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Dosage Groups (dosage + groups)
Selected AbstractsOral bioavailability and toxicokinetics of 3,3,,4,4,,5-pentachlorobiphenyl in northern leopard frogs, Rana pipiensENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2000Yue-wern Huang Abstract This study is the first report on oral bioavailability, whole-body elimination, and distribution of a specific polychlorinated biphenyl (PCB) congener on an amphibian species, northern leopard frogs. Each frog was orally dosed once with either 0.35 or 5.0 mg/kg PCB 126 (based on frog wet wt), including tracer 14C-PCB 126 (3,,4,,5,-phenyl-ring- 14C) by force feeding it a cricket injected with the PCB. We found no statistical difference (t = 0.917, df = 5, p = 0.401) in the average 48-h oral bioavailabilities of 0.35- and 5.0-mg/kg dosage groups, which were 84.6 ± 5.8% (mean ± SE, n = 4) and 90.9 ± 1.5% (n = 3), respectively. Statistical analysis indicated that time was the only independent variable affecting the retention of whole-body 14C content. Kinetics were apparently first order because elimination rate was independent of dose. Assuming a single pool and one elimination rate, the t1/2 value for whole-body elimination of PCB-derived 14C was 763 d. Liver, fat bodies (corpora adiposa), carcass (head, bone, cartilage materials, and residues of other tissues), skin, and muscle were the major organs for PCB 126 retention in both dosage groups. The concentrations of 14C residue in fat bodies were relatively constant throughout the experiment. However, total residues in fat bodies declined throughout the experiment in both dosage groups in correlation with declining masses of fat bodies. Gonad, kidney, stomach, intestine, and a tissue pool including esophagus, lung, spleen, heart, and cloacal materials each accumulated <1% of the initial total 14C residue. The egg follicles in 19 females contained 1 to 23% of the initial total 14C residue, with an average of 10.0 ± 9.2% (mean ± SE, n = 19). [source] A 90 day repeated oral toxicity study on plantamajoside concentrate from Plantago asiaticaPHYTOTHERAPY RESEARCH, Issue 12 2007Byung-Gyu Park Abstract Plantago asiatica is distributed widely in East Asia. Since ancient times it has been used as a diuretic to treat acute urinary infections, and as an antiinflammatory, antiasthmatic, antioxidant, antibacterial, antihyperlipidemic and antihepatitis drug. The major compound, plantamajoside from P. asiatica, which is used as a marker compound in chemotaxonomic studies, was reported to have antibacterial activity, inhibition activity against cAMP phosphodiesterase and 5-lipoxygenase and antioxidant activity. However, there are no reports on the safety of plantamajoside. This study assessed the toxic effects of plantamajoside concentrate (PC), the purity of which was above 80%, in rats following administration at dose levels of 0, 500, 1000 and 2000 mg/kg body weight/day for 13 weeks, as recommended by the OECD guidelines. The results showed that there were no differences in body weight, food intake, water consumption, relative organ weight or the hematological and serum biochemical values among the different dosage groups. No death or abnormal clinical signs were observed during the experimental period. Therefore, the results suggested that no observed adverse effect level (NOAEL) of the PC in rats after oral administration is considered to be greater than 2000 mg/kg in rats under the conditions employed in this study. Copyright © 2007 John Wiley & Sons, Ltd. [source] Tocilizumab in systemic lupus erythematosus: Data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study,ARTHRITIS & RHEUMATISM, Issue 2 2010Gabor G. Illei Objective To assess the safety of interleukin-6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE). Methods In an open-label phase I dosage-escalation study, 16 patients with mild-to-moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks. Results The infusions were well tolerated. Tocilizumab treatment led to dosage-related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of ,4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti,double-stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody-producing cells. Conclusion Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy. [source] Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol,conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study,ARTHRITIS & RHEUMATISM, Issue 9 2008John S. Sundy Objective To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of <6 mg/dl in gