidence of a dose-response effect. Mean bone age/chronological age ratios in the low- and high-dose groups were significantly increased compared with baseline, being significantly greater in the high-dose group at 5 yr after treatment initiation. Delayed bone age at baseline was close to chronological age following GH treatment. GH treatment, especially high-dose GH, induced advanced bone age in short children born SGA. PMID:28458458

Vaccination response to tetanus toxoid and 23-valent pneumococcal vaccines following administration of a single dose of abatacept: a randomized, open-label, parallel group study in healthy subjects

PubMed Central

Tay, Lee; Leon, Francisco; Vratsanos, George; Raymond, Ralph; Corbo, Michael

2007-01-01

The effect of abatacept, a selective T-cell co-stimulation modulator, on vaccination has not been previously investigated. In this open-label, single-dose, randomized, parallel-group, controlled study, the effect of a single 750 mg infusion of abatacept on the antibody response to the intramuscular tetanus toxoid vaccine (primarily a memory response to a T-cell-dependent peptide antigen) and the intramuscular 23-valent pneumococcal vaccine (a less T-cell-dependent response to a polysaccharide antigen) was measured in 80 normal healthy volunteers. Subjects were uniformly randomized to receive one of four treatments: Group A (control group), subjects received vaccines on day 1 only; Group B, subjects received vaccines 2 weeks before abatacept; Group C, subjects received vaccines 2 weeks after abatacept; and Group D, subjects received vaccines 8 weeks after abatacept. Anti-tetanus and anti-pneumococcal (Danish serotypes 2, 6B, 8, 9V, 14, 19F and 23F) antibody titers were measured 14 and 28 days after vaccination. While there were no statistically significant differences between the dosing groups, geometric mean titers following tetanus or pneumococcal vaccination were generally lower in subjects who were vaccinated 2 weeks after receiving abatacept, compared with control subjects. A positive response (defined as a twofold increase in antibody titer from baseline) to tetanus vaccination at 28 days was seen, however, in ≥ 60% of subjects across all treatment groups versus 75% of control subjects. Similarly, over 70% of abatacept-treated subjects versus all control subjects (100%) responded to at least three pneumococcal serotypes, and approximately 25–30% of abatacept-treated subjects versus 45% of control subjects responded to at least six serotypes. PMID:17425783

Comparison of the IAEA TRS-398 and AAPM TG-51 absorbed dose to water protocols in the dosimetry of high-energy photon and electron beams

NASA Astrophysics Data System (ADS)

Saiful Huq, M.; Andreo, Pedro; Song, Haijun

2001-11-01

The International Atomic Energy Agency (IAEA TRS-398) and the American Association of Physicists in Medicine (AAPM TG-51) have published new protocols for the calibration of radiotherapy beams. These protocols are based on the use of an ionization chamber calibrated in terms of absorbed dose to water in a standards laboratory's reference quality beam. This paper compares the recommendations of the two protocols in two ways: (i) by analysing in detail the differences in the basic data included in the two protocols for photon and electron beam dosimetry and (ii) by performing measurements in clinical photon and electron beams and determining the absorbed dose to water following the recommendations of the two protocols. Measurements were made with two Farmer-type ionization chambers and three plane-parallel ionization chamber types in 6, 18 and 25 MV photon beams and 6, 8, 10, 12, 15 and 18 MeV electron beams. The Farmer-type chambers used were NE 2571 and PTW 30001, and the plane-parallel chambers were a Scanditronix-Wellhöfer NACP and Roos, and a PTW Markus chamber. For photon beams, the measured ratios TG-51/TRS-398 of absorbed dose to water Dw ranged between 0.997 and 1.001, with a mean value of 0.999. The ratios for the beam quality correction factors kQ were found to agree to within about +/-0.2% despite significant differences in the method of beam quality specification for photon beams and in the basic data entering into kQ. For electron beams, dose measurements were made using direct ND,w calibrations of cylindrical and plane-parallel chambers in a 60Co gamma-ray beam, as well as cross-calibrations of plane-parallel chambers in a high-energy electron beam. For the direct ND,w calibrations the ratios TG-51/TRS-398 of absorbed dose to water Dw were found to lie between 0.994 and 1.018 depending upon the chamber and electron beam energy used, with mean values of 0.996, 1.006, and 1.017, respectively, for the cylindrical, well-guarded and not well-guarded plane-parallel chambers. The Dw ratios measured for the cross-calibration procedures varied between 0.993 and 0.997. The largest discrepancies for electron beams between the two protocols arise from the use of different data for the perturbation correction factors pwall and pdis of cylindrical and plane-parallel chambers, all in 60Co. A detailed analysis of the reasons for the discrepancies is made which includes comparing the formalisms, correction factors and the quantities in the two protocols.

Local infiltration of the surgical wounds with levobupivacaine, dexibuprofen, and norepinephrine to reduce postoperative pain: A randomized, vehicle-controlled, and preclinical study.

PubMed

Gao, Zongwen; Cui, Feng; Cao, Xuemei; Wang, Dejun; Li, Xiao; Li, Tianzuo

2017-08-01

Postoperative pain may lead to poor wound healing, insomnia, and increased postoperative hospitalization. The objective of the study was to explore the effect of local infiltration of the surgical wound with levobupivacaine, dexibuprofen, and norepinephrine in postoperative pain. A randomized, parallel experimental design was applied in 40, 9-11-week-old Wister albino rats. A laparotomy was performed in all groups of 10 rats each. During surgery, the sutured muscle was infiltrated with 40μL of a normal saline (vehicle group), a normal saline containing 0.25% v/v levobupivacaine, 0.2mg/mL dexibuprofen, and 0.1mg/mL norepinephrine (treatment group) before skin closure. The same combination (negative control group) and a 10-fold higher dose (positive control group) were administered systematically. Rat Grimace Scale scores, based on facial expression, 24h after suturing of the tissues, histopathology and tensile strength of the surgical wound, two weeks after suturing of the tissues were measured. The one-way ANOVA and the two-tailed paired t-test/the Dunnett multiple comparisons test were used to compare the Rat Grimace Scale scores for pain within the group and between groups. The Kruskal-Wallis test and the one-way ANOVA/the Dunnett multiple comparisons test were used to compare the histopathology study and the tensile strength. The difference for statistical analysis was considered significant at the 95% of confidence level. The mean Rat Grimace Scale score at 24h for the treatment, negative control, and positive control groups was 1.945 (p=0.0025; q=3.257), 1.1 (p=0.1), and 1.95 (p=0.0021 q=3.547) respectively. The reduction in postoperative pain started within 1h after the suturing of the tissues in the treatment group. There were significant difference for epidermal and dermal regeneration (p=0.043), granulation tissue thickness (p=0.025), and angiogenesis (p=0.002) between treatment group and vehicle group. Tensile strength for the treatment group was 0.82±0.013N/cm 2 (p=0.003; q=5.231). The rapid infiltration of surgical wounds with a low-dose levobupivacaine, dexibuprofen, and norepinephrine may reduce postoperative pain and increase the wound regeneration process. Copyright © 2017. Published by Elsevier Masson SAS.

Preventive role of aluminosilicate clay against induction of micronuclei and chromosome aberrations in bone-marrow cells of Balb/c mice treated with Zearalenone.

PubMed

Abbès, Samir; Ouanes, Zouhour; Salah-Abbès, Jalila Ben; Abdel-Wahhab, Mosaad A; Oueslati, Ridha; Bacha, Hassen

2007-07-28

Zearalenone (ZEN) is a potent estrogenic metabolite produced by some Fusarium species. No treatment has been successfully employed to remove ZEN contamination in foods. This study was conducted to evaluate the ability of hydrated sodium calcium aluminosilicate (HSCAS) to protect Balb/c mice against cytotoxicity and genotoxicity induced by ZEN. HSCAS was given via the oral route, either alone or simultaneously with a toxic intra-gastric dose of ZEN. The experimental approach comprised treatments of seven groups of mice. The first three groups received 400, 600 or 800 mg/kg bw of HSCAS. Two experimental groups received, respectively, ZEN alone (40 mg/kg bw, representing 8% of the LD(50)) and ZEN in combination with HSCAS at 400 mg/kg bw. The two control groups received distilled water and olive oil, respectively. The positive control groups received colchicine (4 mg/kg bw) for the micronucleus assay and mitomycin C (1mg/kg bw) for the chromosome aberration test. Forty-eight hours after treatment, the femur and tibia were dissected out and analyzed. The results show that ZEN was cytotoxic and genotoxic to Balb/c mice, as indicated by the increase in the frequencies of micronucleated polychromatic erythrocytes (PCEMN) and of chromosomal aberrations in bone-marrow cells. The simultaneous intra-gastric administration of HSCAS with ZEN resulted in a reduction in the number of PCEMN and a decrease of the chromosomal aberration frequency, and an increase in the number of polychromatic erythrocytes (PCE) in bone-marrow cells, compared with those in the group treated with ZEN alone. It could be concluded that HSCAS itself was safe and efficient in the prevention of the toxic effects of ZEN in the gastrointestinal tract.

Rational design and synthesis of 2-anilinopyridinyl-benzothiazole Schiff bases as antimitotic agents.

PubMed

Shaik, Thokhir B; Hussaini, S M Ali; Nayak, V Lakshma; Sucharitha, M Lakshmi; Malik, M Shaheer; Kamal, Ahmed

2017-06-01

Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI 50 value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of the biological activity of the most common sublingual allergen solutions made by two European manufacturers.

PubMed

Mösges, Ralph; Pasch, Norbert; Schlierenkämper, Ulf; Lehmacher, Walter

2006-01-01

The clinical efficacy of sublingual immunotherapy has been documented in numerous studies and meta-analyses and is argued to be a favored alternative to the subcutaneous route if allergic symptoms are treated with a high-dose therapy. What is still lacking is a 'conversion rate' between the biological activities of different allergen solutions to determine the one with the higher concentration. A randomized, double-blind, parallel-group study was done with three groups sensitized to the allergens birch, grass or house dust mite via skin prick test. Staloral in the concentrations 10, 100 and 300 IR and SLITone in the concentration of 1,000 STU per milliliter were used for a computer-based comparison of the geometric mean wheal sizes of the different solutions. For each patient, individual regression curves led to the calculation of a mean corresponding IR value for the SLITone solution. A total of 47 patients took part in this clinical trial, most of whom were sensitized to more than one allergen. Values for birch (30 patients) showed that 1,000 STU corresponded to 77 IR, for grass (29 patients) 1,000 STU matched 78 IR and for house dust mite (30 patients) 1,000 STU matched 27 IR based on dose-response relationships. The Wilcoxon test showed that for all allergens the allergenic activity of the SLITone solution was significantly higher than the 10 IR solution and significantly lower than the 100- and 300-IR solutions. We established a conversion rate between the two leading sublingual allergen solutions on the European market to compare different units of measurement. Copyright (c) 2006 S. Karger AG, Basel.

Gastrointestinal adverse events during methylphenidate treatment of children and adolescents with attention deficit hyperactivity disorder: A systematic review with meta-analysis and Trial Sequential Analysis of randomised clinical trials

PubMed Central

Holmskov, Mathilde; Storebø, Ole Jakob; Moreira-Maia, Carlos R.; Ramstad, Erica; Magnusson, Frederik Løgstrup; Krogh, Helle B.; Groth, Camilla; Gillies, Donna; Zwi, Morris; Skoog, Maria; Gluud, Christian; Simonsen, Erik

2017-01-01

Objectives To study in more depth the relationship between type, dose, or duration of methylphenidate offered to children and adolescents with attention deficit hyperactivity disorder and their risks of gastrointestinal adverse events based on our Cochrane systematic review. Methods and findings We use data from our review including 185 randomised clinical trials. Randomised parallel-group trials and cross-over trials reporting gastrointestinal adverse events associated with methylphenidate were included. Data were extracted and quality assessed according to Cochrane guidelines. Data were summarised as risk ratios (RR) with 95% confidence intervals (CI) using the inverse variance method. Bias risks were assessed according to domains. Trial Sequential Analysis (TSA) was used to control random errors. Eighteen parallel group trials and 43 cross-over trials reported gastrointestinal adverse events. All trials were at high risk of bias. In parallel group trials, methylphenidate decreased appetite (RR 3.66, 95% CI 2.56 to 5.23) and weight (RR 3.89, 95% CI 1.43 to 10.59). In cross-over trials, methylphenidate increased abdominal pain (RR 1.61, 95% CI 1.27 to 2.04). We found no significant differences in the risk according to type, dose, or duration of administration. The required information size was achieved in three out of four outcomes. Conclusion Methylphenidate increases the risks of decreased appetite, weight loss, and abdominal pain in children and adolescents with attention deficit hyperactivity disorder. No differences in the risks of gastrointestinal adverse events according to type, dose, or duration of administration were found. PMID:28617801

The Acute Effect of Methylphenidate in Brazilian Male Children and Adolescents with ADHD: A Randomized Clinical Trial

ERIC Educational Resources Information Center

Szobot, C. M.; Ketzer, C.; Parente, M. A.; Biederman, J.; Rohde, L. A.

2004-01-01

Objective: To evaluate the acute efficacy of methylphenidate (MPH) in Brazilian male children and adolescents with ADHD. Method: In a 4-day, double-blind, placebo-controlled, randomized, fix dose escalating, parallel-group trial, 36 ADHD children and adolescents were allocated to two groups: MPH (n = 19) and placebo (n = 17). Participants were…

Method and apparatus for analyzing error conditions in a massively parallel computer system by identifying anomalous nodes within a communicator set

DOEpatents

Gooding, Thomas Michael [Rochester, MN

2011-04-19

An analytical mechanism for a massively parallel computer system automatically analyzes data retrieved from the system, and identifies nodes which exhibit anomalous behavior in comparison to their immediate neighbors. Preferably, anomalous behavior is determined by comparing call-return stack tracebacks for each node, grouping like nodes together, and identifying neighboring nodes which do not themselves belong to the group. A node, not itself in the group, having a large number of neighbors in the group, is a likely locality of error. The analyzer preferably presents this information to the user by sorting the neighbors according to number of adjoining members of the group.

Effects of Intravenous Patient-Controlled Sufentanil Analgesia and Music Therapy on Pain and Hemodynamics After Surgery for Lung Cancer: A Randomized Parallel Study.

PubMed

Wang, Yichun; Tang, Haoke; Guo, Qulian; Liu, Jingshi; Liu, Xiaohong; Luo, Junming; Yang, Wenqian

2015-11-01

Postoperative pain is caused by surgical injury and trauma; is stressful to patients; and includes a series of physiologic, psychological, and behavioral reactions. Effective postoperative analgesia helps improve postoperative pain, perioperative safety, and hospital discharge rates. This study aimed to observe the influence of postoperative intravenous sufentanil patient-controlled analgesia combined with music therapy versus sufentanil alone on hemodynamics and analgesia in patients with lung cancer. This was a randomized parallel study performed in 60 patients in American Society of Anesthesiologists class I or II undergoing lung cancer resection at the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University. Patients were randomly assigned to a music therapy (MT) group and a control (C) group. The MT group underwent preoperative and postoperative music intervention while the C group did not. Both groups received intravenous patient-controlled sufentanil analgesia. The primary outcome was the visual analogue scale (VAS) score at 24 hours after surgery. The secondary outcomes included hemodynamic changes (systolic blood pressure, diastolic blood pressure, heart rate), changes on the Self-Rating Anxiety Scale (SAS), total consumption of sufentanil, number of uses, sedation, and adverse effects. The postoperative sufentanil dose and analgesia frequency were recorded. Compared with the C group, the MT group had significantly lower VAS score, systolic and diastolic blood pressure, heart rate, and SAS score within 24 hours after surgery (p < 0.01). In addition, postoperative analgesia frequency and sufentanil dose were reduced in the MT group (p < 0.01). Combined music therapy and sufentanil improves intravenous patient-controlled analgesia effects compared with sufentanil alone after lung cancer surgery. Lower doses of sufentanil could be administered to more effectively improve patients' cardiovascular parameters.

The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial.

PubMed

Sharafaddinzadeh, Naser; Moghtaderi, Ali; Kashipazha, Davood; Majdinasab, Nastaran; Shalbafan, Bita

2010-08-01

Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire. A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups. Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study. The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

The impact of arm position on the measurement of orthostatic blood pressure.

PubMed

Guss, David A; Abdelnur, Diego; Hemingway, Thomas J

2008-05-01

Blood pressure is a standard vital sign in patients evaluated in an Emergency Department. The American Heart Association has recommended a preferred position of the arm and cuff when measuring blood pressure. There is no formal recommendation for arm position when measuring orthostatic blood pressure. The objective of this study was to assess the impact of different arm positions on the measurement of postural changes in blood pressure. This was a prospective, unblinded, convenience study involving Emergency Department patients with complaints unrelated to cardiovascular instability. Repeated blood pressure measurements were obtained using an automatic non-invasive device with each subject in a supine and standing position and with the arm parallel and perpendicular to the torso. Orthostatic hypotension was defined as a difference of >or= 20 mm Hg systolic or >or= 10 mm Hg diastolic when subtracting standing from supine measurements. There were four comparisons made: group W, arm perpendicular supine and standing; group X, arm parallel supine and standing; group Y, arm parallel supine and perpendicular standing; and group Z, arm perpendicular supine and parallel standing. There were 100 patients enrolled, 55 men, mean age 44 years. Four blood pressure measurements were obtained on each patient. The percentage of patients meeting orthostatic hypotension criteria in each group was: W systolic 6% (95% CI 1%, 11%), diastolic 4% (95% CI 0%, 8%), X systolic 8% (95% CI 3%, 13%), diastolic 9% (95% CI 3%, 13%), Y systolic 19% (95% CI 11%, 27%), diastolic 30% (95% CI 21%, 39%), Z systolic 2% (95% CI 0%, 5%), diastolic 2% (95% CI 0%, 5%). Comparison of Group Y vs. X, Z, and W was statistically significant (p < 0.0001). Arm position has a significant impact on determination of postural changes in blood pressure. The combination of the arm parallel when supine and perpendicular when standing may significantly overestimate the orthostatic change. Arm position should be held constant in supine and standing positions when assessing for orthostatic change in blood pressure.

Discovery and Optimization of Novel 5-Indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrile Derivatives as Potent Antitubulin Agents Targeting Colchicine-binding Site

NASA Astrophysics Data System (ADS)

Zhai, Xin; Wang, Xiaoqiang; Wang, Jiao; Liu, Jin; Zuo, Daiying; Jiang, Nan; Zeng, Tianfang; Yang, Xiuxiu; Jing, Tongfei; Gong, Ping

2017-02-01

Aiming at development of potent antitubulin agents targeting colchicine-binding site, a series of novel 5-indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrilederivatives (5a-5v and 7a-7h) were designed based on bioisosterism and hybridization strategies. All these compounds were concisely synthesized via a three-step process and examined against five human cancer cell lines (HT-29, A549, MKN-45, MDA-MB-231 and SMMC-7721) along with a normal human cell (L02) in vitro. A structure-activity relationships (SARs) study was carried out and optimization towards this series of compounds in cellular assay resulted in the discovery of 5k, which displayed similar or better antitumor potency against the tested cancer cells with IC50 value ranging from 0.02 to 1.22 μM superior to CA-4 and Crolibulin. Significantly, a cell cycle study disclosed the ability of 5k to arrest cell cycle at the G2/M phase, and immunofluorescence assay as well as a colchicine competition assay revealed that tubulin polymerization was disturbed by 5k by binding to the colchicine site. Moreover, the molecular modeling mode showed the posture of 5k and Crolibulin was similar in the colchcine-binding pocket of tubulin as identified with the SARs and pharmacological results. Together, all these results rationalized 5k might serve as a promising lead for a novel class of antitubulin agents for cancer treatments.

Characterization of Statin-Associated Myopathy Case Reports in Thailand Using the Health Product Vigilance Center Database.

PubMed

Boonmuang, Pornwalai; Nathisuwan, Surakit; Chaiyakunapruk, Nathorn; Suwankesawong, Wimon; Pokhagul, Pattreya; Teerawattanapong, Nattawat; Supsongserm, Pairin

2013-09-01

HMG-CoA reductase inhibitors [statins], a widely prescribed cholesterol-lowering therapy, are associated with muscle-related adverse events. While characteristics of such events are well documented in Western countries, little data exists for the Thai population. The aim of this study was to determine the characteristics of patients, type and dosing of statin, and to identify patterns of drug use that may be associated with such adverse events using the national pharmacovigilance database known as Thai Vigibase. Muscle-related adverse events involving statins in the Thai Vigibase from 1996 to December 2009 were identified. For each report, the following information was extracted: patient demographics, co-morbidities, detailed information of adverse event, detailed information of suspected drug, treatment and outcome, as well as causality assessment and quality of reports. Descriptive statistics were performed for all study variables. A total of 198 cases of statin-associated muscle-related adverse events were identified. Mean age was 61.4 ± 12.4 years of age and 59.6% were female. Simvastatin, atorvastatin, rosuvastatin and cerivastatin were implicated as the suspected drug in 163 (82.3%), 24 (12.1%), 10 (5.1%) and 1 (0.5%) cases, respectively. Rhabdomyolysis accounted for 55.6% of all muscle-related adverse events. Drug interactions known to enhance such toxicity of statins were identified in 40.9% of the total set of reports. Similar to studies from Western countries, fibrates, HIV protease inhibitors, non-dihydropyridine calcium channel blockers, azole antifungals and macrolides were commonly found in such cases. Interestingly, colchicine has been identified as the second most common drug interaction in our database. Case fatality rates were 0.9, 1.6 and 16.7%, when there were 0, 1 and ≥2 interacting drugs, respectively. Characteristics of muscle-related adverse events with statins in the Thai population showed some similarities and differences compared with Western countries. Such similarities included advanced age, female sex, certain co-morbidities and drug interactions. While the majority of interacting drugs are well known, a big proportion of cases of statin-colchicine interaction attributed to long-term use of colchicine in Thailand was noted and should be further investigated. Based on these results, an attempt to avoid dangerous and well-known drug interactions among statin users should be implemented nationwide.

Separating the Laparoscopic Camera Cord From the Monopolar "Bovie" Cord Reduces Unintended Thermal Injury From Antenna Coupling: A Randomized Controlled Trial.

PubMed

Robinson, Thomas N; Jones, Edward L; Dunn, Christina L; Dunne, Bruce; Johnson, Elizabeth; Townsend, Nicole T; Paniccia, Alessandro; Stiegmann, Greg V

2015-06-01

The monopolar "Bovie" is used in virtually every laparoscopic operation. The active electrode and its cord emit radiofrequency energy that couples (or transfers) to nearby conductive material without direct contact. This phenomenon is increased when the active electrode cord is oriented parallel to another wire/cord. The parallel orientation of the "Bovie" and laparoscopic camera cords cause transfer of energy to the camera cord resulting in cutaneous burns at the camera trocar incision. We hypothesized that separating the active electrode/camera cords would reduce thermal injury occurring at the camera trocar incision in comparison to parallel oriented active electrode/camera cords. In this prospective, blinded, randomized controlled trial, patients undergoing standardized laparoscopic cholecystectomy were randomized to separated active electrode/camera cords or parallel oriented active electrode/camera cords. The primary outcome variable was thermal injury determined by histology from skin biopsied at the camera trocar incision. Eighty-four patients participated. Baseline demographics were similar in the groups for age, sex, preoperative diagnosis, operative time, and blood loss. Thermal injury at the camera trocar incision was lower in the separated versus parallel group (31% vs 57%; P = 0.027). Separation of the laparoscopic camera cord from the active electrode cord decreases thermal injury from antenna coupling at the camera trocar incision in comparison to the parallel orientation of these cords. Therefore, parallel orientation of these cords (an arrangement promoted by integrated operating rooms) should be abandoned. The findings of this study should influence the operating room setup for all laparoscopic cases.

Comparison of cortisol exposures and pharmacodynamic adrenal steroid responses to hydrocortisone suspension vs. commercial tablets.

PubMed

Sarafoglou, Kyriakie; Gonzalez-Bolanos, Maria T; Zimmerman, Cheryl L; Boonstra, Timothy; Yaw Addo, O; Brundage, Richard

2015-04-01

The Endocrine Society Clinical Practice Guidelines on congenital adrenal hyperplasia (CAH) recommend against using hydrocortisone suspension based on a study that examined a commercial suspension. Our objective was to examine the absorption of an extemporaneously prepared hydrocortisone suspension and compare it to tablets. Secondary objectives were to evaluate the 17-hydroxyprogesterone and androstenedione adrenal steroid responses. Using a parallel design, 34 children diagnosed with CAH received either suspension (n = 9; median age 1.8 years) or tablets (n = 25; median age 7.5 years). Patients were given their usual morning hydrocortisone formulation and dose; 12 serial blood samples were obtained and the area under the curve (AUC) was calculated. The mg/m(2) dose-normalized cortisol AUCs were no different in the suspension and tablet groups (P = ·06), nor was there a significant difference in the C(max) or T(max) (P = .08 and P = .41, respectively). Although there were no differences in the 17-hydroxyprogesterone change-from-baseline AUCs, baseline concentrations, or the nadir concentrations when comparing suspension and tablet formulations, the androstenedione values were significantly lower as expected in the younger aged suspension group. Our results offer compelling evidence that an extemporaneously prepared hydrocortisone suspension provides comparable cortisol exposures to commercially available tablet formulations in children and can be used to safely and effectively treat CAH. © 2014, The American College of Clinical Pharmacology.

Hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site microtubule inhibitors with anti-leukemic activity

PubMed Central

TRIPATHI, ASHUTOSH; DURRANT, DAVID; LEE, RAY M.; BARUCHELLO, RICCARDO; ROMAGNOLI, ROMEO; SIMONI, DANIELE; KELLOGG, GLEN E.

2009-01-01

The crucial role of the microtubule in the cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin inhibitors that bind at the αβ-tubulin colchicine site. Computational docking along with HINT score analysis fitted these inhibitors into the colchicine site and revealed detailed structure-activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 μM) such that calculated and measured free energies of binding correlate with an r2 of 0.89 (standard error ± 0.85 kcal mol−1). This correlation suggests that the activity of unknown compounds may be predicted. PMID:19912057

Recurrent pericarditis: new and emerging therapeutic options.

PubMed

Imazio, Massimo; Lazaros, George; Brucato, Antonio; Gaita, Fiorenzo

2016-02-01

Recurrent pericarditis is one of the most common and troublesome complications after an episode of pericarditis, and affects 20-50% of patients treated for pericarditis. In most of these patients, the pericarditis remains idiopathic, although an immune-mediated (either autoimmune or autoinflammatory) pathogenesis is often presumed. The mainstay of therapy for recurrences is aspirin or NSAIDs, with the adjunct of colchicine. Corticosteroids are a second-line option to be considered for specific indications, such as connective tissue disease or pregnancy; contraindications or intolerance to aspirin, NSAIDs, and/or colchicine; or insufficient response to these medications. Furthermore, corticosteroids can be added to NSAIDs and colchicine in patients with persistent symptoms. In patients who do not respond adequately to any of these conventional therapies, alternative treatment options include azathioprine, intravenous human immunoglobulins, and anakinra. An improved understanding of how recurrent pericarditis develops after an initiating event is critical to prevent this complication, and further research is needed into the pathogenesis of recurrences. We discuss the aetiology and diagnosis of recurrent pericarditis, and extensively review the treatment options for this condition.

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

PubMed

Abbas, Richat; Hug, Bruce A; Leister, Cathie; Sonnichsen, Daryl

2012-07-01

Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

Hepatitis B virus-related mortality in rheumatoid arthritis patients undergoing long-term low-dose glucocorticoid treatment: A population-based study.

PubMed

Yang, Sheng-Shun; Hung, Chin-Tun; Li, Shu-Fen; Lee, Horng-Mo; Chung, Yueh-Chin; Chen, Hsin-Hua; Chang, Shu-Chuan

2017-09-04

Glucocorticoids (GC) are commonly used in rheumatoid arthritis (RA) patients which bears a risk of hepatitis B virus (HBV) reactivation. The purpose of this study was to investigate the risk of HBV-related mortality under long-term low-dose GCs in Taiwanese RA patients. We retrospectively analyzed 45,423 RA patients using National Health Insurance Research Database from January 1999 to December 2011. Of them, 2204 patients had the diagnosis of HBV and were classified into four groups according to GCs regimens. Outcome comparison by Cox model analysis for liver-related mortality was performed. In this cohort, 90.5% were older than 40. One hundred and five patients had been treated with short-term large-dose GCs (Group A); 862 patients received GCs ≥20 mg/day for ≥3 days or a variable dose but did not meet Group C criteria (Group B); 689 patients were continuously treated with low-dose (<20 mg/day) GCs for ≥3 months for at least one session (Group C); and 548 patients had never been exposed to GCs (Group D). Two hundred and sixty-one patients had been exposed to antiviral agents, which was significantly higher in Group C. Fifty-eight patients (2.63%) died of acute hepatic failure, while no statistically significant difference between each groups (p = 0.074). Groups C and D comparison by two-sample test showed that long-term low-dose GC treatment was not associated with liver-related death after adjusting for malignancy. Long-term low-dose GC treatment was not associated with liver-related mortality in RA with concomitant HBV patients probably due to commonly applied antiviral therapy by rheumatologists. Copyright © 2017. Published by Elsevier B.V.

Nizatidine versus placebo in active benign gastric ulcer disease: an eight-week, multicenter, randomized, double-blind comparison. The Nizatidine Benign Gastric Ulcer Disease Study Group.

PubMed

Cloud, M L; Enas, N; Offen, W W

1992-09-01

To determine if 150 mg nizatidine twice daily or 300 mg nizatidine at bedtime are similarly effective and to compare each dose with placebo in healing benign gastric ulcers and relieving peptic ulcer symptoms. This study was a randomized, double-blind, placebo-controlled parallel comparison. The study was conducted at 74 gastroenterology and internal medicine clinics in the United States and Canada. Four hundred fifty-six patients with active benign gastric ulcer documented by endoscopy participated in the study. On the basis of a computer-generated randomization list, patients were assigned sequentially to receive either 150 mg nizatidine twice daily (n = 151), 300 mg nizatidine once daily at bedtime and identically appearing placebo capsules in the morning (n = 153), or placebo capsules twice daily (n = 152). Treatment lasted for 8 weeks unless healing was documented by endoscopy after 4 weeks. Antacid tablets (aluminum hydroxide, magnesium hydroxide, simethicone combination) were supplied for relief of symptoms. Both doses of nizatidine significantly improved healing rates at 8 weeks compared with placebo. Daytime and nighttime symptom severity was improved by both nizatidine regimens at end point (p less than 0.015 versus placebo, two-tailed test). Antacid use was similar for all groups in the end point analysis. Patient well-being was significantly better in patients treated with nizatidine than in patients in the placebo group ((p less than 0.04, two-tailed test). No clinically significant differences in the incidence of adverse clinical or laboratory events were noted. Nizatidine, 300 mg at bedtime and 150 mg twice daily, resulted in greater healing of benign gastric ulcers than placebo treatment after 8 weeks. Relief of the symptoms of gastric ulcer was significantly better in the patients receiving nizatidine treatment versus placebo treatment.

SU-E-T-301: Dosimetric Comparison Between Adaptive and Rectilinear Template-Based Prostate Seed Implants

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

Sugar, E Neubauer; Buzurovic, I; O’Farrell, D

2015-06-15

Purpose: To compare the dosimetry of a standard rectilinear and an adaptive technique used in I125 prostate seed implants. Methods: To achieve favorable dosimetry in prostate implants we used adaptive needle updates to match actual positions in real-time. The seed locations were optimized based on actual needle locations. The seeds were delivered automatically with a robotic device seedSelectron™ (Elekta Brachytherapy). In this study, we evaluated the former approach against the standard rectilinear technique in which the needles have a parallel distribution. The treatment plans for 10 patients were analyzed. For comparison, the actual treatment plans were revised so each needlemore » was repositioned to its original parallel location through the template. The analysis was performed by comparing the target coverage and dose to the organs at risk. The comparison was done using the following planning goals: the target D90> 90%, V100% > 90%, V50% <70% and V200% <30%; the urethra V125% < 1cm3 and V150%= 0cm3; and the Rectum V100%<1cm3 and V69% < 8cm3. The prescription dose to the target was 145Gy. Results: The average target volume and number of seeds were 44.39cm3(SD=11.14) and 74(SD=12), respectively. The D90 for adaptive and rectilinear plans was 159.9Gy(SD=2.99) and 155.53Gy(SD=4.04) resulting in a 2.74% difference for the average target coverage. A similar difference (1.75%) was noticed in the target V100[%]. No significant difference was noticed in the dose to the urethra and rectum. All planning goals were met with both the adaptive and rectilinear approach for each plan. Conclusion: The study reveals enhanced coverage of the target when using the adaptive needle adjustments as compared to the rectilinear approach for the analyzed cases. However, the differences in dosimetry did not translate to meaningful clinical outcomes.« less

Anti-fibrotic effect of Cordyceps sinensis polysaccharide: Inhibiting HSC activation, TGF-β1/Smad signalling, MMPs and TIMPs.

PubMed

Peng, Jinghua; Li, Xuemei; Feng, Qin; Chen, Liang; Xu, Lili; Hu, Yiyang

2013-06-01

Cordyceps sinensis has been used to treat liver disease in traditional Chinese medicine for thousands of years. Polysaccharide extracted from cultured Cordyceps sinensis mycelia (CS-PS) is the major active components of cordyceps sinensis with anti-liver injury effects. In the present study, the effects of CS-PS on hepatic stellate cell (HSC) activation, transforming growth factor-β1 (TGF-β1)/Smad pathway, as well as matrix metalloproteinase (MMP) 2, MMP9 and tissue inhibitor of metalloproteinase (TIMP) 1, TIMP2, were investigated in liver fibrosis in rats induced by carbon tetrachloride (CCl4). Colchicine was used as a positive control. The effect of CS-PS inhibition liver injury and fibrosis was confirmed by decreasing serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, hepatic hydroxyproline and increasing serum albumin, as well as alleviation of histological changes, which was comparable to that of colchicine. With CS-PS treatment, hepatic α-smooth muscle actin, TGF-β1, TGF-β1 receptor (TβR)-I, TβR-II, p-Smad2, p-Smad3 and TIMP2 proteins expression were down-regulated comparing to that in CCl4 group. The activities of MMP2 and MMP9 in liver tissue were also inhibited in CS-PS-treated group. It is indicated that the effects of CS-PS anti-liver fibrosis are probably associated with the inhibition on HSC activation, TGF-β1/Smads signalling pathway, as well as MMP2, MMP9 activity and TIMP2 expression.

Did augmenting the VERB campaign advertising in select communities have an effect on awareness, attitudes, and physical activity?

PubMed

Berkowitz, Judy M; Huhman, Marian; Nolin, Mary Jo

2008-06-01

Although VERB was designed as a national media campaign, funding and donated media time enabled more-intensive advertising and marketing in certain communities. To investigate the effect of increased advertising on physical activity outcomes, six "high-dose" communities were selected to receive more hours of advertising and additional promotional activities. Longitudinal quasi-experimental design comparing outcomes in six communities that received additional VERB marketing activities with outcomes in a comparison group that received only the national dose of advertising. Two cohorts of dyads of youth aged 9-13 years (tweens) and one parent at baseline (2002), followed for 2 years. During the first year of the VERB campaign, each of the six high-dose communities received 50% more advertising and conducted special campaign activities. During the second year, only four of the six communities received the larger dose of advertising and additional promotional activities because of reduced funding. Awareness and understanding of VERB messages; attitudes about physical activity (self-efficacy, social influences, and outcome expectations); and physical activity behaviors. After 1 year, tweens in the high-dose communities reported higher levels of awareness and understanding of VERB and scored higher on the social influences scale than did tweens in a comparison group in areas that received only the national dose of advertising. After 2 years, tweens in the high-dose communities reported higher awareness and understanding of VERB, greater self-efficacy, more sessions of free-time physical activity per week, and were more active on the day before being surveyed than tweens in the comparison group who received the average national dose. Providing communities with a higher dose of marketing activities and sustaining those activities over time yields more positive outcomes.

Pharmacokinetics, safety, and tolerability of varenicline in healthy adolescent smokers: a multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

PubMed

Faessel, Helene; Ravva, Patanjali; Williams, Kathryn

2009-01-01

Varenicline is approved as an aid to smoking cessation in adults aged > or =18 years. The goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers. This multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12- to 16-year-old smokers (> or =3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (< or =55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling. The high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C(max) approximately 30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC(0-24), was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by > or =1 subject in any treatment group, > or =92% were mild in intensity. No subject discontinued the study because of an AE. Varenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (< or =55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.

Successive construction of cellulase hyperproducers of Trichoderma using hyperpolyploids.

PubMed

Toyama, H; Toyama, N

2000-01-01

When the swollen conidia of Trichoderma reesei QM 6a are treated with 0.1% (w/v) colchicine solution, huge autopolyploid nuclei can be formed in those swollen conidia. When a mycelial mat derived from such a conidum is treated with a haploidizing reagent, benomyl, many fan-shaped sectors are produced from the colony, and cellulase hyperproducers are selected from conidia on the colony. When colchicine and benomyl treatments are repeated on cellulase hyperproducers, new hyperproducers can be constructed successively and systematically. Moreover, when conidia derived from autopolyploids are treated with ethylmethanesulfonate solution, another type of cellulase hyperproducers (polyploids) can be obtained.

Comparison of a step-down dose of once-daily ciclesonide with a continued dose of twice-daily fluticasone propionate in maintaining control of asthma.

PubMed

Knox, A; Langan, J; Martinot, J-B; Gruss, C; Häfner, D

2007-10-01

To compare a step-down approach in well-controlled asthma patients, as recommended by treatment guidelines, from fluticasone propionate 250 microg twice daily (FP250 BID), or equivalent, to ciclesonide 160 microg once daily (CIC160 OD) with continued FP250 BID treatment. Patients with well-controlled asthma prior to study entry were included in two identical, randomized, double-blind, double-dummy, parallel-group studies. After a 2-week run-in period with FP250 BID, patients were randomized to CIC160 OD (n = 58) or FP250 BID (n = 53) for 12 weeks. Primary endpoints were percentage of days with asthma control, asthma symptom-free days, rescue medication-free days and nocturnal awakening-free days. Secondary endpoints included lung function variables, asthma symptom scores, rescue medication use and asthma exacerbations. Safety variables were also recorded. Patients had >or= 97% of days with asthma control, 98% asthma symptom-free days and 100% of days free from rescue medication use and nocturnal awakenings in both treatment groups (median values). There were no significant between-treatment differences for any of the primary or secondary efficacy variables. Overall, 42 treatment-emergent adverse events (TEAEs) were reported in the CIC160 OD group and 49 TEAEs were reported in the FP250 BID group. There were no clinically relevant changes from baseline in the safety variables in either treatment group. Patients well controlled on FP250 BID, or equivalent, who were stepped down to CIC160 OD, maintained similar asthma control compared with patients who received continued treatment standardized to FP250 BID.

Safety and Pharmacokinetics of Multiple 750-Milligram Doses of Intravenous Levofloxacin in Healthy Volunteers

PubMed Central

Chow, Andrew T.; Fowler, Cynthia; Williams, R. Rex; Morgan, Nancy; Kaminski, Susan; Natarajan, Jaya

2001-01-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation. PMID:11408234

Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers.

PubMed

Chow, A T; Fowler, C; Williams, R R; Morgan, N; Kaminski, S; Natarajan, J

2001-07-01

The safety and pharmacokinetics of a once-daily high intravenous dose of levofloxacin (750 mg) in 18 healthy volunteers were studied in a double-blind, randomized, placebo-controlled, single-center parallel group study. Levofloxacin was well tolerated, and higher maximum concentration of drug in serum and area under the concentration-time curve values were achieved. For difficult-to-treat infections, high daily doses of levofloxacin may be beneficial, and intravenous administration may be preferred in certain clinical settings, such as when treating patients in intensive care units, warranting further evaluation.

Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs.

PubMed

Bortolozzi, Roberta; Mattiuzzo, Elena; Dal Pra, Matteo; Sturlese, Mattia; Moro, Stefano; Hamel, Ernest; Carta, Davide; Viola, Giampietro; Ferlin, Maria Grazia

2018-01-01

Earlier studies had confirmed that the 7-phenylpyrroloquinolinone (7-PPyQ) nucleus was an important scaffold for new chemotherapeutic drugs targeting microtubules. For wide-ranging SARs, a series of derivatives were synthesized through a robust procedure. For comparison with the reference 3-ethyl-7-PPyQ 31, the angular geometry and substituents at the 3 and 7 positions were varied to explore interactions inside the colchicine site of tubulin. Of the new compounds synthesized, potent cytotoxicity (low and sub-nanomolar GI 50 values) was observed with 21 and 24, both more potent than 31, in both leukemic and solid tumor cell lines. Neither compound 21 nor 24 induced significant cell death in normal human lymphocytes, suggesting that the compounds may be selectively active against cancer cells. In particular, 24 was a potent inducer of apoptosis in the A549 and HeLa cell lines. With both compounds, induction of apoptosis was associated with dissipation of the mitochondrial transmembrane potential and production of reactive oxygen species, indicating that cells treated with the compounds followed the intrinsic pathway of apoptosis. Moreover, immunoblot analysis revealed that compound 24 even at 50 nM reduced the expression of anti-apoptotic proteins such as Bcl-2 and Mcl-1. Finally, molecular docking studies of the newly synthesized compounds demonstrate that active pyrroloquinolinone derivatives strongly bind in the colchicine site of β-tubulin. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Diazepam dose-dependently increases or decreases implicit priming of alcohol associations in problem drinkers.

PubMed

Zack, Martin; Poulos, Constantine X; Woodford, Tracy M

2006-01-01

Words denoting negative affect (NEG) have been found to prime alcohol-related words (ALC) on semantic priming tasks, and this effect is tied to severity of addiction. Previous research suggested that high doses of benzodiazepines may dampen NEG-ALC priming. The present study tested this possibility and the role of motivation for alcohol in this process. A placebo-controlled, double blind, between-within, counterbalanced design was employed. Two groups of male problem drinkers (n = 6/group) received a high (15-mg) or low (5-mg) dose of diazepam versus placebo on two identical test sessions. A lexical decision task assessed priming. Under placebo, significant NEG-->ALC priming emerged in each group. High-dose diazepam selectively reversed this effect, while low-dose selectively enhanced it. Correlations between NEG-->ALC priming and desire for alcohol provided further support that semantic priming of ALC concepts reflects a motivational process. The bi-directional effects found here parallel the effects of high- versus low-dose benzodiazepines on alcohol self-administration in animals. High-dose diazepam reduces prime-induced activation of ALC concepts in problem drinkers. Low-dose diazepam facilitates this process, and cross-priming of motivation for alcohol appears to explain this effect. Neurochemical modulation of the alcohol memory network may contribute to the motivational effects of benzodiazepines in problem drinkers.

Xyloglucan for the treatment of acute diarrhea: results of a randomized, controlled, open-label, parallel group, multicentre, national clinical trial.

PubMed

Gnessi, Lucio; Bacarea, Vladimir; Marusteri, Marius; Piqué, Núria

2015-10-30

There is a strong rationale for the use of agents with film-forming protective properties, like xyloglucan, for the treatment of acute diarrhea. However, few data from clinical trials are available. A randomized, controlled, open-label, parallel group, multicentre, clinical trial was performed to evaluate the efficacy and safety of xyloglucan, in comparison with diosmectite and Saccharomyces in adult patients with acute diarrhea due to different causes. Patients were randomized to receive a 3-day treatment. Symptoms (stools type, nausea, vomiting, abdominal pain and flatulence) were assessed by a self-administered ad-hoc questionnaire 1, 3, 6, 12, 24, 48 and 72 h following the first dose administration. Adverse events were also recorded. A total of 150 patients (69.3 % women and 30.7 % men, mean age 47.3 ± 14.7 years) were included (n = 50 in each group). A faster onset of action was observed in the xyloglucan group compared with the diosmectite and S. bouliardii groups. At 6 h xyloglucan produced a statistically significant higher decrease in the mean number of type 6 and 7 stools compared with diosmectite (p = 0.031). Xyloglucan was the most efficient treatment in reducing the percentage of patients with nausea throughout the study period, particularly during the first hours (from 26 % at baseline to 4 % after 6 and 12 h). An important improvement of vomiting was observed in all three treatment groups. Xyloglucan was more effective than diosmectite and S. bouliardii in reducing abdominal pain, with a constant improvement observed throughout the study. The clinical evolution of flatulence followed similar patterns in the three groups, with continuous improvement of the symptom. All treatments were well tolerated, without reported adverse events. Xyloglucan is a fast, efficacious and safe option for the treatment of acute diarrhea. EudraCT number 2014-001814-24 (date: 2014-04-28) ISRCTN number: 90311828.

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Comparison of single and combination diuretics on glucose tolerance (PATHWAY-3): protocol for a randomised double-blind trial in patients with essential hypertension.

PubMed

Brown, Morris J; Williams, Bryan; MacDonald, Thomas M; Caulfield, Mark; Cruickshank, J Kennedy; McInnes, Gordon; Sever, Peter; Webb, David J; Salsbury, Jackie; Morant, Steve; Ford, Ian

2015-08-07

Thiazide diuretics are associated with increased risk of diabetes mellitus. This risk may arise from K(+)-depletion. We hypothesised that a K(+)-sparing diuretic will improve glucose tolerance, and that combination of low-dose thiazide with K(+)-sparing diuretic will improve both blood pressure reduction and glucose tolerance, compared to a high-dose thiazide. This is a parallel-group, randomised, double-blind, multicentre trial, comparing hydrochlorothiazide 25-50 mg, amiloride 10-20 mg and combination of both diuretics at half these doses. A single-blind placebo run-in of 1 month is followed by 24 weeks of blinded active treatment. There is forced dose-doubling after 3 months. The Primary end point is the blood glucose 2 h after oral ingestion of a 75 g glucose drink (OGTT), following overnight fasting. The primary outcome is the difference between 2 h glucose at weeks 0, 12 and 24. Secondary outcomes include the changes in home systolic blood pressure (BP) and glycated haemoglobin and prediction of response by baseline plasma renin. Eligibility criteria are: age 18-79, systolic BP on permitted background treatment ≥ 140 mm Hg and home BP ≥ 130 mm Hg and one component of the metabolic syndrome additional to hypertension. Principal exclusions are diabetes, estimated-glomerular filtration rate <45 mL/min, abnormal plasma K(+), clinic SBP >200 mm Hg or DBP >120 mm Hg (box 2). The sample size calculation indicates that 486 patients will give 80% power at α=0.01 to detect a difference in means of 1 mmol/L (SD=2.2) between 2 h glucose on hydrochlorothiazide and comparators. PATHWAY-3 was approved by Cambridge South Ethics Committee, number 09/H035/19. The trial results will be published in a peer-reviewed scientific journal. Eudract number 2009-010068-41 and clinical trials registration number: NCT02351973. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Comparison of Levalbuterol and Racemic Albuterol Based on Cardiac Adverse Effects in Children

PubMed Central

Bio, Laura L.; Willey, Vincent J.; Poon, Cathy Y.

2011-01-01

OBJECTIVE To compare the cardiac effects of levalbuterol with those of racemic albuterol based on changes in heart rate (HR) in pediatric patients. METHODS The medical records of hospitalized children ages 1 month to 12 years, who received either levalbuterol or racemic albuterol via nebulizer for 3 consecutive doses between January 2006 and December 2008 were reviewed. The documented HR was collected prior to and after each administered dose of bronchodilator. The primary outcome was the largest percentage of change in HR between groups. Secondary outcomes of comparisons of the number of patients who had more than a 10% change in HR and incidence of tachycardia were included. RESULTS A total of 50 patients, 25 in each group, was included in the study. All patients in the racemic albuterol group received 2.5 mg per dose, while most of the patients in the levalbuterol group received 0.63 mg per dose (19 patients, 76%). Only 6 levalbuterol patients received a dose of 1.25 mg. Nineteen of 25 patients (76%) in the levalbuterol group were tachycardic prior to the first recorded dose compared to 15 patients (60%) in the racemic albuterol group (p = 0.36). The median of the largest percentage of change in HR was 4.1% (interquartile range [IQR], 1.8–8.7) in the levalbuterol group compared to 5% (IQR, 1.9–7.8) in the racemic albuterol group (p = 0.763). Four patients in the levalbuterol group experienced an HR increase of more than 10% compared to 5 patients in the racemic albuterol group (p = 1.0). CONCLUSION Levalbuterol and racemic albuterol bronchodilator therapies produced similar effects on HR. No clinically significant differences were detected in HR changes between the two treatment groups, despite administration of a larger equipotent albuterol dose in the racemic albuterol group than in the levalbuterol group. PMID:22479161

SU-E-T-783: Using Matrixx to Determine Transit Dose Contribution Over Clinically Useful Limits of HDR Source Activity

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

Bhagwat, M; O’Farrell, D; Wagar, M

2015-06-15

Purpose: Most HDR brachytherapy treatment planning systems (TPS) use TG-43 formalism to calculate dose without including transit dose corrections. Historically, measurement of this contribution has required sophisticated apparatus unavailable in most hospitals. We use Matrixx to investigate several scenarios where transit dose contribution may effect a clinical treatment. Methods: Treatment plans were generated using Oncentra Brachy TPS (Version 4.3.0.410, Nucletron ) on a CT scan of a 24-catheter Freiburg applicator (Nucletron ) laid flat on the MatriXX (IBA) detector. This detector is an array of 1020 parallel plate ion chambers. All 24 catheters were digitized and dwells within a centralmore » square region of 5×5cm of the applicator were activated. Each of the active catheters had 6 dwells in increments of 1.0cm. The plans were normalized to 10mm. This places the 100% isodose line at the correct effective point of measurement, which lies half-way between the parallel plates of the ion chambers. It is also within the clinically relevant treatment depth for superficial applications. A total of 6 plans were delivered for 3 prescription doses, 1Gy, 2Gy and 4Gy using source activities of 2.9Ci and 11.2Ci. The MatriXX array was operated to capture dosimetric snaps every 500ms and yielded an integral dose at the end of treatment. Results: A comparison of integral dose from 2 different source activities shows that the transit dose contribution is larger when the source activity is higher. It is also observed that the relative transit dose contribution decreases as prescription dose increases. This is quantified by the Gamma analysis. Conclusion: We have demonstrated that the Matrixx detector can be used to evaluate the contribution for a HDR source during transit from the HDR afterloader to a dwell location, and between adjacent dwell locations.« less

Periradicular Infiltration of the Cervical Spine: How New CT Scanner Techniques and Protocol Modifications Contribute to the Achievement of Low-Dose Interventions.

PubMed

Elsholtz, Fabian Henry Jürgen; Kamp, Julia Evi-Katrin; Vahldiek, Janis Lucas; Hamm, Bernd; Niehues, Stefan Markus

2018-06-18

 CT-guided periradicular infiltration of the cervical spine is an effective symptomatic treatment in patients with radiculopathy-associated pain syndromes. This study evaluates the robustness and safety of a low-dose protocol on a CT scanner with iterative reconstruction software.  A total of 183 patients who underwent periradicular infiltration therapy of the cervical spine were included in this study. 82 interventions were performed on a new CT scanner with a new intervention protocol using an iterative reconstruction algorithm. Spot scanning was implemented for planning and a basic low-dose setup of 80 kVp and 5 mAs was established during intermittent fluoroscopy. The comparison group included 101 prior interventions on a scanner without iterative reconstruction. The dose-length product (DLP), number of acquisitions, pain reduction on a numeric analog scale, and protocol changes to achieve a safe intervention were recorded.  The median DLP for the whole intervention was 24.3 mGy*cm in the comparison group and 1.8 mGy*cm in the study group. The median pain reduction was -3 in the study group and -2 in the comparison group. A 5 mAs increase in the tube current-time product was required in 5 patients of the study group.  Implementation of a new scanner and intervention protocol resulted in a 92.6 % dose reduction without a compromise in safety and pain relief. The dose needed here is more than 75 % lower than doses used for similar interventions in published studies. An increase of the tube current-time product was needed in only 6 % of interventions.   · The presented ultra-low-dose protocol allows for a significant dose reduction without compromising outcome.. · The protocol includes spot scanning for planning purposes and a basic setup of 80 kVp and 5 mAs.. · The iterative reconstruction algorithm is activated during fluoroscopy.. · Elsholtz FH, Kamp JE, Vahldiek JL et al. Periradicular Infiltration of the Cervical Spine: How New CT Scanner Techniques and Protocol Modifications Contribute to the Achievement of Low-Dose Interventions. Fortschr Röntgenstr 2018; DOI: 10.1055/a-0632-3930. © Georg Thieme Verlag KG Stuttgart · New York.

The influence of angiotensin converting enzyme inhibitors on lipid peroxidation in sera and aorta of rabbits in diet-induced hypercholesterolemia.

PubMed

Wojakowski, W; Gminski, J; Siemianowicz, K; Goss, M; Machalski, M

2000-11-01

In hypercholesterolemia increased lipid and lipoprotein peroxidation occurs. The renin-angiotensin system plays an important role in atherogenesis. Angiotensin II induces smooth muscle cells proliferation and stimulates oxidation of LDL particles and foam cell accumulation. Inhibition of ang II production leads to decrease in lipid peroxide production. The aim of this study was to assess the lipid peroxidation expressed as concentration of thiobarbituric acid reactive species (TBARS) in sera and aorta homogenates after administration of two doses of angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril and quinapril) in diet-induced hypercholesterolemia in rabbits. Sixty-four New Zealand rabbits were used. Animals were fed with standard fodder, special diet (1% cholesterol content) or special diet + tested ACEI. Two doses of ACE inhibitors were used: i), equivalent to applied to humans, ii), dose 10 times higher. The animals were divided into 8 groups: control, standard fodder; B, special diet; C1, C2, special diet + captopril in doses 2.5 and 25 mg/kg/24 h, respectively; E1, E2, special diet + enalapril in doses 0.75 and 7.5 mg/kg/24 h, respectively; Q1 and Q2, special diet + quinapril in doses 0.75 and 7.5 mg/kg per day, respectively. In cholesterol-fed rabbits and in groups receiving lower doses of tested ACE inhibitors, the serum TBARS concentration at 6 months was significantly higher in comparison to the control. The higher doses of enalapril, quinapril and captopril, prevented the cholesterol-induced rise in TBARS concentration. Lower dose of captopril attenuated the rise in TBARS concentration, it was significantly lower in comparison to group B, but higher than in the control group. In animals from groups B, E1, C1, Q1 TBARS concentration in aortae was significantly higher as compared to control group. Both doses of captopril and higher doses of enalapril and quinapril inhibited the rise of lipid peroxides concentration induced by cholesterol-rich diet.

Protocols for the dosimetry of high-energy photon and electron beams: a comparison of the IAEA TRS-398 and previous international Codes of Practice

NASA Astrophysics Data System (ADS)

Andreo, Pedro; Saiful Huq, M.; Westermark, Mathias; Song, Haijun; Tilikidis, Aris; DeWerd, Larry; Shortt, Ken

2002-09-01

A new international Code of Practice for radiotherapy dosimetry co-sponsored by several international organizations has been published by the IAEA, TRS-398. It is based on standards of absorbed dose to water, whereas previous protocols (TRS-381 and TRS-277) were based on air kerma standards. To estimate the changes in beam calibration caused by the introduction of TRS-398, a detailed experimental comparison of the dose determination in reference conditions in high-energy photon and electron beams has been made using the different IAEA protocols. A summary of the formulation and reference conditions in the various Codes of Practice, as well as of their basic data, is presented first. Accurate measurements have been made in 25 photon and electron beams from 10 clinical accelerators using 12 different cylindrical and plane-parallel chambers, and dose ratios under different conditions of TRS-398 to the other protocols determined. A strict step-by-step checklist was followed by the two participating clinical institutions to ascertain that the resulting calculations agreed within tenths of a per cent. The maximum differences found between TRS-398 and the previous Codes of Practice TRS-277 (2nd edn) and TRS-381 are of the order of 1.5-2.0%. TRS-398 yields absorbed doses larger than the previous protocols, around 1.0% for photons (TRS-277) and for electrons (TRS-381 and TRS-277) when plane-parallel chambers are cross-calibrated. For the Markus chamber, results show a very large variation, although a fortuitous cancellation of the old stopping powers with the ND,w/NK ratios makes the overall discrepancy between TRS-398 and TRS-277 in this case smaller than for well-guarded plane-parallel chambers. Chambers of the Roos-type with a 60Co ND,w calibration yield the maximum discrepancy in absorbed dose, which varies between 1.0% and 1.5% for TRS-381 and between 1.5% and 2.0% for TRS-277. Photon beam calibrations using directly measured or calculated TPR20,10 from a percentage dose data at SSD = 100 cm were found to be indistinguishable. Considering that approximately 0.8% of the differences between TRS-398 and the NK-based protocols are caused by the change to the new type of standards, the remaining difference in absolute dose is due either to a close similarity in basic data or to a fortuitous cancellation of the discrepancies in data and type of chamber calibration. It is emphasized that the NK-ND,air and ND,w formalisms have very similar uncertainty when the same criteria are used for both procedures. Arguments are provided in support of the recommendation for a change in reference dosimetry based on standards of absorbed dose to water.

[Met]- and [Leu]enkephalin-like immunoreactive cell bodies and nerve fibres in the coeliac ganglion of the cat.

PubMed

Julé, Y; Clerc, N; Niel, J P; Condamin, M

1986-06-01

The occurrence and distribution of methionine- and leucine-enkephalin-like immunoreactivity were investigated in the cat coeliac ganglion using either the indirect immunoperoxidase method or the peroxidase-antiperoxidase technique. Several antisera raised to methionine- and leucine-enkephalin were used. Their specificity was assessed by incubating sections of the coeliac ganglion with increasing dilutions of antisera and with antisera saturated with their respective antigen. The present study was performed both in untreated and in colchicine-treated cats. Immunoreactive methionine- and leucine-enkephalin-like cell bodies were only visualized in colchicine-treated cats. Two types of labeled cells were observed. The first type had a size similar to that of unlabeled principal ganglion cells. These labeled cells were numerous and scattered throughout the ganglion; they probably represented enkephalin-containing ganglion cells. The second type of immunoreactive cells were of a much smaller size. They were always gathered in small clusters of about 5-15 cells and were not numerous; they presumably represented enkephalin-containing small intensely fluorescent cells. Immunoreactive nerve fibres were mainly observed in untreated cats and accessorily in colchicine-treated cats. In untreated animals dense networks of methionine- and leucine-enkephalin-like immunoreactive fibres were found in the coeliac ganglion. These fibres had numerous varicosities which often closely surrounded unlabeled principal ganglion cells. In colchicine-treated cats some immunoreactive fibres surrounded labeled principal ganglion cell bodies. The present results establish for the first time the presence of enkephalin-like immunoreactive principal ganglion cells in a mammalian sympathetic prevertebral ganglion. The presence of enkephalin-containing principal ganglion cells, small intensely fluorescent cells and nerve terminals, supports an important role of enkephalins in the integrative synaptic activities of cat coeliac ganglion cells.

Synthesis and Turnover of Embryonic Sea Urchin Ciliary Proteins during Selective Inhibition of Tubulin Synthesis and Assembly

PubMed Central

Stephens, Raymond E.

1997-01-01

When ciliogenesis first occurs in sea urchin embryos, the major building block proteins, tubulin and dynein, exist in substantial pools, but most 9+2 architectural proteins must be synthesized de novo. Pulse-chase labeling with [3H]leucine demonstrates that these proteins are coordinately up-regulated in response to deciliation so that regeneration ensues and the tubulin and dynein pools are replenished. Protein labeling and incorporation into already-assembled cilia is high, indicating constitutive ciliary gene expression and steady-state turnover. To determine whether either the synthesis of tubulin or the size of its available pool is coupled to the synthesis or turnover of the other 9+2 proteins in some feedback manner, fully-ciliated mid- or late-gastrula stage Strongylocentrotus droebachiensis embryos were pulse labeled in the presence of colchicine or taxol at concentrations that block ciliary growth. As a consequence of tubulin autoregulation mediated by increased free tubulin, no labeling of ciliary tubulin occurred in colchicine-treated embryos. However, most other proteins were labeled and incorporated into steady-state cilia at near-control levels in the presence of colchicine or taxol. With taxol, tubulin was labeled as well. An axoneme-associated 78 kDa cognate of the molecular chaperone HSP70 correlated with length during regeneration; neither colchicine nor taxol influenced the association of this protein in steady-state cilia. These data indicate that 1) ciliary protein synthesis and turnover is independent of tubulin synthesis or tubulin pool size; 2) steady-state incorporation of labeled proteins cannot be due to formation or elongation of cilia; 3) substantial tubulin exchange takes place in fully-motile cilia; and 4) chaperone presence and association in steady-state cilia is independent of background ciliogenesis, tubulin synthesis, and tubulin assembly state. PMID:9362062

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

PubMed

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

2018-06-01

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

Low-dose vs standard-dose unfractionated heparin for percutaneous coronary intervention in acute coronary syndromes treated with fondaparinux: the FUTURA/OASIS-8 randomized trial.

PubMed

Steg, Philippe Gabriel; Jolly, Sanjit S; Mehta, Shamir R; Afzal, Rizwan; Xavier, Denis; Rupprecht, Hans-Jurgen; López-Sendón, Jose L; Budaj, Andrzej; Diaz, Rafael; Avezum, Alvaro; Widimsky, Petr; Rao, Sunil V; Chrolavicius, Susan; Meeks, Brandi; Joyner, Campbell; Pogue, Janice; Yusuf, Salim

2010-09-22

The optimal unfractionated heparin regimen for percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes treated with fondaparinux is uncertain. To compare the safety of 2 unfractionated heparin regimens during PCI in high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. Double-blind randomized parallel-group trial in 179 hospitals in 18 countries involving 2026 patients undergoing PCI within 72 hours, nested within a cohort of 3235 high-risk patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux enrolled from February 2009 to March 2010. Patients received intravenously either low-dose unfractionated heparin, 50 U/kg, regardless of use of glycoprotein IIb/IIIa (GpIIb-IIIa) inhibitors or standard-dose unfractionated heparin, 85 U/kg (60 U/kg with GpIIb-IIIa inhibitors), adjusted by blinded activated clotting time (ACT). Composite of major bleeding, minor bleeding, or major vascular access-site complications up to 48 hours after PCI. Key secondary outcomes include composite of major bleeding at 48 hours with death, myocardial infarction, or target vessel revascularization within day 30. The primary outcome occurred in 4.7% of those in the low-dose group vs 5.8% in the standard-dose group (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.54-1.19; P = .27). The rates of major bleeding were not different but the rates of minor bleeding were lower with 0.7% in the low-dose group vs 1.7% in the standard-dose group (OR, 0.40; 95% CI, 0.16-0.97; P = .04). For the key secondary outcome, the rates for low-dose group were 5.8% vs 3.9% in the standard-dose group (OR, 1.51; 95% CI, 1.00-2.28; P = .05) and for death, myocardial infarction, or target vessel revascularization it was 4.5% for the low-dose group vs 2.9% for the standard-dose group (OR, 1.58; 95% CI, 0.98-2.53; P = .06). Catheter thrombus rates were very low (0.5% in the low-dose group and 0.1% in the standard-dose group, P = .15). Low-dose compared with standard-dose unfractionated heparin did not reduce major peri-PCI bleeding and vascular access-site complications. clinicaltrials.gov Identifier: NCT00790907.

Experimental determination of the effective point of measurement of cylindrical ionization chambers for high-energy photon and electron beams.

PubMed

Huang, Yanxiao; Willomitzer, Christian; Zakaria, Golam Abu; Hartmann, Guenther H

2010-01-01

Measurements of depth-dose curves in water phantom using a cylindrical ionization chamber require that its effective point of measurement is located at the measuring depth. Recommendations for the position of the effective point of measurement with respect to the central axis valid for high-energy electron and photon beams are given in dosimetry protocols. According to these protocols, the use of a constant shift P(eff) is currently recommended. However, this is still based on a very limited set of experimental results. It is therefore expected that an improved knowledge of the exact position of the effective point of measurement will further improve the accuracy of dosimetry. Recent publications have revealed that the position of the effective point of measurement is indeed varying with beam energy, field size and also with chamber geometry. The aim of this study is to investigate whether the shift of P(eff) can be taken to be constant and independent from the beam energy. An experimental determination of the effective point of measurement is presented based on a comparison between cylindrical chambers and a plane-parallel chamber using conventional dosimetry equipment. For electron beams, the determination is based on the comparison of halfvalue depth R(50) between the cylindrical chamber of interest and a well guarded plane-parallel Roos chamber. For photon beams, the depth of dose maximum, d(max), the depth of 80% dose, d(80), and the dose parameter PDD(10) were used. It was again found that the effective point of measurement for both, electron and photon beams Dosimetry, depends on the beam energy. The deviation from a constant value remains very small for photons, whereas significant deviations were found for electrons. It is therefore concluded that use of a single upstream shift value from the centre of the cylindrical chamber as recommended in current dosimetry protocols is adequate for photons, however inadequate for accurate electron beam dosimetry.

SU-G-201-05: Comparison of Different Methods for Output Verification of Eleckta Nucletron’s Valencia Skin Applicators

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

Barrett, J; Yudelev, M

2016-06-15

Purpose: The provided output factors for Elekta Nucletron’s skin applicators are based on Monte Carlo simulations. These outputs have not been independently verified, and there is no recognized method for output verification of the vendor’s applicators. The purpose of this work is to validate the outputs provided by the vendor experimentally. Methods: Using a Flexitron Ir-192 HDR unit, three experimental methods were employed to determine dose with the 30 mm diameter Valencia applicator: first a gradient method using extrapolation ionization chamber (Far West Technology, EIC-1) measurements in solid water phantom at 3 mm SCD was used. The dose was derivedmore » based on first principles. Secondly a combination of a parallel plate chamber (Exradin A-10) and the EIC-1 was used to determine air kerma at 3 mm SCD. The air kerma was converted to dose to water in line with TG-61 formalism by using a muen ratio and a scatter factor measured with the skin applicators. Similarly a combination of the A-10 parallel plate chamber and gafchromic film (EBT 3) was also used. The Nk factor for the A-10 chamber was obtained through linear interpolation between ADCL supplied Nk factors for Cs-137 and M250. Results: EIC-1 measurements in solid water defined the outputs factor at 3 mm as 0.1343 cGy/U hr. The combination of A-10/ EIC-1 and A-10/EBT3 lead to output factors of 0.1383 and 0.1568 cGy/U hr, respectively. For comparison the output recommended by the vendor is 0.1659 cGy/U hr. Conclusion: All determined dose rates were lower than the vendor supplied values. The observed discrepancy between extrapolation chamber and film methods can be ascribed to extracameral gradient effects that may not be fully accounted for by the former method.« less

The Effects of Nanoparticles Containing Iron on Blood and Inflammatory Markers in Comparison to Ferrous Sulfate in Anemic Rats

PubMed Central

Shafie, Elaheh Honarkar; Keshavarz, Seyed Ali; Kefayati, Mohammad Esmaiel; Taheri, Fatemeh; Sarbakhsh, Parvin; Vafa, Mohammad Reza

2016-01-01

Background: Ferrous sulfate is the most used supplement for treating anemia, but it can result in unfavorable side effects. Nowadays, nanotechnology is used as a way to increase bioavailability and decrease the side effects of drugs and nutrients. This study investigates the effects of nanoparticles containing iron on blood and inflammatory markers in comparison to ferrous sulfate in anemic rats. Methods: To induce the model of hemolytic anemia, 50 mg/kg bw phenylhydrazine was injected intraperitoneally in rats on the 1st day and 25 mg/kg bw for the four following days. Then, rats were randomly divided into five groups. No material was added to the nipple of the Group 1 (control). Group 2 received 0.4 mg/day nanoparticles of iron; Group 3 received 0.4 mg/day ferrous sulfate, and Groups 4 and 5 received double dose of iron nanoparticle and ferrous sulfate, respectively for ten days. Results: Hemoglobin and red blood cell (RBC) in Group 2 were significantly higher than Group 3 (P < 0.05). In addition, hemoglobin and RBC in Group 4 and 5 were significantly higher than Group 3 (P < 0.05). The average level of serum iron in Groups 2 and 4 was remarkably more than the groups received ferrous sulfate with similar doses (P < 0.05). C-reactive protein in Group 3 was more than Group 2 and in Group 5 was more compare to all other groups. Conclusions: Single dose of nanoparticles had more bioavailability compare to ferrous sulfate, but this did not occur for the double dose. Furthermore, both doses of nanoparticles caused lower inflammation than ferrous sulfate. PMID:27857830

Weekly, low-dose docetaxel combined with estramustine for Japanese castration-resistant prostate cancer: its efficacy and safety profile compared with tri-weekly standard-dose treatment.

PubMed

Nakai, Yasutomo; Nishimura, Kazuo; Nakayama, Masashi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio; Tsujimura, Akira

2014-02-01

We retrospectively investigated the efficacy and safety profile of weekly low-dose docetaxel (DTX) with estramustine in comparison with triweekly standard-dose DTX treatment for Japanese patients with castration-resistant prostate cancer (CRPC). Between April 2002 and January 2011, 75 CRPC patients were treated with triweekly DTX (60-75 mg/m(2) every 3 weeks) (standard-dose group), and 76 CRPC patients were treated with weekly low-dose DTX (20-30 mg/m(2) on days 2 and 9 with estramustine 560 mg on days 1-3 and 8-10) every 3 weeks (low-dose group). Prostate-specific antigen (PSA) response and progression-free and overall survival were analyzed in each group. Median serum PSA level of the standard-dose group and low-dose group was 25.0 and 35.5 ng/ml, respectively. In the standard-dose and low-dose groups, 57.8 and 65.2 % of patients, respectively, achieved a PSA decline ≥ 50 %. There was no significant difference in either median time to progression between the standard-dose group (10.0 months) and low-dose group (7.1 months) or in median duration of survival between the standard-dose group (24.2 months) and low-dose group (30.6 months). Multivariate analysis with a Cox proportional hazards regression model showed that DTX treatment protocol did not influence the risk of death. Incidences of grade 3-4 neutropenia, febrile neutropenia, and thrombocytopenia were significantly higher in the standard-dose versus low-dose group (58.7 vs. 7.9 %, 16.0 vs. 3.9 %, and 8.0 vs. 0 %, respectively). For Japanese CRPC patients, weekly low-dose DTX combined with estramustine has similar efficacy to standard-dose DTX but with fewer adverse events.

Characteristics of a p-Si detector in high energy electron fields.

PubMed

Rikner, G

1985-01-01

Comparison of depth ionization distributions from a silicon semiconductor detector and depth dose curves from a plane parallel ionization chamber show that a semiconductor detector of p-type is well suited for relative electron dosimetry in the energy range of 6 to 20 MeV in Ep,0. Maximum deviations of the order of 1.5 per cent and of 1 mm were obtained down to a phantom depth of about 1 mm. The directional dependence of the detector was about 4 per cent.

A Comparison of Fospropofol to Midazolam for Moderate Sedation During Outpatient Dental Procedures

PubMed Central

Yen, Philip; Prior, Simon; Riley, Cara; Johnston, William; Smiley, Megann; Thikkurissy, Sarat

2013-01-01

Moderate intravenous (IV) sedation combined with local anesthesia is common for outpatient oral surgery procedures. An ideal sedative agent must be safe and well tolerated by patients and practitioners. This study evaluated fospropofol, a relatively new sedative/hypnotic, in comparison to midazolam, a commonly used benzodiazepine, for IV moderate sedation during oral and maxillofacial surgery. Sixty patients were randomly assigned to either the fospropofol or the midazolam group. Each participant received 1 μg/kg of fentanyl prior to administration of the selected sedative. Those in the fospropofol group received an initial dose of 6.5 mg/kg, with 1.6 mg/kg supplemental doses as needed. Those in the midazolam group received initial doses of 0.05 mg/kg, followed by 0.02 mg/kg supplemental doses. The quality of sedation in each patient was evaluated with regard to (a) onset of sedation, maintenance, and recovery profile; (b) patient and surgeon satisfaction; and (c) hemodynamic stability and adverse effects. The fospropofol group demonstrated shorter physical recovery times than midazolam patients, taking a mean of 11.6 minutes versus 18.4 minutes for physical recovery (P = .007). Cognitive recovery comparison did not find any difference with a mean of 7.5 minutes versus 8.8 minutes between the 2 drug groups (P = .123). The fospropofol group had a higher rate of local anesthetic injection recall (90.5 vs 44.4%, P = .004). Other parameters of recall were comparable. Two adverse effects demonstrated significance, with more patients in the midazolam group experiencing tachycardia (48.2 vs 9.4%, P = .001), and more patients in the fospropofol group experiencing perineal discomfort (40.6 vs 0, P < .001). No significant difference was found in any other measures of sedation safety, maintenance, or satisfaction. Fospropofol, when administered intravenously by a dentist anesthesiologist at the indicated dose in this study, appears to be a safe, well-tolerated alternative to midazolam for intravenous moderate sedation during minor oral surgery procedures. PMID:24423419

A comparison of sumanirole versus placebo or ropinirole for the treatment of patients with early Parkinson's disease.

PubMed

Singer, Carlos; Lamb, Janice; Ellis, Amanda; Layton, Gary

2007-03-15

To assess the safety and efficacy of sumanirole, a highly selective dopamine agonist, versus placebo and demonstrate its noninferiority to ropinirole, 614 patients with early Parkinson's disease (PD) were treated with sumanirole, 1 to 16 mg/day; ropinirole, 0.75 to 24 mg/day; or placebo. Primary end point in this flexible-dose, double-blind, double-dummy, parallel-group study of 40 weeks was the change in total sum of the United Parkinson's Disease Rating Scale (UPDRS) Parts II + III scores from baseline to end of maintenance. Approximately half the subjects in the sumanirole and placebo groups withdrew early from the study, most (51.8% and 68.5%, respectively) due to lack of efficacy. Of the ropinirole subjects who withdrew (50.5%), most discontinued because of adverse events. In sumanirole and ropinirole groups, mean changes from baseline of -2.48 and -5.20 in UPDRS II + III mean scores were significant versus 0.38 in the placebo group (P

Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controlled, outpatient study.

PubMed

Roth, Thomas; Krystal, Andrew; Steinberg, Frank J; Singh, Nikhilesh N; Moline, Margaret

2013-02-01

To evaluate efficacy and safety of 3.5-mg zolpidem tartrate sublingual tablets (ZST) on latency to sleep onset after middle-of-the-night (MOTN) awakenings in patients with insomnia characterized by difficulty returning to sleep after MOTN awakenings. Multicenter randomized, double-blind, placebo-controlled, parallel-group. Outpatient. There were 295 adults (median age 43 y; 68.1% female) with primary insomnia and difficulty returning to sleep after MOTN awakenings (three or more MOTN awakenings/wk during screening). After a 2-wk, single-blind placebo eligibility period, participants were randomized 1:1 to as-needed MOTN dosing with 3.5 mg ZST or placebo for 28 nights. An interactive voice response system determined if the study drug could be taken and recorded sleep/wake efficacy measures. ZST significantly (P < 0.0001) decreased latency to sleep onset over 4 wk (baseline 68.1 min; ZST 38.2 min) compared with placebo (baseline 69.4 min; placebo 56.4 min). Ratings of morning sleepiness/alertness significantly (P = 0.0041) favored the ZST group on nights medication was taken but not on other nights. Participants in the ZST group took the study drug on 62% of nights during the 4 wk; members of the placebo group took study medication on 64% of nights. Adverse events were generally mild and at the same rate (19.3% of participants) in both groups. There were no treatment-related serious adverse events (SAEs), and one adverse event-related study discontinuation from the placebo group. Dosing/week did not increase across the study. 3.5 mg ZST used as needed significantly reduced latency to return to sleep in comparison with placebo in these patients with insomnia. Sleep quality was improved, and morning sleepiness/alertness scores also improved. ZST was well tolerated. These data demonstrate the utility of a sleep-promoting agent when used as needed in the MOTN. NCT00466193: "A Study of Zolpidem Tartrate Tablet in Adult Patients with Insomnia" http://www.clinicaltrials.gov/ct2/show/NCT00466193?spons=%22Transcept+Pharmaceuticals%22&spons_ex=Y&rank=2

Effects of conventional vs high-dose rocuronium on the QTc interval during anesthesia induction and intubation in patients undergoing coronary artery surgery: a randomized, double-blind, parallel trial

PubMed Central

Öztürk, T.; Ağdanlı, D.; Bayturan, Ö.; Çıkrıkcı, C.; Keleş, G.T.

2015-01-01

Myocardial ischemia, as well as the induction agents used in anesthesia, may cause corrected QT interval (QTc) prolongation. The objective of this randomized, double-blind trial was to determine the effects of high- vs conventional-dose bolus rocuronium on QTc duration and the incidence of dysrhythmias following anesthesia induction and intubation. Fifty patients about to undergo coronary artery surgery were randomly allocated to receive conventional-dose (0.6 mg/kg, group C, n=25) or high-dose (1.2 mg/kg, group H, n=25) rocuronium after induction with etomidate and fentanyl. QTc, heart rate, and mean arterial pressure were recorded before induction (T0), after induction (T1), after rocuronium (just before laryngoscopy; T2), 2 min after intubation (T3), and 5 min after intubation (T4). The occurrence of dysrhythmias was recorded. In both groups, QTc was significantly longer at T3 than at baseline [475 vs 429 ms in group C (P=0.001), and 459 vs 434 ms in group H (P=0.005)]. The incidence of dysrhythmias in group C (28%) and in group H (24%) was similar. The QTc after high-dose rocuronium was not significantly longer than after conventional-dose rocuronium in patients about to undergo coronary artery surgery who were induced with etomidate and fentanyl. In both groups, compared with baseline, QTc was most prolonged at 2 min after intubation, suggesting that QTc prolongation may be due to the nociceptive stimulus of intubation. PMID:25714880

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

PubMed Central

Da, Chenxiao; Mooberry, Susan L.; Gupton, John T.; Kellogg, Glen E.

2013-01-01

αβ-tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q2 of 0.616, r2 of 0.949 and r2pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the ~3.6 Å available for αβ-tubulin. PMID:23961916

Interaction of phenylbutazone and colchicine in binding to serum albumin in rheumatoid therapy: 1H NMR study

NASA Astrophysics Data System (ADS)

Maciążek-Jurczyk, M.; Sułkowska, A.; Bojko, B.; Równicka-Zubik, J.; Sułkowski, W. W.

2009-09-01

The monitoring of drug concentration in blood serum is necessary in multi-drug therapy. Mechanism of drug binding with serum albumin (SA) is one of the most important factors which determine drug concentration and its transport to the destination tissues. In rheumatoid diseases drugs which can induce various adverse effects are commonly used in combination therapy. Such proceeding may result in the enhancement of those side effects due to drug interaction. Interaction of phenylbutazone and colchicine in binding to serum albumin and competition between them in gout has been studied by proton nuclear magnetic resonance ( 1H NMR) technique. The aim of the study was to determine the low affinity binding sites, the strength and kind of interaction between serum albumin and drugs used in combination therapy. The study of competition between phenylbutazone and colchicine in binding to serum albumin points to the change of their affinity to serum albumin in the ternary systems. This should be taken into account in multi-drug therapy. This work is a subsequent part of the spectroscopic study on Phe-COL-SA interactions [A. Sułkowska, et al., J. Mol. Struct. 881 (2008) 97-106].

Synthesis and biological evaluation of pyrimidine bridged combretastatin derivatives as potential anticancer agents and mechanistic studies.

PubMed

Kumar, Bhupinder; Sharma, Praveen; Gupta, Vivek Prakash; Khullar, Madhu; Singh, Sandeep; Dogra, Nilambra; Kumar, Vinod

2018-08-01

A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC 50 values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC 50 values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket. Copyright © 2018 Elsevier Inc. All rights reserved.

Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents

PubMed Central

Chen, Jianjun; Wang, Zhao; Li, Chien-Ming; Lu, Yan; Vaddady, Pavan K.; Meibohm, Bernd; Dalton, James T.; Miller, Duane D.; Li, Wei

2010-01-01

A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4-carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl-thiazoles (SMART). The average IC50 of the most active compound (5da) was 15.7 nM. ABI analogs have substantially improved aqueous solubility (48.9 μg/mL for 5ga vs. 0.909 μg/mL for SMART-1, 0.137 μg/mL for paclitaxel, and 1.04 μg/mL for Combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogs is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors. PMID:20919720

Aircraft crew radiation workplaces: comparison of measured and calculated ambient dose equivalent rate data using the EURADOS in-flight radiation data base.

PubMed

Beck, Peter; Bartlett, David; Lindborg, Lennart; McAulay, Ian; Schnuer, Klaus; Schraube, Hans; Spurny, Frantisek

2006-01-01

In May 2000, the chairman of the European Radiation Dosimetry Group (EURADOS) invited a number of experts with experience of cosmic radiation dosimetry to form a working group (WG 5) on aircraft crew dosimetry. Three observers from the Article 31 Group of Experts as well as one observer from the Joint Aviation Authorities (JAA) were also appointed. The European Commission funded the meetings. Full meetings were organised in January 2001 and in November 2001. An editorial group, who are the authors of this publication, started late in 2002 to finalise a draft report, which was submitted to the Article 31 Group of Experts in June 2003. The methods and data reported are the product of the work of 26 research institutes from the EU, USA and Canada. Some of the work was supported by contracts with the European Commission, Directorate General XII, Science, Research and Development. A first overview of the EC report was published late in 2004. In this publication we focus on a comparison of measured and calculated ambient dose rate data using the EURADOS In-Flight Data Base. The evaluation of results obtained by different methods and groups, and comparison of measurement results and the results of calculations were performed in terms of the operational quantity ambient dose equivalent, H*(10). Aspects of measurement uncertainty are reported also. The paper discusses the estimation of annual doses for given flight hours and gives an outline of further research needed in the field of aircraft crew dosimetry, such as the influence of solar particle events.

Efficacy of Continuous Dosing of Tadalafil Once Daily vs Tadalafil On Demand in Clinical Subgroups of Men With Erectile Dysfunction: A Descriptive Comparison Using the Integrated Tadalafil Databases.

PubMed

Brock, Gerald; Ni, Xiao; Oelke, Matthias; Mulhall, John; Rosenberg, Matt; Seftel, Allen; D'Souza, Deborah; Barry, Jane

2016-05-01

Various factors play a role in the development of erectile dysfunction (ED). To provide a descriptive comparison of erectile function response for tadalafil on-demand (PRN) and once-daily (OAD) dosing regimens in patients with common comorbid conditions, treatments, or risk factors that can be considered when treating ED. In total, 17 PRN and 4 OAD placebo-controlled studies were included in the integrated database in these pooled analyses. Data were analyzed from patients treated with placebo, tadalafil 10 mg (low dose), and 20 mg (high dose) for the PRN studies and placebo, tadalafil 2.5 mg (low dose), and 5 mg (high dose) for the OAD studies. The effects of tadalafil were measured using the International Index of Erectile Function administered from baseline to week 12. A descriptive comparison of the efficacy of tadalafil PRN vs OAD was examined in the clinical populations. Baseline characteristics of 4,354 men were comparable between the PRN and OAD groups, with differences seen only in the variables of race, body mass index (BMI) of at least 30 kg/m(2), and alcohol use. Tadalafil was efficacious at improving erectile function for all clinical populations, except for the low-dose OAD group, which demonstrated a weaker effect vs placebo than the high-dose OAD group, and the low- and high-dose PRN groups vs placebo for patients with BMI of at least 30 kg/m(2) for patients without a cardiovascular disorder, smokers, patients with ED duration shorter than 1 year, and patients without previous phosphodiesterase type 5 inhibitor use. Tadalafil was efficacious for patients with or without diabetes mellitus, arterial hypertension, hyperlipidemia, and alcohol use at baseline. Tadalafil OAD and PRN regimens showed efficacy in patients with ED. No clinical populations of patients with ED seemed to benefit overwhelmingly from one dose regimen over the other. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

PubMed

Sellers, Edward M; Schoedel, Kerri; Bartlett, Cindy; Romach, Myroslava; Russo, Ethan B; Stott, Colin G; Wright, Stephen; White, Linda; Duncombe, Paul; Chen, Chien-Feng

2013-07-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. © The Author(s) 2013.

An Open Label, Randomized, Comparative, Parallel Group, Multicenter, Prospective, Interventional, Clinical Study to Evaluate Efficacy and Safety of "AHPL/AYTOP/0113" in Comparison with "Framycetin Sulphate Cream" in Acute Wounds.

PubMed

Nipanikar, Sanjay U; Gajare, Kamalakar V; Vaidya, Vidyadhar G; Kamthe, Amol B; Upasani, Sachin A; Kumbhar, Vidyadhar S

2017-01-01

The main objective of the present study was to assess efficacy and safety of AHPL/AYTOP/0113 cream, a polyherbal formulation in comparison with Framycetin sulphate cream in acute wounds. It was an open label, randomized, comparative, parallel group and multi-center clinical study. Total 47 subjects were randomly assigned to Group-A (AHPL/AYTOP/0113 cream) and 42 subjects were randomly assigned to Group-B (Framycetin sulphate cream). All the subjects were advised to apply study drug, thrice daily for 21 days or up to complete wound healing (whichever was earlier). All the subjects were called for follow up on days 2, 4, 7, 10, 14, 17 and 21 or up to the day of complete wound healing. Data describing quantitative measures are expressed as mean ± SD. Comparison of variables representing categorical data was performed using Chi-square test. Group-A subjects took significantly less ( P < 0.05) i.e., (mean) 7.77 days than (mean) 9.87 days of Group-B subjects for wound healing. At the end of the study, statistically significant better ( P < 0.05) results were observed in Group-A than Group-B in mean wound surface area, wound healing parameters and pain associated with wound. Excellent overall efficacy and tolerability was observed in subjects of both the groups. No adverse event or adverse drug reaction was noted in any subject of both the groups. AHPL/AYTOP/0113 cream proved to be superior to Framycetin sulphate cream in healing of acute wounds.

The efficacy of low dose azathioprine/6-mercaptopurine in patients with inflammatory bowel disease.

PubMed

Kim, Dong Uk; Kim, Young-Ho; Kim, Beom Jin; Chang, Dong Kyung; Son, Hee Jung; Rhee, Poong-Lyul; Kim, Jae J; Rhee, Jong Chul

2009-01-01

Azathioprine (AZA) and 6-mercaptopurine (6-MP) have been widely used in patients with ulcerative colitis (UC) and Crohn's disease (CD). However, some patients cannot tolerate standard doses (2-2.5 mg/kg for AZA or 1-1.5 mg/kg for 6-MP) due to side effects such as leukopenialneutropenia. The aim of this study was to evaluate the efficacy of low dose AZA/6-MP compared to the standard dose. From 1995 to 2005, 122 patients with UC or CD treated with AZA/6-MP at Samsung Medical Center in Korea were enrolled. We divided these patients into 2 groups (standard dose group versus low dose group) according to the maintenance dose. Among the 122 patients, 17 received the standard dose and 105 received a low dose. The mean maintenance doses were 2.25 mg/kg for the standard dose group and 1.35mg/kg for the low dose group. The clinical outcomes of remission induction, maintenance of remission and relapse rate showed no significant difference in comparisons between these two groups. Low dose AZA/6-MP was as effective as the standard dose for remission induction and maintenance of remission in patients with UC and CD. For patients that develop leukopenia/neutropenia during dose escalation, maintenance therapy with low dose AZA/6-MP should be considered.

Build-up and surface dose measurements on phantoms using micro-MOSFET in 6 and 10 MV x-ray beams and comparisons with Monte Carlo calculations.

PubMed

Xiang, Hong F; Song, Jun S; Chin, David W H; Cormack, Robert A; Tishler, Roy B; Makrigiorgos, G Mike; Court, Laurence E; Chin, Lee M

2007-04-01

This work is intended to investigate the application and accuracy of micro-MOSFET for superficial dose measurement under clinically used MV x-ray beams. Dose response of micro-MOSFET in the build-up region and on surface under MV x-ray beams were measured and compared to Monte Carlo calculations. First, percentage-depth-doses were measured with micro-MOSFET under 6 and 10 MV beams of normal incidence onto a flat solid water phantom. Micro-MOSFET data were compared with the measurements from a parallel plate ionization chamber and Monte Carlo dose calculation in the build-up region. Then, percentage-depth-doses were measured for oblique beams at 0 degrees-80 degrees onto the flat solid water phantom with micro-MOSFET placed at depths of 2 cm, 1 cm, and 2 mm below the surface. Measurements were compared to Monte Carlo calculations under these settings. Finally, measurements were performed with micro-MOSFET embedded in the first 1 mm layer of bolus placed on a flat phantom and a curved phantom of semi-cylindrical shape. Results were compared to superficial dose calculated from Monte Carlo for a 2 mm thin layer that extends from the surface to a depth of 2 mm. Results were (1) Comparison of measurements with MC calculation in the build-up region showed that micro-MOSFET has a water-equivalence thickness (WET) of 0.87 mm for 6 MV beam and 0.99 mm for 10 MV beam from the flat side, and a WET of 0.72 mm for 6 MV beam and 0.76 mm for 10 MV beam from the epoxy side. (2) For normal beam incidences, percentage depth dose agree within 3%-5% among micro-MOSFET measurements, parallel-plate ionization chamber measurements, and MC calculations. (3) For oblique incidence on the flat phantom with micro-MOSFET placed at depths of 2 cm, 1 cm, and 2 mm, measurements were consistent with MC calculations within a typical uncertainty of 3%-5%. (4) For oblique incidence on the flat phantom and a curved-surface phantom, measurements with micro-MOSFET placed at 1.0 mm agrees with the MC calculation within 6%, including uncertainties of micro-MOSFET measurements of 2%-3% (1 standard deviation), MOSFET angular dependence of 3.0%-3.5%, and 1%-2% systematical error due to phantom setup geometry asymmetry. Micro-MOSFET can be used for skin dose measurements in 6 and 10 MV beams with an estimated accuracy of +/- 6%.

Ten-day quadruple therapy comprising low-dose rabeprazole, bismuth, amoxicillin and tetracycline is an effective and safe first-line treatment for Helicobacter pylori infection in population with high antibiotic resistance: a prospective, multicenter, randomized, parallel-controlled clinical trial in China.

PubMed

Xie, Yong; Zhu, Zhenhua; Wang, Jiangbin; Zhang, Lingxia; Zhang, Zhenyu; Lu, Hong; Zeng, Zhirong; Chen, Shiyao; Liu, Dongsheng; Lv, Nonghua

2018-06-18

Objectives: To investigate the efficacy and safety of 10-day bismuth quadruple therapy with amoxicillin, tetracycline or clarithromycin and different doses of rabeprazole for first-line treatment of Helicobacter pylori infection. Methods: This multicenter, randomized, parallel-controlled clinical trial was conducted between March 2013 and August 2014. A total of 431 H. pylori -infected patients with duodenal ulcers were enrolled and randomized into four treatment groups (1:1:1:1) for 10 days: 1. LR-BAC Group, which received rabeprazole 10 mg b.i.d., bismuth, amoxicillin and clarithromycin; 2. LR-BAT Group, which received rabeprazole 10mg b.i.d., bismuth, amoxicillin and tetracycline; 3. HR-BAC Group, which received rabeprazole 20 mg b.i.d., and bismuth, amoxicillin and clarithromycin; and 4. HR-BAT Group, which received rabeprazole 20 mg b.i.d., bismuth, amoxicillin, tetracycline. Antimicrobial susceptibility was assessed by the E-test method. The primary outcome was H. pylori eradication at 4 weeks after the treatment. Results: The per-protocol (PP) eradication rates in the LR-BAC, LR-BAT, HR-BAC, and HR-BAT groups were 94.1%, 91.9%, 94.8% and 91.9%, respectively, while the intention-to-treat (ITT) eradication rates in those groups were 87.2%, 87.2%, 87.7% and 86%, respectively. There was no significant difference between four groups in PP analysis( P =0.799) and ITT analysis( P =0.985). The efficacies of four treatment therapy were not affected by antibiotics resistance. The adverse events in four treatment groups were similar, CNS and gastrointestinal symptoms were the most common reported. Conclusions: Bismuth-containing quadruple therapy with low-dose rabeprazole, amoxicillin and tetracycline is a good option for first-line treatment of H. pylori infection in population with high antibiotic resistance. Copyright © 2018 Xie et al.

A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, FIXED-DOSE PHASE III STUDY OF VILAZODONE IN PATIENTS WITH GENERALIZED ANXIETY DISORDER

PubMed Central

Gommoll, Carl; Durgam, Suresh; Mathews, Maju; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Thase, Michael E

2015-01-01

Background Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). Methods A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. Results The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (–1.80 [–3.26, –0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. Conclusions Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified. PMID:25891440

A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder.

PubMed

Gommoll, Carl; Durgam, Suresh; Mathews, Maju; Forero, Giovanna; Nunez, Rene; Tang, Xiongwen; Thase, Michael E

2015-06-01

Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist, is approved for treating major depressive disorder in adults. This study (NCT01629966 ClinicalTrials.gov) evaluated the efficacy and safety of vilazodone in adults with generalized anxiety disorder (GAD). A multicenter, double-blind, parallel-group, placebo-controlled, fixed-dose study in patients with GAD randomized (1:1:1) to placebo (n = 223), or vilazodone 20 mg/day (n = 230) or 40 mg/day (n = 227). Primary and secondary efficacy parameters were total score change from baseline to week 8 on the Hamilton Rating Scale for Anxiety (HAMA) and Sheehan Disability Scale (SDS), respectively, analyzed using a predefined mixed-effect model for repeated measures (MMRM). Safety outcomes were presented by descriptive statistics. The least squares mean difference (95% confidence interval) in HAMA total score change from baseline (MMRM) was statistically significant for vilazodone 40 mg/day versus placebo (-1.80 [-3.26, -0.34]; P = .0312 [adjusted for multiple comparisons]), but not for vilazodone 20 mg/day versus placebo. Mean change from baseline in SDS total score was not significantly different for either dose of vilazodone versus placebo when adjusted for multiplicity; significant improvement versus placebo was noted for vilazodone 40 mg/day without adjustment for multiplicity (P = .0349). The incidence of adverse events was similar for vilazodone 20 and 40 mg/day (∼71%) and slightly lower for placebo (62%). Nausea, diarrhea, dizziness, vomiting, and fatigue were reported in ≥5% of patients in either vilazodone group and at least twice the rate of placebo. Vilazodone was effective in treating anxiety symptoms of GAD. No new safety concerns were identified. © 2015 The Authors. Depression and Anxiety published by Wiley Periodicals, Inc.

Long-term safety of once-daily lixisenatide in Japanese patients with type 2 diabetes mellitus: GetGoal-Mono-Japan.

PubMed

Seino, Yutaka; Yabe, Daisuke; Takami, Akane; Niemoeller, Elisabeth; Takagi, Hiroki

2015-01-01

This 76-week, open-label, parallel-group study assessed the long-term safety of once-daily lixisenatide monotherapy in Japanese patients with type 2 diabetes mellitus. Patients were randomized to receive lixisenatide in a 2-step or a 1-step dose-increase regimen. The primary objective was to assess the safety of lixisenatide at week 24 by a descriptive comparison of the 2- and 1-step groups. As expected with treatment with a glucagon-like peptide-1 agonist, nausea was the most common treatment-emergent adverse event (2-step group: n=12/33 [36.4%] vs 1-step group: n=18/36 [50.0%] up to week 24). In total, 5/33 patients (15.2%; 2-step group) and 2/36 patients (5.6%; 1-step group) prematurely discontinued treatment up to week 24, mainly due to adverse events. Serious treatment-emergent adverse events occurred in 2/33 patients (6.1%; 2-step group) versus 0/36 patients (0%; 1-step group) up to week 24. Symptomatic hypoglycemia occurred in 2/33 patients (6.1%; 2-step group) versus 1/36 patients (2.8%; 1-step group) up to week 24, with no severe events reported. Glycated hemoglobin, fasting plasma glucose, and body weight were reduced from baseline at weeks 24 and 76. In Japanese patients with type 2 diabetes mellitus, once-daily lixisenatide monotherapy was well tolerated, with less nausea with the 2-step regimen. Copyright © 2015. Published by Elsevier Inc.

Pharmacokinetics of doxylamine, a component of Bendectin, in the rhesus monkey.

PubMed

Slikker, W; Holder, C L; Lipe, G W; Bailey, J R; Young, J F

1989-01-01

The elimination of doxylamine and metabolites was determined after iv administration of [14C]doxylamine succinate at 0.7 and 13.3 mg/kg to the adult female rhesus monkey. Although the total recovery of radioactivity was the same for the low- and high-dose studies (90.2%), the rate of plasma elimination of doxylamine and its demethylated metabolite (desmethyldoxylamine) was slower for the high dose group. The 24 hr urinary excretion of doxylamine metabolites, desmethyl- and didesmethyldoxylamine, was significantly increased and the polar doxylamine metabolites were significantly decreased as the iv doxylamine succinate dose was increased. The plasma elimination of gas chromatograph (GC)-detected doxylamine was determined after oral administration of Bendectin (doxylamine succinate and pyridoxine hydrochloride) at 7, 13.3, and 27 mg/kg to adult female rhesus monkeys. As the dose increased, the clearance of doxylamine decreased. A statistically evaluated fit of the oral data to a single-compartment, parallel first-order elimination model and a single-compartment, parallel first- and second-order (Michaelis-Menten) elimination model indicated that the more complex model containing the second-order process was most consistent with the observed elimination data.

Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors.

PubMed

Hosoya, Kenji; Couto, C Guillermo; London, Cheryl A; Kisseberth, William C; Phelps, Mitchell A; Dalton, James T

2014-01-01

To evaluate the clinical toxicity and activity of orally administered artemisinin in dogs with spontaneous tumors, 24 client-owned dogs were randomly divided into two groups and received either low-continuous dose (3 mg/kg q 24 hr) or high-dose intermittent (three doses of 45 mg/kg q 6 hr repeated q 1 wk) of artemisinin per os. Treatment was continued for 21 days. Dogs were evaluated weekly for clinical effect and at the end of the treatment for hematologic and biochemical adverse events. Whole blood concentrations of artemisinin and dihydroartemisinin were measured by liquid chromatography/tandem mass spectrometry after the first dose of artemisinin in three dogs in each group. Blood concentrations of artemisinin and dihydroartemisinin were <0.1 μM at all time points, and there was no difference in blood concentration between the two dosing groups. The most frequent adverse event was anorexia, which was observed in 11% of the low-dose group and 29% of the high-dose group. Oral artemisinin, both in low-dose continuous and high-dose intermittent, is well tolerated in dogs but results in low bioavailability. Parenteral administration should be considered for future studies.

Multicenter, double-blind, parallel group study investigating the non-inferiority of efficacy and safety of a 2% miconazole nitrate shampoo in comparison with a 2% ketoconazole shampoo in the treatment of seborrhoeic dermatitis of the scalp.

PubMed

Buechner, Stanislaw A

2014-06-01

This study investigated the non-inferiority of efficacy and tolerance of 2% miconazole nitrate shampoo in comparison with 2% ketoconazole shampoo in the treatment of scalp seborrheic dermatitis. A randomized, double-blind, comparative, parallel group, multicenter study was done. A total of 274 patients (145 miconazole, 129 ketoconazole) were enrolled. Treatment was twice-weekly for 4 weeks. Safety and efficacy assessments were made at baseline and at weeks 2 and 4. Assessments included symptoms of erythema, itching, scaling ['Symptom Scale of Seborrhoeic Dermatitis' (SSSD)], disease severity and global change [Clinical Global Impressions (CGIs) and Patient Global Impressions (PGIs)]. Miconazole shampoo is at least as effective and safe as ketoconazole shampoo in treating scalp seborrheic dermatitis scalp.

Determination of absorbed dose to water for high-energy photon and electron beams-comparison of the standards DIN 6800-2 (1997), IAEA TRS 398 (2000) and DIN 6800-2 (2006)

PubMed Central

Zakaria, Golam Abu; Schuette, Wilhelm

2007-01-01

For the determination of the absorbed dose to water for high-energy photon and electron beams the IAEA code of practice TRS-398 (2000) is applied internationally. In Germany, the German dosimetry protocol DIN 6800-2 (1997) is used. Recently, the DIN standard has been revised and published as Draft National Standard DIN 6800-2 (2006). It has adopted widely the methodology and dosimetric data of the code of practice. This paper compares these three dosimetry protocols systematically and identifies similarities as well as differences. The investigation was done with 6 and 18 MV photon as well as 5 to 21 MeV electron beams. While only cylindrical chambers were used for photon beams, measurements of electron beams were performed using cylindrical as well as plane-parallel chambers. The discrepancies in the determination of absorbed dose to water between the three protocols were 0.4% for photon beams and 1.5% for electron beams. Comparative measurements showed a deviation of less than 0.5% between our measurements following protocol DIN 6800-2 (2006) and TLD inter-comparison procedure in an external audit. PMID:21217912

Determination of absorbed dose to water for high-energy photon and electron beams-comparison of the standards DIN 6800-2 (1997), IAEA TRS 398 (2000) and DIN 6800-2 (2006).

PubMed

Zakaria, Golam Abu; Schuette, Wilhelm

2007-01-01

For the determination of the absorbed dose to water for high-energy photon and electron beams the IAEA code of practice TRS-398 (2000) is applied internationally. In Germany, the German dosimetry protocol DIN 6800-2 (1997) is used. Recently, the DIN standard has been revised and published as Draft National Standard DIN 6800-2 (2006). It has adopted widely the methodology and dosimetric data of the code of practice. This paper compares these three dosimetry protocols systematically and identifies similarities as well as differences. The investigation was done with 6 and 18 MV photon as well as 5 to 21 MeV electron beams. While only cylindrical chambers were used for photon beams, measurements of electron beams were performed using cylindrical as well as plane-parallel chambers. The discrepancies in the determination of absorbed dose to water between the three protocols were 0.4% for photon beams and 1.5% for electron beams. Comparative measurements showed a deviation of less than 0.5% between our measurements following protocol DIN 6800-2 (2006) and TLD inter-comparison procedure in an external audit.

[Chronic recurrent annular neutrophilic dermatosis].

PubMed

Croci-Torti, A; Guillot, B; Rigau, V; Bessis, D

2017-05-01

Chronic recurrent annular neutrophilic dermatosis (CRAND) is a rare form of neutrophilic dermatosis characterised by chronic annular progression, histological impairment similar to that seen in Sweet's syndrome and the absence of association with generalised signs, abnormal laboratory values or underlying systemic disease. Herein we report two new cases. Case n o  1. A 41-year-old woman had presented with four annular lesions on the forearms and neckline which she had had for one year. Examination revealed a 5-cm annular lesion on the right forearm and four similar adjacent lesions. The condition spontaneously resolved after 4 weeks. Treatment with hydroxychloroquine 400mg per day for three months proved ineffective in preventing a further episode. However, following treatment with colchicine at a daily dose of 1mg for two months, no further relapses in the rash occurred over a 10-year observation period. Case n o  2. A 38-year-old woman consulted for recurrent annular erythema confined to the legs. Examination showed the presence of a red papular annular lesion on the right leg, encircling a yellowish macule with a central ring of fine scale; the lesion had been present for three weeks. Treatment with colchicine was initiated but the patient was lost to follow-up. In both cases, histological examination was evocative of Sweet's syndrome but no inflammatory or neutrophilic syndrome and no underlying systemic disease were demonstrated. CRAND presents as a stereotypical and benign form of neutrophilic dermatosis. A diagnosis of chronic recurrent annular dermatosis with gyrate progression should be considered in the absence of general signs, neutrophilia or underlying systemic disease. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

5-Fluorouracil, colchicine, benzo[a]pyrene and cytosine arabinoside tested in the in vitro mammalian cell micronucleus test (MNvit) in Chinese hamster V79 cells at Covance Laboratories, Harrogate, UK in support of OECD draft Test Guideline 487.

PubMed

Whitwell, James; Fowler, Paul; Allars, Sarah; Jenner, Karen; Lloyd, Melvyn; Wood, Debbie; Smith, Katie; Young, Jamie; Jeffrey, Laura; Kirkland, David

2010-10-29

The reference genotoxic agents 5-fluorouracil (a nucleoside analogue, characterised by a steep dose response profile), colchicine (an aneugen that inhibits tubulin polymerisation), benzo[a]pyrene (a polycyclic aromatic hydrocarbon requiring metabolic activation) and cytosine arabinoside (a nucleoside analogue that inhibits the gap-filling step of excision repair) were tested in the in vitro micronucleus assay using the Chinese hamster V79 cell line at Covance Laboratories, Harrogate, UK. All chemicals were treated in the absence and presence of cytokinesis block (via addition of cytochalasin B) with this work forming part of a collaborative evaluation of the toxicity measures recommended in the draft OECD Test Guideline 487 on the In Vitro Mammalian Cell Micronucleus Test (MNvit). The toxicity measures used, detecting a possible combination of both cytostasis and cell death (though not cell death directly), were relative population doubling, relative increase in cell counts and relative cell counts for treatments in the absence of cytokinesis block, and replication index in the presence of cytokinesis block. All of the chemicals tested either gave marked increases in the percentage of micronucleated cells with and without cytokinesis block, or did not induce micronuclei at concentrations giving approximately 50-60% toxicity (cytostasis and cell death) or less by all of the toxicity measures used. The outcome from this series of tests supports the use of relative increase in cell counts and relative population doubling, as well as relative cell counts, as appropriate measures of cytotoxicity for the non-cytokinesis blocked in vitro micronucleus assay. Copyright © 2010 Elsevier B.V. All rights reserved.

Dramatic response to IL1-RA treatment in longstanding multidrug resistant Schnitzler's syndrome: a case report and literature review.

PubMed

Besada, Emilio; Nossent, Hans

2010-05-01

We report a case of longstanding multidrug resistant Schnitzler's syndrome that finally went into clinical remission upon treatment with anakinra and review the literature concerning IL1-RA treatment for Schnitzler's syndrome. A now 71-year-old patient presenting with recurring episodes of urticaria and fever and secondary weight loss for the past 16 years as well as arthralgia, hearing loss. The patient has anemia, leucocytosis with neutrophilia, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, lymphadenopathy and a monoclonal IgM kappa band that later became oligoclonal with two IgM kappa bands and one IgM lambda band. The patient was treated with moderate effect with combination of prednisolone, azathioprine, and colchicine. In March 2009, anakinra 100 mg daily sc was added during a disease flare. Within 24 h after the first injection, both the urticaria and the fever disappeared and have not recurred. For the past 6 months, the patient has been in clinical and biochemical remission. Colchicine has been stopped while the azathioprine and prednisolone doses are being reduced. Twenty-four patients with Schnitzler's syndrome, including three patients with a variant of Schnitzler's syndrome and three patients with a Schnitzler-like syndrome, have been successfully treated with anakinra. Nevertheless, seven out of seven patients, that either interrupted or used anakinra every other day, had relapse of their symptoms within 24-48 h; anakinra was restarted in all patients with the same clinical efficiency. The current case history and the literature review already suggest an important role for IL-1 as a mediator in the pathophysiology of Schnitzler's syndrome.

Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas.

PubMed

Clifford, Royce E; Coleman, John K M; Balough, Ben J; Liu, Jianzhong; Kopke, Richard D; Jackson, Ronald L

2011-12-01

Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. Laboratory. All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05). Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

Submillisievert standard-pitch CT pulmonary angiography with ultra-low dose contrast media administration: A comparison to standard CT imaging.

PubMed

Suntharalingam, Saravanabavaan; Mikat, Christian; Stenzel, Elena; Erfanian, Youssef; Wetter, Axel; Schlosser, Thomas; Forsting, Michael; Nassenstein, Kai

2017-01-01

To evaluate the image quality and radiation dose of submillisievert standard-pitch CT pulmonary angiography (CTPA) with ultra-low dose contrast media administration in comparison to standard CTPA. Hundred patients (56 females, 44 males, mean age 69.6±15.4 years; median BMI: 26.6, IQR: 5.9) with suspected pulmonary embolism were examined with two different protocols (n = 50 each, group A: 80 kVp, ref. mAs 115, 25 ml of contrast medium; group B: 100 kVp, ref. mAs 150, 60 ml of contrast medium) using a dual-source CT equipped with automated exposure control. Objective and subjective image qualities, radiation exposure as well as the frequency of pulmonary embolism were evaluated. There was no significant difference in subjective image quality scores between two groups regarding pulmonary arteries (p = 0.776), whereby the interobserver agreement was excellent (group A: k = 0.9; group B k = 1.0). Objective image analysis revealed that signal intensities (SI), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the pulmonary arteries were equal or significantly higher in group B. There was no significant difference in the frequency of pulmonary embolism (p = 0.65). Using the low dose and low contrast media protocol resulted in a radiation dose reduction by 71.8% (2.4 vs. 0.7 mSv; p<0.001). This 80 kVp standard pitch CTPA protocol with 25 ml contrast agent volume can obtain sufficient image quality to exclude or diagnose pulmonary emboli while reducing radiation dose by approximately 71%.

A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly.

PubMed

Trainer, Peter J; Newell-Price, John; Ayuk, John; Aylwin, Simon; Rees, D Aled; Drake, Wm; Chanson, Philippe; Brue, Thierry; Webb, Susan M; Montañana, Carmen Fajardo; Aller, Javier; McCormack, Ann I; Torpy, David J; Tachas, George; Atley, Lynne; Ryder, David; Bidlingmaier, Martin

2018-05-22

ATL1103 is a second-generation antisense oligomer targeting the human GH receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. 26 patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once- or twice-weekly for 13 weeks, and monitored for a further 8-week washout period. The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, ALS, GH, GHBP), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups, respectivey. Compared to baseline, at week 14 twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (p=0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (p=0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and at week 21 remained lower than at baseline by a median of 18.7% (p=0.0005). Compared to baseline, by week 14 IGFBP3 and ALS had declined by a median of 8.9% (p=0.027) and 16.7% (p=0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (p=0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (p=0.027 and p=0.005), respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild to moderate injection-site reactions (ISR). This study provides proof-of-concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.

Biomarkers of Dose and Effect of Inhaled Ozone in Resting versus Exercising Human Subjects: Comparison with Resting Rats

PubMed Central

Hatch, Gary E.; McKee, John; Brown, James; McDonnell, William; Seal, Elston; Soukup, Joleen; Slade, Ralph; Crissman, Kay; Devlin, Robert

2013-01-01

To determine the influence of exercise on pulmonary dose of inhaled pollutants, we compared biomarkers of inhaled ozone (O3) dose and toxic effect between exercise levels in humans, and between humans and rats. Resting human subjects were exposed to labeled O3 (18O3, 0.4 ppm, for 2 hours) and alveolar O3 dose measured as the concentration of excess 18O in cells and extracellular material of nasal, bronchial, and bronchoalveolar lavage fluid (BALF). We related O3 dose to effects (changes in BALF protein, LDH, IL-6, and antioxidant substances) measurable in the BALF. A parallel study of resting subjects examined lung function (FEV1) changes following O3. Subjects exposed while resting had 18O concentrations in BALF cells that were 1/5th of those of exercising subjects and directly proportional to the amount of O3 breathed during exposure. Quantitative measures of alveolar O3 dose and toxicity that were observed previously in exercising subjects were greatly reduced or non-observable in O3 exposed resting subjects. Resting rats and resting humans were found to have a similar alveolar O3 dose. PMID:23761957

Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus.

PubMed

Kothare, Prajakti A; Linnebjerg, Helle; Isaka, Yoshitaka; Uenaka, Kazunori; Yamamura, Ayuko; Yeo, Kwee Poo; de la Peña, Amparo; Teng, Choo Hua; Mace, Kenneth; Fineman, Mark; Shigeta, Hirofumi; Sakata, Yukikuni; Irie, Shin

2008-12-01

In this single-blind, parallel, placebo-controlled study, the pharmacokinetics, pharmacodynamics, tolerability, and safety of subcutaneous exenatide were evaluated in 40 Japanese patients with type 2 diabetes. Patients were allocated to 4 groups and randomized to receive exenatide (n = 8/group) or placebo (n = 2/group), with all receiving placebo on day 1. On day 2, patients received single-dose exenatide (2.5 microg [group A] or 5 microg [groups B, C, and D]) or placebo and then bid on days 3 to 5. On days 6 to 10, groups A and B continued on 2.5 and 5 microg bid; groups C and D received 10 and 15 microg bid, respectively. The last dose was given on the morning of day 10. All adverse events were mild or moderate in severity. Exenatide was generally well tolerated up to 10 microg. Exenatide was well absorbed with a median t(max) of 1.5 hours and mean t((1/2)) of 1.6 hours; exposure increased with dose. Up to 10 microg, exenatide reduced postprandial glucose concentrations in a dose-dependent fashion compared with placebo; decreases were similar for 10 and 15 microg. An E(max) model demonstrated that doses higher than 2.5 microg were necessary for adequate glycemic response. Based on tolerability and pharmacokinetic/pharmacodynamic relationships, 5 and 10 microg exenatide may be considered for further clinical development in Japanese patients with type 2 diabetes.

Efficacy, safety and tolerability of ongoing statin plus ezetimibe versus doubling the ongoing statin dose in hypercholesterolemic Taiwanese patients: an open-label, randomized clinical trial

PubMed Central

2012-01-01

Background Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia. Methods This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks. Results At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments. Conclusion Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing. Trial registration Registered at ClinicalTrials.gov: NCT00652327 PMID:22621316

Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep

PubMed Central

Chang, Dennis H-T; Ladd, Leigh A; Copeland, Susan; Iglesias, Miguel A; Plummer, John L; Mather, Laurence E

2001-01-01

The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (∼50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 μmol (≈amp;2.5 mg) in 8 μmol increments, to either a fatal outcome or a 40 μmol (≈amp;12.5 mg) maximum. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean±s.e.mean actual fatal dose: 21.8±6.4 μmol), five of seven with levobupivacaine (22.9±3.5 μmol), four of six with ropivacaine (22.9±5.9 μmol). No significant differences in survival or in fatal doses between these drugs were found. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage. PMID:11159717

Use of automatic exposure control in multislice computed tomography of the coronaries: comparison of 16‐slice and 64‐slice scanner data with conventional coronary angiography

PubMed Central

Deetjen, Anja; Möllmann, Susanne; Conradi, Guido; Rolf, Andreas; Schmermund, Axel; Hamm, Christian W; Dill, Thorsten

2007-01-01

Objective To evaluate the radiation‐dose‐reduction potential of automatic exposure control (AEC) in 16‐slice and 64‐slice multislice computed tomography (MSCT) of the coronary arteries (computed tomography angiography, CTA) in patients. The rapid growth in MSCT CTA emphasises the necessity of adjusting technique factors to reduce radiation dose exposure. Design A retrospective data analysis was performed for 154 patients who had undergone MSCT CTA. Group 1 (n = 56) had undergone 16‐slice MSCT without AEC, and group 2 (n = 51), with AEC. In group 1, invasive coronary angiography (ICA) had been performed in addition. Group 3 (n = 47) had been examined using a 64‐slice scanner (with AEC, without ECG‐triggered tube current modulation). Results In group 1, the mean (SD) effective dose (ED) for MSCT CTA was 9.76 (1.84) mSv and for ICA it was 2.6 (1.27) mSv. In group 2, the mean ED for MSCT CTA was 5.83 (1.73) mSv, which signifies a 42.8% dose reduction for CTA by the use of AEC. In comparison to ICA, MSCT CTA without AEC shows a 3.8‐fold increase in radiation dose, and the radiation dose of CTA with AEC was increased by a factor of 1.9. In group 3, the mean ED for MSCT CTA was 13.58 (2.80) mSV. Conclusions This is the first study to show the significant dose‐reduction potential (42.8%) of AEC in MSCT CTA in patients. This relatively new technique can be used to optimise the radiation dose levels in MSCT CTA. PMID:17395667

TIME COURSE AND DOSE RESPONSE ASSESSMENT OF CHOLINESTERASE (CHE) INHIBITION IN ADULT RATS TREATED ACUTELY WITH CARBARYL, METHOMYL, METHIOCARB, OXAMYL, OR PROPOXUR.

EPA Science Inventory

To compare the toxicity of 5 N-methyl carbamates, the time course and dose response profiles for ChE inhibition were established for each. For the time course comparison, adult male Long Evans rats (n=5 dose group) were dosed orally with either carbaryl (CB; 30 mg/kg in corn oi...

The Impact of Azilsartan Medoxomil Treatment (Capsule Formulation) at Doses Ranging From 10 to 80 mg: Significant, Rapid Reductions in Clinic Diastolic and Systolic Blood Pressure.

PubMed

Perez, Alfonso; Cao, Charlie

2017-03-01

In this phase 2, multicenter, parallel-group, double-blind, dose-ranging study, hypertensive adults (n=449) were randomized to receive one of five doses of a capsule formulation of azilsartan medoxomil (AZL-M; 5, 10, 20, 40, 80 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. AZL-M provided rapid statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) vs placebo at all doses except 5 mg. Placebo-subtracted changes were greatest with the 40 mg dose (DBP, -5.7 mm Hg; SBP, -12.3 mm Hg). Clinic changes with AZL-M (all doses) were statistically indistinguishable vs OLM, although there were greater reductions with AZL-M 40 mg using 24-hour ambulatory blood pressure. Adverse event frequency was similar in the AZL-M and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL-M tablet in the dose range of 20 to 80 mg/d. ©2016 Wiley Periodicals, Inc.

An improved MCNP version of the NORMAN voxel phantom for dosimetry studies.

PubMed

Ferrari, P; Gualdrini, G

2005-09-21

In recent years voxel phantoms have been developed on the basis of tomographic data of real individuals allowing new sets of conversion coefficients to be calculated for effective dose. Progress in radiation studies brought ICRP to revise its recommendations and a new report, already circulated in draft form, is expected to change the actual effective dose evaluation method. In the present paper the voxel phantom NORMAN developed at HPA, formerly NRPB, was employed with MCNP Monte Carlo code. A modified version of the phantom, NORMAN-05, was developed to take into account the new set of tissues and weighting factors proposed in the cited ICRP draft. Air kerma to organ equivalent dose and effective dose conversion coefficients for antero-posterior and postero-anterior parallel photon beam irradiations, from 20 keV to 10 MeV, have been calculated and compared with data obtained in other laboratories using different numerical phantoms. Obtained results are in good agreement with published data with some differences for the effective dose calculated employing the proposed new tissue weighting factors set in comparison with previous evaluations based on the ICRP 60 report.

TH-EF-BRB-11: Volumetric Modulated Arc Therapy for Total Body Irradiation

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

Ouyang, L; Folkerts, M; Hrycushko, B

Purpose: To develop a modern, patient-comfortable total body irradiation (TBI) technique suitable for standard-sized linac vaults. Methods: An indexed rotatable immobilization system (IRIS) was developed to make possible total-body CT imaging and radiation delivery on conventional couches. Treatment consists of multi-isocentric volumetric modulated arc therapy (VMAT) to the upper body and parallel-opposed fields to the lower body. Each isocenter is indexed to the couch and includes a 180° IRIS rotation between the upper and lower body fields. VMAT fields are optimized to satisfy lung dose objectives while achieving a uniform therapeutic dose to the torso. End-to-end tests with a randomore » phantom were used to verify dosimetric characteristics. Treatment plan robustness regarding setup uncertainty was assessed by simulating global and regional isocenter setup shifts on patient data sets. Dosimetric comparisons were made with conventional extended distance, standing TBI (cTBI) plans using a Monte Carlo-based calculation. Treatment efficiency was assessed for eight courses of patient treatment. Results: The IRIS system is level and orthogonal to the scanned CT image plane, with lateral shifts <2mm following rotation. End-to-end tests showed surface doses within ±10% of the prescription dose, field junction doses within ±15% of prescription dose. Plan robustness tests showed <15% changes in dose with global setup errors up to 5mm in each direction. Local 5mm relative setup errors in the chest resulted in < 5% dose changes. Local 5mm shift errors in the pelvic and upper leg junction resulted in <10% dose changes while a 10mm shift error causes dose changes up to 25%. Dosimetric comparison with cTBI showed VMAT-TBI has advantages in preserving chest wall dose with flexibility in leveraging the PTV-body and PTV-lung dose. Conclusion: VMAT-TBI with the IRIS system was shown clinically feasible as a cost-effective approach to TBI for standard-sized linac vaults.« less

Immunogenicity and safety of a high-dose hepatitis B vaccine among patients receiving methadone maintenance treatment: A randomized, double-blinded, parallel-controlled trial.

PubMed

Shi, Jing; Feng, Yongliang; Gao, Linying; Feng, Dan; Yao, Tian; Shi, Shan; Zhang, Yawei; Liang, Xiaofeng; Wang, Suping

2017-04-25

To explore whether the immunization with high-dose (60μg) hepatitis B vaccines in patients receiving methadone maintenance treatment (MMT) could yield a superior protection against hepatitis B infection than did the standard dose (20μg). We conducted a randomized, double-blinded, parallel-controlled trial in MMT patients. Patients with serologically negative hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were randomized in a ratio of 1:1 to receive three intramuscular injections of 20μg or 60μg recombinant hepatitis B vaccine at months 0, 1, and 6. Serum HBsAg and anti-HBs were measured at months 7 and 12 post-vaccination to assess the immunogenicity. A total of 196 MMT patients were randomized and 195 received at least one injection (98 and 97 in 20 and 60μg vaccine groups, respectively). The 60μg vaccine group showed a seroconversion of anti-HBs of 87.3%, high-level response rate of 56.3%, and GMC of 742.9mIU/mL at month 7. While these results were numerically higher than the 20μg group, a statistical difference was not found. HIV infection and concomitant drug abuse were negatively associated with the robust immune responses. 7.7% of MMT patients receiving at least one dose of vaccine reported solicited adverse reactions within 7days after vaccination, 2.6% reported unsolicited adverse reactions within 28days after vaccination. None of the MMT patients reported serious adverse events or became HBsAg positive during the follow-up. The three-dose regimen of 60μg recombinant hepatitis B vaccine at months 0, 1, and 6 can yield a similar immunogenicity among MMT patients as compared to the 20μg vaccine. ClinicalTrials.gov identifier: NCT02991599. Copyright © 2017. Published by Elsevier Ltd.

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study.

PubMed

Amalraj, Augustine; Varma, Karthik; Jacob, Joby; Divya, Chandradhara; Kunnumakkara, Ajaikumar B; Stohs, Sidney J; Gopi, Sreeraj

2017-10-01

Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three-arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects.

A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia.

PubMed

Hill, S Kristian; Reilly, James L; Harris, Margret S H; Rosen, Cherise; Marvin, Robert W; Deleon, Ovidio; Sweeney, John A

2009-09-01

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n=41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.

Evaluation of the single-dose pharmacokinetics of bilastine in subjects with various degrees of renal insufficiency.

PubMed

Lasseter, Kenneth C; Sologuren, Ander; La Noce, Anna; Dilzer, Stacy C

2013-09-01

Bilastine is a novel second-generation H1 antihistamine, which has not shown sedative or cardiotoxic effects in clinical trials and in post-marketing experience so far, developed for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. It has recently been granted marketing authorization for these therapeutic indications in adults and adolescents at a once-daily oral dose of 20 mg in several European countries. This study was conducted to determine the pharmacokinetics of bilastine at a single oral dose of 20 mg in renally impaired subjects. The need for a dose adjustment in patients with renal insufficiency was assessed by comparing the exposure to bilastine in these subjects with the estimated exposure of a dose corresponding to the safety margin. The study was an open-label, single-dose, parallel-group study of the pharmacokinetics and safety of a single dose of bilastine. The study was conducted as an in-patient setting at a clinical pharmacology facility. A total of 24 male or female subjects aged 18-80 years were to be enrolled in four groups of six subjects each. The groups were as follows: (1) healthy [glomerular filtration rate (GFR) >80 mL/min/1.73 m(2)]; (2) mild renal insufficiency (GFR 50-80 mL/min/1.73 m(2)); (3) moderate renal insufficiency (GFR 30-50 mL/min/1.73 m(2)); and (4) severe renal insufficiency (GFR ≤30 mL/min/1.73 m(2)). A single 20 mg bilastine tablet was administered in a fasted state. Blood and urine samples were collected from pre-dose up to 72 h post-dose for bilastine pharmacokinetic analysis. Pharmacokinetic results were summarized using appropriate descriptive statistics. There was a clear trend of increasing area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C(max)) through the groups 1-4. The mean AUC from time zero to infinity (AUC(∞)) ranged from 737.4 to 1708.5 ng·h/mL in healthy subjects and severely impaired subjects, respectively. No significant differences among groups in median time to reach Cmax (tmax) or in the mean terminal disposition rate constants for bilastine were found. Renal and plasma clearance paralleled GFR. In all groups of renally impaired subjects the corresponding 90 % confidence interval of both AUC(∞) and AUC from time zero to time of last measurable plasma concentration (AUC(last)) were not within the 0.8-1.25 interval, indicating that bioequivalence between groups could not be demonstrated. The majority of bilastine was excreted within the first 12 h, and elimination was essentially complete by 72 h. An oral dose of bilastine (20 mg) was well-tolerated in renal insufficiency, despite the increase in exposure. The oral plasma clearance to renal clearance ratio [(CL(P)/F)/CL(R)] was approximately equal in the different groups, suggesting that renal excretion was the main elimination route for bilastine, and no alternative elimination routes were used even in severe renal insufficiency. Although exposure to bilastine was higher in renally impaired subjects, it remained well within the safety margins, thus allowing the conclusion that a 20-mg daily dose can be safely administered to subjects with different degrees of renal insufficiency without the need for dose adjustments.

SU-E-T-157: Evaluation and Comparison of Doses to Pelvic Lymph Nodes and to Point B with 3D Image Guided Treatment Planning for High Dose Brachytherapy for Treatment of Cervical Cancer

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

Bhandare, N.

2014-06-01

Purpose: To estimate and compare the doses received by the obturator, external and internal iliac lymph nodes and point Methods: CT-MR fused image sets of 15 patients obtained for each of 5 fractions of HDR brachytherapy using tandem and ring applicator, were used to generate treatment plans optimized to deliver a prescription dose to HRCTV-D90 and to minimize the doses to organs at risk (OARs). For each set of image, target volume (GTV, HRCTV) OARs (Bladder, Rectum, Sigmoid), and both left and right pelvic lymph nodes (obturator, external and internal iliac lymph nodes) were delineated. Dose-volume histograms (DVH) were generatedmore » for pelvic nodal groups (left and right obturator group, internal and external iliac chains) Per fraction DVH parameters used for dose comparison included dose to 100% volume (D100), and dose received by 2cc (D2cc), 1cc (D1cc) and 0.1 cc (D0.1cc) of nodal volume. Dose to point B was compared with each DVH parameter using 2 sided t-test. Pearson correlation were determined to examine relationship of point B dose with nodal DVH parameters. Results: FIGO clinical stage varied from 1B1 to IIIB. The median pretreatment tumor diameter measured on MRI was 4.5 cm (2.7– 6.4cm).The median dose to bilateral point B was 1.20 Gy ± 0.12 or 20% of the prescription dose. The correlation coefficients were all <0.60 for all nodal DVH parameters indicating low degree of correlation. Only 2 cc of obturator nodes was not significantly different from point B dose on t-test. Conclusion: Dose to point B does not adequately represent the dose to any specific pelvic nodal group. When using image guided 3D dose-volume optimized treatment nodal groups should be individually identified and delineated to obtain the doses received by pelvic nodes.« less

A novel and selective sodium-glucose cotransporter-2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus.

PubMed

Ikeda, S; Takano, Y; Cynshi, O; Tanaka, R; Christ, A D; Boerlin, V; Beyer, U; Beck, A; Ciorciaro, C; Meyer, M; Kadowaki, T

2015-10-01

To assess the efficacy, safety and tolerability of different doses of tofogliflozin, a novel, highly selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM). In a 12-week, multicentre, multinational, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study, patients with inadequate glycaemic control from diet and exercise alone, or from diet and exercise plus a stable dose of metformin, were randomized to one of five doses of tofogliflozin (2.5, 5, 10, 20, or 40 mg) or placebo. The primary efficacy endpoint was absolute change at week 12 from baseline in glycated haemoglobin (HbA1c), minus the change in the placebo group. Statistically significant dose-dependent reductions in HbA1c were shown in all treated groups except the 2.5-mg dose group, with a maximum reduction of 0.56% (placebo-subtracted) at the 40-mg dose, along with increased urinary glucose excretion. Metformin treatment had no substantial influence on tofogliflozin efficacy. Dose-dependent reductions in fasting plasma glucose and body weight were observed, and glucose intolerance was improved, with a trend towards blood pressure reduction. Slight increases were observed for mean ketone bodies with no abnormal change in ketone body ratio. No deaths or treatment-related serious adverse events were reported. The incidence of adverse events was similar in the placebo (37.9%) to that in the tofogliflozin group (35.9-46.3%). Withdrawal because of adverse events was rare (≤2 patients per treatment group), with similar rates of withdrawal in the placebo and tofogliflozin groups. A once-daily dose of tofogliflozin for 12 weeks was an effective, safe and well-tolerated treatment for T2DM. © 2015 John Wiley & Sons Ltd.

Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients.

PubMed

Wade, Derick T; Makela, Petra; Robson, Philip; House, Heather; Bateman, Cynthia

2004-08-01

The objective was to determine whether a cannabis-based medicinal extract (CBME) benefits a range of symptoms due to multiple sclerosis (MS). A parallel group, double-blind, randomized, placebo-controlled study was undertaken in three centres, recruiting 160 outpatients with MS experiencing significant problems from at least one of the following: spasticity, spasms, bladder problems, tremor or pain. The interventions were oromucosal sprays of matched placebo, or whole plant CBME containing equal amounts of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) at a dose of 2.5-120 mg of each daily, in divided doses. The primary outcome measure was a Visual Analogue Scale (VAS) score for each patient's most troublesome symptom. Additional measures included VAS scores of other symptoms, and measures of disability, cognition, mood, sleep and fatigue. Following CBME the primary symptom score reduced from mean (SE) 74.36 (11.1) to 48.89 (22.0) following CBME and from 74.31 (12.5) to 54.79 (26.3) following placebo [ns]. Spasticity VAS scores were significantly reduced by CBME (Sativex) in comparison with placebo (P =0.001). There were no significant adverse effects on cognition or mood and intoxication was generally mild.

Effects of music aerobic exercise on depression and brain-derived neurotrophic factor levels in community dwelling women.

PubMed

Yeh, Shu-Hui; Lin, Li-Wei; Chuang, Yu Kuan; Liu, Cheng-Ling; Tsai, Lu-Jen; Tsuei, Feng-Shiou; Lee, Ming-Tsung; Hsiao, Chiu-Yueh; Yang, Kuender D

2015-01-01

A randomized clinical trial was utilized to compare the improvement of depression and brain-derived neurotrophic factor (BDNF) levels between community women with and without music aerobic exercise (MAE) for 12 weeks. The MAE group involved 47 eligible participants, whereas the comparison group had 59 participants. No significant differences were recorded in the demographic characteristics between the participants in the MAE group and the comparison group. Forty-one participants in the MAE group and 26 in the comparison group completed a pre- and posttest. The MAE group displayed significant improvement in depression scores (p = 0.016), decreased depression symptoms in crying (p = 0.03), appetite (p = 0.006), and fatigue (p = 0.011). The BDNF levels of the participants significantly increased after the 12-week MAE (p = 0.042). The parallel comparison group revealed no significant changes in depression scores or BDNF levels. In summary, the 12-week MAE had a significant impact on the enhancement of BDNF levels and improvement of depression symptoms. Middle-aged community women are encouraged to exercise moderately to improve their depression symptoms and BDNF levels.

THE ROLE OF THREE CYTOPLASMIC FIBERS IN BHK-21 CELL MOTILITY

PubMed Central

Goldman, Robert D.

1971-01-01

Microtubule breakdown in the presence of 5 or 40 µg/ml of colchicine is observed in BHK-21/C13 fibroblast-like cells. Several morphological and physiological effects are noted in the absence of microtubules: (a) the cells transform from fibroblast-like to epithelial-like cells; (b) the normal pattern of intracellular birefringence changes and a juxtanuclear cap of birefringent filaments is formed; (c) time-lapse cinematography demonstrates that cell locomotion is inhibited in colchicine-treated cells, even though membrane ruffling persists. The results are discussed in terms of the specific roles of microtubules in cultured cell motility and possible functional relationships of the three types of cytoplasmic fibers seen in BHK-21 cells. PMID:4942774

Pre-operative use of dexamethasone does not reduce incidence or intensity of bleaching-induced tooth sensitivity. A triple-blind, parallel-design, randomized clinical trial.

PubMed

da Costa Poubel, Luiz Augusto; de Gouvea, Cresus Vinicius Deppes; Calazans, Fernanda Signorelli; Dip, Etyene Castro; Alves, Wesley Veltri; Marins, Stella Soares; Barcelos, Roberta; Barceleiro, Marcos Oliveira

2018-04-25

This study evaluated the effect of the administration of pre-operative dexamethasone on tooth sensitivity stemming from in-office bleaching. A triple-blind, parallel-design, randomized clinical trial was conducted on 70 volunteers who received dexamethasone or placebo capsules. The drugs were administered in a protocol of three daily 8-mg doses of the drug, starting 48 h before the in-office bleaching treatment. Two bleaching sessions with 37.5% hydrogen peroxide gel were performed with a 1-week interval. Tooth sensitivity (TS) was recorded on visual analog scales (VAS) and numeric rating scales (NRS) in different periods up to 48 h after bleaching. The color evaluations were also performed. The absolute risk of TS and its intensity were evaluated by using Fisher's exact test. Comparisons of the TS intensity (NRS and VAS data) were performed by using the Mann-Whitney U test and a two-way repeated measures ANOVA and Tukey's test, respectively. In both groups, a high risk of TS (Dexa 80% x Placebo 94%) was detected. No significant difference was observed in terms of TS intensity. A whitening of approximately 3 shade guide units of the VITA Classical was detected in both groups, which were statistically similar. It was concluded that the administration pre-operatively of dexamethasone, in the proposed protocol, does not reduce the incidence or intensity of bleaching-induced tooth sensitivity. The use of dexamethasone drug before in-office bleaching treatment does not reduce incidence or intensity of tooth sensitivity. NCT02956070.

The effect of dosing regimen on the pharmacokinetics of risedronate

PubMed Central

Mitchell, David Y; Heise, Mark A; Pallone, Karen A; Clay, Marian E; Nesbitt, John D; Russell, Darrell A; Melson, Chad W

1999-01-01

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. Methods A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. Results Extent of risedronate absorption (AUC and Ae) was comparable (P = 0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. PMID:10583024

Azilsartan in Patients With Mild to Moderate Hypertension Using Clinic and Ambulatory Blood Pressure Measurements.

PubMed

Perez, Alfonso; Cao, Charlie

2017-01-01

This was a phase 2, multicenter, randomized, parallel-group, double-blind dose-ranging study. Hypertensive adults (n=555) received one of five doses of azilsartan (AZL; 2.5, 5, 10, 20, 40 mg), olmesartan medoxomil (OLM) 20 mg, or placebo once daily. The primary endpoint was change in trough clinic diastolic blood pressure (DBP) at week 8. Compared with placebo, all AZL doses (except 2.5 mg) provided statistically and clinically significant reductions in DBP and systolic blood pressure (SBP) based on both clinic blood pressure (BP) and 24-hour ambulatory BP monitoring (ABPM). AZL 40 mg was statistically superior vs OLM. Clinic BP was associated with a pronounced placebo effect (-6 mm Hg), whereas this was negligible with ABPM (±0.5 mm Hg). Adverse event frequency was similar in the AZL and placebo groups. Based on these and other findings, subsequent trials investigated the commercial AZL medoxomil tablet at doses 20 to 80 mg/d using 24-hour ABPM. ©2016 Wiley Periodicals, Inc.

Improving blood pressure control: increase the dose of diuretic or switch to a fixed-dose angiotensin receptor blocker/diuretic? the valsartan hydrochlorothiazide diuretic for initial control and titration to achieve optimal therapeutic effect (Val-DICTATE) trial.

PubMed

White, William B; Calhoun, David A; Samuel, Rita; Taylor, Addison A; Zappe, Dion H; Purkayastha, Das

2008-06-01

To assess the strategy of increasing the dose of a diuretic compared with using an angiotensin receptor blocker in combination with a diuretic, the authors performed a multicenter, randomized, parallel group trial in hypertensive patients (baseline blood pressure [BP], 153/97 mm Hg) whose BP remained uncontrolled on initial low-dose diuretic monotherapy (hydrochlorothiazide [HCTZ] 12.5 mg Hg). Patients with stage 1 and 2 hypertension were randomized to treatment with valsartan/HCTZ (160/12.5 mg) or to doubling of the HCTZ dose (25 mg). The primary end point was the percentage of patients whose clinic BP values were <140/90 mm Hg following 4 weeks of double-blind therapy. A significantly higher proportion (P<.001) of hypertensive patients met BP control levels in the valsartan/HCTZ (160/12.5 mg) group compared with the HCTZ 25 mg group (37% vs 16%). Changes from baseline in BP were significantly greater (P<.001) for both systolic BP and diastolic BP in the combination therapy arm compared with the diuretic monotherapy arm (-12. 4/-7.5 mm Hg in valsartan/HCTZ 160/12.5 mg group vs -5.6/-2.1 mm Hg in HCTZ 25 mg group). Tolerability and adverse events were similar in the 2 treatment groups. This study suggests that in the management of hypertension, utilizing an angiotensin receptor blocker/diuretic combination was more effective in lowering BP and achieving BP goals when compared with increasing the dose of the diuretic.

Treatment of migraine attacks with sumatriptan. The Subcutaneous Sumatriptan International Study Group.

PubMed

1991-08-01

The headache in migraine attacks may be caused by dilatation of certain cranial arteries or arteriovenous anastomoses, by neurogenic dural plasma extravasation, or by both of these mechanisms. Sumatriptan, a novel selective agonist of 5-hydroxytryptamine-like receptors, blocks these phenomena. We investigated its efficacy in migraine. We studied 639 patients with migraine attacks in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. We assessed the effect of subcutaneous injections of 6 or 8 mg of sumatriptan or placebo on the severity of headache and associated migrane symptoms 30, 60, and 120 minutes after treatment. Patients who were not free of pain after 60 minutes subsequently received placebo if they had initially received placebo or 8 mg of sumatriptan, and 6 mg of sumatriptan or placebo if they had initially received 6 mg of sumatriptan. After 60 minutes, the severity of headache was decreased in 72 percent (95 percent confidence interval, 68 to 76 percent) of the 422 patients given 6 mg of sumatriptan, 79 percent (95 percent confidence interval, 71 to 87 percent) of the 109 patients given 8 mg of sumatriptan, and 25 percent (95 percent confidence interval, 17 to 33 percent) of the 105 patients given placebo (data on 3 patients could not be evaluated). As compared with the placebo group, 47 percent (95 percent confidence interval, 38 to 57 percent) more patients who had received 6 mg of sumatriptan and 54 percent (95 percent confidence interval, 43 to 65 percent) more patients who had received 8 mg of sumatriptan had a decrease in the severity of headache (P less than 0.001 for both comparisons). After 120 minutes, 86 to 92 percent of the 511 patients treated with sumatriptan (202 assigned to 6 mg plus placebo, 203 to 6 mg plus 6 mg, and 106 to 8 mg plus placebo) had improvement in the severity of headache, as compared with only 37 percent of the 104 patients who received placebo once or twice (P less than 0.001 for all comparisons). Twenty-one patients were excluded from the analysis because of missing data (19) or protocol violations (2). The response rates did not differ significantly among the sumatriptan regimens. Adverse events were minor and transient in all groups. We conclude that a single 6-mg dose of sumatriptan given subcutaneously is a highly effective, rapid-acting, and well-tolerated treatment for migrane attacks. The administration of a second dose 60 minutes later to patients not responding well to an initial dose affords little additional benefit.

Mortality from cardiovascular diseases in the Semipalatinsk historical cohort, 1960-1999, and its relationship to radiation exposure.

PubMed

Grosche, Bernd; Lackland, Daniel T; Land, Charles E; Simon, Steven L; Apsalikov, Kazbek N; Pivina, Ludmilla M; Bauer, Susanne; Gusev, Boris I

2011-11-01

The data on risk of mortality from cardiovascular disease due to radiation exposure at low or medium doses are inconsistent. This paper reports an analysis of the Semipalatinsk historical cohort exposed to radioactive fallout from nuclear testing in the vicinity of the Semipalatinsk Nuclear Test Site, Kazakhstan. The cohort study, which includes 19,545 persons of exposed and comparison villages in the Semipalatinsk region, had been set up in the 1960s and comprises 582,656 person-years of follow-up between 1960 and 1999. A dosimetric approach developed by the U.S. National Cancer Institute (NCI) has been used. Radiation dose estimates in this cohort range from 0 to 630 mGy (whole-body external). Overall, the exposed population showed a high mortality from cardiovascular disease. Rates of mortality from cardiovascular disease in the exposed group substantially exceeded those of the comparison group. Dose-response analyses were conducted for both the entire cohort and the exposed group only. A dose-response relationship that was found when analyzing the entire cohort could be explained completely by differences between the baseline rates in exposed and unexposed groups. When taking this difference into account, no statistically significant dose-response relationship for all cardiovascular disease, for heart disease, or for stroke was found. Our results suggest that within this population and at the level of doses estimated, there is no detectable risk of radiation-related mortality from cardiovascular disease.

NOTE: Calibration of low-energy electron beams from a mobile linear accelerator with plane-parallel chambers using both TG-51 and TG-21 protocols

NASA Astrophysics Data System (ADS)

Beddar, A. S.; Tailor, R. C.

2004-04-01

A new approach to intraoperative radiation therapy led to the development of mobile linear electron accelerators that provide lower electron energy beams than the usual conventional accelerators commonly encountered in radiotherapy. Such mobile electron accelerators produce electron beams that have nominal energies of 4, 6, 9 and 12 MeV. This work compares the absorbed dose output calibrations using both the AAPM TG-51 and TG-21 dose calibration protocols for two types of ion chambers: a plane-parallel (PP) ionization chamber and a cylindrical ionization chamber. Our results indicate that the use of a 'Markus' PP chamber causes 2 3% overestimation in dose output determination if accredited dosimetry-calibration laboratory based chamber factors \\big(N_{{\\rm D},{\\rm w}}^{{}^{60}{\\rm Co}}, N_x\\big) are used. However, if the ionization chamber factors are derived using a cross-comparison at a high-energy electron beam, then a good agreement is obtained (within 1%) with a calibrated cylindrical chamber over the entire energy range down to 4 MeV. Furthermore, even though the TG-51 does not recommend using cylindrical chambers at the low energies, our results show that the cylindrical chamber has a good agreement with the PP chamber not only at 6 MeV but also down to 4 MeV electron beams.

Case report: fatal poisoning with Colchicum autumnale.

PubMed

Brvar, Miran; Ploj, Tom; Kozelj, Gordana; Mozina, Martin; Noc, Marko; Bunc, Matjaz

2004-02-01

Colchicum autumnale, commonly known as the autumn crocus, contains alkaloid colchicine with antimitotic properties. A 76-year-old man with a history of alcoholic liver disease and renal insufficiency, who mistakenly ingested Colchicum autumnale instead of wild garlic (Aliium ursinum), presented with nausea, vomiting and diarrhea 12 hours after ingestion. On admission the patient had laboratory signs of dehydration. On the second day the patient became somnolent and developed respiratory insufficiency. The echocardiogram showed heart dilatation with diffuse hypokinesia with positive troponin I. The respiratory insufficiency was further deteriorated by pneumonia, confirmed by chest X-ray and later on by autopsy. Laboratory tests also revealed rhabdomyolysis, coagulopathy and deterioration of renal function and hepatic function. The toxicological analysis disclosed colchicine in the patient's urine (6 microgram/l) and serum (9 microgram/l) on the second day. Therapy was supportive with hydration, vasopressors, mechanical ventilation and antibiotics. On the third day the patient died due to asystolic cardiac arrest. Colchicine poisoning should be considered in patients with gastroenterocolitis after a meal of wild plants. Management includes only intensive support therapy. A more severe clinical presentation should be expected in patients with pre-existing liver and renal diseases. The main reasons for death are cardiovascular collapse, respiratory failure and leukopenia with infection.

Attenuation of neurobehavioral and neurochemical abnormalities in animal model of cognitive deficits of Alzheimer's disease by fermented soybean nanonutraceutical.

PubMed

Bhatt, Prakash Chandra; Pathak, Shruti; Kumar, Vikas; Panda, Bibhu Prasad

2018-02-01

The present study was performed to evaluate the efficacy of nanonutraceuticals (NN) for attenuation of neurobehavioral and neurochemical abnormalities in Alzheimer's disease. Solid-state fermentation of soybean with Bacillus subtilis was performed to produce different metabolites (nattokinase, daidzin, genistin and glycitin and menaquinone-7). Intoxication of rats with colchicine caused impairment in learning and memory which was demonstrated in neurobehavioral paradigms (Morris water maze and passive avoidance) linked with decreased activity of acetylcholinesterase (AChE). NN treatment led to a significant increase in TLT in the retention trials as compared to acquisition trial TLT suggesting an improved learning and memory in rats. Further, treatment of NN caused an increase in the activity of AChE (42%), accompanied with a reduced activity of glutathione (42%), superoxide dismutase (43%) and catalase (41%). It also decreased the level of lipid peroxidation (28%) and protein carbonyl contents (30%) in hippocampus as compared to those treated with colchicine alone, suggesting a possible neuroprotective efficacy of NN. Interestingly, in silico studies also demonstrated an effective amyloid-β and BACE-1 inhibition activity. These findings clearly indicated that NN reversed colchicine-induced behavioral and neurochemical alterations through potent antioxidant activity and could possibly impart beneficial effects in cognitive defects associated with Alzheimer's disease.

Novel colchicine-site binders with a cyclohexanedione scaffold identified through a ligand-based virtual screening approach.

PubMed

Canela, María-Dolores; Pérez-Pérez, María-Jesús; Noppen, Sam; Sáez-Calvo, Gonzalo; Díaz, J Fernando; Camarasa, María-José; Liekens, Sandra; Priego, Eva-María

2014-05-22

Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the α,β-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)amino)ethylidene)-5-phenylcyclohexane-1,3-dione (compound 16c) with an IC50 = 0.09 ± 0.01 μM in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound 16c caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with N,N'-ethylenebis(iodoacetamide) and by fluorescence spectroscopy. Moreover, 16c destroyed an established endothelial tubular network at 1 μM and inhibited the migration and invasion of human breast carcinoma cells at 0.4 μM. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties.

Constitutive properties of hypertrophied myocardium: cellular contribution to changes in myocardial stiffness

NASA Technical Reports Server (NTRS)

Harris, Todd S.; Baicu, Catalin F.; Conrad, Chester H.; Koide, Masaaki; Buckley, J. Michael; Barnes, Mary; Cooper, George 4th; Zile, Michael R.

2002-01-01

Recent studies have suggested that pressure overload hypertrophy (POH) alters the viscoelastic properties of individual cardiocytes when studied in isolation. However, whether these changes in cardiocyte properties contribute causally to changes in the material properties of the cardiac muscle as a whole is unknown. Accordingly, a selective, isolated, acute change in cardiocyte constitutive properties was imposed in an in vitro system capable of measuring the resultant effect on the material properties of the composite cardiac muscle. POH caused an increase in both myocardial elastic stiffness, from 20.5 +/- 1.3 to 28.4 +/- 1.8, and viscous damping, from 15.2 +/- 1.1 to 19.8 +/- 1.5 s (normal vs. POH, P < 0.05), respectively. Recent studies have shown that cardiocyte constitutive properties could be acutely altered by depolymerizing the microtubules with colchicine. Colchicine caused a significant decrease in the viscous damping in POH muscles (19.8 +/- 1.5 s at baseline vs. 14.7 +/- 1.3 s after colchicine, P < 0.05). Therefore, myocardial material properties can be altered by selectively changing the constitutive properties of one element within this muscle tissue, the cardiocyte. Changes in the constitutive properties of the cardiocytes themselves contribute to the abnormalities in myocardial stiffness and viscosity that develop during POH.

Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs.

PubMed

Tipold, A; Keefe, T J; Löscher, W; Rundfeldt, C; de Vries, F

2015-04-01

The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client-owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital-treated dogs, significantly increased levels of alkaline phosphatase, gamma-glutamyl-transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no-observed-adverse-event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Aircraft Crew Radiation Exposure in Aviation Altitudes During Quiet and Solar Storm Periods

NASA Astrophysics Data System (ADS)

Beck, Peter

The European Commission Directorate General Transport and Energy published in 2004 a summary report of research on aircrew dosimetry carried out by the EURADOS working group WG5 (European Radiation Dosimetry Group, http://www.eurados.org/). The aim of the EURADOS working group WG5 was to bring together, in particular from European research groups, the available, preferably published, experimental data and results of calculations, together with detailed descriptions of the methods of measurement and calculation. The purpose is to provide a dataset for all European Union Member States for the assessment of individual doses and/or to assess the validity of different approaches, and to provide an input to technical recommendations by the experts and the European Commission. Furthermore EURADOS (European Radiation Dosimetry Group, http://www.eurados.org/) started to coordinate research activities in model improvements for dose assessment of solar particle events. Preliminary results related to the European research project CONRAD (Coordinated Network for Radiation Dosimetry) on complex mixed radiation fields at workplaces are presented. The major aim of this work is the validation of models for dose assessment of solar particle events, using data from neutron ground level monitors, in-flight measurement results obtained during a solar particle event and proton satellite data. The radiation protection quantity of interest is effective dose, E (ISO), but the comparison of measurement results obtained by different methods or groups, and comparison of measurement results and the results of calculations, is done in terms of the operational quantity ambient dose equivalent, H* (10). This paper gives an overview of aircrew radiation exposure measurements during quiet and solar storm conditions and focuses on dose results using the EURADOS In-Flight Radiation Data Base and published data on solar particle events

Submillisievert standard-pitch CT pulmonary angiography with ultra-low dose contrast media administration: A comparison to standard CT imaging

PubMed Central

Mikat, Christian; Stenzel, Elena; Erfanian, Youssef; Wetter, Axel; Schlosser, Thomas; Forsting, Michael

2017-01-01

Objectives To evaluate the image quality and radiation dose of submillisievert standard-pitch CT pulmonary angiography (CTPA) with ultra-low dose contrast media administration in comparison to standard CTPA. Materials and methods Hundred patients (56 females, 44 males, mean age 69.6±15.4 years; median BMI: 26.6, IQR: 5.9) with suspected pulmonary embolism were examined with two different protocols (n = 50 each, group A: 80 kVp, ref. mAs 115, 25 ml of contrast medium; group B: 100 kVp, ref. mAs 150, 60 ml of contrast medium) using a dual-source CT equipped with automated exposure control. Objective and subjective image qualities, radiation exposure as well as the frequency of pulmonary embolism were evaluated. Results There was no significant difference in subjective image quality scores between two groups regarding pulmonary arteries (p = 0.776), whereby the interobserver agreement was excellent (group A: k = 0.9; group B k = 1.0). Objective image analysis revealed that signal intensities (SI), signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the pulmonary arteries were equal or significantly higher in group B. There was no significant difference in the frequency of pulmonary embolism (p = 0.65). Using the low dose and low contrast media protocol resulted in a radiation dose reduction by 71.8% (2.4 vs. 0.7 mSv; p<0.001). Conclusions This 80 kVp standard pitch CTPA protocol with 25 ml contrast agent volume can obtain sufficient image quality to exclude or diagnose pulmonary emboli while reducing radiation dose by approximately 71%. PMID:29045463

Stereochemical preference toward oncotarget: Design, synthesis and in vitro anticancer evaluation of diastereomeric β-lactams.

PubMed

Olazarán-Santibáñez, Fabián; Bandyopadhyay, Debasish; Carranza-Rosales, Pilar; Rivera, Gildardo; Balderas-Rentería, Isaías

2017-06-06

In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam-β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis-3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Stereochemical preferences of the cis-β-lactams over their trans-counterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro.

Stereochemical preference toward oncotarget: Design, synthesis and in vitro anticancer evaluation of diastereomeric β-lactams

PubMed Central

Olazarán-Santibáñez, Fabián; Bandyopadhyay, Debasish; Carranza-Rosales, Pilar; Rivera, Gildardo; Balderas-Rentería, Isaías

2017-01-01

Purpose In the battle against cancer discovery of new and novel chemotherapeutic agent demands extreme obligation. Development of anticancer compounds with higher potency and reduced side-effects is timely and challenging. Experimental Design A small series of fourteen diastereomeric β-lactams (seven pairs) were synthesized through multi-step process exploring [2+2] ketene-imine cycloaddition as the key step. Comparative stereochemical preferences were studied through computational docking and validated by in vitro evaluation. β-tubulin was considered as possible molecular target and in vitro anticancer evaluation was conducted against SiHa, B16F10, K562 and Chang cell lines. Caspase-3 activation assay and hematoxylin/eosin staining of the cells were also accomplished. Results Better docking scores of the cis- over the trans-β-lactams indicated favorable β-lactam—β-tubulin interactions in cis-geometry. In vitro (IC50) evaluation confirmed better anticancer activity of the cis-diastereoisomers. Apoptosis-induced cell death was supported by caspase-3 activation study. A cis-β-lactam [(±)-Cis-3-amino-1-phenyl-4-(p-tolyl) azetidin-2-one, 6C] was found to be more active (in vitro) than the marketed natural drug colchicine against SiHa and B16F10 (six times higher potency) cell lines. Reduced toxicity (compared to colchicine) in Chang cells confirmed better site-selectivity (accordingly less side-effects) of 6C than colchicine. Aside from 6C, most of the reported molecules demonstrated good to strong in vitro anticancer activity against SiHa and B16F10 cancer cell lines. Conclusions Stereochemical preferences of the cis-β-lactams over their trans-counterparts, toward the molecular target β-tubulin, was confirmed by docking studies and in vitro anticancer evaluation. Apoptosis was identified as the cause of cell death. The lead 6C exhibited higher potency and selectivity than the marketed drug colchicine both in silico as well as in vitro. PMID:28562328

Effect of chronic kidney disease on warfarin management in a pharmacist-managed anticoagulation clinic.

PubMed

Kleinow, Megan E; Garwood, Candice L; Clemente, Jennifer L; Whittaker, Peter

2011-09-01

There is growing evidence that kidney disease affects hepatically cleared drugs. Accordingly, we hypothesized that chronic kidney disease (CKD) would disrupt anticoagulation of warfarin-treated patients and thereby increase the amount of management required to maintain appropriate anticoagulation. Specifically, we anticipated that more dose manipulations (both dose changes and transient dose adjustments) and shorter times between scheduled clinic visits would be required for anticoagulation patients with CKD. To determine how CKD affected warfarin maintenance dose, anticoagulation stability, the proportion of clinic visits that necessitated a dose manipulation (either a change in the prescribed weekly dose or a transient dose adjustment), and the length of time between scheduled visits in 2 pharmacist-managed anticoagulation clinics. Our retrospective, cohort chart review investigated warfarin response in anticoagulation clinic patients. From the clinic database of patients with an international normalized ratio (INR) target range of 2.0-3.0, we matched 20 of 24 patients with CKD (estimated creatinine clearance less than 60 mL per minute) to 20 comparison group patients (estimated creatinine clearance greater than 60 mL per minute) based on parameters demonstrated to affect warfarin dose: ethnicity, gender, age, body surface area, and simvastatin use. We calculated the average weekly dose used to maintain target INR (assessment period range=116-1,408 days). To evaluate anticoagulation stability and patient management, we quantified several parameters, including the percentage of total time in therapeutic range, the proportion of clinic visits that required a dose change, and the time between scheduled visits. We compared group means using t-tests, and categorical data were compared using Fisher's exact test. Our population was predominantly female (75%) and of African ancestry (95%); average age 60 years. Patients with CKD required a 24% lower dose than the comparison group (mean [SD]=35.9 [10.7] vs. 47.0 [11.2] mg per week, P=0.003) and spent less time in therapeutic range required increased clinic management versus the comparison group, as indicated by a significantly higher proportion of clinic visits at which dose changes occurred (22% vs. 12%, P<0.001) and a decreased time between scheduled visits (mean [SD] of 16.0 [3.2] days vs. 19.7 [3.4] days, respectively, P=0.001). CKD was associated with both decreased warfarin maintenance dose and decreased anticoagulation stability which, in turn, required more frequent and intensive anticoagulation clinic management.

Safety of orally administered, USP-compliant levothyroxine sodium tablets in dogs.

PubMed

Hare, J E; Morrow, C M K; Caldwell, J; Lloyd, W E

2018-04-01

The safety of synthetic levothyroxine sodium tablets (Thyro-Tabs® Canine; LLOYD, Inc.) in dogs was evaluated in a randomized, sham-dose controlled, parallel-group study. Young, healthy, euthyroid Beagle dogs were randomized into four groups (four females and four males per group) and received single daily doses of 0×, 2× (0.044 mg/kg), 6× (0.132 mg/kg), or 10× (0.22 mg/kg) the labeled starting dose of 0.022 mg kg -1  day -1 for 182 days. Every 2 weeks, physical examinations, electrocardiology examinations, and sample collections for thyroid panel, hematology, serum biochemistry, coagulation panel, and urinalysis were performed. At the end of the study, the dogs were euthanized and full necropsies performed. The most overt finding was the expected dose-dependent increase in serum concentrations of total and free thyroxine with dose-dependent suppression of the hypothalamic-pituitary-thyroid axis as evidenced by decreased serum thyroid-stimulating hormone concentrations, decreased thyroid+parathyroid/body weight ratios, and a trend for decreased pituitary weight/brain weight ratios. Clinical signs of thyrotoxicosis (excitation, tachypnea, tachycardia) in the treated dogs were sporadic with no dose-response relationship. Other findings statistically associated with levothyroxine treatment were generally mild and not clinically important. In summary, doses of levothyroxine sodium up to 10× the labeled starting dose were well tolerated in healthy dogs. © 2017 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Effect of Metoprolol Succinate in Patients with Stable Angina and Elevated Heart Rate Receiving Low-Dose β-Blocker Therapy.

PubMed

Jiang, Jie; Cong, Hongliang; Zhang, Yan; Li, Zhanquan; Tao, Guizhou; Li, Xiaodong; Qing, Liang; Tan, Ning; Zhao, Zhichen; Dong, Yugang; Ji, Zheng; Chen, Yundai; Ge, Junbo; He, Ben; Sun, Yingxian; Cao, Kejiang; Huo, Yong

2017-01-01

Aims: β-blockers are underused in Chinese patients with coronary heart disease. The prescribed dose is often low. The aim of this study was to investigate the effect of metoprolol succinate doses of 95 mg and 190 mg on heart rate (HR) control, as well as drug tolerance, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Methods: This was a multicenter, randomized, open-label, parallel-group trial in 15 clinical sites. Patients with stable angina, taking low-dose β-blockers (equivalent to metoprolol succinate 23.75-47.5 mg/day), and having a resting HR of ≥ 65 bpm were enrolled and randomized to either the metoprolol 95-mg group or the 190-mg group. The change in 24-h average HR from baseline recorded by Holter monitoring and the percentages of patients with resting HR controlled to ≤ 60 bpm were compared between the two groups. Results: Two hundred thirty-one patients entered the intent-to-treat population for the main analysis. The change in 24-h average HR from baseline was -0.62 ± 0.66 bpm in the 95 mg group and -2.99 ± 0.62 bpm in the 190 mg group (p = 0.0077) after 8 weeks of treatment. The percentages of patients with resting HR controlled to ≤ 60 bpm were 24.1% (95% CI: 16.35%, 31.93%) and 40.0% (95% CI: 31.05%, 48.95%), respectively (p = 0.0019). Only 4 and 2 of the patients, respectively, discontinued the study drugs because of hypotension or bradycardia. Conclusions: The metoprolol succinate dose of 190 mg is superior to the 95 mg dose in terms of HR control, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Both doses were well tolerated.

Effect of Metoprolol Succinate in Patients with Stable Angina and Elevated Heart Rate Receiving Low-Dose β-Blocker Therapy

PubMed Central

Jiang, Jie; Cong, Hongliang; Zhang, Yan; Li, Zhanquan; Tao, Guizhou; Li, Xiaodong; Qing, Liang; Tan, Ning; Zhao, Zhichen; Dong, Yugang; Ji, Zheng; Chen, Yundai; Ge, Junbo; He, Ben; Sun, Yingxian; Cao, Kejiang; Huo, Yong

2017-01-01

Aims: β-blockers are underused in Chinese patients with coronary heart disease. The prescribed dose is often low. The aim of this study was to investigate the effect of metoprolol succinate doses of 95 mg and 190 mg on heart rate (HR) control, as well as drug tolerance, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Methods: This was a multicenter, randomized, open-label, parallel-group trial in 15 clinical sites. Patients with stable angina, taking low-dose β-blockers (equivalent to metoprolol succinate 23.75-47.5 mg/day), and having a resting HR of ≥ 65 bpm were enrolled and randomized to either the metoprolol 95-mg group or the 190-mg group. The change in 24-h average HR from baseline recorded by Holter monitoring and the percentages of patients with resting HR controlled to ≤ 60 bpm were compared between the two groups. Results: Two hundred thirty-one patients entered the intent-to-treat population for the main analysis. The change in 24-h average HR from baseline was -0.62 ± 0.66 bpm in the 95 mg group and -2.99 ± 0.62 bpm in the 190 mg group (p = 0.0077) after 8 weeks of treatment. The percentages of patients with resting HR controlled to ≤ 60 bpm were 24.1% (95% CI: 16.35%, 31.93%) and 40.0% (95% CI: 31.05%, 48.95%), respectively (p = 0.0019). Only 4 and 2 of the patients, respectively, discontinued the study drugs because of hypotension or bradycardia. Conclusions: The metoprolol succinate dose of 190 mg is superior to the 95 mg dose in terms of HR control, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Both doses were well tolerated. PMID:28539824

Reference Dosimetry according to the New German Protocol DIN 6800-2 and Comparison with IAEA TRS 398 and AAPM TG 51*

PubMed Central

Zakaria, A; Schuette, W; Younan, C

2011-01-01

The preceding DIN 6800-2 (1997) protocol has been revised by a German task group and its latest version was published in March 2008 as the national standard dosimetry protocol DIN 6800-2 (2008 March). Since then, in Germany the determination of absorbed dose to water for high-energy photon and electron beams has to be performed according to this new German dosimetry protocol. The IAEA Code of Practice TRS 398 (2000) and the AAPM TG-51 are the two main protocols applied internationally. The new German version has widely adapted the methodology and dosimetric data of TRS-398. This paper investigates systematically the DIN 6800-2 protocol and compares it with the procedures and results obtained by using the international protocols. The investigation was performed with 6 MV and 18 MV photon beams as well as with electron beams from 5 MeV to 21 MeV. While only cylindrical chambers were used for photon beams, the measurements of electron beams were performed by using cylindrical and plane-parallel chambers. It was found that the discrepancies in the determination of absorbed dose to water among the three protocols were 0.23% for photon beams and 1.2% for electron beams. The determination of water absorbed dose was also checked by a national audit procedure using TLDs. The comparison between the measurements following the DIN 6800-2 protocol and the TLD audit-procedure confirmed a difference of less than 2%. The advantage of the new German protocol DIN 6800-2 lies in the renouncement on the cross calibration procedure as well as its clear presentation of formulas and parameters. In the past, the different protocols evoluted differently from time to time. Fortunately today, a good convergence has been obtained in concepts and methods. PMID:22287987

Reference Dosimetry according to the New German Protocol DIN 6800-2 and Comparison with IAEA TRS 398 and AAPM TG 51.

PubMed

Zakaria, A; Schuette, W; Younan, C

2011-04-01

The preceding DIN 6800-2 (1997) protocol has been revised by a German task group and its latest version was published in March 2008 as the national standard dosimetry protocol DIN 6800-2 (2008 March). Since then, in Germany the determination of absorbed dose to water for high-energy photon and electron beams has to be performed according to this new German dosimetry protocol. The IAEA Code of Practice TRS 398 (2000) and the AAPM TG-51 are the two main protocols applied internationally. The new German version has widely adapted the methodology and dosimetric data of TRS-398. This paper investigates systematically the DIN 6800-2 protocol and compares it with the procedures and results obtained by using the international protocols. The investigation was performed with 6 MV and 18 MV photon beams as well as with electron beams from 5 MeV to 21 MeV. While only cylindrical chambers were used for photon beams, the measurements of electron beams were performed by using cylindrical and plane-parallel chambers. It was found that the discrepancies in the determination of absorbed dose to water among the three protocols were 0.23% for photon beams and 1.2% for electron beams. The determination of water absorbed dose was also checked by a national audit procedure using TLDs. The comparison between the measurements following the DIN 6800-2 protocol and the TLD audit-procedure confirmed a difference of less than 2%. The advantage of the new German protocol DIN 6800-2 lies in the renouncement on the cross calibration procedure as well as its clear presentation of formulas and parameters. In the past, the different protocols evoluted differently from time to time. Fortunately today, a good convergence has been obtained in concepts and methods.

Combined extracts of Urtica dioica and Pygeum africanum in the treatment of benign prostatic hyperplasia: double-blind comparison of two doses.

PubMed

Krzeski, T; Kazón, M; Borkowski, A; Witeska, A; Kuczera, J

1993-01-01

The 134 patients (aged 53 to 84 years) with symptoms of benign prostatic hyperplasia were drawn from two medical centers in Warsaw. The patients were randomly assigned to receive two capsules of the standard dose of an urtica/pygeum preparation (300 mg of Urtica dioica root extract combined with 25 mg of Pygeum africanum bark extract) or two capsules containing half the standard dose twice daily for 8 weeks. After 28 days' treatment, urine flow, residual urine, and nycturia were significantly reduced in both treatment groups. After 56 days' treatment, further significant decreases were found in residual urine (half-dose group) and in nycturia (both groups). There were no between-group differences in these measures of efficacy. Five patients reported adverse effects of treatment; treatment was not discontinued in any patient because of side effects. It is concluded that half doses of the urtica/pygeum extract are as safe and effective as the recommended full doses.

High dose vitamin D may improve lower urinary tract symptoms in postmenopausal women.

PubMed

Oberg, Johanna; Verelst, Margareta; Jorde, Rolf; Cashman, Kevin; Grimnes, Guri

2017-10-01

Lower urinary tract symptoms (LUTS) are common in postmenopausal women, and have been reported inversely associated with vitamin D intake and serum 25-hydroxyvitamin D (25(OH)D) levels. The aim of this study was to investigate if high dose vitamin D supplementation would affect LUTS in comparison to standard dose. In a randomized controlled study including 297 postmenopausal women with low bone mineral density, the participants were allocated to receive capsules of 20 000IU of vitamin D 3 twice a week (high dose group) or similar looking placebo (standard dose group). In addition, all the participants received 1g of calcium and 800IU of vitamin D daily. A validated questionnaire regarding LUTS was filled in at baseline and after 12 months. At baseline, 76 women in the high dose group and 82 in the standard dose group reported any LUTS. Levels of serum 25(OH)D increased significantly more in the high dose group (from 64.7 to 164.1nmol/l compared to from 64.1 to 81.8nmol/l, p<0.01). No differences between the groups were seen regarding change in LUTS except for a statistically significant reduction in the reported severity of urine incontinence in the high dose group as compared to the standard dose group after one year (p<0.05). The results need confirmation in a study specifically designed for this purpose. Copyright © 2017 Elsevier Ltd. All rights reserved.

A comparison between orthogonal and parallel plating methods for distal humerus fractures: a prospective randomized trial.

PubMed

Lee, Sang Ki; Kim, Kap Jung; Park, Kyung Hoon; Choy, Won Sik

2014-10-01

With the continuing improvements in implants for distal humerus fractures, it is expected that newer types of plates, which are anatomically precontoured, thinner and less irritating to soft tissue, would have comparable outcomes when used in a clinical study. The purpose of this study was to compare the clinical and radiographic outcomes in patients with distal humerus fractures who were treated with orthogonal and parallel plating methods using precontoured distal humerus plates. Sixty-seven patients with a mean age of 55.4 years (range 22-90 years) were included in this prospective study. The subjects were randomly assigned to receive 1 of 2 treatments: orthogonal or parallel plating. The following results were assessed: operating time, time to fracture union, presence of a step or gap at the articular margin, varus-valgus angulation, functional recovery, and complications. No intergroup differences were observed based on radiological and clinical results between the groups. In our practice, no significant differences were found between the orthogonal and parallel plating methods in terms of clinical outcomes, mean operation time, union time, or complication rates. There were no cases of fracture nonunion in either group; heterotrophic ossification was found 3 patients in orthogonal plating group and 2 patients in parallel plating group. In our practice, no significant differences were found between the orthogonal and parallel plating methods in terms of clinical outcomes or complication rates. However, orthogonal plating method may be preferred in cases of coronal shear fractures, where posterior to anterior fixation may provide additional stability to the intraarticular fractures. Additionally, parallel plating method may be the preferred technique used for fractures that occur at the most distal end of the humerus.

Technical Note: Scanning of parallel-plate ionization chamber and diamond detector for measurements of water-dose profiles in the vicinity of a narrow x-ray microbeam.

PubMed

Nariyama, Nobuteru

2017-12-01

Scanning of dosimeters facilitates dose distribution measurements with fine spatial resolutions. This paper presents a method of conversion of the scanning results to water-dose profiles and provides an experimental verification. An Advanced Markus chamber and a diamond detector were scanned at a resolution of 6 μm near the beam edges during irradiation with a 25-μm-wide white narrow x-ray beam from a synchrotron radiation source. For comparison, GafChromic films HD-810 and HD-V2 were also irradiated. The conversion procedure for the water dose values was simulated with Monte Carlo photon-electron transport code as a function of the x-ray incidence position. This method was deduced from nonstandard beam reference-dosimetry protocols used for high-energy x-rays. Among the calculated nonstandard beam correction factors, P wall , which is the ratio of the absorbed dose in the sensitive volume of the chamber with water wall to that with a polymethyl methacrylate wall, was found to be the most influential correction factor in most conditions. The total correction factor ranged from 1.7 to 2.7 for the Advanced Markus chamber and from 1.15 to 1.86 for the diamond detector as a function of the x-ray incidence position. The water dose values obtained with the Advanced Markus chamber and the HD-810 film were in agreement in the vicinity of the beam, within 35% and 18% for the upper and lower sides of the beam respectively. The beam width obtained from the diamond detector was greater, and the doses out of the beam were smaller than the doses of the others. The comparison between the Advanced Markus chamber and HD-810 revealed that the dose obtained with the scanned chamber could be converted to the water dose around the beam by applying nonstandard beam reference-dosimetry protocols. © 2017 American Association of Physicists in Medicine.

Mechanistic simulation of normal-tissue damage in radiotherapy—implications for dose-volume analyses

NASA Astrophysics Data System (ADS)

Rutkowska, Eva; Baker, Colin; Nahum, Alan

2010-04-01

A radiobiologically based 3D model of normal tissue has been developed in which complications are generated when 'irradiated'. The aim is to provide insight into the connection between dose-distribution characteristics, different organ architectures and complication rates beyond that obtainable with simple DVH-based analytical NTCP models. In this model the organ consists of a large number of functional subunits (FSUs), populated by stem cells which are killed according to the LQ model. A complication is triggered if the density of FSUs in any 'critical functioning volume' (CFV) falls below some threshold. The (fractional) CFV determines the organ architecture and can be varied continuously from small (series-like behaviour) to large (parallel-like). A key feature of the model is its ability to account for the spatial dependence of dose distributions. Simulations were carried out to investigate correlations between dose-volume parameters and the incidence of 'complications' using different pseudo-clinical dose distributions. Correlations between dose-volume parameters and outcome depended on characteristics of the dose distributions and on organ architecture. As anticipated, the mean dose and V20 correlated most strongly with outcome for a parallel organ, and the maximum dose for a serial organ. Interestingly better correlation was obtained between the 3D computer model and the LKB model with dose distributions typical for serial organs than with those typical for parallel organs. This work links the results of dose-volume analyses to dataset characteristics typical for serial and parallel organs and it may help investigators interpret the results from clinical studies.

Oral antiviral therapy for prevention of genital herpes outbreaks in immunocompetent and nonpregnant patients.

PubMed

Le Cleach, Laurence; Trinquart, Ludovic; Do, Giao; Maruani, Annabel; Lebrun-Vignes, Benedicte; Ravaud, Philippe; Chosidow, Olivier

2014-08-03

Genital herpes is caused by herpes simplex virus 1 (HSV-1) or 2 (HSV-2). Some infected people experience outbreaks of genital herpes, typically, characterized by vesicular and erosive localized painful genital lesions. To compare the effectiveness and safety of three oral antiviral drugs (acyclovir, famciclovir and valacyclovir) prescribed to suppress genital herpes outbreaks in non-pregnant patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the search portal of the World Health Organization International Clinical Trials Registry Platform and pharmaceutical company databases up to February 2014. We also searched US Food and Drug Administration databases and proceedings of seven congresses to a maximum of 10 years. We contacted trial authors and pharmaceutical companies. We selected parallel-group and cross-over randomized controlled trials including patients with recurrent genital herpes caused by HSV, whatever the type (HSV-1, HSV-2, or undetermined), with at least four recurrences per year (trials concerning human immunodeficiency virus (HIV)-positive patients or pregnant women were not eligible) and comparing suppressive oral antiviral treatment with oral acyclovir, famciclovir, and valacyclovir versus placebo or another suppressive oral antiviral treatment. Two review authors independently selected eligible trials and extracted data. The Risk of bias tool was used to assess risk of bias. Treatment effect was measured by the risk ratio (RR) of having at least one genital herpes recurrence. Pooled RRs were derived by conventional pairwise meta-analyses. A network meta-analysis allowed for estimation of all possible two-by-two comparisons between antiviral drugs. A total of 26 trials (among which six had a cross-over design) were included. Among the 6950 randomly assigned participants, 54% (range 0 to 100%) were female, mean age was 35 years (range 26 to 45.1), and the mean number of recurrences per year was 11 (range 6.3 to 17.8). Duration of treatment was two to 12 months. Risk of bias was considered high for half of the studies and unclear for the other half. A total of 14 trials compared acyclovir versus placebo, four trials compared valacyclovir versus placebo and 2 trials compared valacyclovir versus no treatment. Three trials compared famciclovir versus placebo. Two trials compared valacyclovir versus famciclovir and one trial compared acyclovir versus valacyclovir versus placebo.We analyzed data from 22 trials for the outcome: risk of having at least one clinical recurrence. We could not obtain the outcome data for four trials. In placebo-controlled trials, there was a low quality evidence that the risk of having at least one clinical recurrence was reduced with acyclovir (nine parallel-group trials, n = 2049; pooled RR 0.48, 95% confidence interval (CI) 0.39 to 0.58), valacyclovir (four trials, n = 1788; pooled RR 0.41, 95% CI 0.24 to 0.69), or famciclovir (two trials, n = 732; pooled RR 0.57, 95% CI 0.50 to 0.64). The six cross-over trials showed larger treatment effects on average than the parallel-group trials. We found evidence of a small-study effect for acyclovir placebo-controlled trials (adjusted pooled RR 0.61, 95% CI 0.49 to 0.75). In analyzing parallel-group trials by daily dose, no clear evidence was found of a dose-response relationship for any drug. In head-to-head trials, the risk of having at least one recurrence was increased with valacyclovir rather than acyclovir (one trial, n = 1345; RR 1.16, 95% CI 1.01 to 1.34) and was not significantly different from that seen with famciclovir as compared with valacyclovir (one trial, n = 320; RR 1.18, 95% CI 0.86 to 1.63).We included 16 parallel-arm trials in a network meta-analysis and we were unable to determine which of the drugs was most effective in reducing the risk of at least one clinical recurrence (after adjustment for small-study effects, pooled RR 0.83, 95% CI 0.61 to 1.11 for valacyclovir vs acyclovir; pooled RR 1.04, 95% CI, 0.71 to 1.49 for famciclovir vs acyclovir; and pooled RR 1.26, 95% CI 0.89 to 1.75 for famciclovir vs valacyclovir). Safety data were sought but were reported as total numbers of adverse events. Owing to risk of bias and inconsistency, there is low quality evidence that suppressive antiviral therapy with acyclovir, valacyclovir or famciclovir in pacients experiencing at least four recurrences of genital herpes per year decreases the number of pacients with at least one recurrence as compared with placebo. Network meta-analysis of the few direct comparisons and the indirect comparisons did not show superiority of one drug over another.

[Meta analysis of parallel versus perpendicular double plating for distal humerus fracture of type C in adults].

PubMed

Li, B B; Lin, F; Cai, L H; Chen, Y; Lin, Z J

2017-08-01

Objective: To evaluate the effects of parallel versus perpendicular double plating for distal humerus fracture of type C. Methods: A standardized comprehensive literature search was performed by PubMed, Embase, Cochrane library, CMB, CNKI and Medline datebase.Randomized controlled studies on comparison between parallel versus perpendicular double plating for distal humerus fracture of type C before December 2015 were enrolled in the study.All date were analyzed by the RevMan 5.2 software. Results: Six studies, including 284 patients, met the inclusion criteria.There were 155 patients in perpendicular double plating group, 129 patients in parallel double plating group.The results of Meta-analysis indicated that there were statistically significant difference between the two groups in complications ( OR =2.59, 95% CI : 1.03 to 6.53, P =0.04). There was no significant difference between the two groups in surgical duration ( MD =-1.84, 95% CI : -9.06 to 5.39, P =0.62), bone union time ( MD =0.09, 95% CI : -0.06 to 0.24, P =0.22), Mayo Elbow Performance Score ( MD =0.09, 95% CI : -0.06 to 0.24, P =0.22), Range of Motions ( MD =-0.92, 95% CI : -4.65 to 2.81, P =0.63) and the rate of excellent and good results ( OR =0.64, 95% CI : 0.27 to 1.52, P =0.31). Conclusion: Both perpendicular and parallel double plating are effective in distal humerus fracture of type C, parallel double plating has less complications.

A study on the suitability of the PTW microDiamond detector for kilovoltage x-ray beam dosimetry.

PubMed

Damodar, Joshita; Odgers, David; Pope, Dane; Hill, Robin

2018-05-01

Kilovoltage x-ray beams are widely used in treating skin cancers and in biological irradiators. In this work, we have evaluated four dosimeters (ionization chambers and solid state detectors) in their suitability for relative dosimetry of kilovoltage x-ray beams in the energy range of 50 - 280kVp. The solid state detectors, which have not been investigated with low energy x-rays, were the PTW 60019 microDiamond synthetic diamond detector and the PTW 60012 diode. The two ionization chambers used were the PTW Advanced Markus parallel plate chamber and the PTW PinPoint small volume chamber. For each of the dosimeters, percentage depth doses were measured in water over the full range of x-ray beams and for field sizes ranging from 2cm diameter to 12 × 12cm. In addition, depth doses were measured for a narrow aperture (7mm diameter) using the PTW microDiamond detector. For comparison, the measured data was compared with Monte Carlo calculated doses using the EGSnrc Monte Carlo package. The depth dose results indicate that the Advanced Markus parallel plate and PinPoint ionization chambers were suitable for depth dose measurements in the beam quality range with an uncertainty of less than 3%, including in the regions closer to the surface of the water as compared with Monte Carlo depth dose data for all six energy beams. The response of the PTW Diode E detector was accurate to within 4% for all field sizes in the energy range of 50-125kVp but showed larger variations for higher energies of up to 12% with the 12 × 12cm field size. In comparison, the microDiamond detector had good agreement over all energies for both smaller and larger field sizes generally within 1% as compared to the Advanced Markus chamber field and Monte Carlo calculations. The only exceptions were in measuring the dose at the surface of the water phantom where larger differences were found. For the 7mm diameter field, the agreement between the microDiamond detector and Monte Carlo calculations was good being better than 1% except at the surface. Based on these results, the PTW microDiamond detector has shown to be a suitable detector for relative dosimetry of low energy x-ray beams over a wide range of x-ray beam energies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparison of metoprolol succinate versus carvedilol in time to cardiovascular admission in a Veterans Affairs healthcare system: An observational study.

PubMed

Church, Kara M; Henalt, Robert; Baker, Errol; Smith, Gary L; Brennan, Michael T; Joseph, Jacob

2015-12-01

To determine if metoprolol succinate or carvedilol is more effective in delaying the time to first cardiovascular disease hospital admission in systolic heart failure patients. As a secondary objective, to determine the most effective dose of each agent in delaying first cardiovascular disease hospital admission, including but not limited to heart failure exacerbation, myocardial infarction, ischemic heart disease, cardiac arrhythmias, or death. This study was a retrospective chart review of 272 veterans at the VA Boston Healthcare System newly started on metoprolol succinate (n = 157) or carvedilol (n = 115) between January 2000 and December 2008. After an 8-week study medication titration period, subjects were subcategorized into low-, medium-, and high-dose ranging groups and followed until the first cardiovascular disease hospitalization, death, or 365 days. The main outcome measure was time to first cardiovascular hospitalization or death. The mean age (69.9 years vs. 67.9 years) and ejection fraction (26% vs. 25%) were comparable between study arms at baseline. Mean time to first cardiovascular disease hospitalization was significantly different (p = 0.001) between study groups with 330.6 days with in metoprolol succinate group vs. 282.6 days in the carvedilol groups. High-dose carvedilol significantly delayed time to first hospitalization in comparison to medium or low carvedilol doses (p = 0.015, p = 0.005). Low- and high-dose metoprolol succinate were not significantly different (p = 0.509) in time to first event, and both dosing groups fared better compared to medium dose metoprolol succinate (p = 0.046). In this veteran patient population in need of additional heart failure treatments, metoprolol succinate use resulted in a delayed time to first cardiovascular disease hospitalization or death compared to carvedilol. Both low and high doses of metoprolol succinate showed a significant delay of time to first cardiovascular hospitalization compared to medium doses of metoprolol succinate. Higher doses of carvedilol showed a significant delay of time to cardiovascular hospitalization than lower carvedilol doses. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Radiation exposure due to local fallout from Soviet atmospheric nuclear weapons testing in Kazakhstan: solid cancer mortality in the Semipalatinsk historical cohort, 1960-1999.

PubMed

Bauer, Susanne; Gusev, Boris I; Pivina, Ludmila M; Apsalikov, Kazbek N; Grosche, Bernd

2005-10-01

Little information is available on the health effects of exposures to fallout from Soviet nuclear weapons testing and on the combined external and internal environmental exposures that have resulted from these tests. This paper reports the first analysis of the Semipalatinsk historical cohort exposed in the vicinity of the Semipalatinsk nuclear test site, Kazakhstan. The cohort study, which includes 19,545 inhabitants of exposed and comparison villages of the Semipalatinsk region, was set up in the 1960s and comprises 582,750 person-years of follow-up between 1960 and 1999. Cumulative effective radiation dose estimates in this cohort range from 20 mSv to approximately 4 Sv. Rates of mortality and cancer mortality in the exposed group substantially exceeded those of the comparison group. Dose-response analyses within the exposed group confirmed a significant trend with dose for all solid cancers (P < 0.0001) and for digestive and respiratory cancers (P = 0.0255 and P < 0.0001), whereas no consistent dose-response trend was found for all causes of death (P = 0.4296). Regarding specific cancer sites, a significant trend with dose was observed for lung cancer (P = 0.0001), stomach cancer (P = 0.0050), and female breast cancer (P = 0.0040) as well as for esophagus cancer in women (P = 0.0030). The excess relative risk per sievert for all solid cancers combined was 1.77 (1.35; 2.27) based on the total cohort data, yet a selection bias regarding the comparison group could not be entirely ruled out. The excess relative risk per sievert based on the cohort's exposed group was 0.81 (0.46; 1.33) for all solid cancers combined and thus still exceeds current risk estimates from the Life Span Study. Future epidemiological assessments based on this cohort will benefit from extension of follow-up and ongoing validation of dosimetric data.

A controlled trial of nandrolone decanoate in the treatment of rheumatoid arthritis in postmenopausal women.

PubMed Central

Bird, H A; Burkinshaw, L; Pearson, D; Atkinson, P J; Leatham, P A; Hill, J; Raven, A; Wright, V

1987-01-01

To determine whether an anabolic steroid had any benefit in the treatment of rheumatoid arthritis 47 patients entered a parallel group study. Twenty four received nandrolone decanoate 50 mg intramuscularly every third week for two years and 23 patients received no anabolic steroids. Other therapy was unaltered. Patients attended for clinical and biochemical assessments as well as the objective assessments of elementary body composition by in vivo neutron activation analysis and measurement of the mineral content of the distal femur by single photon absorptiometry on five occasions. A modest clinical deterioration (except for grip strength) was seen in both groups. No significant changes in calcium or alkaline phosphatase were seen. There was no significant change in total body calcium, total body phosphorus, body weight, or bone index/bone width measurements in either group. Significant increases occurred in total body nitrogen, total body potassium, haemoglobin, and packed cell volume (by six months) in the group treated with nandrolone decanoate. Comparison of 10 patients in the group treated with nandrolone decanoate also receiving oral steroid therapy with 14 patients in this group not receiving oral steroid therapy showed no significant differences. The main side effect of nandrolone decanoate was hoarseness. No radiological changes were seen. Nandrolone decanoate, in a dose that produces a significant anabolic effect, has no demonstrable action on bone metabolism in rheumatoid arthritis but may improve the chronic anaemia by six months. PMID:3555359

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

PubMed

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

2017-12-01

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

Comparative response to single or divided doses of parenteral iron for functional iron deficiency in hemodialysis patients receiving erythropoietin (EPO).

PubMed

Saltissi, D; Sauvage, D; Westhuyzen, J

1998-01-01

EPO treatment rapidly corrects anemia in patients with end-stage renal failure treated with hemodialysis, as long as sufficient iron is available. Absolute and relative (to demand) iron deficiency blunts the erythropoietic response and parenteral iron is frequently required during the course of therapy to restore EPO efficacy. Since the optimum time course of iron administration to restore EPO response in the short term is unknown, we compared three protocols of i.v. iron dextran administration in apparent functionally iron-deficient HD patients on oral iron therapy (hemoglobin < 10.0 g/dl plus ferritin < 100 micrograms/l and/or transferrin saturation < 20%). Intravenous iron (Imferon; Fisons Pty Ltd.) was given either as a single 600 mg dose (n = 15, Group I) or in divided doses of 100 mg administered on 6 successive dialyses (n = 14, Group II) or weekly for 6 weeks (n = 14, Group III). Response was monitored for 8 weeks. No adverse effects were observed. Collectively, mean hemoglobin increased (p < 0.01) by 0.4-0.5 g/dl plateauing at 4 weeks (between group comparison, p = 0.92). Mean ferritin concentrations changed with time (p < 0.01), peaking at 2 weeks in Groups I and II and at 4 weeks in Group III. Mean transferrin saturation levels also increased during the study (p < 0.001). The between group comparisons for the trends in iron indices were significant (p < 0.01 and 0.05 respectively). As there were no clinically significant differences in hemoglobin response at 4 weeks, single dose iron infusion would seem to be the most expedient in the short term, however frequent small doses are similarly effective.

Three years of GH treatment in Turner's syndrome: complex effect of GH dosage on growth parameters. French Pediatric Clinics and Sanofi-Winthrop.

PubMed

Bertrand, A M; Chaussain, J L; Job, B; Mariani, R; Ponte, C; Rappaport, R; Rochiccioll, P; Chatelain, P

1996-06-01

There have been few studies of GH dose responses in Turner's syndrome. We have therefore compared the growth effect of two doses of subcutaneous GH: 0.45 (D1) or 0.90 (D2) IU/kg/week. Multicentre study with two parallel randomized groups treated with D1 or D2 dose for one year, then with D2 for the second and third years in both groups. Ninety-seven girls with Turner's syndrome aged from 4.8 to 16.5 years. The first mean height velocity (HV) was significantly higher with D2. At one year the girls changed from D1 to D2 showed a further acceleration in HV. During second and third years HV remained above the mean for untreated Turner girls, in both groups. Mean cumulative height gains over the 3 years were 1.06 and 1.17 SDS/CA (Ranke's Turner standard) in groups G1 and G2 respectively. Bone maturation, over 36 months, was 33.7 (G1) and 31.9 (G2) months. These results suggest that, if a higher initial GH dose is associated with a greater net initial height gain, the duration of treatment might affect the long-term results. Intermittent treatment should be considered.

SU-F-T-578: Characterization of Vidar DosimetryPro Advantage RED Scanner with Application to SBRT and SRS QA

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

Dumas, M; Wen, N

Purpose: To use Gafchromic EBT3 film to quantify key dosimetric characteristics of the Vidar DosimetryPro Advantage RED film scanner for use in SBRT/SRS QA, by analyzing scanner uniformity and dose sensitivity. Method: Gafchromic EBT3 film was used in this study. Films were irradiated using 6MV FFF and 10MV FFF beams from a Varian Edge linear accelerator, with setup of 100cm SAD at depth 5 cm. Nine doses were delivered per film, with calibration dose ranges of 1–10 Gy and 3–24 Gy for 6MV FFF, and 3–27 Gy for 10MV FFF. Films were scanned with the long side of the filmmore » parallel to the detector array. Dose calibration curves were fitted to a 3rd degree polynomial. The derivative of a calibration curve was taken to determine the scanner’s sensitivity per dose delivered (OD/Gy). Scanner non-uniformity was calculated in 2 dimensions by taking the mean of standard deviation in each row and column. Absolute dose SRS/SBRT Gamma analyses were performed with passing criteria of 3% and 1mm DTA. For comparison, Gamma analyses were also performed using an Epson Expression 10000 XL. Results: Uniformity for the Vidar scanner was 0.37% +/− 0.03% in the perpendicular to scan direction and 0.67% +/− 0.05% in the parallel to scan direction, with an overall uniformity of 0.52% +/− 0.03%. Epson red channel uniformity was 0.85% +/− 0.05% and 0.88% +/− 0.08% for the green channel. The Vidar average dose sensitivity from 1–10 Gy was 0.112 OD/Gy and 0.061 OD/Gy for 3–24 Gy. SBRT/SRS Gamma pass rates were 97.8 +/− 1.4 for Vidar and 97.5 +/− 1.4 for Epson. Conclusion: The Vidar scanner has 41% less non-uniformity compared to Epson XL10000 green channel. The dose sensitivity is 2–3 time greater for the Vidar scanner compared to the Epson in the SRS/SBRT dose range of 5–24 Gy.« less

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

PubMed

Mallat, Samir G; Tanios, Bassem Y; Itani, Houssam S; Lotfi, Tamara; McMullan, Ciaran; Gabardi, Steven; Akl, Elie A; Azzi, Jamil R

2017-08-07

The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m 2 ; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. We found moderate- to high-quality evidence of reduced risk of cytomegalovirus infection in renal transplant recipients in the mTOR inhibitor-based compared with the calcineurin inhibitor-based regimen. Our review also suggested that a combination of a mTOR inhibitor and a reduced dose of calcineurin inhibitor may be associated with similar eGFR and rates of acute rejections and serious adverse events compared with a standard calcineurin inhibitor-based regimen at the expense of higher incidence of proteinuria and wound-healing complications. Copyright © 2017 by the American Society of Nephrology.

Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer.

PubMed

Eisbruch, A; Kim, H M; Terrell, J E; Marsh, L H; Dawson, L A; Ship, J A

2001-07-01

To assess long-term xerostomia in patients receiving parotid-sparing radiation therapy (RT) for head-and-neck cancer, and to find the patient and therapy-related factors that affect its severity. From March 1994 through January 2000, 84 patients received comprehensive bilateral neck RT using conformal and multisegmental intensity-modulated RT (IMRT) aiming to spare the major salivary glands. Before RT and periodically through 2 years after the completion of RT, salivary flow rates from each of the major salivary glands were selectively measured. At the same time intervals, each patient completed an 8-item self-reported xerostomia-specific questionnaire (XQ). To gain a relative measure of the effect of RT on the minor salivary glands, whose output could not be measured, the surfaces of the oral cavity (extending to include the surface of the base of tongue) were outlined in the planning CT scans. The mean doses to the new organ ("oral cavity") were recorded. Forty-eight patients receiving unilateral neck RT were similarly studied and served as a benchmark for comparison. Factors predicting the XQ scores were analyzed using a random-effects model. The XQ was found to be reliable and valid in measuring patient-reported xerostomia. The spared salivary glands which had received moderate doses in the bilateral RT group recovered to their baseline salivary flow rates during the second year after RT, and the spared glands in the unilateral RT group, which had received very low doses, demonstrated increased salivary production beyond their pre-RT levels. The increase in the salivary flow rates during the second year after RT paralleled an improvement in xerostomia in both patient groups. The improvement in xerostomia was faster in the unilateral compared with the bilateral RT group, but the difference narrowed at 2 years. The major salivary gland flow rates had only a weak correlation with the xerostomia scores. Factors found to be independently associated with the xerostomia scores were the pre-RT baseline scores, the time since RT, and the mean doses to the major salivary glands (notably to the submandibular glands) and to the oral cavity. An improvement over time in xerostomia, occurring in tandem with rising salivary production from the spared major salivary glands, suggests a long-term clinical benefit from their sparing. The oral cavity mean dose, representing RT effect on the minor salivary glands, was found to be a significant, independent predictor of xerostomia. Thus, in addition to the major salivary glands, sparing the uninvolved oral cavity should be considered as a planning objective to further reduce xerostomia.

Monosodium glutamate induced testicular toxicity and the possible ameliorative role of vitamin E or selenium in male rats.

PubMed

Hamza, Reham Z; Al-Harbi, Mohammad S

2014-01-01

Monosodium glutamate (MSG) has been recognized as flavor enhancer that adversely affects male reproductive systems. The present study was carried out to evaluate the potential protective role of vitamin E (vit E) or selenium against MSG induced oxidative stress and histopathological changes in testis tissues of rats. Mature male Wistar rats weighing 150-200 g BW were allocated to evenly twelve groups each group of ten animals, the first group was maintained as control group, the 2nd, 3rd and 4th groups were administered MSG in three different dose levels (low, medium and high) (6, 17.5 and 60 mg/kg BW), the 5th and 6th groups were given vit E in two doses (low and high) (150 and 200 mg/kg), the 7th and 8th groups were administered selenium in two doses (low and high) (0.25 and 1 mg/kg) daily via gavage for a period of 30 days. Meanwhile the 9th and 10th groups were given combinations of MSG (high dose) and vit E while, the 11th and 12th groups were given MSG (high dose) plus selenium in two recommended doses for each one. Monosodium glutamate caused an elevation in lipid peroxidation level parallel with significant decline in SOD, CAT as well as GPx activities in testis tissues. Administration of vit E or selenium to MSG-treated groups declined lipid peroxidation, increased SOD, CAT, GPx activities. Selenium or vit E significantly reduced MSG induced histopathological changes by the entire restoration of the histological structures and the testicular antioxidant status to great extent in treated rats. In conclusion, supplementation of selenium or vit E could ameliorate the MSG induced testicular toxicity to great extent and reduce the oxidative stress on testis tissues.

Effects of Music Aerobic Exercise on Depression and Brain-Derived Neurotrophic Factor Levels in Community Dwelling Women

PubMed Central

Yeh, Shu-Hui; Lin, Li-Wei; Chuang, Yu Kuan; Liu, Cheng-Ling; Tsai, Lu-Jen; Tsuei, Feng-Shiou; Lee, Ming-Tsung; Hsiao, Chiu-Yueh; Yang, Kuender D.

2015-01-01

A randomized clinical trial was utilized to compare the improvement of depression and brain-derived neurotrophic factor (BDNF) levels between community women with and without music aerobic exercise (MAE) for 12 weeks. The MAE group involved 47 eligible participants, whereas the comparison group had 59 participants. No significant differences were recorded in the demographic characteristics between the participants in the MAE group and the comparison group. Forty-one participants in the MAE group and 26 in the comparison group completed a pre- and posttest. The MAE group displayed significant improvement in depression scores (p = 0.016), decreased depression symptoms in crying (p = 0.03), appetite (p = 0.006), and fatigue (p = 0.011). The BDNF levels of the participants significantly increased after the 12-week MAE (p = 0.042). The parallel comparison group revealed no significant changes in depression scores or BDNF levels. In summary, the 12-week MAE had a significant impact on the enhancement of BDNF levels and improvement of depression symptoms. Middle-aged community women are encouraged to exercise moderately to improve their depression symptoms and BDNF levels. PMID:26075212

Biological equivalence between LDR and PDR in cervical cancer: multifactor analysis using the linear-quadratic model.

PubMed

Couto, José Guilherme; Bravo, Isabel; Pirraco, Rui

2011-09-01

The purpose of this work was the biological comparison between Low Dose Rate (LDR) and Pulsed Dose Rate (PDR) in cervical cancer regarding the discontinuation of the afterloading system used for the LDR treatments at our Institution since December 2009. In the first phase we studied the influence of the pulse dose and the pulse time in the biological equivalence between LDR and PDR treatments using the Linear Quadratic Model (LQM). In the second phase, the equivalent dose in 2 Gy/fraction (EQD(2)) for the tumor, rectum and bladder in treatments performed with both techniques was evaluated and statistically compared. All evaluated patients had stage IIB cervical cancer and were treated with External Beam Radiotherapy (EBRT) plus two Brachytherapy (BT) applications. Data were collected from 48 patients (26 patients treated with LDR and 22 patients with PDR). In the analyses of the influence of PDR parameters in the biological equivalence between LDR and PDR treatments (Phase 1), it was calculated that if the pulse dose in PDR was kept equal to the LDR dose rate, a small the-rapeutic loss was expected. If the pulse dose was decreased, the therapeutic window became larger, but a correction in the prescribed dose was necessary. In PDR schemes with 1 hour interval between pulses, the pulse time did not influence significantly the equivalent dose. In the comparison between the groups treated with LDR and PDR (Phase 2) we concluded that they were not equivalent, because in the PDR group the total EQD(2) for the tumor, rectum and bladder was smaller than in the LDR group; the LQM estimated that a correction in the prescribed dose of 6% to 10% was ne-cessary to avoid therapeutic loss. A correction in the prescribed dose was necessary; this correction should be achieved by calculating the PDR dose equivalent to the desired LDR total dose.

Biological equivalence between LDR and PDR in cervical cancer: multifactor analysis using the linear-quadratic model

PubMed Central

Bravo, Isabel; Pirraco, Rui

2011-01-01

Purpose The purpose of this work was the biological comparison between Low Dose Rate (LDR) and Pulsed Dose Rate (PDR) in cervical cancer regarding the discontinuation of the afterloading system used for the LDR treatments at our Institution since December 2009. Material and methods In the first phase we studied the influence of the pulse dose and the pulse time in the biological equivalence between LDR and PDR treatments using the Linear Quadratic Model (LQM). In the second phase, the equivalent dose in 2 Gy/fraction (EQD2) for the tumor, rectum and bladder in treatments performed with both techniques was evaluated and statistically compared. All evaluated patients had stage IIB cervical cancer and were treated with External Beam Radiotherapy (EBRT) plus two Brachytherapy (BT) applications. Data were collected from 48 patients (26 patients treated with LDR and 22 patients with PDR). Results In the analyses of the influence of PDR parameters in the biological equivalence between LDR and PDR treatments (Phase 1), it was calculated that if the pulse dose in PDR was kept equal to the LDR dose rate, a small the-rapeutic loss was expected. If the pulse dose was decreased, the therapeutic window became larger, but a correction in the prescribed dose was necessary. In PDR schemes with 1 hour interval between pulses, the pulse time did not influence significantly the equivalent dose. In the comparison between the groups treated with LDR and PDR (Phase 2) we concluded that they were not equivalent, because in the PDR group the total EQD2 for the tumor, rectum and bladder was smaller than in the LDR group; the LQM estimated that a correction in the prescribed dose of 6% to 10% was ne-cessary to avoid therapeutic loss. Conclusions A correction in the prescribed dose was necessary; this correction should be achieved by calculating the PDR dose equivalent to the desired LDR total dose. PMID:23346123

Dose perturbation effect of metallic spinal implants in proton beam therapy.

PubMed

Jia, Yingcui; Zhao, Li; Cheng, Chee-Wai; McDonald, Mark W; Das, Indra J

2015-09-08

The purpose of this study was to investigate the effect of dose perturbations for two metallic spinal screw implants in proton beam therapy in the perpendicular and parallel beam geometry. A 5.5 mm (diameter) by 45 mm (length) stainless steel (SS) screw and a 5.5 mm by 35 mm titanium (Ti) screw commonly used for spinal fixation were CT-scanned in a hybrid phantom of water and solid water. The CT data were processed with an orthopedic metal artifact reduction (O-MAR) algorithm. Treatment plans were generated for each metal screw with a proton beam oriented, first parallel and then perpendicular, to the longitudinal axis of the screw. The calculated dose profiles were compared with measured results from a plane-parallel ion chamber and Gafchromic EBT2 films. For the perpendicular setup, the measured dose immediately downstream from the screw exhibited dose enhancement up to 12% for SS and 8% for Ti, respectively, but such dose perturbation was not observed outside the lateral edges of the screws. The TPS showed 5% and 2% dose reductions immediately at the interface for the SS nd Ti screws, respectively, and up to 9% dose enhancements within 1 cm outside of the lateral edges of the screws. The measured dose enhancement was only observed within 5 mm from the interface along the beam path. At deeper depths, the lateral dose profiles appeared to be similar between the measurement and TPS, with dose reduction in the screw shadow region and dose enhancement within 1-2 cm outside of the lateral edges of the metals. For the parallel setup, no significant dose perturbation was detected at lateral distance beyond 3 mm away from both screws. Significant dose discrepancies exist between TPS calculations and ion chamber and film measurements in close proximity of high-Z inhomogeneities. The observed dose enhancement effect with proton therapy is not correctly modeled by TPS. An extra measure of caution should be taken when evaluating dosimetry with spinal metallic implants.

Efficacy and safety of budesonide/formoterol pMDI vs budesonide pMDI in asthmatic children (6-<12 years).

PubMed

Pearlman, David S; Eckerwall, Göran; McLaren, Julie; Lamarca, Rosa; Puu, Margareta; Gilbert, Ileen; Jorup, Carin; Sandin, Kristina; Lanz, Miguel J

2017-04-01

The efficacy and safety of budesonide/formoterol pressurized metered-dose inhaler (pMDI) have been demonstrated in patients with asthma at least 12 years old. To evaluate the efficacy of 2 formoterol doses added to budesonide as fixed combinations vs budesonide alone in children 6 to younger than 12 years with asthma. This randomized, double-blinded, parallel-group, multicenter study (NCT02091986; CHASE 3) included children 6 to younger than 12 years with asthma previously receiving a medium-dose inhaled corticosteroid (ICS) or an ICS plus a long-acting β 2 -agonist. Children symptomatic during a 7-28-day run-in on low-dose ICS, 1 inhalation of budesonide dry powder inhaler 90 μg twice daily (BID), were randomized to receive 2 inhalations of budesonide/formoterol pMDI 80/4.5 μg (160/9 μg) BID (n = 92), budesonide/formoterol pMDI 80/2.25 μg (160/4.5 μg) BID (n = 95), or budesonide pMDI 80 μg (160 μg) BID (n = 92) for 12 weeks. Change in forced expiratory volume in 1 second from baseline to 1 hour after dosing (primary end point), change in forced expiratory volume in 1 second 15 minutes after dosing, and peak expiratory flow 1 hour after dosing at week 12 were statistically significantly greater for budesonide/formoterol 160/9 μg vs budesonide (P ≤ .015 for all comparisons), but not for budesonide/formoterol 160/4.5 μg vs budesonide. Bronchodilator effects, evident 15 minutes after the dose on day 1, were maintained at week 12. Incidence of protocol-defined asthma exacerbations and improvements in asthma symptom-related and quality-of-life outcomes were similar across treatments. There were no notable safety differences among treatments. Budesonide/formoterol pMDI 160/9 μg showed statistically significant and clinically meaningful lung function improvements vs budesonide pMDI 160 μg, demonstrating appropriateness as a therapeutic option for children 6 to younger than 12 years with asthma symptomatic on ICS alone. ClinicalTrials.gov Identifier: NCT02091986. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

SU-F-T-327: Total Body Irradiation In-Vivo Dose Measurements Using Optically Stimulated Luminescence (OSL) NanoDots and Farmer Type Ion Chamber

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

Kaur, H; Kumar, S; Sarkar, B

Purpose: This study was performed to analyze the agreement between optically stimulated luminescence (OSL) nanoDots measured doses and 0.6 cc Farmer type ionization chamber measured doses during total body irradiation (TBI). Methods: In-vivo dose measurements using OSL nanoDots and Farmer chamber were done in a total of twelve patients who received TBI at our center by bilateral parallel-opposed beams technique. In this technique, the patient is kept inside the TBI box which is filled with rice bags and irradiated using two bilateral parallel opposed beams of 40×40 cm{sup 2} size with 45° collimator rotation at an SSD of 333.5 cmmore » in an Elekta Synergy linear accelerator. All patients received a dose of 2 Gy in single fraction as conditioning regimen. The beams were equally weighted at the midplane of the box. The nanoDots were placed over forehead, right and left neck, right and left lung, umbilicus, right and left abdomen, medial part of thigh, knee and toe. A 0.6 cc Farmer chamber was placed in between the thighs of the patient. Measured doses are reported along with the statistical comparisons using paired sample t-test. Results: For the above sites the mean doses were 212.2±21.1, 218.2±7.6, 218.7±9.3, 215.6±9.5, 217.5±11.5, 214.5±7.7, 218.3±6.8, 221.5±15, 229.1±11.0, 220.5±7.7 and 223.3±5.1 cGy respectively. For all OSL measurements the mean dose was 218.6±11.8 cGy. Farmer chamber measurements yielded a mean dose of 208.8±15.6 cGy. Statistical analysis revealed that there was no significant difference between OSL measured doses in forehead, right and left neck, right and left lung, umbilicus, right and left abdomen and toe and Farmer chamber measured doses (0.72≤p≤0.06). However the mean OSL doses at thigh and knee were statistically different (p<0.05) from the Farmer chamber measurements. Conclusion: OSL measurements were found to be in agreement with Farmer type ionization chamber measurements in in-vivo dosimetry of TBI.« less

Using translational medicine to understand clinical differences between botulinum toxin formulations.

PubMed

Aoki, K R; Ranoux, D; Wissel, J

2006-12-01

When using botulinum toxin-based products, the physician must decide the optimal location and dose required to alleviate symptoms and improve the patient's quality of life. To deliver effective treatment, the physician needs to understand the importance of accurate target muscle selection and localization and the implications of each product's migration properties when diluted in different volumes. Pre-clinical mouse models of efficacy and safety have been utilized to compare local and distal muscle relaxation effects following defined intramuscular administration. Data from the model allow the products to be ranked based on their propensity for local efficacy versus their distal migration properties. Using standardized dilutions, the non-parallel dose-response curves for the various formulations demonstrate that they have different efficacy profiles. Distal effects were also noted at different treatment doses, which are reflected in the different safety and/or therapeutic margins. Based on these pre-clinical data, the safety and therapeutic margin rankings are ordered, largest to smallest, as BOTOX, Dysport and Myobloc. The results of subsequent clinical trials are variable and dose comparisons are inconclusive, thus supporting the regulatory position that the dose units of the individual preparations are unique and cannot be simply converted between products.

Physical and chemical mutagenesis on a mycophagous nematode Aphelenchoides composticola (M.T. Franklin, 1957) (in French)

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

Person, F.; Brun, J.

1974-01-01

Chemical mutagens as EMS, acriflavine, acridine, colchicine, nitrous acide and physical mutagens, such as X rays, have been used on the gonochoric mycophagous Nematode Aphelenchoides composticola. They show a nematicid activity due, to their toxicity on treated Nematodes and to the induction of lethal mutations affecting particularly early stages of gametogenesis. They produce abnormal strains dwarfs or giants (up to 25% of the population). Concentrations of chemical mutagens varying from 0.2 to 0.5% correspond to the optimal production of abnormalities. Similar results were obtained by irradiation near to 2000r. The action of the mutagens shows some differences: EMS and Xmore » rays generally produce dwarfs, whereas acriflavine, acridine, colchicine or nitrous acid induced only giants. Abnormal strains appear: in the F$sub 1$, generation by X rays or acridine treatments; in the F$sub 2$ or F$sub 3$ generation by acriflavine, colchicine, nitrous acid or EMS action. The abnormal strains could be either variants or mutants and from these we select: four dwarfs B, C, D, E, induced by EMS 0.5% for 24 hours appearing in the F$sub 3$ generation; or dwarf F induced by irradiation of 1500r appearing in the F$sub 1$ generation. All these selected mutants are autosomal recessive single factors D and C controlled by two alleles of the some locus. (FR)« less

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation

PubMed Central

Demidowich, Andrew P.; Davis, Angela I.; Dedhia, Nicket; Yanovski, Jack A.

2016-01-01

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. PMID:27241260

Colchicine to decrease NLRP3-activated inflammation and improve obesity-related metabolic dysregulation.

PubMed

Demidowich, Andrew P; Davis, Angela I; Dedhia, Nicket; Yanovski, Jack A

2016-07-01

Obesity is a major risk-factor for the development of insulin resistance, type 2 diabetes, and cardiovascular disease. Circulating molecules associated with obesity, such as saturated fatty acids and cholesterol crystals, stimulate the innate immune system to incite a chronic inflammatory state. Studies in mouse models suggest that suppressing the obesity-induced chronic inflammatory state may prevent or reverse obesity-associated metabolic dysregulation. Human studies, however, have been far less positive, possibly because targeted interventions were too far downstream of the inciting inflammatory events. Recently, it has been shown that, within adipose tissue macrophages, assembly of a multi-protein member of the innate immune system, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, is essential for the induction of this inflammatory state. Microtubules enable the necessary spatial arrangement of the components of the NLRP3 inflammasome in the cell, leading to its activation and propagation of the inflammatory cascade. Colchicine, a medication classically used for gout, mediates its anti-inflammatory effect by inhibiting tubulin polymerization, and has been shown to attenuate macrophage NLRP3 inflammasome arrangement and activation in vitro and in vivo. Given these findings, we hypothesize that, in at-risk individuals (those with obesity-induced inflammation and metabolic dysregulation), long-term colchicine use will lead to suppression of inflammation and thus cause improvements in insulin sensitivity and other obesity-related metabolic impairments. Published by Elsevier Ltd.

Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases.

PubMed

Crippa, Valeria; D'Agostino, Vito G; Cristofani, Riccardo; Rusmini, Paola; Cicardi, Maria E; Messi, Elio; Loffredo, Rosa; Pancher, Michael; Piccolella, Margherita; Galbiati, Mariarita; Meroni, Marco; Cereda, Cristina; Carra, Serena; Provenzani, Alessandro; Poletti, Angelo

2016-03-10

Neurodegenerative diseases (NDs) are often associated with the presence of misfolded protein inclusions. The chaperone HSPB8 is upregulated in mice, the human brain and muscle structures affected during NDs progression. HSPB8 exerts a potent pro-degradative activity on several misfolded proteins responsible for familial NDs forms. Here, we demonstrated that HSPB8 also counteracts accumulation of aberrantly localized misfolded forms of TDP-43 and its 25 KDa fragment involved in most sporadic cases of Amyotrophic Lateral Sclerosis (sALS) and of Fronto Lateral Temporal Dementia (FLTD). HSPB8 acts with BAG3 and the HSP70/HSC70-CHIP complex enhancing the autophagic removal of misfolded proteins. We performed a high-through put screening (HTS) to find small molecules capable of inducing HSPB8 in neurons for therapeutic purposes. We identified two compounds, colchicine and doxorubicin, that robustly up-regulated HSPB8 expression. Both colchicine and doxorubicin increased the expression of the master regulator of autophagy TFEB, the autophagy linker p62/SQSTM1 and the autophagosome component LC3. In line, both drugs counteracted the accumulation of TDP-43 and TDP-25 misfolded species responsible for motoneuronal death in sALS. Thus, analogs of colchicine and doxorubicin able to induce HSPB8 and with better safety and tolerability may result beneficial in NDs models.

Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate.

PubMed

Choi, Sung Won; Ryu, Ok Hee; Choi, Sun Jin; Song, In Sun; Bleyer, Anthony J; Hart, Thomas C

2005-10-01

As a consequence of uromodulin gene mutations, individuals develop precocious hyperuricemia, gout, and progressive renal failure. In vitro studies suggest that pathologic accumulation of uromodulin/Tamm-Horsfall glycoprotein (THP) occurs in the endoplasmic reticulum (ER), but the pathophysiology of renal damage is unclear. It was hypothesized that programmed cell death triggered by accumulation of misfolded THP in the ER causes progressive renal disease. Stably transfected human embryonic kidney 293 cells and immortalized thick ascending limb of Henle's loop cells with wild-type and mutated uromodulin cDNA were evaluated to test this hypothesis. Immunocytochemistry, ELISA, and deglycosylation studies indicated that accumulation of mutant THP occurred in the ER. FACS analyses showed a significant increase in early apoptosis signal in human embryonic kidney 293 and thick ascending limb of Henle's loop cells that were transfected with mutant uromodulin constructs. Colchicine and sodium 4-phenylbutyrate treatment increased secretion of THP from the ER to the cell membrane and into the culture media and significantly improved cell viability. These findings indicate that intracellular accumulation of THP facilitates apoptosis and that this may provide the pathologic mechanism responsible for the progressive renal damage associated with uromodulin gene mutations. Colchicine and sodium 4-phenylbutyrate reverse these processes and could potentially be beneficial in ameliorating the progressive renal damage in uromodulin-associated kidney diseases.

MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation.

PubMed

Zhang, Zhixiang; Meng, Tao; Yang, Na; Wang, Wei; Xiong, Bing; Chen, Yi; Ma, Lanping; Shen, Jingkang; Miao, Ze-Hong; Ding, Jian

2011-07-01

Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) -ethyl]-9-[(pyridine-3-ylmethyl)amino]pyrido[2',1':2,3]imida-zo[4,5-c]isoquinolin-5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited tubulin polymerization significantly both in tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified tubulin directly, with the K(D) value of 10.6 μM. The binding of MT119 in turn caused tubulin conformational changes as evidenced by the quenched tryptophan fluorescence, the reduction of the bis-ANS reactivity and the decreased DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to tubulin at its colchicine site. Consequently, by inhibiting tubulin polymerization, MT119 arrested different tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to vincristine-, adriamycin- or mitoxantrone-resistant cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of colchicine-site-targeted inhibitors against tubulin polymerization, which might be a promising starting point for future cancer therapeutics. Copyright © 2010 UICC.

Neuroprotection and aging of the cholinergic system: a role for the ergoline derivative nicergoline (Sermion).

PubMed

Giardino, L; Giuliani, A; Battaglia, A; Carfagna, N; Aloe, L; Calza', L

2002-01-01

The aging brain is characterized by selective neurochemical changes involving several neural populations. A deficit in the cholinergic system of the basal forebrain is thought to contribute to the development of cognitive symptoms of dementia. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. In this paper we provide evidence for the protective effect of nicergoline (Sermion) on the degeneration of cholinergic neurons induced by nerve growth factor deprivation. Nerve growth factor deprivation was induced by colchicine administration in rats 13 and 18 months old. Colchicine induces a rapid and substantial down-regulation of choline acetyltransferase messenger RNA level in the basal forebrain in untreated adult, middle-aged and old rats. Colchicine failed to cause these effects in old rats treated for 120 days with nicergoline 10 mg/kg/day, orally. Moreover, a concomitant increase of both nerve growth factor and brain-derived neurotrophic factor content was measured in the basal forebrain of old, nicergoline-treated rats. Additionally, the level of messenger RNA for the brain isoform of nitric oxide synthase in neurons of the basal forebrain was also increased in these animals. Based on the present findings, nicergoline proved to be an effective drug for preventing neuronal vulnerability due to experimentally induced nerve growth factor deprivation.

Dexmedetomidine reduces pain associated with rocuronium injection without causing a decrease in BIS values: a dose-response study.

PubMed

Joo, Jin; Baek, Jungwon; Lee, Jaemin

2014-09-01

To examine whether dexmedetomidine reduces the injection pain of propofol and rocuronium and to investigate whether the decrease in injection pain is associated with the known sedative action of dexmedetomidine. Randomized, double-blind, placebo-controlled clinical comparison study. Patients undergoing general anesthesia with intubation received 40 mg of 1% lidocaine (lidocaine group; n = 28), 0.25 μg/kg of dexmedetomidine (low-dose group; n = 27), 0.5 μg/kg of dexmedetomidine (subclinical dose group; n = 28), 1.0 μg/kg of dexmedetomidine (clinical dose group, n = 27), or normal saline (saline group; n = 28) before anesthetic induction. Pain associated with propofol and rocuronium injection was assessed using a 10-point verbal analog scale (VAS) and a 4-point withdrawal movement scale, respectively. The BIS value was measured 60 seconds after administration of the study drug, and at the time of rocuronium injection and intubation. The overall incidence of withdrawal movements due to rocuronium decreased significantly as the dose of dexmedetomidine increased (92.8%, 85.2%, 78.6%, and 51.9% in the saline, low-dose, subclinical dose, and clinical dose groups, respectively; P = 0.001). There was no significant difference in BIS values among the groups 60 seconds after study drug administration or at the time of rocuronium injection. Dexmedetomidine reduced pain associated with rocuronium injection in a dose-dependent manner. This effect was not associated with the decrease in BIS value. Copyright © 2014 Elsevier Inc. All rights reserved.

Comparison of preservative-free latanoprost and preservative-free bimatoprost in a multicenter, randomized, investigator-masked cross-over clinical trial, the SPORT trial.

PubMed

Stalmans, Ingeborg; Oddone, Francesco; Cordeiro, Maria Francesca; Hommer, Anton; Montesano, Giovanni; Ribeiro, Luisa; Sunaric-Mégevand, Gordana; Rossetti, Luca

2016-06-01

The aim of this study was to investigate the efficacy and safety of Bimatoprost Unit Dose Preservative Free (BUDPF) and Latanoprost Unit Dose Preservative Free (LUDPF). A prospective, randomized, investigator-masked, cross-over comparison was used. Inclusion criteria were ocular hypertension (OHT) or open-angle glaucoma (OAG) with a maximum intraocular pressure (IOP) of 21 mmHg on a preserved prostaglandin monotherapy. After 6 weeks washout, patients were randomized to BUDPF or LUDPF for 3 months and then switched to the other treatment for 3 months. IOP curves were performed at baseline and after each treatment period. Statistical analysis was performed in a R programming environment. Linear mixed modeling was used to account for repeated measures on the same subject and clustering of observations from the same center. Safety outcomes included visual acuity, adverse events, slit-lamp biomicroscopy, ocular tolerability, and optic nerve assessment. Analysis at 6 months (primary outcome) showed a 1.6 ± 0.5-mmHg difference in IOP values between LUDPF and BUDPF (p < 0.01). A mean intra-subject IOP difference of 0.9 ± 0.2 mmHg (LUDPF - BUDPF) was observed (p < 0.01).. Significant differences in IOP were observed for both drugs at 3 and at 6 months compared to baseline: -4,0 ± 0.5 mmHg for both BUDPF and LUDPF at 3 months (p < 0.01 for both drugs; p = 0.32 between the two drugs); -5.2 ± 0.5 and -3.4 ± 0.5 mmHg for BUDPF and LUDPF, respectively (both p < 0.01), at 6 months. Both drugs were tolerated well, the only statistically significant difference being lower hyperemia scores for LUDPF (albeit low for both drugs). This study demonstrates a superior efficacy of BUDPF over LUDPF in lowering IOP. The results are consistent both in the parallel comparison between the two treatment groups at 6 months as well as in the intra-subject pressure comparison.

Application of probabilistic fiber-tracking method of MR imaging to measure impact of cranial irradiation on structural brain connectivity in children treated for medulloblastoma

NASA Astrophysics Data System (ADS)

Duncan, Elizabeth C.; Reddick, Wilburn E.; Glass, John O.; Hyun, Jung Won; Ji, Qing; Li, Yimei; Gajjar, Amar

2016-03-01

We applied a modified probabilistic fiber-tracking method for the extraction of fiber pathways to quantify decreased white matter integrity as a surrogate of structural loss in connectivity due to cranial radiation therapy (CRT) as treatment for pediatric medulloblastoma. Thirty subjects were examined (n=8 average-risk, n=22 high-risk) and the groups did not differ significantly in age at examination. The pathway analysis created a structural connectome focused on sub-networks within the central executive network (CEN) for comparison between baseline and post-CRT scans and for comparison between standard and high dose CRT. A paired-wise comparison of the connectivity between baseline and post-CRT scans showed the irradiation did have a significant detrimental impact on white matter integrity (decreased fractional anisotropy (FA) and decreased axial diffusivity (AX)) in most of the CEN sub-networks. Group comparisons of the change in the connectivity revealed that patients receiving high dose CRT experienced significant AX decreases in all sub-networks while the patients receiving standard dose CRT had relatively stable AX measures across time. This study on pediatric patients with medulloblastoma demonstrated the utility of this method to identify specific sub-networks within the developing brain affected by CRT.

TH-CD-201-05: Characterization of a Novel Light-Collimating Tank Optical-CT System for 3D Dosimetry

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

Miles, D; Yoon, S; Adamovics, J

Purpose: Comprehensive 3D dosimetry is highly desirable for advanced clinical QA, but costly optical readout techniques have hindered widespread implementation. Here, we present the first results from a cost-effective Integrated-lens Dry-tank Optical Scanner (IDOS), designed for convenient 3D dosimetry readout of radiochromic plastic dosimeters (e.g. PRESAGE). Methods: The scanner incorporates a novel transparent light-collimating tank, which collimates a point light source into parallel-ray CT geometry. The tank was designed using an in-house Monte-Carlo optical ray-tracing simulation, and was cast in polyurethane using a 3D printed mould. IDOS spatial accuracy was evaluated by imaging a set of custom optical phantoms, withmore » comparison to x-ray CT images. IDOS dose measurement performance was assessed by imaging PRESAGE dosimeters irradiated with simple known dose distributions (e.g., 4 field box 6MV treatment with Varian Linac). Direct comparisons were made to images from our gold standard DLOS scanner and calculated dose distributions from a commissioned Eclipse planning system. Results: All optical CT images were reconstructed at 1mm isotropic resolution. Comparison of IDOS and x-ray CT images of the geometric phantom demonstrated excellent IDOS geometric accuracy (sub-mm) throughout the dosimeter. IDOS measured 3D dose distribution agreed well with prediction from Eclipse, with 95% gamma pass rate at 3%/3mm. Cross-scanner dose measurement gamma analysis shows >90% of pixels passing at 3%/3mm. Conclusion: The first prototype of the IDOS system has demonstrated promising performance, with accurate dosimeter readout and negligible spatial distortion. The use of optical simulations and 3D printing to create a light collimating-tank has dramatically increased convenience and reduced costs by removing the need for expensive lenses and large volumes of refractive matching fluids.« less

Determination of MLC model parameters for Monaco using commercial diode arrays.

PubMed

Kinsella, Paul; Shields, Laura; McCavana, Patrick; McClean, Brendan; Langan, Brian

2016-07-08

Multileaf collimators (MLCs) need to be characterized accurately in treatment planning systems to facilitate accurate intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT). The aim of this study was to examine the use of MapCHECK 2 and ArcCHECK diode arrays for optimizing MLC parameters in Monaco X-ray voxel Monte Carlo (XVMC) dose calculation algorithm. A series of radiation test beams designed to evaluate MLC model parameters were delivered to MapCHECK 2, ArcCHECK, and EBT3 Gafchromic film for comparison. Initial comparison of the calculated and ArcCHECK-measured dose distributions revealed it was unclear how to change the MLC parameters to gain agreement. This ambiguity arose due to an insufficient sampling of the test field dose distributions and unexpected discrepancies in the open parts of some test fields. Consequently, the XVMC MLC parameters were optimized based on MapCHECK 2 measurements. Gafchromic EBT3 film was used to verify the accuracy of MapCHECK 2 measured dose distributions. It was found that adjustment of the MLC parameters from their default values resulted in improved global gamma analysis pass rates for MapCHECK 2 measurements versus calculated dose. The lowest pass rate of any MLC-modulated test beam improved from 68.5% to 93.5% with 3% and 2 mm gamma criteria. Given the close agreement of the optimized model to both MapCHECK 2 and film, the optimized model was used as a benchmark to highlight the relatively large discrepancies in some of the test field dose distributions found with ArcCHECK. Comparison between the optimized model-calculated dose and ArcCHECK-measured dose resulted in global gamma pass rates which ranged from 70.0%-97.9% for gamma criteria of 3% and 2 mm. The simple square fields yielded high pass rates. The lower gamma pass rates were attributed to the ArcCHECK overestimating the dose in-field for the rectangular test fields whose long axis was parallel to the long axis of the ArcCHECK. Considering ArcCHECK measurement issues and the lower gamma pass rates for the MLC-modulated test beams, it was concluded that MapCHECK 2 was a more suitable detector than ArcCHECK for the optimization process. © 2016 The Authors

Clarithromycin

MedlinePlus

... used in combination with other medications to eliminate H. pylori, a bacterium that causes ulcers. Clarithromycin is ... available in U.S.), colchicine (Colcrys, Mitigare), dihydroergotamine (D.H.E. 45, Migranal), ergotamine (Ergomar, in Cafergot, in ...

Monte Carlo dose calculations of beta-emitting sources for intravascular brachytherapy: a comparison between EGS4, EGSnrc, and MCNP.

PubMed

Wang, R; Li, X A

2001-02-01

The dose parameters for the beta-particle emitting 90Sr/90Y source for intravascular brachytherapy (IVBT) have been calculated by different investigators. At a distant distance from the source, noticeable differences are seen in these parameters calculated using different Monte Carlo codes. The purpose of this work is to quantify as well as to understand these differences. We have compared a series of calculations using an EGS4, an EGSnrc, and the MCNP Monte Carlo codes. Data calculated and compared include the depth dose curve for a broad parallel beam of electrons, and radial dose distributions for point electron sources (monoenergetic or polyenergetic) and for a real 90Sr/90Y source. For the 90Sr/90Y source, the doses at the reference position (2 mm radial distance) calculated by the three code agree within 2%. However, the differences between the dose calculated by the three codes can be over 20% in the radial distance range interested in IVBT. The difference increases with radial distance from source, and reaches 30% at the tail of dose curve. These differences may be partially attributed to the different multiple scattering theories and Monte Carlo models for electron transport adopted in these three codes. Doses calculated by the EGSnrc code are more accurate than those by the EGS4. The two calculations agree within 5% for radial distance <6 mm.

Phase I trial and pharmacokinetics of the tubulin inhibitor 1069C85--a synthetic agent binding at the colchicine site designed to overcome multidrug resistance.

PubMed Central

Judson, I.; Briasoulis, E.; Raynaud, F.; Hanwell, J.; Berry, C.; Lacey, H.

1997-01-01

The orally administered tubulin-binding agent 1069C85 was developed with the hope of overcoming the multidrug resistance associated with existing anti-tubulin agents, such as the vinca alkaloids. A phase I study was performed using a single oral dose every 3 weeks, administered as a suspension reconstituted in 0.1% Tween 80 and 0.9% saline. The starting dose was 2.8 mg m-2, and dose doubling was permitted until the area under curve (AUC) was > or = 40% of that at the mouse LD10; thereafter, a modified Fibonacci scheme was used. The formulation proved to be unsatisfactory, resulting in inconsistent absorption. The terminal elimination half-life was prolonged (range 18-73.5 h). Sporadic central neurotoxicity was observed, which was grade 3 in one patient treated at 200 mg m-2. A revised formulation with micronized drug was more easily suspended and appeared to increase the bioavailability by a factor of 2-4. Severe central neurotoxicity, up to grade 4, was then observed at doses of 50-100 mg m-2. Unfortunately, toxicity was not predictable and one patient, with a previous history of partial intestinal obstruction, treated at 50 mg m-2, cleared the drug very slowly, possibly because of prolonged, delayed absorption. This patient died from pancytopenia and severe gastrointestinal damage. It was concluded that such unpredictable behaviour would be incompatible with safe evaluation in phase II studies; the trial was closed and further clinical development abandoned. PMID:9052420

Plasma homovanillic acid in schizophrenics: supportive evidence for the two-subtype hypothesis.

PubMed

Chen, T Y; Lee, C F; Lung, F W; Lee, T C; Lin, W L; Hu, W H; Yeh, E K; Chang, W H

1989-06-01

Plasma levels of homovanillic acid (pHVA), a major metabolite of dopamine (DA), were measured in a group of 51 schizophrenic inpatients before and during 6 weeks of neuroleptic treatment. Steady-state plasma drug concentrations were monitored in parallel with pHVA. Good responders (n = 22) had higher pretreatment pHVA levels as compared to poor responders (n = 22). Differential pHVA changes during neuroleptic treatment were also found between each group. The two groups did not differ significantly in terms of age, duration of illness, severity of presenting symptoms, neuroleptic, dose, or plasma drug concentration. Two hypothetical subtypes in the group of schizophrenics were proposed.

SU-D-213-05: Design, Evaluation and First Applications of a Off-Site State-Of-The-Art 3D Dosimetry System

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

Malcolm, J; Mein, S; McNiven, A

2015-06-15

Purpose: To design, construct and commission a prototype in-house three dimensional (3D) dose verification system for stereotatic body radiotherapy (SBRT) verification at an off-site partner institution. To investigate the potential of this system to achieve sufficient performance (1mm resolution, 3% noise, within 3% of true dose reading) for SBRT verification. Methods: The system was designed utilizing a parallel ray geometry instigated by precision telecentric lenses and an LED 630nm light source. Using a radiochromic dosimeter, a 3D dosimetric comparison with our gold-standard system and treatment planning software (Eclipse) was done for a four-field box treatment, under gamma passing criteria ofmore » 3%/3mm/10% dose threshold. Post off-site installation, deviations in the system’s dose readout performance was assessed by rescanning the four-field box irradiated dosimeter and using line-profiles to compare on-site and off-site mean and noise levels in four distinct dose regions. As a final step, an end-to-end test of the system was completed at the off-site location, including CT-simulation, irradiation of the dosimeter and a 3D dosimetric comparison of the planned (Pinnacle{sup 3}) to delivered dose for a spinal SBRT treatment(12 Gy per fraction). Results: The noise level in the high and medium dose regions of the four field box treatment was relatively 5% pre and post installation. This reflects the reduction in positional uncertainty through the new design. This At 1mm dose voxels, the gamma pass rates(3%,3mm) for our in-house gold standard system and the off-site system were comparable at 95.8% and 93.2% respectively. Conclusion: This work will describe the end-to-end process and results of designing, installing, and commissioning a state-of-the-art 3D dosimetry system created for verification of advanced radiation treatments including spinal radiosurgery.« less

PAEDIATRIC CT EXPOSURE PRACTICE IN THE COUNTY OF RIO DE JANEIRO: THE NEED TO ESTABLISH DIAGNOSTIC REFERENCE LEVELS.

PubMed

de Jesus, Fillipe M; Magalhães, Luis A G; Kodlulovich, Simone

2016-11-01

A pilot study of dose indicators in paediatric computed tomography (CT) was conducted to prove the need to establish diagnostic reference levels (DRLs) for the county of Rio de Janeiro. The dose descriptors were estimated from the beam dosimetry by applying the protocols used in each examination. The total patient sample included 279 children. Regarding the comparison of the dose-length product values among the hospitals, the high-resolution chest CT scans were distinguished among the three types of examinations, due to the discrepancies of 1148 % (1-5 y age group) and 2248 % (5-10 y age group) presented in Hospital A's dose-length product values relative to Hospital D's dose-length product values. The results showed that without DRL, the dose variation can be significant between hospitals in the same county for the same age group in the same examination. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Different kinetic pathways of the binding of two biphenyl analogues of colchicine to tubulin.

PubMed

Dumortier, C; Gorbunoff, M J; Andreu, J M; Engelborghs, Y

1996-04-09

The kinetics of the interaction of tubulin with two biphenyl analogues of colchicine were measured by fluorescence stopped flow. The ligands were 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB) and 2,3,4-trimethoxy-4'-acetyl-1,1'-biphenyl (TKB). The binding of both analogues is accompanied by a fluorescence increase with monophasic kinetics, which indicates that these drugs, unlike colchicine, do not discriminate between the isoforms of tubulin. The observed pseudo-first-order rate constant increases in a nonlinear way with the drug concentration, indicating that the binding of the biphenyl analogues to tubulin occurs, like colchicine, in two steps: a fast reversible equilibrium followed by an isomerization of the initial complex. Kinetic analysis shows that TCB and TKB exhibit differences in their K1 values. At 25 degrees C, these are 114,000 +/- 15,000 M(-1) for TCB and 8,300 +/- 900 M(-1) for TKB. Both molecules show a much higher affinity than colchicine for the initial binding site. Also at 25 degrees C, the k2 value is 0.66 +/- 0.04 s(-1) for TCB and 3.0 +/- 0.2 s(-1) for TKB. From the temperature dependence, a reaction enthalpy change for the initial binding (deltaH(zero)1) of 44 +/- 9 kJ x mol(-1) (TCB) and -40 +/- 14 kJ x mol(-1) (TKB) and an activation energy for the second forward step of 64 +/- 2 kJ x mol(-1) (TCB) and 101 +/- 10 kJ x mol(-1) (TKB) were calculated. The dissociation kinetics were studied by displacement experiments, in which podophyllotoxin was used as a displacing ligand. The rate constant for the second step in the off direction (k(-2)) is 0.25 +/- 0.05 s(-1) for TCB and 0.093 +/- 0.009 s(-1) for TKB at 25 degrees C. The activation energies for the backward isomerization of the complexes were found to be 86 +/- 20 kJ x mol(-1) (TCB) and 79 +/- 5 kJ x mol(-1) (TKB). Combination of these results with the kinetic parameters for association gives a full characterization of the enthalpy pathway for the binding of TCB and TKB. The pathway of TCB binding is shown to differ considerably from that of TKB binding. Since their structural difference is located in ring C', this result points to their use of the ring C' in the first binding step. The competitiveness of the binding of TCB and TKB with those of podophyllotoxin, MTC, and MDL 27048 indicates that the two biphenyls interact as well with the trimethoxyphenyl-specific subsite.

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

Granton, Patrick V.; Dubois, Ludwig; Elmpt, Wouter van

Purpose: In lung cancer radiation therapy, the dose constraints are determined mostly by healthy lung toxicity. Preclinical microirradiators are a new tool to evaluate treatment strategies closer to clinical irradiation devices. In this study, we quantified local changes in lung density symptomatic of radiation-induced lung fibrosis (RILF) after partial lung irradiation in mice by using a precision image-guided small animal irradiator integrated with micro-computed tomography (CT) imaging. Methods and Materials: C57BL/6 adult male mice (n=76) were divided into 6 groups: a control group (0 Gy) and groups irradiated with a single fraction of 4, 8, 12, 16, or 20 Gy using 5-mmmore » circular parallel-opposed fields targeting the upper right lung. A Monte Carlo model of the small animal irradiator was used for dose calculations. Following irradiation, all mice were imaged at regular intervals over 39 weeks (10 time points total). Nonrigid deformation was used to register the initial micro-CT scan to all subsequent scans. Results: Significant differences could be observed between the 3 highest (>10 Gy) and 3 lowest irradiation (<10 Gy) dose levels. A mean difference of 120 ± 10 HU between the 0- and 20-Gy groups was observed at week 39. RILF was found to be spatially limited to the irradiated portion of the lung. Conclusions: The data suggest that the severity of RILF in partial lung irradiation compared to large field irradiation in mice for the same dose is reduced, and therefore higher doses can be tolerated.« less

Evaluation of analgesic activity of Terminalia arjuna (Roxb.) Wight and Arn bark: A tribal claim.

PubMed

Gupta, Anurag; Nishteswar, K; Shukla, Vinay J; Ashok, B K

2014-01-01

Plants occupy an important place in folk medicine all over the world for centuries and indigenous communities have developed their own specific knowledge on plant resources, uses, management, and conservation. Research interest and activities in the area of ethno medicine have increased tremendously in the last decade. Currently, scientists are evincing keen interest in the scientific evaluation of ethno medical claims. Bark powder of Arjuna (Terminalia arjuna [Roxb.] Wight and Arn) is used by tribals for the management of some painful conditions. To evaluate analgesic activity of T. arjuna bark in rodents. For evaluation of analgesic activity, different experimental models, that is, the acetic acid-induced writhing syndrome in mice, formaldehyde-induced paw licking response and tail flick test in rats were designed. Experiments were carried out at two-dose levels, that is, therapeutically equivalent dose (TED) and TED × 2. Animals were divided into three groups (six animals in each group), first group serving as a control group, second and third group labeled as test drug group. Test drug at both the doses significantly decreased the writhing syndrome in comparison to control the group. In comparison to control the group, incidences of formalin-induced paw licking were reduced in test drug groups in both early and late phases of pain. In tail flick response, threshold was significantly increased in both test drug groups at every time intervals. Study showed that stem bark of T. arjuna possesses analgesic activity in all experimental models.

Superiority of 3 over 2 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine for the prevention of malaria during pregnancy in mali: a randomized controlled trial.

PubMed

Diakite, Oumou S Maïga; Maiga, Oumou M; Kayentao, Kassoum; Traoré, Boubacar T; Djimde, Abdoulaye; Traoré, Bouyagui; Diallo, Mouctar; Traoré, Mouctar; Ongoiba, Aissata; Doumtabé, Didier; Doumbo, Safiatou; Traoré, Mamadou S; Dara, Antoine; Guindo, Oumar; Karim, Diawara M; Coulibaly, Siraman; Bougoudogo, Flabou; Ter Kuile, Feiko O; Danis, Martin; Doumbo, Ogobara K

2011-08-01

In 2003, Mali introduced intermittent preventive therapy in pregnancy (ITPp) with sulfadoxine-pyrimethamine (SP) for the control of malaria in pregnancy, consisting of 2 doses of SP given in the 2nd and 3rd trimester. This widely used regimen, although very effective, leaves many women unprotected from malaria during the last 4-to-8 weeks of gestation, which is a pivotal period for fetal weight gain. The aim of the study was to compare the efficacy and safety of 3-dose versus 2-dose IPTp-SP for the prevention of placental malaria and associated low birth weight (LBW). We conducted a parallel-group, open-label, individually randomized controlled superiority trial involving 814 women of all gravidity, enrolled from April 2006 through March 2008. All women were seen at least 3 times and received either 2 (n = 401) or 3 (n = 413) doses of IPTp-SP. The primary endpoint measured was placental malaria, LBW, preterm births, and maternal anemia were secondary endpoints, and severe maternal skin reactions and neonatal jaundice were safety endpoints. Among the 96% of study subjects who were followed up until delivery, the prevalence of placental malaria was 2-fold lower in the 3-dose group (8.0%) than in the 2-dose group (16.7%); the adjusted prevalence ratio (APR) was 0.48 (95% confidence interval [CI], 0.32-0.71). LBW and preterm births were also reduced; the prevalence of LBW was 6.6% in the 3-dose group versus 13.3% in the 2-dose group (APR, 0.50; 95% CI, 0.32-0.79), and the prevalence of preterm births was 3.2% versus 8.9% (APR, 0.37; 95% CI, 0.19-0.71). No significant reductions in maternal anemia or differences in safety endpoints were observed. Adding a third dose of ITPp-SP halved the risk of placental malaria, LBW, and preterm births in all gravidae, compared with the standard 2-dose regimen, in this area of highly seasonal transmission with low levels of SP resistance. ISRCTN 74189211.

Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.

PubMed

Kopanakis, Konstantinos; Tzepi, Ira-Maria; Pistiki, Aikaterini; Carrer, Dionyssia-Pinelopi; Netea, Mihai G; Georgitsi, Marianna; Lymperi, Maria; Droggiti, Dionyssia-Irini; Liakakos, Theodoros; Machairas, Anastasios; Giamarellos-Bourboulis, Evangelos J

2013-06-01

Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dose titration of repaglinide in patients with inadequately controlled type 2 diabetes.

PubMed

Kølendorf, Klaus; Eriksson, Johan; Birkeland, Kåre I; Kjellström, Thomas; Hreidarsson, Astradur B

2004-04-01

A total of 385 drug-therapy naïve patients, with inadequately controlled type 2 diabetes, were randomised into a multinational, parallel-group study to compare two strategies for dose titration of the oral hypoglycaemic agent repaglinide. Patients were allocated to either a fasting blood glucose (FBG) monitoring group with titration target 4.4-6.1 mmol/l or to a post-prandial blood glucose (PPBG) monitoring group with titration target 4.4-8.0 mmol/l. An initial titration period of up to 8 weeks was followed by a 12-week treatment period. Glycaemic control and hypoglycaemic outcomes were compared for the respective groups. HbA(1c) decreased significantly more in the FBG monitoring group by a mean of 1.38% compared to the PPBG group by a mean of 1.22% (P=0.03). The glycaemic control targets were met by fewer patients in the FBG group than in the PPBG group (57% versus 86% (P<0.001)) despite a higher mean dose of repaglinide in the FBG group. The within-patient blood glucose variability was significantly lower in the FBG group than in the PPBG group (P<0.001). In conclusion, repaglinide lowered the HbA(1c) effectively and safely in both groups and self-monitored FBG is a suitable parameter for titration of repaglinide. Whether a lower PPBG target might be as good a guide as FBG for titration of repaglinide should be addressed in a future study.

Biomechanical Comparison of Parallel and Crossed Suture Repair for Longitudinal Meniscus Tears.

PubMed

Milchteim, Charles; Branch, Eric A; Maughon, Ty; Hughey, Jay; Anz, Adam W

2016-04-01

Longitudinal meniscus tears are commonly encountered in clinical practice. Meniscus repair devices have been previously tested and presented; however, prior studies have not evaluated repair construct designs head to head. This study compared a new-generation meniscus repair device, SpeedCinch, with a similar established device, Fast-Fix 360, and a parallel repair construct to a crossed construct. Both devices utilize self-adjusting No. 2-0 ultra-high molecular weight polyethylene (UHMWPE) and 2 polyether ether ketone (PEEK) anchors. Crossed suture repair constructs have higher failure loads and stiffness compared with simple parallel constructs. The newer repair device would exhibit similar performance to an established device. Controlled laboratory study. Sutures were placed in an open fashion into the body and posterior horn regions of the medial and lateral menisci in 16 cadaveric knees. Evaluation of 2 repair devices and 2 repair constructs created 4 groups: 2 parallel vertical sutures created with the Fast-Fix 360 (2PFF), 2 crossed vertical sutures created with the Fast-Fix 360 (2XFF), 2 parallel vertical sutures created with the SpeedCinch (2PSC), and 2 crossed vertical sutures created with the SpeedCinch (2XSC). After open placement of the repair construct, each meniscus was explanted and tested to failure on a uniaxial material testing machine. All data were checked for normality of distribution, and 1-way analysis of variance by ranks was chosen to evaluate for statistical significance of maximum failure load and stiffness between groups. Statistical significance was defined as P < .05. The mean maximum failure loads ± 95% CI (range) were 89.6 ± 16.3 N (125.7-47.8 N) (2PFF), 72.1 ± 11.7 N (103.4-47.6 N) (2XFF), 71.9 ± 15.5 N (109.4-41.3 N) (2PSC), and 79.5 ± 25.4 N (119.1-30.9 N) (2XSC). Interconstruct comparison revealed no statistical difference between all 4 constructs regarding maximum failure loads (P = .49). Stiffness values were also similar, with no statistical difference on comparison (P = .28). Both devices in the current study had similar failure load and stiffness when 2 vertical or 2 crossed sutures were tested in cadaveric human menisci. Simple parallel vertical sutures perform similarly to crossed suture patterns at the time of implantation.

Optimizing insulin secretagogue therapy in patients with type 2 diabetes: a randomized double-blind study with repaglinide.

PubMed

Schmitz, Ole; Lund, Sten; Andersen, Per Heden; Jønler, Morten; Pørksen, Nils

2002-02-01

Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA(1c) 7.3%, and BMI 32 kg/m(2)). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment. Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA(1c) levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA(1c) levels) than the same total dose of repaglinide divided into morning and evening mealtime doses. These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes.

SU-E-T-466: Implementation of An Extension Module for Dose Response Models in the TOPAS Monte Carlo Toolkit

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

Ramos-Mendez, J; Faddegon, B; Perl, J

2015-06-15

Purpose: To develop and verify an extension to TOPAS for calculation of dose response models (TCP/NTCP). TOPAS wraps and extends Geant4. Methods: The TOPAS DICOM interface was extended to include structure contours, for subsequent calculation of DVH’s and TCP/NTCP. The following dose response models were implemented: Lyman-Kutcher-Burman (LKB), critical element (CE), population based critical volume (CV), parallel-serials, a sigmoid-based model of Niemierko for NTCP and TCP, and a Poisson-based model for TCP. For verification, results for the parallel-serial and Poisson models, with 6 MV x-ray dose distributions calculated with TOPAS and Pinnacle v9.2, were compared to data from the benchmarkmore » configuration of the AAPM Task Group 166 (TG166). We provide a benchmark configuration suitable for proton therapy along with results for the implementation of the Niemierko, CV and CE models. Results: The maximum difference in DVH calculated with Pinnacle and TOPAS was 2%. Differences between TG166 data and Monte Carlo calculations of up to 4.2%±6.1% were found for the parallel-serial model and up to 1.0%±0.7% for the Poisson model (including the uncertainty due to lack of knowledge of the point spacing in TG166). For CE, CV and Niemierko models, the discrepancies between the Pinnacle and TOPAS results are 74.5%, 34.8% and 52.1% when using 29.7 cGy point spacing, the differences being highly sensitive to dose spacing. On the other hand, with our proposed benchmark configuration, the largest differences were 12.05%±0.38%, 3.74%±1.6%, 1.57%±4.9% and 1.97%±4.6% for the CE, CV, Niemierko and LKB models, respectively. Conclusion: Several dose response models were successfully implemented with the extension module. Reference data was calculated for future benchmarking. Dose response calculated for the different models varied much more widely for the TG166 benchmark than for the proposed benchmark, which had much lower sensitivity to the choice of DVH dose points. This work was supported by National Cancer Institute Grant R01CA140735.« less

TU-AB-BRC-12: Optimized Parallel MonteCarlo Dose Calculations for Secondary MU Checks

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

French, S; Nazareth, D; Bellor, M

Purpose: Secondary MU checks are an important tool used during a physics review of a treatment plan. Commercial software packages offer varying degrees of theoretical dose calculation accuracy, depending on the modality involved. Dose calculations of VMAT plans are especially prone to error due to the large approximations involved. Monte Carlo (MC) methods are not commonly used due to their long run times. We investigated two methods to increase the computational efficiency of MC dose simulations with the BEAMnrc code. Distributed computing resources, along with optimized code compilation, will allow for accurate and efficient VMAT dose calculations. Methods: The BEAMnrcmore » package was installed on a high performance computing cluster accessible to our clinic. MATLAB and PYTHON scripts were developed to convert a clinical VMAT DICOM plan into BEAMnrc input files. The BEAMnrc installation was optimized by running the VMAT simulations through profiling tools which indicated the behavior of the constituent routines in the code, e.g. the bremsstrahlung splitting routine, and the specified random number generator. This information aided in determining the most efficient compiling parallel configuration for the specific CPU’s available on our cluster, resulting in the fastest VMAT simulation times. Our method was evaluated with calculations involving 10{sup 8} – 10{sup 9} particle histories which are sufficient to verify patient dose using VMAT. Results: Parallelization allowed the calculation of patient dose on the order of 10 – 15 hours with 100 parallel jobs. Due to the compiler optimization process, further speed increases of 23% were achieved when compared with the open-source compiler BEAMnrc packages. Conclusion: Analysis of the BEAMnrc code allowed us to optimize the compiler configuration for VMAT dose calculations. In future work, the optimized MC code, in conjunction with the parallel processing capabilities of BEAMnrc, will be applied to provide accurate and efficient secondary MU checks.« less

[The role of dosed walking in the combination with elements of cognitive training in the comprehensive treatment of the patients presenting with Alzheimer's disease].

PubMed

Zimushkina, N A; Kosareva, P V; Cherkasova, V G

The objective of the present study was to evaluate the effectiveness of dosed physical exercises for the combined treatment of the patients presenting with mild to moderate dementia associated with Alzheimer's disease (AD). The comprehensive examination involved 41 patients (32 women and 9 men) with the confirmed diagnosis of 'probable' AD with stages 1 and 2 of dementia and 17 healthy volunteers comprising the group of comparison. In all the patients, the neurological examination was supplemented by neuropsychological testing. Two treatment modalities were applied, one being conventional therapy with the use of memantine at the average effective dose, the other with the combination of memantine and dosed physical exercises including elements of cognitive training. In the group of patients treated with memantine alone, changes in cognitive performances among the men did not suggest any statistically significant positive trendency whereas the results of estimation in the women based on the clock drawing test (CDT) and the Mini-Mental State Examination (MMSE) scores revealed the significant improvement of cognitive performances. The most pronounced effects were documented in the women who had received combined therapy with the inclusion of dosed physical exercises in the form of walking. The comparison of the results of the treatment with observations of the patients included in the comparison group demonstrated the improvement of frontal cognitive functioning in the patients of both sexes under the influence of the combined treatment which manifested itself as the absence of the statistically significant differences between the results of the evaluation based on the Frontal Assessment Battery (FAB) scale. The prescription of dosed physical exercises with elements of cognitive training to be applied for the treatment of the patients presenting with dementia of different severity associated with Alzheimer's disease makes it possible to optimize the outcome of the conventional medical treatment and thereby to improve the results of scoring assessments of cognitive performances based on the MMSE, FAB, and CDT scales.

Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial

PubMed Central

Rösler, Michael; Anand, Ravi; Cicin-Sain, Ana; Gauthier, Serge; Agid, Yves; Dal-Bianco, Peter; Stähelin, Hannes B; Hartman, Richard; Gharabawi, Marguirguis

1999-01-01

Objectives To assess the effects of rivastigmine on the core domains of Alzheimer’s disease. Design Prospective, randomised, multicentre, double blind, placebo controlled, parallel group trial. Patients received either placebo, 1-4 mg/day (lower dose) rivastigmine, or 6-12 mg/day (higher dose) rivastigmine. Doses were increased in one of two fixed dose ranges (1-4 mg/day or 6-12 mg/day) over the first 12 weeks with a subsequent assessment period of 14 weeks. Setting 45 centres in Europe and North America. Participants 725 patients with mild to moderately severe probable Alzheimer’s disease diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, and the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association. Outcome measures Cognitive subscale of the Alzheimer’s disease assessment scale, rating on the clinician interview based impression of change incorporating caregiver information scale, and the progressive deterioration scale. Results At the end of the study cognitive function had deteriorated among those in the placebo group. Scores on the Alzheimer’s disease assessment scale improved in patients in the higher dose group when compared with patients taking placebo (P<0.05). Significantly more patients in the higher dose group had improved by 4 points or more than had improved in the placebo group (24% (57/242) v 16% (39/238)). Global function as rated by the clinician interview scale had significantly improved among those in the higher dose group compared with those taking placebo (P<0.001), and significantly more patients in the higher dose group showed improvement than did in the placebo group (37% (80/219) v 20% (46/230)). Mean scores on the progressive deterioration scale improved from baseline in patients in the higher dose group but fell in the placebo group. Adverse events were predominantly gastrointestinal, of mild to moderate severity, transient, and occurred mainly during escalation of the dose. 23% (55/242) of those in the higher dose group, 7% (18/242) of those in the lower dose group, and 7% (16/239) of those in the placebo group discontinued treatment because of adverse events. Conclusions Rivastigmine is well tolerated and effective. It improves cognition, participation in activities of daily living, and global evaluation ratings in patients with mild to moderately severe Alzheimer’s disease. This is the first treatment to show compelling evidence of efficacy in a predominantly European population. Key messagesIn a 6 month trial rivastigmine was effective in treating the core cognitive and functional symptoms of patients with mild to moderate Alzheimer’s diseaseRivastigmine at doses of 6-12 mg/day produces clinically relevant and statistically significant improvements in cognitive and global assessments, and in activities of daily livingThe effects of rivastigmine are dose dependentRivastigmine was well tolerated in this population of elderly patients PMID:10066203

A double-blind, randomized, pilot dose-finding study of maca root (L. meyenii) for the management of SSRI-induced sexual dysfunction.

PubMed

Dording, Christina M; Fisher, Lauren; Papakostas, George; Farabaugh, Amy; Sonawalla, Shamsah; Fava, Maurizio; Mischoulon, David

2008-01-01

We sought to determine whether maca, a Peruvian plant, is effective for selective-serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction. We conducted a double-blind, randomized, parallel group dose-finding pilot study comparing a low-dose (1.5 g/day) to a high-dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36+/-13 years; 17 women) with SSRI-induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH-SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent-to-treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8+/-3.8 to 16.9+/-6.2; z=-2.20, P=0.028) and in MGH-SFQ scores (from 24.1+/-1.9 to 17.0+/-5.7; z=-2.39, P=0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P<0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI-induced sexual dysfunction, and there may be a dose-related effect. Maca may also have a beneficial effect on libido.

Comparison of two dosing schedules for subcutaneous injections of low-dose anti-CD20 veltuzumab in relapsed immune thrombocytopenia

PubMed Central

Liebman, Howard A.; Saleh, Mansoor N.; Bussel, James B.; Negrea, O. George; Horne, Heather; Wegener, William A.; Goldenberg, David M.

2016-01-01

We compared two dosing schedules for subcutaneous injections of a low-dose humanized anti-CD20 antibody, veltuzumab, in immune thrombocytopenia. Fifty adults with primary immune thrombocytopenia, in whom one or more lines of standard therapy had failed and who had a platelet count <30×109/L but no major bleeding, initially received escalating 80, 160, or 320 mg doses of subcutaneous veltuzumab administered twice, 2 weeks apart; the last group received once-weekly doses of 320 mg for 4 weeks. In all dose groups, injection reactions were transient and mild to moderate; there were no other safety issues. Forty-seven response-evaluable patients had 23 (49%) objective responses (platelet counts ≥30×109/L and ≥2 × baseline) including 15 (32%) complete responses (platelets ≥100×109/L). Responses (including complete responses) and bleeding reduction occurred in all dose groups and were not dose-dependent. In contrast, response duration increased progressively with total dose, reaching a median of 2.7 years with the four once-weekly 320-mg doses. Among nine responders retreated at relapse, three at higher dose levels responded again, including one patient who was retreated four times. In all dose groups, B-cell depletion occurred after the first dose until recovery starting 12 to 16 weeks after treatment. Veltuzumab serum levels increased with dose group according to total dose administered, but terminal half-life and clearance were comparable. Human anti-veltuzumab antibody titers developed without apparent dose dependence in nine patients, of whom six responded including five who had complete responses. Subcutaneous veltuzumab was convenient, well-tolerated, and active, without causing significant safety concerns. Platelet responses and bleeding reduction occurred in all dose groups, and response durability appeared to improve with higher doses. Clinicaltrials.gov identifier: NCT00547066 PMID:27515248

[Comparison of antibody persistence between live attenuated and inactivated hepatitis A vaccines].

PubMed

Liu, Huai-Feng; Zhang, Xin-Jiang; Zhang, Jian-Li

2009-08-01

To study the antibody persistence of live attenuated hepatitits A vaccine, and to compare the antibody between with inactivated vaccine. 211 HAV susceptible children were divided randomly into three groups, Group A was injected three doses HepA-L at 0, 6 and 12 monthes; Group B was administrated two dose HepA-L at 0 and 6 months, and group C was immunized with inactivated vaccine at month 0 and 6. Serum samples were detected for Anti-HAV at 1, 6, 7, 12, 13, 24, 84 months after vaccination in each group. The seroconversion rates reached 100% after 2nd dose in all groups. The highest GMC was 2938.1 mlU/ml, founded in group C, and it was 1315.6 mlU/ml and 1586 mlU/ml in group A and B respectively. After the 3rd dose at month 12 in group A, the antibody increased dramatic, which reached 1945.3 mlU/ml. 84 months after first dose in each group, the antibody can be detected from all subjects. Though the GMC in group A declined to 336.8 mlU/ml, it was significant higher than that in group B and C. The good booster effect with HepA-L was well observed in a short-term. The immune response induced by 2 to 3 doses HepA-L could compete with inactivated hepatitis A vaccine. However, long-term effects of both vaccines need further study.

Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder.

PubMed

Findling, Robert L; Quinn, Declan; Hatch, Simon J; Cameron, Sara J; DeCory, Heleen H; McDowell, Michael

2006-12-01

To compare the efficacy and safety of two methylphenidate (MPH) formulations--once-daily modified-release MPH (EqXL, Equasym XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin)--and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Children aged 6-12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher's IOWA Conners' Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (-1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.

A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab

PubMed Central

Kaur, Primal; Chow, Vincent; Zhang, Nan; Moxness, Michael; Kaliyaperumal, Arunan; Markus, Richard

2017-01-01

Objective To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. Methods Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax). Secondary end points included safety and immunogenicity. Results AUCinf and Cmax were similar across the three groups. Geometrical mean ratio (GMR) of AUCinf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of Cmax was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUCinf and Cmax were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. Conclusions Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. Trial registration number EudraCT number 2012-000785-37; Results. PMID:27466231

2-Aminoanthracene, 5-fluorouracil, colchicine, benzo[a]pyrene, cadmium chloride and cytosine arabinoside tested in the in vitro mammalian cell micronucleus test (MNvit) in Chinese hamster ovary (CHO) cells at Covance Laboratories, Harrogate UK in support of OECD draft Test Guideline 487.

PubMed

Whitwell, James; Fowler, Paul; Allars, Sarah; Jenner, Karen; Lloyd, Melvyn; Wood, Debbie; Smith, Katie; Young, Jamie; Jeffrey, Laura; Kirkland, David

2010-10-29

The reference genotoxic agents 2-aminoanthracene (a metabolism dependent weak clastogen), 5-fluorouracil (a nucleoside analogue, characterised by a steep dose response profile), colchicine (an aneugen that inhibits tubulin polymerisation), benzo[a]pyrene (a polycyclic aromatic hydrocarbon requiring metabolic activation), cadmium chloride (an inorganic carcinogen), and cytosine arabinoside (a nucleoside analogue that inhibits the gap-filling step of excision repair) were tested in the in vitro micronucleus assay using the Chinese hamster ovary (CHO) cell line at Covance Laboratories, Harrogate, UK. All chemicals were treated in the absence and presence of cytokinesis block (via addition of cytochalasin B) with this work forming part of a collaborative evaluation of the toxicity measures recommended in the draft OECD Test Guideline 487 on the In vitro Mammalian Cell Micronucleus Test (MNvit). The toxicity measures used, detecting a possible combination of both cytostasis and cell death (though not cell death directly), were relative population doubling, relative increase in cell counts and relative cell counts for treatments in the absence of cytokinesis block, and replication index in the presence of cytokinesis block. All of the chemicals tested either gave marked positive increases in the percentage of micronucleated cells with and without cytokinesis block, or did not induce micronuclei at concentrations giving approximately 50-60% toxicity (cytostasis and cell death) or less by all of the toxicity measures used. The outcome from this series of tests supports the use of relative increase in cell counts and relative population doubling, as well as relative cell counts, as appropriate measures of cytotoxicity for the non-cytokinesis blocked in vitro micronucleus assay. Copyright © 2010 Elsevier B.V. All rights reserved.

Vitamin K3 disrupts the microtubule networks by binding to tubulin: a novel mechanism of its antiproliferative activity.

PubMed

Acharya, Bipul R; Choudhury, Diptiman; Das, Amlan; Chakrabarti, Gopal

2009-07-28

Vitamin K3 (2-methyl-1,4-naphthoquinone), also known as menadione, is the synthetic precursor of all the naturally occurring vitamin K in the body. Vitamin K is necessary for the production of prothrombin and five other blood-clotting factors in humans. We have examined the effects of menadione on cellular microtubules ex vivo as well as its binding with purified tubulin and microtubules in vitro. Cell viability experiments using human cervical epithelial cancer cells (HeLa) and human oral epithelial cancer cells (KB) indicated that the IC(50) values for menadione are 25.6 +/- 0.6 and 64.3 +/- 0.36 microM, respectively, in those cells. Mendione arrests HeLa cells in mitosis. Immunofluorescence studies using an anti-alpha-tubulin antibody showed a significant irreversible depolymeriztion of the interphase microtubule network and spindle microtubule in a dose-dependent manner. In vitro polymerization of purified tubulin into microtubules is inhibited by menadione with an IC(50) value of 47 +/- 0.65 microM. The binding of menadione with tubulin was studied using menadione fluorescence and intrinsic tryptophan fluorescence of tubulin. Binding of menadione to tubulin is slow, taking 35 min for equilibration at 25 degrees C. The association reaction kinetics is biphasic in nature, and the association rate constants for fast and slow phases are 189.12 +/- 17 and 32.44 +/- 21 M(-1) s(-1) at 25 degrees C, respectively. The stoichiometry of menadione binding to tubulin is 1:1 (molar ratio) with a dissociation constant from 2.44 +/- 0.34 to 3.65 +/- 0.25 microM at 25 degrees C. Menadione competes for the colchicine binding site with a K(i) of 2.5 muM as determined from a modified Dixon plot. The obtained data suggested that menadione binds at the colchicine binding site to tubulin. Thus, we can conclude one novel mechanism of inhibition of cancer cell proliferation by menadione is through tubulin binding.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia.

PubMed

Azevedo, M C; Velloso, E D R P; Buccheri, V; Chamone, D A F; Dorlhiac-Llacer, P E

2015-02-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival.

Possible benefit of consolidation therapy with high-dose cytarabine on overall survival of adults with non-promyelocytic acute myeloid leukemia

PubMed Central

Azevedo, M.C.; Velloso, E.D.R.P.; Buccheri, V.; Chamone, D.A.F.; Dorlhiac-Llacer, P.E.

2014-01-01

In adults with non-promyelocytic acute myeloid leukemia (AML), high-dose cytarabine consolidation therapy has been shown to influence survival in selected patients, although the appropriate doses and schemes have not been defined. We evaluated survival after calculating the actual dose of cytarabine that patients received for consolidation therapy and divided them into 3 groups according to dose. We conducted a single-center, retrospective study involving 311 non-promyelocytic AML patients with a median age of 36 years (16-79 years) who received curative treatment between 1978 and 2007. The 131 patients who received cytarabine consolidation were assigned to study groups by their cytarabine dose protocol. Group 1 (n=69) received <1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles. The remaining patients received high-dose cytarabine (≥1.5 g/m2 every 12 h on 3 alternate days for up to 4 cycles). The actual dose received during the entire consolidation period in these patients was calculated, allowing us to divide these patients into 2 additional groups. Group 2 (n=27) received an intermediate-high-dose (<27 g/m2), and group 3 (n=35) received a very-high-dose (≥27 g/m2). Among the 311 patients receiving curative treatment, the 5-year survival rate was 20.2% (63 patients). The cytarabine consolidation dose was an independent determinant of survival in multivariate analysis; age, karyotype, induction protocol, French-American-British classification, and de novo leukemia were not. Comparisons showed that the risk of death was higher in the intermediate-high-dose group 2 (hazard ratio [HR]=4.51; 95% confidence interval [CI]: 1.81-11.21) and the low-dose group 1 (HR=4.43; 95% CI: 1.97-9.96) than in the very-high-dose group 3, with no significant difference between those two groups. Our findings indicated that very-high-dose cytarabine during consolidation in adults with non-promyelocytic AML may improve survival. PMID:25517921

Effect of Enrofloxacin on Histochemistry, Immunohistochemistry and Molecular Changes in Lamb Articular Cartilage.

PubMed

Khazaeel, Kaveh; Mazaheri, Yazdan; Hashemi Tabar, Mahmood; Najafzadeh, Hossein; Morovvati, Hassan; Ghadrdan, Alireza

2015-01-01

Enrofloxacin is a synthetic chemotherapeutic agent from the class of the fluoroquinolones that is widely used to treat bacterial infections. It is metabolized to ciprofloxacin in the body as active metabolite. Fluoroquinolones change in the articular cartilage, especially with high doses and more than two weeks use. So, due to relatively excessive use of enrofloxacin in mammals and similarity of lambs to human subjects with respect to skeletal activity cycles, this study was done to investigate the effects of enrofloxacin on some cellular and molecular changes in growing lamb articular cartilage to evaluate some possible mechanisms involved these changes. Twelve, 2-month-old male lambs divided into three groups: control group received only normal saline; therapeutic group received 5mg/kg enrofloxacin subcutaneously, daily, for 15 days and toxic group received 35 mg/kg enrofloxacin in the same manner as therapeutic group. Twenty four hours after the last dose, the animals were sacrificed, and their stifle joints were dissected. Sampling from distal femoral and proximal tibial extremities was done quickly for further histological and molecular studies. Collagen-п content was studied with avidin-biotin immunohistochemistry method in different groups. Expression of Sox9 and caspase-3 was evaluated by Real-time PCR. Immunohistochemical changes were included decreases of matrix proteoglycans, carbohydrates, and Collagen-п in the toxic group. Some of these changes were observed in the therapeutic group with less intensity in comparison to the toxic group. Enrofloxacin were significantly decreased (P≤0.05). Sox9 expression in therapeutic and toxic groups compared to control group. But caspase -3 expressions in the toxic group significantly increased (P≤0.0001) with a comparison to other groups, while, between control and therapeutic groups, there were no significant differences. So, it can be concluded that enrofloxacin increases apoptosis in chondrocytes and decreases their numbers. Enrofloxacin use in growing lambs even at recommended therapeutic dose is not completely safe on articular cartilage. Moreover, higher doses of enrofloxacin induce severe changes in lamb articular cartilage.

Dose response of PEG 3350 for the treatment of childhood fecal impaction.

PubMed

Youssef, Nader N; Peters, John M; Henderson, Wendy; Shultz-Peters, Sandra; Lockhart, Danielle K; Di Lorenzo, Carlo

2002-09-01

To investigate the efficacy and safety of polyethylene glycol (PEG) 3350 in the treatment of childhood fecal impaction. This was a prospective, double-blind, parallel, randomized study of 4 doses of PEG 3350; 0.25 g/kg per day, 0.5 g/kg per day, 1 g/kg per day, 1.5 g/kg per day, given for 3 days in children with constipation for >3 months and evidence of fecal impaction. Forty patients completed the study (27 boys, median age 7.5, range 3.3-13.1 years). Disimpaction occurred in 75% of children, with a significant difference between the two higher doses and the lower doses (95% vs 55%, P <.005). All groups had an increased number of bowel movements during the 5-day study versus baseline, respectively: 6.5 versus 1.1 (P <.005), 8.0 versus 1.3 (P <.005), 10.9 versus 1.7 (P <.005), and 12.3 versus 1.4 (P <.005). Adverse effects included nausea (5%), vomiting (5%), bloating (18%), cramping (5%), and diarrhea (13%). Diarrhea and bloating were more prevalent (P <.02) in the higher-dose than in the lower-dose group. No clinically significant changes in electrolytes were noted. The 3-day administration of PEG 3350 is safe and effective in the treatment of childhood fecal impaction at doses of 1 and 1.5 g/kg per day.

Cost-effectiveness analysis of hypertension treatment: controlled release nifedipine and candesartan low-dose combination therapy in patients with essential hypertension--the Nifedipine and Candesartan Combination (NICE-Combi) Study.

PubMed

Fujikawa, Keita; Hasebe, Naoyuki; Kikuchi, Kenjiro

2005-07-01

Societal interest in pharmaco-economic analysis is increasing in Japan. In this study, the cost-effectiveness of low-dose combination therapy with controlled release nifedipine plus candesartan and up-titrated monotherapy with candesartan was estimated, based on the results of the NICE-Combi study. The NICE-Combi study was a double-blind, parallel arm, randomized clinical trial to compare the efficacy of low-dose combination therapy of controlled release nifedipine (20 mg/day) plus candesartan (8 mg/day) vs. up-titrated monotherapy of candesartan (12 mg/day) on blood pressure control in Japanese patients with mild to severe essential hypertension who were not sufficiently controlled by the conventional dose of candesartan (8 mg/ day). The incremental cost effectiveness of each cohort during the 8-week randomization period was compared, from the perspective of a third-party payer (i.e., insurers). The average total cost per patient was 29,943 Japanese yen for the combination therapy group and 33,182 Japanese yen for the candesartan monotherapy group, while the rate of achievement of the target blood pressure was significantly higher in the combination therapy group than in the up-titrated monotherapy group. In the combination therapy group, higher efficacy and lower incremental treatment cost ("Dominance") were observed when compared to the monotherapy group. The sensitivity analyses also supported the results. In conclusion, these results suggest that combination therapy with controlled release nifedipine and low-dose candesartan (8 mg) is "dominant" to up-titrated candesartan monotherapy for the management of essential hypertension. This conclusion was robust to sensitivity analysis.

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice.

PubMed

Jackson, B S; Mokoena, T

2017-02-08

People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups-HIV-uninfected and HIV-infected patients not on ARVs. There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

On-line MR imaging for dose validation of abdominal radiotherapy

NASA Astrophysics Data System (ADS)

Glitzner, M.; Crijns, S. P. M.; de Senneville, B. Denis; Kontaxis, C.; Prins, F. M.; Lagendijk, J. J. W.; Raaymakers, B. W.

2015-11-01

For quality assurance and adaptive radiotherapy, validation of the actual delivered dose is crucial. Intrafractional anatomy changes cannot be captured satisfactorily during treatment with hitherto available imaging modalitites. Consequently, dose calculations are based on the assumption of static anatomy throughout the treatment. However, intra- and interfraction anatomy is dynamic and changes can be significant. In this paper, we investigate the use of an MR-linac as a dose tracking modality for the validation of treatments in abdominal targets where both respiratory and long-term peristaltic and drift motion occur. The on-line MR imaging capability of the modality provides the means to perform respiratory gating of both delivery and acquisition yielding a model-free respiratory motion management under free breathing conditions. In parallel to the treatment, the volumetric patient anatomy was captured and used to calculate the applied dose. Subsequently, the individual doses were warped back to the planning grid to obtain the actual dose accumulated over the entire treatment duration. Ultimately, the planned dose was validated by comparison with the accumulated dose. Representative for a site subject to breathing modulation, two kidney cases (25 Gy target dose) demonstrated the working principle on volunteer data and simulated delivery. The proposed workflow successfully showed its ability to track local dosimetric changes. Integration of the on-line anatomy information could reveal local dose variations  -2.3-1.5 Gy in the target volume of a volunteer dataset. In the adjacent organs at risk, high local dose errors ranging from  -2.5 to 1.9 Gy could be traced back.

Lateral topography for reducing effective dose in low-dose chest CT.

PubMed

Bang, Dong-Ho; Lim, Daekeon; Hwang, Wi-Sub; Park, Seong-Hoon; Jeong, Ok-man; Kang, Kyung Wook; Kang, Hohyung

2013-06-01

The purposes of this study were to assess radiation exposure during low-dose chest CT by using lateral topography and to compare the lateral topographic findings with findings obtained with anteroposterior topography alone and anteroposterior and lateral topography combined. From November 2011 to February 2012, 210 male subjects were enrolled in the study. Age, weight, and height of the men were recorded. All subjects were placed into one of three subgroups based on the type of topographic image obtained: anteroposterior topography, lateral topography, and both anteroposterior and lateral topography. Imaging was performed with a 128-MDCT scanner. CT, except for topography, was the same for all subjects. A radiologist analyzed each image, recorded scan length, checked for any insufficiencies in the FOV, and calculated the effective radiation dose. One-way analysis of variance and multiple comparisons were used to compare the effective radiation exposure and scan length between groups. The mean scan length in the anteroposterior topography group was significantly greater than that of the lateral topography group and the combined anteroposterior and lateral topography group (p < 0.001). The mean effective radiation dose for the lateral topography group (0.735 ± 0.033 mSv) was significantly lower than that for the anteroposterior topography group (0.763 ± 0.038 mSv) and the combined anteroposterior and lateral topography group (0.773 ± 0.038) (p < 0.001). Lateral topographic low-dose CT was associated with a lower effective radiation dose and scan length than either anteroposterior topographic low-dose chest CT or low-dose chest CT with both anteroposterior and lateral topograms.

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

PubMed

Kim, Dae Sik; Kang, Ka-Won; Lee, Se Ryeon; Park, Yong; Sung, Hwa Jung; Kim, Seok Jin; Choi, Chul Won; Kim, Byung Soo

2015-09-01

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.

SU-F-J-146: Experimental Validation of 6 MV Photon PDD in Parallel Magnetic Field Calculated by EGSnrc

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

Ghila, A; Steciw, S; Fallone, B

Purpose: Integrated linac-MR systems are uniquely suited for real time tumor tracking during radiation treatment. Understanding the magnetic field dose effects and incorporating them in treatment planning is paramount for linac-MR clinical implementation. We experimentally validated the EGSnrc dose calculations in the presence of a magnetic field parallel to the radiation beam travel. Methods: Two cylindrical bore electromagnets produced a 0.21 T magnetic field parallel to the central axis of a 6 MV photon beam. A parallel plate ion chamber was used to measure the PDD in a polystyrene phantom, placed inside the bore in two setups: phantom top surfacemore » coinciding with the magnet bore center (183 cm SSD), and with the magnet bore’s top surface (170 cm SSD). We measured the field of the magnet at several points and included the exact dimensions of the coils to generate a 3D magnetic field map in a finite element model. BEAMnrc and DOSXYZnrc simulated the PDD experiments in parallel magnetic field (i.e. 3D magnetic field included) and with no magnetic field. Results: With the phantom surface at the top of the electromagnet, the surface dose increased by 10% (compared to no-magnetic field), due to electrons being focused by the smaller fringe fields of the electromagnet. With the phantom surface at the bore center, the surface dose increased by 30% since extra 13 cm of air column was in relatively higher magnetic field (>0.13T) in the magnet bore. EGSnrc Monte Carlo code correctly calculated the radiation dose with and without the magnetic field, and all points passed the 2%, 2 mm Gamma criterion when the ion chamber’s entrance window and air cavity were included in the simulated phantom. Conclusion: A parallel magnetic field increases the surface and buildup dose during irradiation. The EGSnrc package can model these magnetic field dose effects accurately. Dr. Fallone is a co-founder and CEO of MagnetTx Oncology Solutions (under discussions to license Alberta bi-planar linac MR for commercialization).« less

Diurnal fluctuation in the number of hypocretin/orexin and histamine producing: Implication for understanding and treating neuronal loss

PubMed Central

McGregor, Ronald; Shan, Ling; Wu, Ming-Fung

2017-01-01

The loss of specific neuronal phenotypes, as determined by immunohistochemistry, has become a powerful tool for identifying the nature and cause of neurological diseases. Here we show that the number of neurons identified and quantified using this method misses a substantial percentage of extant neurons in a phenotype specific manner. In mice, 24% more hypocretin/orexin (Hcrt) neurons are seen in the night compared to the day, and an additional 17% are seen after inhibiting microtubule polymerization with colchicine. We see no such difference between the number of MCH (melanin concentrating hormone) neurons in dark, light or colchicine conditions, despite MCH and Hcrt both being hypothalamic peptide transmitters. Although the size of Hcrt neurons did not differ between light and dark, the size of MCH neurons was increased by 15% in the light phase. The number of neurons containing histidine decarboxylase (HDC), the histamine synthesizing enzyme, was 34% greater in the dark than in the light, but, like Hcrt, cell size did not differ. We did not find a significant difference in the number or the size of neurons expressing choline acetyltransferase (ChAT), the acetylcholine synthesizing enzyme, in the horizontal diagonal band (HBD) during the dark and light conditions. As expected, colchicine treatment did not increase the number of these neurons. Understanding the function and dynamics of transmitter production within “non-visible” phenotypically defined cells has fundamental implications for our understanding of brain plasticity. PMID:28570646

Insight into microtubule destabilization mechanism of 3,4,5-trimethoxyphenyl indanone derivatives using molecular dynamics simulation and conformational modes analysis

NASA Astrophysics Data System (ADS)

Tripathi, Shubhandra; Srivastava, Gaurava; Singh, Aastha; Prakasham, A. P.; Negi, Arvind S.; Sharma, Ashok

2018-03-01

Colchicine site inhibitors are microtubule destabilizers having promising role in cancer therapeutics. In the current study, four such indanone derivatives (t1, t9, t14 and t17) with 3,4,5-trimethoxyphenyl fragment (ring A) and showing significant microtubule destabilization property have been explored. The interaction mechanism and conformational modes triggered by binding of these indanone derivatives and combretastatin at colchicine binding site (CBS) of αβ-tubulin dimer were studied using molecular dynamics (MD) simulation, principle component analysis and free energy landscape analysis. In the MD results, t1 showed binding similar to colchicine interacting in the deep hydrophobic core at the CBS. While t9, t14 and t17 showed binding conformation similar to combretastatin, with ring A superficially binding at the CBS. Results demonstrated that ring A played a vital role in binding via hydrophobic interactions and got anchored between the S8 and S9 sheets, H8 helix and T7 loop at the CBS. Conformational modes study revealed that twisting and bending conformational motions (as found in the apo system) were nearly absent in the ligand bound systems. Absence of twisting motion might causes loss of lateral contacts in microtubule, thus promoting microtubule destabilization. This study provides detailed account of microtubule destabilization mechanism by indanone ligands and combretastatin, and would be helpful for designing microtubule destabilizers with higher activity.

Endovascular aortic sealing with Nellix reduces intraoperative radiation dose when compared to endovascular aortic repair.

PubMed

Ockert, Stefan; Heinrich, Mirjam; Kaufmann, Thomas; Syburra, Thomas; Lopez, Ruben; Seelos, Robert

2018-04-01

To analyze radiation exposure during endovascular aortic sealing (EVAS) in comparison with standard endovascular aortic repair (EVAR) in clinical practice. From December 2013 to October 2016 (35 months), 60 patients were analyzed for intraoperative radiation exposure during EVAR: 30 consecutive patients (mean age, 73.10 years; 28 male) received EVAS (Nellix Endologix); within the same time frame, 30 patients were treated with standard EVAR (mean age, 71.87 years; 30 male). An indirect dose analysis was performed for both groups of patients, including effective dose and cumulative air kerma. Furthermore, fluoroscopy time (FT), dose area product, and time of procedure were included in the study. The effective dose was significantly reduced in the EVAS group (3.72 mSv) compared with the group treated with standard EVAR (6.8 mSv; P ≤ .001). The cumulative air kerma was also lowered in EVAS (67.65 mGy vs 139 mGy in EVAR; P ≤ .001). FT for the entire group was 13 minutes and was shorter (P < .001) for EVAS (9 minutes) in comparison with EVAR (19 minutes). The dose area product for the entire cohort was 16.95 Gy.cm 2 and was lower during EVAS (12.4 Gy.cm 2 ) than during EVAR (22.6 Gy.cm 2 ; P < .001). The median operating time for the entire group was 123.5 minutes and was significantly shorter (P < .01) for EVAS (119 minutes vs EVAR at 132 minutes). The FT shows a significant correlation with the patient's weight (P = .022), body mass index (P = .004), and time of procedure (P = .005). EVAS is associated with a relevant decrease in indirect measured radiation dose and time of procedure compared with standard EVAR. A relevant reduction in dose during EVAS is highly likely to result in lower exposure to radiation for physicians and staff. Such a result would be highly advantageous and calls for further analysis. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.

Comparison of the Effects of a Sweetened Beverage Intervention on Self-Selected Food Intake

USDA-ARS?s Scientific Manuscript database

Evidence suggests that the intake of added sugar increases the risk of chronic disease and should be targeted for reduction. It is unclear if all types of added sugar have equivalent effects on food intake. This prospective, blinded intervention study compared parallel groups consuming one of five t...

Randomization and Data-Analysis Items in Quality Standards for Single-Case Experimental Studies

ERIC Educational Resources Information Center

Heyvaert, Mieke; Wendt, Oliver; Van den Noortgate, Wim; Onghena, Patrick

2015-01-01

Reporting standards and critical appraisal tools serve as beacons for researchers, reviewers, and research consumers. Parallel to existing guidelines for researchers to report and evaluate group-comparison studies, single-case experimental (SCE) researchers are in need of guidelines for reporting and evaluating SCE studies. A systematic search was…

Double-blind comparison of two types of benzocaine lozenges for the treatment of acute pharyngitis.

PubMed

Busch, Regina; Graubaum, Hans-Joachim; Grünwald, Jörg; Schmidt, Mathias

2010-01-01

In a reference-controlled double-blind trial in patients with acute pharyngitis the effects of a newly developed lozenge containing 8 mg of benzocaine (p-aminobenzoic acid ethyl ester, CAS 94-09-7) were compared with those of an identically dosed commercial pastille. 246 patients were randomized to receive either the lozenges (group A, n = 123) or the pastilles (group B, n = 123). Each patient took a total of six doses within 12 h according to the double-dummy principle, with each single dose spaced by 2 h. The primary parameter was the assessment of the responder rate with = 50 % pain relief within 15 min post application. Further parameters included the relative relief of pain in the course of the study and the tolerability of the formulation. After application of the first unit the comparison of groups yielded very similar and statistically not differing results for efficacy in both groups, with responder rates of 25.2 % and 22.0 % in groups A and B, respectively. One adverse drug reaction was observed in group B (burning and tingling feeling on the tongue), which, however, did not lead to discontinuation of study participation. In all other cases tolerability was stated to be "good to very good". The application of the benzocaine lozenges was statistically non-inferior to the use of the pastilles.

Prescribing patterns and the use of therapeutic drug monitoring of psychotropic medication in a psychiatric high-security unit.

PubMed

Castberg, Ingrid; Spigset, Olav

2008-10-01

The aim of this study was to investigate the use of psychotropic medication and therapeutic drug monitoring in a high-security psychiatric unit and to compare the doses and serum concentrations both with the recommended intervals and with the doses and serum concentrations in a control group. One hundred thirty-two patients were admitted in the period from January 2000 to December 2005. All available samples were used when comparing serum concentrations and doses with the recommended ranges. For the comparison of doses and serum concentration-to-dose (C:D) ratios with the control group only 1 sample from each patient was used. A total of 459 analyses of 27 different drugs in samples from 8 women and 73 men were included. The median number of therapeutic drug monitoring analyses per patient was 4 (range 1-29). Thirty-seven of the 81 patients (46%) used 2 or more antipsychotics at the same time. Clozapine, lamotrigine, olanzapine, quetiapine, ziprasidone, and zuclopenthixol were often given in doses above the recommended. The serum levels were frequently above those recommended for clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and zuclopenthixol. The serum levels were significantly higher in the study group than in the control group for clozapine, lamotrigine, quetiapine, and zuclopenthixol. The given dose was significantly higher in the study group than in the control group for clozapine, lamotrigine and zuclopenthixol. The C:D ratio was significantly lower in the study group than in the control group for olanzapine but higher for quetiapine. The non-evidence based practice of high-dose polypharmacy with several antipsychotics is widely used in this unit. The use of higher doses in the study group than in the control group was not due to differences in metabolism or adherence to treatment between the 2 groups. The frequent use of therapeutic drug monitoring did not seem to have a great impact on the prescribed doses.

Synthesis of 2-aryl-1,2,4-oxadiazolo-benzimidazoles: Tubulin polymerization inhibitors and apoptosis inducing agents.

PubMed

Kamal, Ahmed; Reddy, T Srinivasa; Vishnuvardhan, M V P S; Nimbarte, Vijaykumar D; Subba Rao, A V; Srinivasulu, Vunnam; Shankaraiah, Nagula

2015-08-01

A new series of 2-aryl 1,2,4-oxadiazolo-benzimidazole conjugates have been synthesized and evaluated for their antiproliferative activity in the sixty cancer cell line panel of the National Cancer Institute (NCI). Compounds 5l (NSC: 761109/1) and 5x (NSC: 761814/1) exhibited remarkable cytotoxic activity against most of the cancer cell lines in the one dose assay and were further screened at five dose concentrations (0.01, 0.1, 1, 10 and 100 μM) which showed GI50 values in the range of 0.79-28.2 μM. Flow cytometric data of these compounds showed increased cells in G2/M phase, which is suggestive of G2/M cell cycle arrest. Further, compounds 5l and 5x showed inhibition of tubulin polymerization and disruption of the formation of microtubules. These compounds induce apoptosis by DNA fragmentation and chromatin condensation as well as by mitochondrial membrane depolarization. In addition, structure activity relationship studies within the series are also discussed. Molecular docking studies of compounds 5l and 5x into the colchicine-binding site of the tubulin, revealed the possible mode of interaction by these compounds. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of different dosing strategies of intratracheally instilled budesonide on meconium injured piglet lungs.

PubMed

Lin, Chih-Hsueh; Jeng, Mei-Jy; Yang, Yi-Chiang; Hsiao, Yu-Hsuan; Kou, Yu Ru

2017-07-01

Severe inflammation plays a vital role in the pathogenesis of meconium aspiration syndrome (MAS). Intratracheal (IT) instillation of corticosteroids may be beneficial for MAS in optimizing local effect and reducing systemic adverse effects, but the optimum dosing course remains open to question. Thirty meconium-injured newborn piglets were enrolled into six study groups. The first four groups consisted of the IT instillation of 0.25/0.5 mg/kg using either one (IT-B251/IT-B501) or two (IT-B252/IT-B502) doses of budesonide, while the other two groups were the intravenous (IV) dexamethasone (0.5 mg/kg) (IV-Dex) group and the control group (Ctrl). Vital signs and cardiopulmonary functions were monitored throughout the experiments. Pulmonary histology was examined after completing the experiments. Both the IV-Dex and IT-B501 groups got significant improvement in oxygenation (P < 0.05). Lung compliance became worse after one dose of 0.25 mg/kg of IT budesonide. Pulmonary histology revealed that there were significantly lower lung injury scores for all treatment groups compared to control group, especially at the non-dependent sites of both the IT-B501 and IT-B502 groups. There was no significant difference between double- and single-dose groups, no matter whether 0.25 or 0.5 mg/kg of budesonide was used. IT instillation of one dose of 0.5 mg/kg budesonide is beneficial in treating meconium-injured piglet lungs during the first 8 h of injury, but a second dose at an interval of 4 h does not have a superior beneficial effect compared to one dose. © 2017 Wiley Periodicals, Inc.

Comparison of conventional L-thyroxine withdrawal and moderate hypothyroidism in preparation for whole-body 131-I scan and thyroglobulin testing.

PubMed

Marturano, I; Russo, M; Spadaro, A; Latina, A; Malandrino, P; Regalbuto, C

2015-09-01

After thyroidectomy for thyroid cancer, patients often withdraw L-T4 for diagnostic or therapeutic purposes, showing signs and symptoms of hypothyroidism. A slighter hypothyroidism (reducing L-T4 to one-half) has been proposed to limit these inconveniences. We evaluated half-dose L-T4 protocol, in comparison to conventional L-T4 withdrawal, in terms of effectiveness and improvement of clinical and biochemical disorders. We randomized 55 thyroid cancer patients into two groups: 29 patients underwent 5 weeks of half-dose of previous L-T4 treatment (HD group); 26 patients replaced L-T4 with L-T3 for 3 weeks followed by 2 weeks of withdrawal (TW group). Clinical features (Zulewsky clinical score) and biochemical parameters (lipids, liver, and muscle enzymes) were evaluated in all patients at baseline and after 5 weeks. Total cholesterol, creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase increased at 5 weeks in both groups, but significantly more in TW, but no difference was found by clinical score. Patients who achieved the thyroid-stimulating hormone (TSH) target value (25 µU/ml) were 92.3% in TW group and 48.3% in HD group (p < 0.001). In the HD group, only basal TSH statistically correlated with the achievement of the TSH target. Receiver operating characteristic curves indicated that a basal TSH ≥0.52 μU/ml is required to reach an adequate TSH level. Half-dose L-T4 protocol, compared to conventional L-T4 withdrawal, is associated with less biochemical disorders but no significant clinical advantage. Therefore, the half-dose protocol reaches an adequate TSH target in 48.3% of patients and is not effective unless basal serum TSH is ≥0.52 μU/ml.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.

PubMed

Dornelles, Laura Vargas; Corso, Andréa Lúcia; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

2016-01-01

To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

A Randomized Trial Comparing Intravitreal Triamcinolone Acetonide and Focal/Grid Photocoagulation for Diabetic Macular Edema

PubMed Central

2009-01-01

Objective To evaluate the efficacy and safety of 1 mg and 4 mg doses of preservative-free intravitreal triamcinolone in comparison with focal/grid photocoagulation for the treatment of diabetic macular edema (DME). Design Multi-center randomized clinical trial Participants 840 study eyes of 693 subjects with DME involving the fovea and visual acuity 20/40 to 20/320 Methods Eyes were randomized to focal/grid photocoagulation (N=330), 1 mg intravitreal triamcinolone (N=256), or 4 mg intravitreal triamcinolone (N=254). Retreatment was given for persistent or new edema at 4-month intervals. The primary outcome was at 2 years. Main Outcome Measures Visual acuity measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) method (primary), optical coherence tomography (OCT)-measured retinal thickness (secondary), and safety. Results At 4 months, mean visual acuity was better in the 4 mg triamcinolone group than in either the laser group (P<0.001) or the 1 mg triamcinolone group (P=0.001). By 1 year, there were no significant differences among groups in mean visual acuity. At the 16-month visit and extending through the primary outcome visit at 2 years, mean visual acuity was better in the laser group than in the other two groups (at 2 years, P=0.02 comparing the laser and 1 mg groups, P=0.002 comparing the laser and 4 mg groups, and P=0.49 comparing the 1mg and 4 mg groups). Treatment group differences in the visual acuity outcome could not be attributed solely to cataract formation. OCT results generally paralleled the visual acuity results. Intraocular pressure was increased from baseline by ≥10 mm Hg at any visit in 4%, 16%, and 33% of eyes in the three treatment groups, respectively, and cataract surgery was performed in 13%, 23%, and 51% of eyes in the three treatment groups, respectively. Conclusions Over a 2-year period, focal/grid photocoagulation is more effective and has fewer side effects than 1 mg or 4 mg doses of preservative-free intravitreal triamcinolone for most patients with DME who have characteristics similar to the cohort in this clinical trial. The results of this study also support that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME. PMID:18662829

A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema.

PubMed

2008-09-01

To evaluate the efficacy and safety of 1-mg and 4-mg doses of preservative-free intravitreal triamcinolone in comparison with focal/grid photocoagulation for the treatment of diabetic macular edema (DME). Multicenter, randomized clinical trial. Eight hundred forty study eyes of 693 subjects with DME involving the fovea and with visual acuity of 20/40 to 20/320. Eyes were randomized to focal/grid photocoagulation (n = 330), 1 mg intravitreal triamcinolone (n = 256), or 4 mg intravitreal triamcinolone (n = 254). Retreatment was given for persistent or new edema at 4-month intervals. The primary outcome was evaluated at 2 years. Visual acuity measured with the electronic Early Treatment Diabetic Retinopathy Study method (primary), optical coherence tomography-measured retinal thickness (secondary), and safety. At 4 months, mean visual acuity was better in the 4-mg triamcinolone group than in either the laser group (P<0.001) or the 1-mg triamcinolone group (P = 0.001). By 1 year, there were no significant differences among groups in mean visual acuity. At the 16-month visit and extending through the primary outcome visit at 2 years, mean visual acuity was better in the laser group than in the other 2 groups (at 2 years, P = 0.02 comparing the laser and 1-mg groups, P = 0.002 comparing the laser and 4-mg groups, and P = 0.49 comparing the 1-mg and 4-mg groups). Treatment group differences in the visual acuity outcome could not be attributed solely to cataract formation. Optical coherence tomography results generally paralleled the visual acuity results. Intraocular pressure increased from baseline by 10 mmHg or more at any visit in 4%, 16%, and 33% of eyes in the 3 treatment groups, respectively, and cataract surgery was performed in 13%, 23%, and 51% of eyes in the 3 treatment groups, respectively. Over a 2-year period, focal/grid photocoagulation is more effective and has fewer side effects than 1-mg or 4-mg doses of preservative-free intravitreal triamcinolone for most patients with DME who have characteristics similar to the cohort in this clinical trial. The results of this study also support that focal/grid photocoagulation currently should be the benchmark against which other treatments are compared in clinical trials of DME.

Comparison of ambulatory blood pressure-lowering effects of higher doses of different calcium antagonists in uncontrolled hypertension: the Calcium Antagonist Controlled-Release High-Dose Therapy in Uncontrolled Refractory Hypertensive Patients (CARILLON) Study.

PubMed

Mizuno, Hiroyuki; Hoshide, Satoshi; Tomitani, Naoko; Kario, Kazuomi

2017-10-01

Data are sparse regarding ambulatory blood pressure (BP) reduction of up-titration from a standard dose to a high dose in both nifedipine controlled-release (CR) and amlodipine. This was a prospective, randomized, multicenter, open-label trial. Fifty-one uncontrolled hypertensives medicated by two or more antihypertensive drugs including a renin-angiotensin system inhibitor and a calcium antagonist were randomly assigned to either the nifedipine CR (80 mg)/candesartan (8 mg) group or the amlodipine (10 mg)/candesartan (8 mg) group. The changes in 24-hr BP were comparable between the groups. The nifedipine group demonstrated a significant decrease in their urinary albumin creatinine ratio, whereas the amlodipine group demonstrated a significant decrease in their NTproBNP level. However, there was no significant difference in any biomarkers between the two groups. Nifedipine showed an almost equal effect on ambulatory blood pressure as amlodipine. Their potentially differential effects on renal protection and NTproBNP should be tested in larger samples.

Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain.

PubMed

Johnson, Jeremy R; Burnell-Nugent, Mary; Lossignol, Dominique; Ganae-Motan, Elena Doina; Potts, Richard; Fallon, Marie T

2010-02-01

This study compared the efficacy of a tetrahydrocannabinol:cannabidiol (THC:CBD) extract, a nonopioid analgesic endocannabinoid system modulator, and a THC extract, with placebo, in relieving pain in patients with advanced cancer. In total, 177 patients with cancer pain, who experienced inadequate analgesia despite chronic opioid dosing, entered a two-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial. Patients were randomized to THC:CBD extract (n = 60), THC extract (n = 58), or placebo (n = 59). The primary analysis of change from baseline in mean pain Numerical Rating Scale (NRS) score was statistically significantly in favor of THC:CBD compared with placebo (improvement of -1.37 vs. -0.69), whereas the THC group showed a nonsignificant change (-1.01 vs. -0.69). Twice as many patients taking THC:CBD showed a reduction of more than 30% from baseline pain NRS score when compared with placebo (23 [43%] vs. 12 [21%]). The associated odds ratio was statistically significant, whereas the number of THC group responders was similar to placebo (12 [23%] vs. 12 [21%]) and did not reach statistical significance. There was no change from baseline in median dose of opioid background medication or mean number of doses of breakthrough medication across treatment groups. No significant group differences were found in the NRS sleep quality or nausea scores or the pain control assessment. However, the results from the European Organisation for Research and Treatment of Cancer Quality of Life Cancer Questionnaire showed a worsening in nausea and vomiting with THC:CBD compared with placebo (P = 0.02), whereas THC had no difference (P = 1.0). Most drug-related adverse events were mild/moderate in severity. This study shows that THC:CBD extract is efficacious for relief of pain in patients with advanced cancer pain not fully relieved by strong opioids. Copyright 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

'Boomerang' technique: an improved method for conformal treatment of locally advanced nasopharyngeal cancer.

PubMed

Corry, June; Hornby, Colin; Fisher, Richard; D'Costa, Ieta; Porceddu, Sandro; Rischin, Danny; Peters, Lester J

2004-06-01

The primary aim of the present study was to assess radiation dosimetry and subsequent clinical outcomes in patients with locally advanced nasopharyngeal cancer using a novel radiation technique termed the 'Boomerang'. Dosimetric comparisons were made with both conventional and intensity modulated radiation therapy (IMRT) techniques. This is a study of 22 patients treated with this technique from June 1995 to October 1998. The technique used entailed delivery of 36 Gy in 18 fractions via parallel opposed fields, then 24 Gy in 12 fractions via asymmetric rotating arc fields for a total of 60 Gy in 30 fractions. Patients also received induction and concurrent chemotherapy. The radiation dosimetry was excellent. Dose-volume histograms showed that with the arc fields, 90% of the planning target volume received 94% of the prescribed dose. Relative to other conventional radiation therapy off-cord techniques, the Boomerang technique results in a 27% greater proportion of the prescribed dose being received by 90% of the planning target volume. This translates into an overall 10% greater dose received for the same prescribed dose. At 3 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 91, 75 and 91%, respectively. At 5 years, the actuarial loco-regional control rate, the failure-free survival rate and the overall survival rate were 74, 62 and 71%, respectively. The Boomerang technique provided excellent radiation dosimetry with correspondingly good loco-regional control rates (in conjunction with chemotherapy) and very acceptable acute and late toxicity profiles. Because treatment can be delivered with conventional standard treatment planning and delivery systems, it is a validated treatment option for centres that do not have the capability or capacity for IMRT. A derivative of the Boomerang technique, excluding the parallel opposed component, is now our standard for patients with locally advanced nasopharyngeal cancer when IMRT is not available.

Repaglinide versus glyburide: a one-year comparison trial.

PubMed

Marbury, T; Huang, W C; Strange, P; Lebovitz, H

1999-03-01

This prospective, 1-year, multicenter, double-blind, randomized, parallel-group study was designed to show that repaglinide was at least equivalent to glyburide in patients with type 2 diabetes. Five hundred and seventy-six patients with type 2 diabetes of at least 6 months' duration were randomized to receive monotherapy with repaglinide (n = 383) or glyburide (n = 193). During weeks 1-8, doses were gradually increased to achieve a target fasting plasma glucose (FPG) range of 80-140 mg/dl. The final adjusted dose was maintained for 12 months. Repaglinide patients received a starting dose of 0.5 mg three times/day preprandially, adjusted as necessary to 1, 2 or 4 mg before breakfast, lunch and dinner. Glyburide patients received a starting dose of 2.5 mg before breakfast and placebo before lunch and dinner. Glyburide was increased as necessary to 5 or 10 mg before breakfast (placebo before lunch and dinner) or to 15 mg (10 mg before breakfast, placebo before lunch, and 5 mg before dinner). After study drug was stopped, patients were transferred to an appropriate therapy, as recommended by the investigator. Efficacy was assessed by changes from baseline in glycemic control parameters and in C-peptide, insulin, and lipid profiles. Repaglinide provided glycemic control that was at least as effective and potentially safer than that provided by glyburide. The glucose-lowering effect of repaglinide was most pronounced in pharmacotherapy-naive patients, who showed rapid and marked decreases in mean glycosylated hemoglobin levels from baseline (9.4%) to month 3 (7.6%) and month 12 (7.9%). Mean FPG levels also decreased overall in this group, from 222 mg/dl at baseline, to 175 mg/dl at month 3, to 188 mg/dl at month 12. At endpoint, morning C-peptide levels had increased significantly in glyburide-treated patients compared with those treated with repaglinide, but morning fasting insulin levels did not differ significantly between the two groups. Repaglinide efficacy was sustained over 1 year and was not influenced by age or sex. Overall safety and changes in lipid profile and body weight were similar with both agents, with no significant change after extended pharmacotherapy. Weight gain data for the subset of pharmacotherapy-naïve patients suggest that patients given repaglinide may gain less weight than those given glyburide. Repaglinide, at doses of 0.5-4.0 mg administered three times preprandially, was well tolerated and provided safe and consistently effectiveglycemic control during this 1-year study. Patients using repaglinide received the same therapeutic benefits as those using glyburide, and may have received additional benefits.

Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults.

PubMed

Cooper, Curtis; Thorne, Anona; Klein, Marina; Conway, Brian; Boivin, Guy; Haase, David; Shafran, Stephen; Zubyk, Wendy; Singer, Joel; Halperin, Scott; Walmsley, Sharon

2011-03-25

The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ≥ 40 =  31-58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. ClinicalTrials.gov NCT00764998.

Benefits of High-dose Steroid + Hespander + Mannitol Administration in the Treatment of Bell's Palsy.

PubMed

Furukawa, Takatoshi; Abe, Yasuhiro; Ito, Tsukasa; Kubota, Toshinori; Kakehata, Seiji

2017-02-01

Large-scale investigations have not been recently conducted on the efficacy of high-dose steroid administration of prednisolone (PSL) for Bell's palsy. We compared treatment results between normal-dose steroid (PSL 60 mg/d) and high-dose steroid (PSL 200 mg/d) + Hespander + Mannitol administration. We also investigated the recovery rate for antiviral agents. Retrospective case review. Tertiary referral center. A total of 675 patients with Bell's palsy who had grade V and grade VI on the House-Brackmann (HB) scale were treated in our department between 1995 and 2014. These patients could be divided into a normal-dose group and high-dose group. We separately assessed treatment outcomes for HB grade V patients and HB grade VI patients. Logistic regression analysis was also performed to investigate factors that can impact treatment outcomes, i.e., sex, age, days to start of treatment, PSL dosage, and antiviral drug administration. Recovery rates were significantly better in the high-dose steroid + Hespander + Mannitol group in comparison with the normal-dose steroid group for HB grade V (100% versus 77.7%) and HB grade VI (92.5% versus 68.2%). Additional effects of antiviral agents were only shown in the normal-dose group. Significant factors for treatment outcomes were PSL 200 mg/d administration and early initiation of treatment. Insignificant factors were sex, age, and the antiviral agent. We showed the high-dose steroid + Hespander + Mannitol administration produced significantly better outcomes than normal-dose steroid administration in the treatment of patients with Bell's palsy.

Cytotoxic activity of four Mexican medicinal plants.

PubMed

Vega-Avila, Elisa; Espejo-Serna, Adolfo; Alarcón-Aguilar, Francisco; Velasco-Lezama, Rodolfo

2009-01-01

Ibervillea sonorae Greene, Cucurbita ficifolia Bouché, Tagetes lucida Cav and Justicia spicigera Scheltdd are Mexican native plants used in the treatment of different illnesses. The ethanolic extract of J. spicigera and T. lucida as well as aqueous extracts from I. sonorae, C. ficifolia, T. lucida and J. spicigera were investigated using sulforhodamine B assay. These extracts were assessed using two cell line: T47D (Human Breast cancer) and HeLa (Human cervix cancer). Colchicine was used as the positive control. Data are presented as the dose that inhibited 50% control growth (ED50). All of the assessed extracts were cytotoxic (ED50 < 20 microg/ml) against T47D cell line, meanwhile only the aqueous extract from T. lucida and the ethanolic extract from J. spicigera were cytotoxic to HeLa cell line. Ethanolic extract from J. spicigera presented the best cytotoxic effect. The cytotoxic activity of J. spicigera correlated with one of the popular uses, the treatment of cancer.

Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease.

PubMed

Hatorp, V; Walther, K H; Christensen, M S; Haug-Pihale, G

2000-02-01

Repaglinide is a novel insulin secretagogue developed in response to the need for a fast-acting, oral prandial glucose regulator for the treatment of type 2 (non-insulin-dependent) diabetes mellitus. Repaglinide is metabolized mainly in the liver; its pharmacokinetics may therefore be altered by hepatic dysfunction. This open, parallel-group study compared the pharmacokinetics and tolerability of a single 4 mg dose of repaglinide in healthy subjects (n = 12) and patients with chronic liver disease (CLD) (n = 12). Values for AUC and Cmax were significantly higher in CLD patients compared with healthy subjects, and the MRT was prolonged in CLD patients. Values for tmax did not differ between the groups, but t1/2 was significantly prolonged in CLD patients compared with previously determined values in healthy subjects. AUC was inversely correlated with caffeine clearance in CLD patients but not in healthy subjects. Blood glucose profiles were similar in both groups. Adverse events (principally hypoglycemia) were similar in the two groups; none was serious. Repaglinide clearance is significantly reduced in patients with hepatic impairment; the agent should be used with caution in this group.

Safety of a quadrivalent meningococcal serogroups A, C, W and Y conjugate vaccine (MenACWY-CRM) administered with routine infant vaccinations: results of an open-label, randomized, phase 3b controlled study in healthy infants.

PubMed

Abdelnour, Arturo; Silas, Peter E; Lamas, Marta Raquel Valdés; Aragón, Carlos Fernándo Grazioso; Chiu, Nan-Chang; Chiu, Cheng-Hsun; Acuña, Teobaldo Herrera; Castrejón, Tirza De León; Izu, Allen; Odrljin, Tatjana; Smolenov, Igor; Hohenboken, Matthew; Dull, Peter M

2014-02-12

The highest risk for invasive meningococcal disease (IMD) is in infants aged <1 year. Quadrivalent meningococcal conjugate vaccination has the potential to prevent IMD caused by serogroups A, C, W and Y. This phase 3b, multinational, open-label, randomized, parallel-group, multicenter study evaluated the safety of a 4-dose series of MenACWY-CRM, a quadrivalent meningococcal conjugate vaccine, concomitantly administered with routine vaccinations to healthy infants. Two-month-old infants were randomized 3:1 to receive MenACWY-CRM with routine vaccines or routine vaccines alone at ages 2, 4, 6 and 12 months. Adverse events (AEs) that were medically attended and serious adverse events (SAEs) were collected from all subjects from enrollment through 18 months of age. In a subset, detailed safety data (local and systemic solicited reactions and all AEs) were collected for 7 days post vaccination. The primary objective was a non-inferiority comparison of the percentages of subjects with ≥1 severe systemic reaction during Days 1-7 after any vaccination of MenACWY-CRM plus routine vaccinations versus routine vaccinations alone (criterion: upper limit of 95% confidence interval [CI] of group difference <6%). A total of 7744 subjects were randomized with 1898 in the detailed safety arm. The percentage of subjects with severe systemic reactions was 16% after MenACWY-CRM plus routine vaccines and 13% after routine vaccines alone (group difference 3.0% (95% CI -0.8, 6.4%). Although the non-inferiority criterion was not met, post hoc analysis controlling for significant center and group-by-center differences revealed that MenACWY-CRM plus routine vaccinations was non-inferior to routine vaccinations alone (group difference -0.1% [95% CI -4.9%, 4.7%]). Rates of solicited AEs, medically attended AEs, and SAEs were similar across groups. In a large multinational safety study, a 4-dose series of MenACWY-CRM concomitantly administered with routine vaccines was clinically acceptable with a similar safety profile to routine vaccines given alone. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pharmacokinetics, safety, and tolerability of rotigotine transdermal system in healthy Japanese and Caucasian subjects following multiple-dose administration.

PubMed

Cawello, Willi; Kim, Seong Ryul; Braun, Marina; Elshoff, Jan-Peer; Masahiro, Takeuchi; Ikeda, Junji; Funaki, Tomoo

2016-08-01

Rotigotine is a dopamine receptor agonist indicated for the treatment of Parkinson's disease and moderate-to-severe restless legs syndrome. Continuous transdermal delivery of rotigotine via a silicon-based patch maintains stable plasma concentrations over 24 h. The objective of the study was to evaluate the pharmacokinetics, safety, and tolerability of a multiple-dose schedule of rotigotine transdermal patch in Japanese and Caucasian subjects. In this open-label, repeated-dose, parallel-group study (ClinicalTrials.gov: NCT01854216), healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by gender, body mass index, and age. Subjects underwent a 9-day patch application period. 12 Japanese and 12 Caucasian subjects were included in the pharmacokinetic analyses. Mean apparent doses (actual amount of drug delivered) increased proportionally with rotigotine nominal dosages (1, 2, and 4 mg/24 h) and were similar for both ethnic groups, with large inter-individual variability. Mean plasma concentration-time profiles for unconjugated rotigotine were similar in both ethnic groups at day 3 for each dosage. Peak concentrations (C max,ss) and area under the concentration-time curves from pre-dose to the concentration measured 24 h after administration of patch (AUC(0-24,ss)) showed similar exposure in both groups; higher values in Japanese subjects were explained by differences in body weight. For total rotigotine, C max,ss and AUC(0-24,ss) values were higher in Caucasian subjects and could be explained by small differences in apparent dose. Rotigotine was generally well tolerated following multiple applications up to 4 mg/24 h. These findings suggest similar dosage requirements for rotigotine transdermal system in Japanese and Caucasian populations.

[Suppression of VEGF protein expression by arctigenin in oral squamous cell carcinoma].

PubMed

Pu, Guang-rui; Liu, Fa-yu; Wang, Bo

2015-08-01

To observe arctigenin's inhibitory effect on oral squamous cell carcinoma, and explore the possible mechanism. The expression of VEGF in 32 cases of oral squamous cell cancer and 20 adjacent tissue specimen were detected with immunohistochemistry. Human nude mouse transplantation tumor model of oral squamous cell cancer was prepared with HSC-3 cells line. Transplanted tumor growth and VEGF expression in transplanted tumor tissues were assayed after treatment with arctigenin. One-way ANOVA was used for comparison between groups with SPSS 16.0 software package. Compared with the adjacent tissue, immunohistochemical staining score of VEGF was significantly higher (P<0.01) in oral squamous cell carcinoma tissues. After treatment with arctigenin, the growth of oral squamous cell transplanted tumors in nude mouse was inhibited (P<0.05), and decreased weight in end point of observation was noted (P<0.05). There were significant differences between high dose group and low dose group (P<0.05). Compared with the nude mouse model group, the optical density of VEGF staining was significantly lower in arctigenin group (P<0.05). There were significant differences between high dose group and low dose group (P<0.05). Arctigenin can dose-dependently inhibit the growth of oral squamous cell carcinomas, and this effect may be related to down regulation of VEGF expression.

First-dose analgesic effect of the cyclo-oxygenase-2 selective inhibitor lumiracoxib in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled comparison with celecoxib [NCT00267215

PubMed Central

Wittenberg, Ralf H; Schell, Ernest; Krehan, Gerhard; Maeumbaed, Roland; Runge, Hans; Schlüter, Peter; Fashola, Taiwo OA; Thurston, Helen J; Burger, Klaus J; Trechsel, Ulrich

2006-01-01

Cyclo-oxygenase-2 selective inhibitors are frequently used to manage osteoarthritis. We compared the analgesic efficacy of the novel cyclo-oxygenase-2 selective inhibitor lumiracoxib (Prexige®) versus placebo and celecoxib in patients with knee osteoarthritis. This seven day, double-blind, placebo and active comparator controlled, parallel group study included 364 patients aged ≥50 years with moderate-to-severe symptomatic knee osteoarthritis. Patients received lumiracoxib 400 mg/day (four times the recommended chronic dose in osteoarthritis; n = 144), placebo (n = 75), or celecoxib 200 mg twice daily (n = 145). The primary variable was actual pain intensity difference (100 mm visual–analogue scale) between baseline and the mean of three hour and five hour assessments after the first dose. Actual pain intensity difference, average and worst pain, pain relief and functional status (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC™]) were measured over seven days. Patients also completed a global evaluation of treatment effect at study end or premature discontinuation. For the primary variable, the superiority of lumiracoxib versus placebo, the noninferiority of lumiracoxib versus celecoxib, and the superiority of lumiracoxib versus celecoxib were assessed by closed test procedure adjusting for multiplicity, thereby maintaining the overall 5% significance level. In addition, celecoxib was assessed versus placebo in a predefined exploratory manner to assess trial sensitivity. Lumiracoxib provided better analgesia than placebo 3–5 hours after the first dose (P = 0.004) through to study end. The estimated difference between lumiracoxib and celecoxib 3–5 hours after the first dose was not significant (P = 0.185). Celecoxib was not significantly different from placebo in this analysis (P = 0.069). At study end 13.9% of lumiracoxib-treated patients reported complete pain relief versus 5.5% and 5.3% of celecoxib and placebo recipients, respectively. WOMAC™ total and subscales improved for both active treatments versus placebo except for difficulty in performing daily activities, for which celecoxib just failed to achieve significance (P = 0.056). In the patient's global evaluation of treatment effect, 58.1% of patients receiving lumiracoxib rated treatment as 'excellent' or 'good', versus 48.6% of celecoxib and 25.3% of placebo patients. Lumiracoxib was well tolerated. The overall incidence of adverse events was similar across treatment groups. PMID:16469112

Fast, high-resolution 3D dosimetry utilizing a novel optical-CT scanner incorporating tertiary telecentric collimation

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

Sakhalkar, H. S.; Oldham, M.

2008-01-15

This study introduces a charge coupled device (CCD) area detector based optical-computed tomography (optical-CT) scanner for comprehensive verification of radiation dose distributions recorded in nonscattering radiochromic dosimeters. Defining characteristics include: (i) a very fast scanning time of {approx}5 min to acquire a complete three-dimensional (3D) dataset, (ii) improved image formation through the use of custom telecentric optics, which ensures accurate projection images and minimizes artifacts from scattered and stray-light sources, and (iii) high resolution (potentially 50 {mu}m) isotropic 3D dose readout. The performance of the CCD scanner for 3D dose readout was evaluated by comparison with independent 3D readout frommore » the single laser beam OCTOPUS-scanner for the same PRESAGE dosimeters. The OCTOPUS scanner was considered the 'gold standard' technique in light of prior studies demonstrating its accuracy. Additional comparisons were made against calculated dose distributions from the ECLIPSE treatment-planning system. Dose readout for the following treatments were investigated: (i) a single rectangular beam irradiation to investigate small field and very steep dose gradient dosimetry away from edge effects, (ii) a 2-field open beam parallel-opposed irradiation to investigate dosimetry along steep dose gradients, and (iii) a 7-field intensity modulated radiation therapy (IMRT) irradiation to investigate dosimetry for complex treatment delivery involving modulation of fluence and for dosimetry along moderate dose gradients. Dose profiles, dose-difference plots, and gamma maps were employed to evaluate quantitative estimates of agreement between independently measured and calculated dose distributions. Results indicated that dose readout from the CCD scanner was in agreement with independent gold-standard readout from the OCTOPUS-scanner as well as the calculated ECLIPSE dose distribution for all treatments, except in regions within a few millimeters of the edge of the dosimeter, where edge artifact is predominant. Agreement of line profiles was observed, even along steep dose gradients. Dose difference plots indicated that the CCD scanner dose readout differed from the OCTOPUSscanner readout and ECLIPSE calculations by {approx}10% along steep dose gradients and by {approx}5% along moderate dose gradients. Gamma maps (3% dose-difference and 3 mm distance-to-agreement acceptance criteria) revealed agreement, except for regions within 5 mm of the edge of the dosimeter where the edge artifact occurs. In summary, the data demonstrate feasibility of using the fast, high-resolution CCD scanner for comprehensive 3D dosimetry in all applications, except where dose readout is required close to the edges of the dosimeter. Further work is ongoing to reduce this artifact.« less

An ex vivo human aqueous humor-concentration comparison of two commercial bromfenac formulations

PubMed Central

Walters, Thomas R; Smyth-Medina, Robert J; Cockrum, Paul C

2018-01-01

Purpose The purpose of this study was to quantify the concentration of bromfenac in the aqueous humor utilizing high-performance liquid chromatography mass spectrometry between two commercial nonsteroidal anti-inflammatory drugs, using aqueous humor concentrations to characterize pharmacokinetic proportional differences between 0.075% bromfenac ophthalmic solution in DuraSite (BromSite®) and 0.09% bromfenac ophthalmic solution (Bromday®). Methods In this multicenter, randomized, double-masked, two-arm, parallel-group, comparative, Phase II clinical trial, subjects were assigned to receive bromfenac in DuraSite or bromfenac ophthalmic solution in a 1:1 ratio. One drop of the masked test article was instilled into the study eye once a day for 2 days prior to and 3 hours prior (last instillation) to the subject’s cataract surgery. Aqueous humor samples were collected upon initial cataract incision for analysis of bromfenac levels. The primary end point was aqueous humor concentration of bromfenac at Day 3, at the initiation of cataract surgery. Aqueous humor samples were collected and analyzed for bromfenac levels. Results A total of 60 subjects completed the study, 30 in each group. The mean bromfenac aqueous humor concentration in subjects who received bromfenac in DuraSite was more than twice (49.33±41.87 ng/mL, P=0.004) that of subjects who received bromfenac ophthalmic solution (23.65±16.31 ng/mL) after three doses. Conclusion Mean bromfenac aqueous humor concentration in subjects receiving the DuraSite-containing bromfenac in DuraSite (0.075%) was significantly higher compared to subjects receiving bromfenac ophthalmic solution (0.09%) after 3 days of dosing. PMID:29849449

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

PubMed

Bell, D; Duffin, A; Jacobs, A; Pediconi, C; Gruss, H J

2014-03-01

The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

Efficacy and tolerability of fimasartan, a new angiotensin receptor blocker, compared with losartan (50/100 mg): a 12-week, phase III, multicenter, prospective, randomized, double-blind, parallel-group, dose escalation clinical trial with an optional 12-week extension phase in adult Korean patients with mild-to-moderate hypertension.

PubMed

Lee, Sang Eun; Kim, Yong-Jin; Lee, Hae-Young; Yang, Han-Mo; Park, Chang-Gyu; Kim, Jae-Joong; Kim, Soon-Kil; Rhee, Moo-Yong; Oh, Byung-Hee

2012-03-01

Angiotensin receptor blockers (ARBs) is an effective and well tolerated first-line antihypertensive drug. Fimasartan is a newly developed ARB that has not been compared with other ARBs with regard to its efficacy and tolerability. The goal of this study was to determine the noninferiority of fimasartan to losartan with regard to its efficacy and tolerability in adult Korean patients with mild-to-moderate hypertension. This was a randomized, multicenter, double-blind, parallel group, dose escalation, Phase III, noninferiority clinical trial. Patients aged 18 to 70 years with mild-to-moderate hypertension were randomized to receive either fimasartan 60/120 mg daily or losartan 50/100 mg daily with optional titration. Antihypertensive efficacy and tolerability were evaluated for 12 weeks. The primary end point was noninferiority of improvement in mean siDBP from baseline to week 12 for fimasartan compared with losartan. The incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were evaluated to assess their tolerability. In addition, some patients whose blood pressure reached goal levels participated in a 24-week extension study for additional assessment of tolerability and efficacy. Five hundred six patients were randomly allocated to receive fimasartan (n = 256) or losartan (n = 250). There was no significant difference in baseline demographic characteristics between the 2 treatment groups (fimasartan-treated group-mean age, 53.96 [8.79] years; mean weight, 70.58 [11.73] kg; male, 68.02%; losartan-treated group-mean age, 53.58 [9.61] years; mean weight, 69.80 [11.08] kg; male, 70.17%). At week 12, siDBP was significantly decreased from baseline in both groups (-11.26 [7.53] mm Hg in the fimasartan group and -8.56 [7.72] mm Hg in the losartan group [P < 0.0001]). The between-group difference was 2.70 mm Hg (P = 0.0002), and the lower limit of the 2-sided 95% CI (1.27 mm Hg) was higher than the prespecified noninferiority margin (-2.5 mm Hg). The incidence of ADRs were 7.84% and 10.40% in the fimasartan and losartan groups, respectively (χ(2) test, P = 0.3181). The efficacy of fimasartan was maintained over 24 weeks, and its tolerability was comparable with losartan in the extension study. In this study with eligible adult Korean patients who had mild-to-moderate hypertension, the reduction of siDBP after 12 weeks of treatment with fimasartan 60/120 mg was noninferior to that of losartan 50/100 mg. By post hoc comparison, between-group differences in siDBP were significant in favor of fimasartan, suggesting superiority to losartan. There was no statistically significant difference in tolerability between the groups. This efficacy and tolerability were maintained throughout the additional 12-week extension study. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Search for mutations altering protein charge and/or function in children of atomic bomb survivors: final report.

PubMed Central

Neel, J V; Satoh, C; Goriki, K; Asakawa, J; Fujita, M; Takahashi, N; Kageoka, T; Hazama, R

1988-01-01

A sample of (1) children whose parents had been proximally exposed (i.e., less than 2,000 m from the hypocenter) at the time of the atomic bombings of Hiroshima and Nagasaki and (2) a suitable comparison group have been examined for the occurrence of mutations altering the electrophoretic mobility or activity of a series of 30 proteins. The examination of the equivalent of 667,404 locus products in the children of proximally exposed persons yielded three mutations altering electrophoretic mobility; the corresponding figure for the comparison group was three mutations in 466,881 tests. The examination of a subset of 60,529 locus products for loss of enzyme activity in the children of proximally exposed persons yielded one mutation; no mutations were encountered in 61,741 determinations on the children of the comparison group. When these two series are compared, the mutation rate observed in the children of proximally exposed persons is thus 0.60 x 10(-5)/locus/generation, with 95% confidence intervals between 0.2 and 1.5 x 10(-5), and that in the comparison children is 0.64 x 10(-5)/locus/generation, with 95% intervals between 0.1 and 1.9 x 10(-5). The average conjoint gonad doses for the proximally exposed parents are estimated to be 0.437 Gy of gamma radiation and 0.002 Gy of neutron radiation. If a relative biological effectiveness of 20 is assigned to the neutron radiation, the combined total gonad dose for the parents becomes 0.477 Sv. (Organ absorbed doses are expressed in gray [1 Gy = 100 rad]; where dose is a mixture of gamma and neutron radiation, it is necessary because of the differing relative biological effectiveness of gamma and neutron radiation to express the combined gamma-neutron gonad exposures in sieverts [1 Sv = 100 rem]). PMID:3358419

Evaluation of Sub-acute Oral Toxicity of Lithium Carbonate Microemulsion (Nano Size) on Liver and Kidney of Mice

PubMed Central

Kalantari, Heibatullah; Salimi, Anayatollah; Rezaie, Anahita; Jazayeri Shushtari, Fereshteh; Goudarzi, Mehdi

2015-01-01

Background: The development of drug delivery systems has improved the therapeutic and toxic properties of existing drugs in therapy. Microemulsion systems are novel vehicles for drug delivery, which have been developed in recent years. These systems are currently of interest to the pharmaceutical scientist because of their considerable potential to act as drug delivery vehicles by incorporating into a wide range of drug molecules. Although these systems improved solubility and bioavailability of drugs, they may have potential toxic effects on the body organs. Objectives: The purpose of this study was to examine a possible hepatotoxic and nephrotoxic effect of lithium carbonate microemulsion (LCME) in a mice model. Materials and Methods: Eighty male Swiss albino mice were randomly allocated to eight experimental groups, as follows: Group 1, as negative control group were treated orally with normal saline (0.9% NaCl); Group 2, received microemulsion base without drug as control group; Groups 3 to 5, received lithium carbonate (LC) solution in doses of 50, 100, and 200 mg/kg, respectively; Groups 6 to 8, received LCME orally in doses of 50, 100, and 200 mg/kg, respectively. All drugs were administered orally for ten consecutive days. Serum glutamate pyruvate aminotransferase (SGPT), serum glutamate oxaloacetate aminotransferase (SGOT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and plasma creatinine (Cr), as markers of liver and kidney toxicity in treated mice, were measured. Furthermore, the changes of tissue were assessed by histopathologic examination. Results: The findings showed that serum activity of ALP, SGOT, and SGPT and the levels of BUN and Cr in microemulsion base group was greater than normal saline group. However, this difference was not significant. Administration of LC and LCME in all doses resulted in a significant increase in the levels of BUN and serum activity of SGOT and SGPT in comparison to normal saline group (P < 0.05). Histopathological changes were observed in mice treated with LC or LCME. Conclusions: This study showed that subacute oral administration of different doses of LCME with severe toxicity in comparison to the same dose of LC. PMID:25866723

Labetalol compared with propranolol in the treatment of black hypertensive patients.

PubMed

Saunders, E; Curry, C; Hinds, J; Kong, B W; Medakovic, M; Poland, M; Roper, K

1987-09-01

A double-blind parallel group study was conducted to examine the effects of oral labetalol, in doses from 100 to 800 mg BID, and propranolol, 40 to 320 mg, in patients with mild to moderate hypertension. The doses of labetalol (n = 74) and propranolol (n = 79) were titrated weekly to achieve a sitting diastolic blood pressure (DBP) of less than 90 mmHg or at least a 10-mmHg decrease from placebo baseline on two consecutive visits. A 2-month fixed-dose maintenance phase followed in which a diuretic could be added if the sitting DBP was greater than or equal to 100 mmHg on maximum doses of either drug. BP and heart rate were measured 8-12 hours after a dose in the sitting and standing positions. Labetalol was significantly more effective at the end of monotherapy than propranolol was in lowering both the sitting (p less than .05) and standing (p less than .04) DBP. The reduction in the systolic, although more pronounced for those on labetalol, was not significantly different; 53% of patients had a "good" response to labetalol compared with 30% of the propranolol group. Propranolol significantly (p less than 0.01) lowered heart rate compared with labetalol. Nine patients in the labetalol group and 10 in the propranolol group required a diuretic. The decrease in BP after the addition of a diuretic was comparable. Changes in plasma lipids were not significant, but HDL increased 9% with labetalol and decreased 2% with propranolol. Triglycerides increased 25% with labetalol and 31% with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Dosimetric and delivery efficiency investigation for treating hepatic lesions with a MLC-equipped robotic radiosurgery-radiotherapy combined system.

PubMed

Jin, Lihui; Price, Robert A; Wang, Lu; Meyer, Joshua; Fan, James Jiajin; Ma, Chang Ming Charlie

2016-02-01

The CyberKnife M6 (CK-M6) Series introduced a multileaf collimator (MLC) for extending its capability from stereotactic radiosurgery/stereotactic radiotherapy (SBRT) to conventionally fractionated radiotherapy. This work is to investigate the dosimetric quality of plans that are generated using MLC-shaped beams on the CK-M6, as well as their delivery time, via comparisons with the intensity modulated radiotherapy plans that were clinically used on a Varian Linac for treating hepatic lesions. Nine patient cases were selected and divided into three groups with three patients in each group: (1) the group-one patients were treated conventionally (25 fractions); (2) the group-two patients were treated with SBRT-like hypofractionation (5 fractions); and (3) the group-three patients were treated similar to group-one patients, but with two planning target volumes (PTVs) and two different prescription dose levels correspondingly. The clinically used plans were generated on the eclipse treatment planning system (TPS) and delivered on a Varian Linac (E-V plans). The multiplan (MP) TPS was used to replan these clinical cases with the MLC as the beam device for the CK-M6 (C-M plans). After plans were normalized to the same PTV dose coverage, comparisons between the C-M and E-V plans were performed based on D(99%) (percentage of prescription dose received by 99% of the PTV), D(0.1cm(3)) (the percentage of prescription dose to 0.1 cm(3) of the PTV), and doses received by critical structures. Then, the delivery times for the C-M plans will be obtained, which are the MP TPS generated estimations assuming having an imaging interval of 60 s. The difference in D(99%) between C-M and E-V plans is +0.6% on average (+ or - indicating a higher or lower dose from C-M plans than from E-V plans) with a range from -4.1% to +3.8%, and the difference in D(0.1cm(3)) was -1.0% on average with a range from -5.1% to +2.9%. The PTV conformity index (CI) for the C-M plans ranges from 1.07 to 1.29 with a mean of 1.19, slightly inferior to the E-V plans, in which the CI ranges from 1.00 to 1.15 with a mean of 1.07. Accounting for all nine patients in three groups, 45% of the critical structures received a lower mean dose for the C-M plans as compared with the E-V plans, and similarly, 48% received a lower maximum dose. Furthermore, the average difference of the mean critical structure dose between the C-M and E-V plans over all critical structures for all patients showed only +2.10% relative to the prescription dose and the similar comparison finds the average difference of the maximum critical structure dose of only +1.24%. The estimated delivery times for the C-M plans on the CK-M6 range from 18 to 24 minutes while they are from 7 to 13.7 min for the E-V plans on the Varian Linac. For treating hepatic lesions, for the C-M plans that are comparable to E-V plans in quality, the times needed to deliver these C-M plans on the CK-M6 are longer than the delivery time for the E-V plans on the Varian Linac, but may be clinically acceptable.

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

2017-01-01

Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

Efficacy and Safety of the Glucagon Receptor Antagonist PF-06291874: A 12-Week, Randomized, Dose-Response Study in Patients With Type 2 Diabetes Mellitus on Background Metformin Therapy.

PubMed

Kazierad, David J; Chidsey, Kristin; Somayaji, Veena R; Bergman, Arthur J; Calle, Roberto A

2018-06-19

To conduct a dose-response assessment of the efficacy and safety of the glucagon receptor antagonist PF-06291874 in adults with type 2 diabetes (T2DM) receiving stable doses of metformin. This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60, or 100 mg once daily) for 12 weeks. Glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), and safety endpoints were assessed at baseline and postbaseline. Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol); and in FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycemia was low and similar between groups receiving PF-06291874. Small, non-dose-dependent increases in LDL cholesterol (<10%) and blood pressure (BP; systolic BP>2 mmHg, diastolic BP>1 mmHg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L versus placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L versus placebo) that were not associated with bilirubin changes. Small increases were observed for body weight (<0.5 kg) in each PF-06291874 group versus placebo. In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated, and had low risk of hypoglycemia. Small, non-dose-related increases in BP, lipids, and hepatic transaminases were observed. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial

PubMed Central

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-01-01

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD. PMID:27552585

Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: a 24-week randomized clinical trial.

PubMed

Kosaka, H; Okamoto, Y; Munesue, T; Yamasue, H; Inohara, K; Fujioka, T; Anme, T; Orisaka, M; Ishitobi, M; Jung, M; Fujisawa, T X; Tanaka, S; Arai, S; Asano, M; Saito, D N; Sadato, N; Tomoda, A; Omori, M; Sato, M; Okazawa, H; Higashida, H; Wada, Y

2016-08-23

Recent studies have suggested that long-term oxytocin administration can alleviate the symptoms of autism spectrum disorder (ASD); however, factors influencing its efficacy are still unclear. We conducted a single-center phase 2, pilot, randomized, double-blind, placebo-controlled, parallel-group, clinical trial in young adults with high-functioning ASD, to determine whether oxytocin dosage and genetic background of the oxytocin receptor affects oxytocin efficacy. This trial consisted of double-blind (12 weeks), open-label (12 weeks) and follow-up phases (8 weeks). To examine dose dependency, 60 participants were randomly assigned to high-dose (32 IU per day) or low-dose intranasal oxytocin (16 IU per day), or placebo groups during the double-blind phase. Next, we measured single-nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR). In the intention-to-treat population, no outcomes were improved after oxytocin administration. However, in male participants, Clinical Global Impression-Improvement (CGI-I) scores in the high-dose group, but not the low-dose group, were significantly higher than in the placebo group. Furthermore, we examined whether oxytocin efficacy, reflected in the CGI-I scores, is influenced by estimated daily dosage and OXTR polymorphisms in male participants. We found that >21 IU per day oxytocin was more effective than ⩽21 IU per day, and that a SNP in OXTR (rs6791619) predicted CGI-I scores for ⩽21 IU per day oxytocin treatment. No severe adverse events occurred. These results suggest that efficacy of long-term oxytocin administration in young men with high-functioning ASD depends on the oxytocin dosage and genetic background of the oxytocin receptor, which contributes to the effectiveness of oxytocin treatment of ASD.

A comparison of parallel and diverging screw angles in the stability of locked plate constructs.

PubMed

Wähnert, D; Windolf, M; Brianza, S; Rothstock, S; Radtke, R; Brighenti, V; Schwieger, K

2011-09-01

We investigated the static and cyclical strength of parallel and angulated locking plate screws using rigid polyurethane foam (0.32 g/cm(3)) and bovine cancellous bone blocks. Custom-made stainless steel plates with two conically threaded screw holes with different angulations (parallel, 10° and 20° divergent) and 5 mm self-tapping locking screws underwent pull-out and cyclical pull and bending tests. The bovine cancellous blocks were only subjected to static pull-out testing. We also performed finite element analysis for the static pull-out test of the parallel and 20° configurations. In both the foam model and the bovine cancellous bone we found the significantly highest pull-out force for the parallel constructs. In the finite element analysis there was a 47% more damage in the 20° divergent constructs than in the parallel configuration. Under cyclical loading, the mean number of cycles to failure was significantly higher for the parallel group, followed by the 10° and 20° divergent configurations. In our laboratory setting we clearly showed the biomechanical disadvantage of a diverging locking screw angle under static and cyclical loading.

Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia.

PubMed

Yang, Nae-Cherng; Chou, Chien-Wen; Chen, Chung-Yin; Hwang, Kai-Lin; Yang, Yi-Chueh

2009-01-01

The purpose of this randomized, double-blind, placebo-controlled, parallel comparison study was to evaluate the lipid-lowering effect of orally administrated nattokinase and nattokinase combined with red yeast rice (RYR) extract on blood lipids in patients with hyperlipidemia. A total of 47 patients with hyperlipidemia were assigned to one of three groups: 1. nattokinase-mono formula (50 mg/capsule), 2. combined formula of nattokinase with RYR (300 mg of extract/capsule) and 3. placebo. Subjects received a twice daily dose of two capsules for six months. The mono formula showed no effects on blood lipids until month six, while the combined formula ameliorated all of measured lipids starting from month one. In the combined group significant decreases were found with regard to: triglycerides (TG) by 15%, total cholesterol (TC) by 25%, low-density lipoprotein cholesterol (LDL-C) by 41%, TC/high-density lipoprotein cholesterol (HDL-C) ratio by 29.5%, and increases in HDL-C by 7.5%. These changes were sustained until the end of study. After controlling for baseline levels, only the combined group, but not mono group, showed a significant difference (p<0.0001) in TC, LDL-C and TC/HDL-C ratio when compared with the placebo group. In summary, this study provides long-term efficacy of nattokinase supplementation and shows that the combined formula has relatively more potent effects than the mono formula on lowering of blood lipids, suggesting that combined nattokinase with RYR will be a better neutraceutical for patients with hyperlipidemia than nattokinase alone.

Effects of a radiation dose reduction strategy for computed tomography in severely injured trauma patients in the emergency department: an observational study.

PubMed

Kim, Soo Hyun; Jung, Seung Eun; Oh, Sang Hoon; Park, Kyu Nam; Youn, Chun Song

2011-11-03

Severely injured trauma patients are exposed to clinically significant radiation doses from computed tomography (CT) imaging in the emergency department. Moreover, this radiation exposure is associated with an increased risk of cancer. The purpose of this study was to determine some effects of a radiation dose reduction strategy for CT in severely injured trauma patients in the emergency department. We implemented the radiation dose reduction strategy in May 2009. A prospective observational study design was used to collect data from patients who met the inclusion criteria during this one year study (intervention group) from May 2009 to April 2010. The prospective data were compared with data collected retrospectively for one year prior to the implementation of the radiation dose reduction strategy (control group). By comparison of the cumulative effective dose and the number of CT examinations in the two groups, we evaluated effects of a radiation dose reduction strategy. All the patients met the institutional adult trauma team activation criteria. The radiation doses calculated by the CT scanner were converted to effective doses by multiplication by a conversion coefficient. A total of 118 patients were included in this study. Among them, 33 were admitted before May 2009 (control group), and 85 were admitted after May 2009 (intervention group). There were no significant differences between the two groups regarding baseline characteristics, such as injury severity and mortality. Additionally, there was no difference between the two groups in the mean number of total CT examinations per patient (4.8 vs. 4.5, respectively; p = 0.227). However, the mean effective dose of the total CT examinations per patient significantly decreased from 78.71 mSv to 29.50 mSv (p < 0.001). The radiation dose reduction strategy for CT in severely injured trauma patients effectively decreased the cumulative effective dose of the total CT examinations in the emergency department. But not effectively decreased the number of CT examinations.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

PubMed

Foegh, Marie; Archer, David F; Stanczyk, Frank Z; Rubin, Arkady; Mishell, Daniel R

2013-02-01

The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined. A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women. Suppression of ovulation during the luteal phase was dose dependent, with the highest dose (AG200-15) preventing progesterone increases in all women (cycles 2-3). In the follicular phase, the lowest-dose patch had the highest rate of increased progesterone in nonobese subjects. Progesterone levels ≥3.0 ng/mL in the follicular phase were more common in obese than nonobese women. AG200-15 suppresses ovulation in obese and nonobese women. All three patches found increased progesterone in the follicular phase, albeit more in obese versus nonobese women. Copyright © 2013 Elsevier Inc. All rights reserved.

Prostate Brachytherapy With Oblique Needles to Treat Large Glands and Overcome Pubic Arch Interference

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

Ryu, Bon; Imaging Research Laboratories, Robarts Research Institute, University of Western Ontario, London, Ontario; Bax, Jeff

2012-08-01

Purpose: First, to show that low-dose-rate prostate brachytherapy plans using oblique needle trajectories are more successful than parallel trajectories for large prostates with pubic arch interference (PAI); second, to test the accuracy of delivering an oblique plan by using a three-dimensional (3D) transrectal ultrasonography (TRUS)-guided mechatronic system. Methods and Materials: Prostates were contoured for 5 subjects' 3D TRUS images showing a maximum PAI of {<=}1 cm and a prostate volume of <50 cc. Two planning studies were done. First, prostate contours were artificially enlarged to 45 to 80 cc in 5- to 10-cc increments for a single subject. Second, allmore » subject prostate contours were enlarged to 60 cc. For each study, three types of plans were manually created for comparison: a parallel needle template (PT) plan, a parallel needle no-template (PNT) plan, and an oblique needle no-template (OBL) plan. Needle positions and angles were not discretized for nontemplate plans. European Society for Therapeutic Radiology and Oncology dose-volume histogram guidelines, iodine-125 (145-Gy prescription, 0.43 U), and needle angles of <15 Degree-Sign were used. An OBL plan was delivered to a pubic arch containing a 60-cc prostate phantom that mimicked the anatomy of the subject with the greatest PAI (23% by volume). Results: In the increasing-prostate volume study, OBL plans were successful for prostates of {<=}80 cc, and PT plans were successful for prostates of <65 cc. In paired, one-sided t tests for the 60-cc volume study, OBL plans showed dosimetric improvements for all organs compared to both of the parallel type plans (p < 0.05); PNT plans showed a benefit only in planning target volumes receiving more than 100 Gy compared to PT plans. A computed tomography scan of the phantom showed submillimeter seed placement accuracy in all directions. Conclusion: OBL plans were significantly better than parallel plans, and an OBL plan was accurately delivered to a 60-cc prostate phantom with 23% PAI by volume.« less

Comparison of Risperidone and Methylphenidate for Reducing ADHD Symptoms in Children and Adolescents with Moderate Mental Retardation.

ERIC Educational Resources Information Center

Filho, Alceu Gomes Correia; Bodanese, Rafael; Silva, Tatiana Laufer; Alvares, Julia Paglioza; Aman, Michael; Rohde, Luis Augusto

2005-01-01

Objective: To evaluate the short-term efficacy and tolerability of risperidone and methylphenidate for reducing symptoms related to attention-deficit/hyperactivity disorder (ADHD) in children and adolescents with moderate mental retardation. Method: In a 4-week, single-blind, parallel-group trial, 45 subjects with moderate mental retardation and…

[Emodin alleviates pulmonary fibrosis through inactivation of TGF-β1/ADAMTS-1 signaling pathway in rats].

PubMed

Liu, Lijing; Qian, Hong; Xiao, Hua; He, Jianbin; Xie, Maofeng; Wang, Zaiyan; Long, Xingyun

2016-10-01

Objective To explore the role of transforming growth factor-β1 (TGF-β1)/a disintegrin-like and metalloproteinase with thrombospondin type 1 motif (ADAMTS-1) signaling pathway in emodin's anti-pulmonary fibrosis. Methods Sixty SD rats were randomly divided into 6 groups: normal control group, sham-operated group, model group, low-dose emodin intervention group (20 mg/kg), high-dose emodin intervention group (80 mg/kg) and prednisone group (5 mg/kg). Each group included 10 animals. Rats in the latter 4 groups were intratracheally injected with bleomycin A5 to induce pulmonary fibrosis, whereas bleomycin A5 was replaced by normal saline in sham-operated group. From the second day, rats in the low- and high-dose emodin intervention groups were intragastrically treated with 2 mL of 20 and 80 mg/kg emodin, respectively. Rats in the prednisone group were intragastrically administrated with 2 mL of 5 mg/kg prednisone acetate. However, rats in the normal control and sham-operated and model groups were treated with 2 mL of normal saline. All rats were sacrificed on day 28 after modeling. Subsequently, blood and pulmonary tissue specimen were taken. The pathological changes of pulmonary tissues were observed using routine HE and Masson staining. The expressions of TGF-β1, ADAMTS-1, collagen type 1 (Col1) and Col3 in pulmonary tissues were measured by quantitative real-time PCR and Western blotting. Serum levels of procollagen type 1 carboxy terminal propeptide (P1CP) and procollagen type 3 aminoterminal propeptide (P3NP) were detected by ELISA. Results Compare with the model group, the alveolitis and pulmonary fibrosis extent in each drug-treated group were significantly alleviated. In comparison with normal control group or sham-operated group, the mRNA and protein levels of TGF-β1, Col1 and Col3 in pulmonary tissues and the serum levels of P1CP and P3NP increased, but the mRNA and protein levels of ADAMTS-1 decreased in model group. After treatment with low- and high-dose emodin or prednisone, the mRNA and protein levels of TGF-β1, Col1 and Col3 in pulmonary tissues and the serum levels of P1CP and P3NP were significantly downregulated, while the mRNA and protein levels of ADAMTS-1 in pulmonary tissues were significantly upregulated as compared with the model group. Moreover, In comparison with the low-dose emodin intervention group, the above indicators were significantly improved in the high-dose emodin intervention or prednisone group. However, the above indicators were not significantly different between the high-dose emodin intervention group and the prednisone group. Conclusion Increased degradation of Col1 and Col3 in pulmonary tissues due to the inactivation of TGF-β1/ADAMTS-1 signaling pathway may be a significant mechanism by which emodin protects rats against pulmonary fibrosis.

Age-specific doses of lormetazepam as a night sedative in cases of chronic sleep disturbance.

PubMed

Jovanović, U J; Ott, H; Heidrich, H; Stephan, K; Schratzer, M

1980-01-01

Lormetazepam, a new benzodiazepine derivative, was tested under double blind conditions in order to find the optimal dosage for different age groups of out-patients. 120 patients suffering from chronic sleep disturbance were included in the study: a younger group (age 20 to 55) and an older group (age 56 to 85 years). Four different doses were given to each age group: 0.5, 1.0, 2.0, and 3.0 mg to the younger group and 0.5, 1.0, 1.5, and 2.0 mg to the older group. A pre-placebo week (i.e. when all patients received placebo) in which baseline data were recorded preceded the two verum weeks, and these were followed by a post-placebo or withdrawal week (again all patients receiving placebo). The level of significance accepted for statistical decisions was alpha = 0.05. No differences in effects between the different doses were observed with regard to sleep pattern variables (sleep latency, sleep duration, frequency of awakenings, sleep quality, occurrence of 'bad' dreams) with the exception of sleep quality which was better in the older group than in the younger group after 0.5 mg in week 2. Considerable differences with regard to hangover feelings the next morning and during the next day (morning feelings, tranquility, alertness, and concentration), comparison of the effects of discontinuing therapy upon the above-mentioned sleep pattern variables and small differences in side effects--which were few--led to the following conclusion: --0.5 mg stood out as the best dose for the older group. --None of the dosages given to the younger group emerged clearly as superior. However, it would seem that the 1 mg dose should be the dose recommended, since fewer unfavourable scores and side effects appeared after this dose.

Comparison Between Prospectively Electrocardiogram-Gated High-Pitch Mode and Retrospectively Electrocardiogram-Gated Mode for Dual-Source CT Coronary Angiography.

PubMed

Koplay, Mustafa; Celik, Mahmut; Avcı, Ahmet; Erdogan, Hasan; Demir, Kenan; Sivri, Mesut; Nayman, Alaaddin

2015-01-01

We aimed to report the image quality, relationship between heart rate and image quality, amount of contrast agent given to the patients and radiation doses in coronary CT angiography (CTA) obtained by using high-pitch prospectively ECG-gated "Flash Spiral" technique (method A) or retrospectively ECG-gated technique (method B) using 128×2-slice dual-source CT. A total of 110 patients who were evaluated with method A and method B technique with a 128×2-detector dual-source CT device were included in the study. Patients were divided into three groups based on their heart rates during the procedure, and a relationship between heart rate and image quality were evaluated. The relationship between heart rate, gender and radiation dose received by the patients was compared. A total of 1760 segments were evaluated in terms of image quality. Comparison of the relationship between heart rate and image quality revealed a significant difference between heart rate <60 beats/min group and >75 beats/min group whereas <60 beats/min and 60-75 beats/min groups did not differ significantly. The average effective dose for coronary CTA was calculated as 1.11 mSv (0.47-2.01 mSv) for method A and 8.22 mSv (2.19-12.88 mSv) for method B. Method A provided high quality images with doses as low as <1 mSv in selected patients who have low heart rates with a high negative predictive value to rule out coronary artery disease. Although method B increases the amount of effective dose, it provides high diagnostic quality images for patients who have a high heart rate and arrhythmia which makes it is difficult to obtain images.

Comparative modelling of human β tubulin isotypes and implications for drug binding

NASA Astrophysics Data System (ADS)

Torin Huzil, J.; Ludueña, Richard F.; Tuszynski, Jack

2006-02-01

The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.

Monogenic Periodic Fever Syndromes: Treatment Options for the Pediatric Patient.

PubMed

Ozen, Seza; Demir, Selcan

2017-08-01

Autoinflammatory diseases are disorders of the innate immune system characterized by uncontrolled inflammation. The most commonly encountered autoinflammatory diseases are the hereditary periodic fever syndromes, which present with fever and other features of the skin, serosal membranes, and musculoskeletal system. The main inherited (monogenic) periodic fever syndromes are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD). Recent advances in our understanding of the molecular and pathophysiological basis of autoinflammatory diseases have provided new treatment strategies. Patients with periodic fever syndromes have clearly benefited from anti-interleukin (IL)-1 treatment. Colchicine is still the mainstay of FMF therapy, but IL-1 blockade is also effective if colchicine fails. Early diagnosis and effective treatment can prevent irreversible organ damage. The scope of pathogenic mutations and more targeted therapy for better management of these rare diseases remains to be defined.

Some Pecularities of the Graviresponse in Vaucheria

NASA Technical Reports Server (NTRS)

Gavrilova, O. V.; Rudanova, E. E.; Voloshko, L. N.; Gabova, A. V.

1996-01-01

The growth and position of nuclei in the siphonaceous alga Vaucheria sessilis were investigated under conditions of hypergravity and hypogravity. Under hypergravity conditions, active sporogenesis was observed. The accumulation of nuclei in the apical and branching zone preceeded the sporogenesis. The anti-microtubular agent, colchicine inhibits sporogenesis and the response of Vaucheria to hypergravity. Under hypogravity conditions, the quantity of nuclei increased throughout the whole branch. Colchicine prevents the migration of nuclei from the apical zone to the basal part of the branch. The anti-actin agent phalloidin prevents the formation of an actin network, and phalloidin-poisoned cells lose a cluster of nuclei in the apical zone. However, the gravity dependent response is less pronounced. It is supposed that, in Vaucheria sessilis, the primary stages of the reception and translation of gravitational signals coincide with those for light signals and active division of nuclei in the growth zone is an integral part of the graviresponse.

CELL POPULATION KINETICS OF EXCISED ROOTS OF PISUM SATIVUM

PubMed Central

Van't Hof, Jack

1965-01-01

The cell population kinetics of excised, cultured pea roots was studied with the use of tritiated thymidine and colchicine to determine (1) the influence of excision, (2) the influence of sucrose concentration, (3) the average mitotic cycle duration, and (4) the duration of mitosis and the G 1, S, and G 2 periods of interphase.1 The results indicate that the process of excision causes a drop in the frequency of mitotic figures when performed either at the beginning of the culture period or after 100 hours in culture. This initial decrease in frequency of cell division is independent of sucrose concentration, but the subsequent rise in frequency of division, after 12 hours in culture, is dependent upon sucrose concentration. Two per cent sucrose maintains the shortest mitotic cycle duration. The use of colchicine indicated an average cycle duration of 20 hours, whereas the use of tritiated thymidine produced an average cycle duration of 17 hours. PMID:5857253

The unwelcome visitor.

PubMed

Teng, Gim Gee; Tong, Chung Yan; How, Choon How; Goh, Lay Hoon

2012-08-01

Gout is a chronic, progressive inflammatory disease with intermittent arthritic flares, which should not be regarded as a minor inconvenience or nuisance. It can be effectively controlled when the patient's serum urate level is reduced to less than 360 μmol/l (6 mg/dL) by consistent use of urate-lowering pharmacotherapy. Colchicine prophylaxis for gouty flares during titration of urate-lowering therapy has been underused. Holistic long-term management of gout must encompass patient education, evidence-based dietary advice, screening and aggressive treatment of comorbidities such as hypertension, diabetes mellitus, dyslipidaemia and renal impairment. Acute therapies for recurrent attacks with non-steroidal anti-inflammatory drugs, colchicine and/or corticosteroids should be used judiciously, especially in the elderly, due to the risk of toxicities. With appreciation of the underlying pathogenesis and artful use of the limited drug options, control of gout can be effectively achieved, bringing tremendous satisfaction to the patient and doctor.

Usefulness of Novel Immunotherapeutic Strategies for Idiopathic Recurrent Pericarditis.

PubMed

Lotan, Dor; Wasserstrum, Yishay; Fardman, Alexander; Kogan, Michael; Adler, Yehuda

2016-03-01

Idiopathic recurrent pericarditis (IRP) is a debilitating illness which leads to great suffering and multiple hospitalizations. Management of acute pericarditis and subsequent recurrences has evolved significantly as the use of colchicine-based strategies become more prevalent, yet there still remains a subset of patients who remain refractory to colchicine therapy, and these patients require prolonged corticosteroid (CS) therapy for the control of symptoms. Since the 1960s, there have been reports of successful management of these cases with immunosuppressive therapy. Current guidelines support the use of anakinra, intravenous immunoglobulins, and azathioprine for management of IRP, with the goals of both control of symptoms and withdrawal of CS. Recent reports supply evidence for both auto-inflammatory and autoimmune activity in these patients. We herein review the current available reports regarding the evidence regarding the pathophysiology and reported cases and case series of IRP cases managed with immunomodulation therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study.

PubMed

Hosomi, Naohisa; Nagai, Yoji; Kohriyama, Tatsuo; Ohtsuki, Toshiho; Aoki, Shiro; Nezu, Tomohisa; Maruyama, Hirofumi; Sunami, Norio; Yokota, Chiaki; Kitagawa, Kazuo; Terayama, Yasuo; Takagi, Makoto; Ibayashi, Setsuro; Nakamura, Masakazu; Origasa, Hideki; Fukushima, Masanori; Mori, Etsuro; Minematsu, Kazuo; Uchiyama, Shinichiro; Shinohara, Yukito; Yamaguchi, Takenori; Matsumoto, Masayasu

2015-09-01

Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients. This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints. Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events. Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis. This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

A comparison between pre-operative carprofen and a long-acting sufentanil formulation for analgesia after ovariohysterectomy in dogs.

PubMed

Slingsby, Louisa S; Murison, Pamela J; Goossens, Lieve; Engelen, Marc; Waterman-Pearson, Avril E

2006-09-01

To assess the analgesic efficacy and adverse effects of a novel, long-acting sufentanil preparation in dogs undergoing ovariohysterectomy (OHE). Blinded, positively controlled, randomized field trial with four parallel treatment groups. Eighty client owned dogs undergoing elective OHE randomly allocated into four treatment groups (each n = 20). Three groups received intramuscular (IM) sufentanil (at 10, 15 and 25 microg kg(-1), respectively) and the control group received subcutaneous (SC) carprofen 4 mg kg(-1) SC plus acepromazine 0.05 mg kg(-1) IM as pre-anaesthetic medication. OHE was performed under thiopental/halothane anaesthesia. Visual Analogue Scale (VAS) scores for pain and sedation were awarded and mechanical nociceptive thresholds were measured at the wound and hock before surgery and up to 24 hours after tracheal extubation. Serum cortisol was measured before surgery, during surgery and up to 24 hours after tracheal extubation. Animals with inadequate post-operative analgesia were given rescue medication. In the carprofen group, VAS pain scores were significantly higher, wound tenderness was greater and requirement for rescue analgesia was more than in the sufentanil-treated groups. Sufentanil produced dose dependent analgesia and sedation. All treatment groups showed similar patterns of change for cortisol concentrations. Use of the sufentanil preparation was associated with a relatively high incidence of adverse events. The long-acting preparation of sufentanil provided excellent post-operative analgesia that was significantly better than that provided by carprofen. However, use of this formulation, in the anaesthetic technique used in the study, resulted in a relatively high incidence of adverse effects. Full mu (MOP) opioid agonists provide significantly better post-operative analgesia than nonsteroidal anti-inflammatory drugs after moderately painful surgery. However, the widely recognized adverse effects of opioids may preclude the use of these agents.

Antitrypanosomal Activity of Fexinidazole Metabolites, Potential New Drug Candidates for Chagas Disease

PubMed Central

Nascimento, Alvaro F. S.; Mazzeti, Ana Lia; Marques, Luiz F.; Gonçalves, Karolina R.; Mota, Ludmilla W. R.; Diniz, Lívia de F.; Caldas, Ivo S.; Talvani, André; Shackleford, David M.; Koltun, Maria; Saunders, Jessica; White, Karen L.; Scandale, Ivan; Charman, Susan A.; Chatelain, Eric

2014-01-01

This study was designed to verify the in vivo efficacy of sulfoxide and sulfone fexinidazole metabolites following oral administration in a murine model of Chagas disease. Female Swiss mice infected with the Y strain of Trypanosoma cruzi were treated orally once per day with each metabolite at doses of 10 to 100 mg/kg of body weight for a period of 20 days. Parasitemia was monitored throughout, and cures were detected by parasitological and PCR assays. The results were compared with those achieved with benznidazole treatment at the same doses. Fexinidazole metabolites were effective in reducing the numbers of circulating parasites and protecting mice against death, compared with untreated mice, but without providing cures at daily doses of 10 and 25 mg/kg. Both metabolites were effective in curing mice at 50 mg/kg/day (30% to 40%) and 100 mg/kg/day (100%). In the benznidazole-treated group, parasitological cure was detected only in animals treated with the higher dose of 100 mg/kg/day (80%). Single-dose pharmacokinetic parameters for each metabolite were obtained from a parallel group of uninfected mice and were used to estimate the profiles following repeated doses. Pharmacokinetic data suggested that biological efficacy most likely resides with the sulfone metabolite (or subsequent reactive metabolites formed following reduction of the nitro group) following administration of either the sulfoxide or the sulfone and that prolonged plasma exposure over the 24-h dosing window is required to achieve high cure rates. Fexinidazole metabolites were effective in treating T. cruzi in a mouse model of acute infection, with cure rates superior to those achieved with either fexinidazole itself or benznidazole. PMID:24841257

Comparison of long-term (10 years) immunogenicity of two- and three-dose regimens of a combined hepatitis A and B vaccine in adolescents.

PubMed

Beran, Jiri; Kervyn, Diane; Wertzova, Veronika; Hobzova, Lenka; Tichy, Petr; Kuriyakose, Sherine; Leyssen, Maarten; Jacquet, Jeanne-Marie

2010-08-23

300 adolescents aged 12-15 years were randomised (1:1) into two groups to compare the long-term (10 years) immunogenicity profile of two doses of an Adult formulation [Group HAB_2D: 150; 0-6 months] vs. three doses of a Paediatric formulation [Group HAB_3D: 150; 0-1-6 months] of a combined hepatitis A and B (HAB) vaccine. At Year 10, anti-HAV seropositivity rate was 100% in both groups, while 85.9% and 85.1% subjects in the HAB_2D and HAB_3D groups, respectively, had anti-HBs antibody concentrations > or =10 mIU/mL. The anti-HAV antibody GMCs (HAB_2D: 429.3 mIU/mL; HAB_3D: 335.5 mIU/mL) and anti-HBs antibody GMCs (HAB_2D: 50.6 mIU/mL; HAB_3D: 60.1 mIU/mL) were similar in both groups. No vaccine-related serious adverse events were reported. Hence, with respect to long-term antibody persistence, the two-dose schedule of the combined HAB vaccine Adult formulation is an effective alternative to the conventional three-dose schedule of the Paediatric formulation in adolescents. Copyright 2010 Elsevier Ltd. All rights reserved.

Massively parallel de novo protein design for targeted therapeutics.

PubMed

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J; Hicks, Derrick R; Vergara, Renan; Murapa, Patience; Bernard, Steffen M; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T; Koday, Merika T; Jenkins, Cody M; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M; Fernández-Velasco, D Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A; Fuller, Deborah H; Baker, David

2017-10-05

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

Massively parallel de novo protein design for targeted therapeutics

NASA Astrophysics Data System (ADS)

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

2017-10-01

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.

EFFECT OF ROENTGEN RADIATION ON $beta$-GLUCURONIDASE IN RAT TESTIS

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

Arata, L.; Santoro, R.; Severi, M.A.

1962-04-30

The testes were irradiated with a single 600-r dose and enzyme activity was determined in homogenates of testis, at 10-day intervals, up to the 50th postirradiation day. In comparison with the control value of 47.9 (units/mg fresh tissue), BETA -glucuronidase activity fell to 30.5 by the 10th day, then progressively rose to 78.4, 126.0, 242.0, and 275.0 in the subsequent 10-day periods. A parallel drop, followed by a rise, occurred in total activity of testis. Testicular weight fell, and seminal vesicular weight fell and then rose, during the 50-day period. Thus, the transient sterility and destruction of germinal epithelium inducedmore » by irradiation were reflected by a decrease in BETA - glucuronidase activity, whereas regeneration of this epithelium followed the rise in enzyme activity. Such parallel changes in epithelial function and enzyme activity were previously noted in vitamin E-deficient rats. (H.H.D.)« less

Massively parallel de novo protein design for targeted therapeutics

PubMed Central

Chevalier, Aaron; Silva, Daniel-Adriano; Rocklin, Gabriel J.; Hicks, Derrick R.; Vergara, Renan; Murapa, Patience; Bernard, Steffen M.; Zhang, Lu; Lam, Kwok-Ho; Yao, Guorui; Bahl, Christopher D.; Miyashita, Shin-Ichiro; Goreshnik, Inna; Fuller, James T.; Koday, Merika T.; Jenkins, Cody M.; Colvin, Tom; Carter, Lauren; Bohn, Alan; Bryan, Cassie M.; Fernández-Velasco, D. Alejandro; Stewart, Lance; Dong, Min; Huang, Xuhui; Jin, Rongsheng; Wilson, Ian A.; Fuller, Deborah H.; Baker, David

2018-01-01

De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37–43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing. PMID:28953867

Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea.

PubMed

Thiboutot, Diane M; Fleischer, Alan B; Del Rosso, James Q; Graupe, Klaus

2008-06-01

Twice-daily azelaic acid (AzA) is the conventional regimen for papulopustular rosacea, but once-daily AzA may be equally effective, with greater convenience and dosing flexibility. In order to test this hypothesis, an exploratory study was conducted. The evaluable efficacy population of this 12-week double-blind, parallel-group study included 72 patients and the population that was used to report safety results included 92 patients. Baseline characteristics were comparable between the once-daily and twice-daily study groups. Evaluations were performed at baseline and at weeks 4, 8, and 12. No significant difference was found between the once-daily and twice-daily groups at the end of study therapy in mean investigator global assessment (IGA) scores, treatment success, or treatment response. The mean number of inflammatory lesions, the intensity of erythema intensity, and the intensity of telangiectasia at treatment end were likewise not significantly different (P>.205 for all). More than 90% of subjects in each group rated cosmetic acceptability of this AzA gel as satisfactory or better. Based on these findings and those of prior studies, once-daily AzA 15% gel can therefore be utilized as a safe, effective, and economical dosing option for the treatment of mild-to-moderate papulopustular rosacea. Once-daily dosing of AzA 15% gel was well accepted by patients and can offer considerable dosing flexibility and convenience for the patient as well as for the dermatologist.

Effect of low dose of vinclozolin on reproductive tract development and sperm parameters in CD1 outbred mice.

PubMed

Elzeinova, Fatima; Novakova, Vendula; Buckiova, Daniela; Kubatova, Alena; Peknicova, Jana

2008-01-01

The effect of a low dose of vinclozolin within the development of the reproductive tract during gestation (VIN-GD 15-22) and puberty (VIN-PND 23-44) in CD1 mice was tested. We found a decrease in the anogenital distance, prostate weight and pathology of testes in both experimental groups. Sperm counts decreased to 46% (VIN-GD) and to 81% (VIN-PND), and also the acrosomal state (evaluated by antiacrosomal antibody) decreased in both groups to 89% in comparison to the control group (100%). Sperm head abnormalities increased by approximately 18% and 13%, respectively. In this connection, the expression of some genes was changed (arosome-related gene (Acr), apoptosis related genes (p53, p21)). In conclusion, a low dose of vinclozolin affected the reproductive tract, sperm parameters and expression of selected genes in both experimental groups.

Fascia iliaca compartment nerve block versus systemic pain control for acute femur fractures in the pediatric emergency department.

PubMed

Neubrand, Tara L; Roswell, Kelley; Deakyne, Sara; Kocher, Kendra; Wathen, Joseph

2014-07-01

To compare management of acute femur fractures in children who received a fascia iliaca compartment nerve block (FICNB) to those who received systemic intravenously administered analgesics in the pediatric emergency department. The comparison evaluated frequency of use, effectiveness, and associated adverse event profiles. Study population was derived from a retrospective chart review of pediatric patients sustaining acute femur fractures between 2005 and 2009. Cases (received FICNB) were compared with controls (only systemic analgesia) in terms of effectiveness and adverse event. Outcomes included total doses of systemic medications received and comparison of preintervention and postintervention pain scores. Two hundred fifty-nine charts were reviewed: 158 who received FICNB versus 101 who did not. The median dose of systemic medications was 1 dose lower in the FICNB group compared with the systemic medications group. This remained significant after controlling for age and preintervention pain scores (P = 0.02). Median postintervention pain scores in the FICNB group were 1.5 points lower than those in the systemic medications group. This remained significant while controlling for preintervention pain scores and age (P < 0.01). There was no difference in the total adverse events between the FICNB and the control group in either the unadjusted or adjusted analyses (P = 0.08). The FICNB group had 2 seizure episodes, one of which had associated subarachnoid hemorrhage. No patient in either group experienced bradycardia, arrhythmia, visual disturbance, abnormal hearing, mouth numbness, motor tremors, pain or bleeding at injection site, or prolonged nerve block. We report on the largest number of FICNBs administered in a pediatric emergency department for acute femur fractures. Effectiveness, as measured by pain scores and total doses of systemic analgesia, was improved in the FICNB group versus the control. There was no difference in adverse events between the groups.

Phase 1, randomized, parallel-group, double-blind, placebo-controlled trial to evaluate the effects of erenumab (AMG 334) and concomitant sumatriptan on blood pressure in healthy volunteers.

PubMed

de Hoon, Jan; Van Hecken, Anne; Vandermeulen, Corinne; Herbots, Marissa; Kubo, Yumi; Lee, Ed; Eisele, Osa; Vargas, Gabriel; Gabriel, Kristin

2018-01-01

Objectives The aim of this study was to assess the effects of concomitant administration of erenumab and sumatriptan on resting blood pressure, pharmacokinetics, safety, and tolerability in healthy subjects. Methods In this phase 1, parallel-group, one-way crossover, double-blind, placebo-controlled study, healthy adult subjects were randomized (1:2) to receive either intravenous placebo and subcutaneous sumatriptan 12 mg (i.e. two 6-mg injections separated by 1 hour) or intravenous erenumab 140 mg and subcutaneous sumatriptan 12 mg. Blood pressure was measured pre-dose and at prespecified times post-dose. The primary endpoint was individual time-weighted averages of mean arterial pressure, measured from 0 hours to 2.5 hours after the first dose of sumatriptan. Pharmacokinetic parameters for sumatriptan were evaluated by calculating geometric mean ratios (erenumab and sumatriptan/placebo and sumatriptan). Adverse events and anti-erenumab antibodies were also evaluated. Results A total of 34 subjects were randomized and included in the analysis. Least squares mean (standard error) time-weighted averages of mean arterial pressure were 87.4 (1.0) mmHg for the placebo and sumatriptan group and 87.4 (1.2) mmHg for the erenumab and sumatriptan group. Mean difference in mean arterial pressure between groups was -0.04 mmHg (90% confidence interval: -2.2, 2.1). Geometric mean ratio estimates for maximum plasma concentration of sumatriptan was 0.95 (90% confidence interval: 0.82, 1.09), area under the plasma concentration-time curve (AUC) from time 0 to 6 hours was 0.98 (90% confidence interval: 0.93, 1.03), and AUC from time 0 to infinity was 1.00 (90% confidence interval: 0.96, 1.05). No clinically relevant safety findings for co-administration of sumatriptan and erenumab were identified. Conclusion Co-administration of erenumab and sumatriptan had no additional effect on resting blood pressure or on pharmacokinetics of sumatriptan. ClinicalTrials.gov, NCT02741310.

Design and Calibration of a X-Ray Millibeam

DTIC Science & Technology

2005-12-01

developed for use in Fricke dosimetry , parallel-plate ionization chambers, Lithium Fluoride thermoluminescent dosimetry ( TLD ), and EBT GafChromic...thermoluminescent dosimetry ( TLD ), and EBT GafChromic film to characterize the spatial distribution and accuracy of the doses produced by the Faxitron. A...absorbed dose calibration factors for use in Fricke dosimetry , parallel-plate ionization chambers, Lithium Fluoride (LiF) TLD , and EBT GafChromic film. The

Simultaneous orthogonal plane imaging.

PubMed

Mickevicius, Nikolai J; Paulson, Eric S

2017-11-01

Intrafraction motion can result in a smearing of planned external beam radiation therapy dose distributions, resulting in an uncertainty in dose actually deposited in tissue. The purpose of this paper is to present a pulse sequence that is capable of imaging a moving target at a high frame rate in two orthogonal planes simultaneously for MR-guided radiotherapy. By balancing the zero gradient moment on all axes, slices in two orthogonal planes may be spatially encoded simultaneously. The orthogonal slice groups may be acquired with equal or nonequal echo times. A Cartesian spoiled gradient echo simultaneous orthogonal plane imaging (SOPI) sequence was tested in phantom and in vivo. Multiplexed SOPI acquisitions were performed in which two parallel slices were imaged along two orthogonal axes simultaneously. An autocalibrating phase-constrained 2D-SENSE-GRAPPA (generalized autocalibrating partially parallel acquisition) algorithm was implemented to reconstruct the multiplexed data. SOPI images without intraslice motion artifacts were reconstructed at a maximum frame rate of 8.16 Hz. The 2D-SENSE-GRAPPA reconstruction separated the parallel slices aliased along each orthogonal axis. The high spatiotemporal resolution provided by SOPI has the potential to be beneficial for intrafraction motion management during MR-guided radiation therapy or other MRI-guided interventions. Magn Reson Med 78:1700-1710, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Biodistribution and toxicity assessment of europium-doped Gd2O3 nanotubes in mice after intraperitoneal injection

NASA Astrophysics Data System (ADS)

Liu, Huifang; Zhang, Cuimiao; Tan, Yanli; Wang, Jianguo; Wang, Ke; Zhao, Yanyan; Jia, Guang; Hou, Yingjian; Wang, Shuxian; Zhang, Jinchao

2014-03-01

In order to evaluate the biodistribution and toxicity of europium-doped Gd2O3 nanotubes, we synthesized Gd2O3:Eu3+ nanotubes via a simple wet-chemical route at ambient pressure. The as-obtained Gd2O3:Eu3+ sample is composed of uniform and well-dispersed nanotubes. The diameters and lengths of the nanotubes are about 50 and 300 nm, respectively. All mice of the experimental groups were administered by intraperitoneal injection everyday over a period of 60 days at doses ranging from 1.25 to 125 mg/kg. Haematological and biochemical parameters and histopathology were examined, and the biodistribution of Gd element in different organs was analyzed. The results indicate that the spleen shows significant higher coefficient than the control, and other organs have no obvious difference from the control in the middle-dose and high-dose groups. There was no significant difference in the blood-elements between the control group and the experimental groups, and no significant change of all parameters can be observed in both low-dose and middle-dose groups. However, in the high-dose group, the ALT, AST, the ratio of AST/ALT, UA, LDH, and HBDH levels was increased significantly in comparison with the control group. The pathology results show that the ischemia of myocardial cell, hemorrhage of lung tissue, hepatocyte necrosis, congestion of renal interstitium, mesangial cell proliferation, and congestion of spleen sinus were induced by high-dose Gd2O3:Eu3+ nanotubes. Biodistribution experiment exhibits that Gd mainly accumulates in spleen, lung, and liver. Therefore, it can be concluded that high-dose Gd2O3:Eu3+ nanotubes were toxic, but low-dose and middle-dose groups did not show significant toxicity. The results provide novel toxicology data of Gd2O3:Eu3+ nanotubes and may be helpful for more rational applications of Gd-based compounds in the future.

Image quality and radiation dose on digital chest imaging: comparison of amorphous silicon and amorphous selenium flat-panel systems.

PubMed

Bacher, Klaus; Smeets, Peter; Vereecken, Ludo; De Hauwere, An; Duyck, Philippe; De Man, Robert; Verstraete, Koenraad; Thierens, Hubert

2006-09-01

The aim of this study was to compare the image quality and radiation dose in chest imaging using an amorphous silicon flat-panel detector system and an amorphous selenium flat-panel detector system. In addition, the low-contrast performance of both systems with standard and low radiation doses was compared. In two groups of 100 patients each, digital chest radiographs were acquired with either an amorphous silicon or an amorphous selenium flat-panel system. The effective dose of the examination was measured using thermoluminescent dosimeters placed in an anthropomorphic Rando phantom. The image quality of the digital chest radiographs was assessed by five experienced radiologists using the European Guidelines on Quality Criteria for Diagnostic Radiographic Images. In addition, a contrast-detail phantom study was set up to assess the low-contrast performance of both systems at different radiation dose levels. Differences between the two groups were tested for significance using the two-tailed Mann-Whitney test. The amorphous silicon flat-panel system allowed an important and significant reduction in effective dose in comparison with the amorphous selenium flat-panel system (p < 0.0001) for both the posteroanterior and lateral views. In addition, clinical image quality analysis showed that the dose reduction was not detrimental to image quality. Compared with the amorphous selenium flat-panel detector system, the amorphous silicon flat-panel detector system performed significantly better in the low-contrast phantom study, with phantom entrance dose values of up to 135 muGy. Chest radiographs can be acquired with a significantly lower patient radiation dose using an amorphous silicon flat-panel system than using an amorphous selenium flat-panel system, thereby producing images that are equal or even superior in quality to those of the amorphous selenium flat-panel detector system.

Three-dimensional radiochromic film dosimetry for volumetric modulated arc therapy using a spiral water phantom.

PubMed

Tanooka, Masao; Doi, Hiroshi; Miura, Hideharu; Inoue, Hiroyuki; Niwa, Yasue; Takada, Yasuhiro; Fujiwara, Masayuki; Sakai, Toshiyuki; Sakamoto, Kiyoshi; Kamikonya, Norihiko; Hirota, Shozo

2013-11-01

We validated 3D radiochromic film dosimetry for volumetric modulated arc therapy (VMAT) using a newly developed spiral water phantom. The phantom consists of a main body and an insert box, each of which has an acrylic wall thickness of 3 mm and is filled with water. The insert box includes a spiral film box used for dose-distribution measurement, and a film holder for positioning a radiochromic film. The film holder has two parallel walls whose facing inner surfaces are equipped with spiral grooves in a mirrored configuration. The film is inserted into the spiral grooves by its side edges and runs along them to be positioned on a spiral plane. Dose calculation was performed by applying clinical VMAT plans to the spiral water phantom using a commercial Monte Carlo-based treatment-planning system, Monaco, whereas dose was measured by delivering the VMAT beams to the phantom. The calculated dose distributions were resampled on the spiral plane, and the dose distributions recorded on the film were scanned. Comparisons between the calculated and measured dose distributions yielded an average gamma-index pass rate of 87.0% (range, 91.2-84.6%) in nine prostate VMAT plans under 3 mm/3% criteria with a dose-calculation grid size of 2 mm. The pass rates were increased beyond 90% (average, 91.1%; range, 90.1-92.0%) when the dose-calculation grid size was decreased to 1 mm. We have confirmed that 3D radiochromic film dosimetry using the spiral water phantom is a simple and cost-effective approach to VMAT dose verification.

Could familial Mediterranean fever gene mutations be related to PFAPA syndrome?

PubMed

Celiksoy, Mehmet H; Ogur, Gonul; Yaman, Elif; Abur, Ummet; Fazla, Semanur; Sancak, Recep; Yildiran, Alisan

2016-02-01

The cause and pathophysiology of PFAPA syndrome is unknown. The aim of this study was to determine all MEFV gene variants relevant to familial Mediterranean fever in children with PFAPA syndrome. All MEFV gene variants were analyzed in patients with PFAPA syndrome. All patients were evaluated using the Gaslini scoring system. Serum immunoglobulin levels were also determined upon admission. We evaluated 64 patients with PFAPA syndrome. The median age at diagnosis was 37.5 (min-max: 6-96) months, and the percentage of male patients was 55.0%. The Gaslini diagnostic score for periodic fever was high in 81.0% of the patients. An MEFV gene mutation was found in 42 (66.0%) children. Mostly, heterozygous or compound heterozygous variants of the MEFV gene were found. Two patients were homozygous for R202Q. MEFV gene mutations were not detected in 22 (34.0%) patients. No significant differences in clinical or laboratory findings were observed between the two groups (p > 0.05), and there were no significant differences in period and duration of the fever episodes (p > 0.05). The fever of all 47 patients (100.0%) who received prednisolone during the episodes decreased within hours and did not recur. Eighteen of the patients using prednisolone underwent prophylaxis with colchicine, and the fever episodes of 9/18 (50.0%) patients using colchicine decreased within months. Most patients presenting with PFAPA syndrome have heterozygous MEFV gene mutations. Whether carrying a heterozygous MEFV gene is the primary cause of this syndrome requires further investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Temporal associations for spatial events: the role of the dentate gyrus.

PubMed

Morris, Andrea M; Curtis, Brian J; Churchwell, John C; Maasberg, David W; Kesner, Raymond P

2013-11-01

Previous research suggests that the dorsal dentate gyrus (DG) hippocampal subregion mediates spatial processing functions. However, a novel role for the DG in temporal processing for spatial information has begun to emerge based on the development of a computational model of neurogenesis. According to this model, adult born granule cells in the DG contribute to a temporal associative integration process for events presented closer in time. Currently, there is a paucity of behavioral evidence to support the temporal integration theory. Therefore, we developed a novel behavioral paradigm to investigate the role of the dDG in temporal integration for proximal and distal spatial events. Male Long-Evans rats were randomly assigned to a control group or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on a cued-recall of sequence paradigm. In this task, animals were allowed to explore identical objects placed in designated spatial locations on a cheeseboard maze across 2 days (e.g., Day 1: A and B; Day 2: C and D). One week later, animals were given a brief cue (A or C) followed by a preference test between spatial location B and D. Control animals had a significant preference for the spatial location previously paired with the cue (the temporal associate) whereas dDG lesioned animals failed to show a preference. These findings suggest that selective colchicine-induced dDG lesions are capable of disrupting the formation of temporal associations between spatial events presented close in time. Copyright © 2013 Elsevier B.V. All rights reserved.

A double-blind comparative multicentre study of remoxipride and haloperidol in schizophrenia.

PubMed

Lindström, L H; Wieselgren, I M; Struwe, G; Kristjansson, E; Akselson, S; Arthur, H; Andersen, T; Lindgren, S; Norman, O; Naimell, L

1990-01-01

In a double-blind multicentre study of parallel group design the efficacy and safety of remoxipride and haloperidol were compared in a total of 96 patients with acute episodes of schizophrenic or schizophreniform disorder according to DSM-III. There were 48 patients in each treatment group; 27 men and 21 women in the remoxipride group, 33 men and 15 women in the haloperidol group. The median duration of illness was 7 years in both groups. The mean daily dose was 437 mg for remoxipride and 10.6 mg for haloperidol during the last week of treatment. No statistically significant differences in total BPRS scores were found between remoxipride and haloperidol. The median total BPRS scores at the start of active treatment were 26 in the remoxipride and 27 in the haloperidol group; these were reduced to 16 and 12.5, respectively, at the last rating. According to Clinical Global Impression (CGI), 43% of patients in the remoxipride group and 68% of those in the haloperidol group improved much or very much during treatment. This difference was not statistically significant. Treatment-emergent extrapyramidal side effects such as akathisia, tremor, and rigidity occurred significantly more frequently in the haloperidol group; this group also made more frequent use of anticholinergic drugs. Neither of the trial drugs seriously affected laboratory or cardiovascular variables. It is concluded that remoxipride has an antipsychotic effect in a dose range of 150-600 mg per day comparable to that of haloperidol in doses up to 20 mg per day but with fewer extrapyramidal side effects.

A randomized primary care trial of steroid titration against mannitol in persistent asthma: STAMINA trial.

PubMed

Lipworth, Brian J; Short, Philip M; Williamson, Peter A; Clearie, Karine L; Fardon, Thomas C; Jackson, Cathy M

2012-03-01

We compared titrating inhaled corticosteroid (ICS) against mannitol airway hyperresponsiveness (AHR) or a reference strategy (control) based on symptoms, reliever use, and lung function in primary care. One hundred sixty-four patients with persistent asthma were randomized in parallel group fashion following an initial ICS tapering. Subsequent ICS doses (as ciclesonide) were titrated against either the provocative dose of mannitol causing a 10% fall in FEV(1) (PD(10)) (AHR strategy) or a control group (reference strategy) over a 1-year period. One hundred nineteen participants (n = 61 AHR, n = 58 control) completed the study. Time to first mild exacerbation was not significantly different: hazard ratio, 1.29; 95% CI, 0.716-2.31; P = .40. Although there were 27% fewer total number of mild exacerbations over 12 months in AHR vs control groups (n = 84 vs n = 115, P = .03), there was no difference in severe exacerbations (n = 12 vs n = 13). No other significant differences were seen between groups with the exception of mannitol PD(10) and ICS dose. There was a 1.52 (95% CI, 0.61-2.42; P = .001) doubling dose difference in mannitol PD(10) between AHR vs control groups. The final mean daily ciclesonide dose was higher (P < .0001) in AHR vs control groups (514 μg vs 208 μg), with no associated significant suppression of overnight urinary cortisol/creatinine. Significant improvements were seen within the AHR group but not the control group for the provocative concentration of methacholine causing a 20% fall in FEV(1) (P < .05), salivary eosinophilic cationic protein (P < .05), exhaled nitric oxide (P < .05), symptoms (P < .005), and reliever use (P < .001). Mannitol challenge was well tolerated in a primary care setting. Using mannitol resulted in exposure to a higher dose of ciclesonide, which was associated with equivocal effects on exacerbations without associated adrenal suppression. Large-scale trials using mannitol in patients with more severe disease may now be warranted to further define its role. ClinicalTrials.gov; No.: NCT01216579; URL: www.clinicaltrials.gov.

Inhibition of proteolysis by cell swelling in the liver requires intact microtubular structures.

PubMed Central

vom Dahl, S; Stoll, B; Gerok, W; Häussinger, D

1995-01-01

In the perfused rat liver, proteolysis is inhibited by cell swelling in response to hypo-osmotic media, glutamine and insulin. Colchicine, an inhibitor of microtubules, did not affect cell swelling in response to these agonists. However, the antiproteolytic action of these effectors was largely blunted in the presence of colchicine or the microtubule inhibitors colcemid and taxol. On the other hand, inhibition of proteolysis by phenylalanine, asparagine or NH4Cl, i.e. compounds which exert their antiproteolytic effects by mechanisms distinct from cell swelling, was not sensitive to colchicine. Swelling-induced inhibition of proteolysis was not affected by cytochalasin B. The anti-proteolytic effect of hypo-osmotic cell swelling and insulin was largely abolished in freshly isolated rat hepatocytes; however, it reappeared upon cultivation of the hepatocytes for 6-10 h. The restoration of the sensitivity of proteolysis to cell volume changes was accompanied by a progressive reorganization of microtubule structures, as shown by immunohistochemical staining for tubulin. It is concluded that intact microtubules are required for the control of proteolysis by cell volume, but not for the control of proteolysis by phenylalanine, asparagine or NH4Cl. These findings may explain why others [Meijer, Gustafson, Luiken, Blommaart, Caro, Van Woerkom, Spronk and Boon (1993) Eur. J. Biochem. 215, 449-454] failed to detect an antiproteolytic effect of hypo-osmotic exposure of freshly isolated hepatocytes. This effect, however, which is consistently found in the intact perfused rat liver, also reappeared in isolated hepatocytes when they were allowed to reorganize their microtubular structures in culture. Images Figure 6 PMID:7772037

[Vaccination against viral hepatitis A and B in adults aged over 40 years--antibody persistence and immune memory].

PubMed

Chlibek, R; Smetana, J; Bostíková, V; Splino, M

2011-09-01

Primary vaccination with combined vaccine against viral hepatitis A (VHA) and viral hepatitis B (VHB) induces higher anti-hepatitis B surface (anti-HBs) antibody responses and similar anti-hepatitis A virus (anti-HAV) antibody responses in adults aged over 40 years in comparison with concomitant monovalent vaccines against VHA and VHB. Th e objectives were to assess, in a clinical study, persistence of anti-HAV and anti-HBs antibodies in adults aged over 40 years four years after primary VHA/VHB vaccination and antibody response following a booster dose of the vaccine. Five hundred and ninety-six subjects aged > 40 years were vaccinated with three doses of the combined VHA/VHB vaccine at Months 0, 1, 6 (HAB group) or with concomitant VHA and VHB vaccines at Months 0, 6 and 0, 1, 6 (ENG+HAV and HBVX+VAQ, respectively). Blood samples were collected one month following primary vaccination (Month 7) and then at one-year intervals for four years after the booster dose with the same vaccine as used for the primary vaccination. The anti-HBs and anti-HAV antibody levels were determined prior to the booster dose and at days 14 and 30 after the booster dose. At Month 7, > 97% of study subjects were seropositive for anti-HAV antibodies in all groups analyzed. Four years after primary vaccination, anti-HAV antibody seropositivity persisted in > 93% of study subjects, increasing to > 99% after the booster dose. At Month 7, the highest proportion of study subjects with anti-HBs antibody levels > or = 10 mIU/ml was found in the HAB group (91.7% versus 79.7% in the ENG+HAV group versus 71.0% in the HBVX+VAQ group). Four years after vaccination, anti-HBs antibody levels of 10 mIU/ml persisted in 57.1% of the HAB study subjects in comparison with 40.1% and 26.6% of the study subjects in the ENG+HAV and HBVX+VAQ groups, respectively. One month after the booster dose, anti-HBs antibody levels increased and antibody levels > or = 10 mIU/ml was achived in 95.2% of study subjects in the HAB group, 90.5% in the ENG+HAV group and 85.3% in the HBVX+VAQ group. In the adults aged over 40 years, an adequate anti-HAV antibody response persisted for at least four years after vaccination and was higher and more sustained in those who received the combined HAB vaccine. A strong antibody response to the booster dose indicative ofthe presence of immune memory was seen in all study groups.

Patiromer Lowers Serum Potassium When Taken without Food: Comparison to Dosing with Food from an Open-Label, Randomized, Parallel Group Hyperkalemia Study.

PubMed

Pergola, Pablo E; Spiegel, David M; Warren, Suzette; Yuan, Jinwei; Weir, Matthew R

2017-01-01

Patiromer is a sodium-free, nonabsorbed, potassium binder approved for treatment of hyperkalemia. This open-label study compares the efficacy and safety of patiromer administered without food versus with food. Adults with hyperkalemia (potassium ≥5.0 mEq/L) were randomized (1:1) to receive patiromer once daily without food or with food for 4 weeks. The dosage was adjusted (maximum: 25.2 g/day) using a prespecified titration schedule to achieve and maintain potassium within a target range (3.8-5.0 mEq/L). The primary efficacy endpoint was the proportion of patients with serum potassium in the target range at either week 3 or week 4. Safety was assessed by adverse events (AEs) and laboratory testing. Efficacy was evaluated in 112 patients; 65.2% were ≥65 years of age, 75.9% had chronic kidney disease, and 82.1% had diabetes. Baseline mean serum potassium was similar in the without-food (5.44 mEq/L) and with-food (5.34 mEq/L) groups. The primary endpoint was achieved by 87.3% (95% CI 75.5-94.7) and 82.5% (95% CI 70.1-91.3) of patients in the with-food and without-food groups, respectively; least squares mean changes in serum potassium from baseline to week 4 were -0.65 and -0.62 mEq/L, respectively (p < 0.0001). The most common AEs were diarrhea and constipation. Serum K+ remained ≥3.5 mEq/L in all patients; 5 patients developed serum magnesium <1.4 mg/dL, including 4 whose baseline magnesium was below the lower limit of normal. Patiromer is equally effective and well tolerated when taken without food or with food, thereby offering the potential for dosing flexibility. © 2017 The Author(s) Published by S. Karger AG, Basel.

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

Associated factors with functional disability and health-related quality of life in Chinese patients with gout: a case-control study.

PubMed

Fu, Ting; Cao, Haixia; Yin, Rulan; Zhang, Lijuan; Zhang, Qiuxiang; Li, Liren; Gu, Zhifeng

2017-11-03

Gout is a painful, inflammatory disease that may cause decreased function and health-related quality of life (HRQoL). Limited study did not take the influence of gout characteristics and anxiety on HRQoL into consideration and there are no studies associated with functional disability in individuals with gout from China. This study aims to investigate the related factors of functional disability and HRQoL in gout patients recruited from China. A total of 226 consecutive gout patients and 232 age- and gender-matched healthy individuals were involved in the study. A series of questionnaires (the Short Form 36 health survey, the Patient Health Questionnaire, the Generalized Anxiety Disorder questionnaire, the 10 cm Visual Analog Scale, and the Health Assessment Questionnaire-Disability Index) were applied. Blood samples were taken to examine the level of serum uric acid. Independent samples t-tests, Chi square tests, U test, Spearman rank correlation, logistic regression modeling, and linear regression were used to analyze the data. After adjusted demographic variables, individuals with gout have poorer HRQoL compared to healthy controls. Univariate tests presented that patients with functional disability had longer disease duration, more frequent flares/last year, more severe total pain, more number of tophi, higher degree of depression and anxiety, with a trend toward diabetes, the treatment of colchicine and corticosteroids use, compared to patients without functional disability. Meanwhile, place of residence, hypertension, DM, disease duration, cardiovascular disease, number of flares/last year, total pain, more number of tophi, presence of tender joints, depression, anxiety, currently using colchicine and corticosteroids were correlated significantly with HRQoL. Additionally, multiple regression analysis identified severe pain, depression, and colchicine use as predictors of functional disability. Cardiovascular disease, total pain, number of flares/last year, presence of tender joints, depression, anxiety, colchicine and corticosteroids use contributed to low HRQoL. After adjusted demographic variables, gout subjects have poorer HRQoL compared to healthy controls. Chinese gout population experiencing poor HRQoL and functional disability were likely to suffer from gout-related features and psychological problems. The results underscore the need of effective interventions including psychological nursing and appropriate treatment approaches to reduce their functional disability and improve their HRQoL.

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.

Comparison of the therapeutic dose of warfarin in HIV-infected and HIV-uninfected patients: a study of clinical practice

PubMed Central

Jackson, B S; Mokoena, T

2017-01-01

Background People infected with HIV are prone to venous thrombosis. Treatment of thrombosis is primarily with warfarin. No studies have addressed the effects of HIV infection on warfarin dose. The aims of this study were to determine whether the therapeutic dose of warfarin and induction time to therapeutic dose in HIV-infected patients differ from that in HIV-uninfected patients. Methods A prospective and retrospective descriptive study of induction time to therapeutic warfarin dose, as well as of ambulant therapeutic warfarin dose, was performed. HIV-infected and HIV-uninfected patients being treated after deep venous thrombosis with or without pulmonary embolism were compared. Sex and use of antiretroviral drugs (ARVs) were also compared in the groups. Results 234 patients were entered into the study. Induction time to therapeutic warfarin dose did not differ between the 2 groups. The mean therapeutic dose of warfarin was higher in the HIV-infected than the HIV-uninfected group: 6.06 vs 5.72 mg/day, but this was not statistically significant (p=0.29). There was no difference in therapeutic warfarin dose between ARV-naïve groups—HIV-uninfected and HIV-infected patients not on ARVs. Conclusions There appears to be little effect of HIV infection on warfarin dosing. Warfarin therapy should be administered conventionally in HIV-infected patients. PMID:28179414

SEMIANNUAL REPORT TO THE ATOMIC ENERGY COMMISSION

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

Jacobson, L.O. ed.

Progress in radiobiology and caneer research is reported. Topics covered include: comparison of the effects of isologous, homologous, and heterologous hematopoietic tissues on post-irradiation survival; survival of transfused blood in rats; erythropoietic response to erythropoietin; inhibition of erythropoiesis by estrogens; tryptophan metabolism; effect of daily exposure to l5-r gamma radiation on susceptibility of mice to experinrental infection; restorailon of serum bactericidal activity and prevention of its loss in x- irradiated mice; immunohistochemical study of Ehrlich ascites tumor; comparison of effects of I/sup 131/-induced hypothyroidism and L-triiodothyronine on irradiated hair roots in mice; modification of radiation responses of tissue by colchicine;more » production and use of I/sup 131/; localization of ocl evaluation of brain scanning system; thick target yield and excitation function for the reaction Rh/sup 103/(p,n)Pb/sup 103/; incorporation of C/sup 14/ and tritium precursors into brain; net synthesis of RNA with a microleial enzyme requiring DNA and four ribonueleoside triphosphates; snythesis of (P/sup 37/) uridine 5'- phosphate; and of 17- alpha -hydroxyprogesterone-4-C/sup 14/-l7 alpha -caproate by homogenates of rat liver and human placenta. (M.C.G.)« less

A randomised, single-blind, single-dose, three-arm, parallel-group study in healthy subjects to demonstrate pharmacokinetic equivalence of ABP 501 and adalimumab.

PubMed

Kaur, Primal; Chow, Vincent; Zhang, Nan; Moxness, Michael; Kaliyaperumal, Arunan; Markus, Richard

2017-03-01

To demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501. Randomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUC inf ) and the maximum observed concentration (C max ). Secondary end points included safety and immunogenicity. AUC inf and C max were similar across the three groups. Geometrical mean ratio (GMR) of AUC inf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of C max was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUC inf and C max were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups. Results of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups. EudraCT number 2012-000785-37; Results. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.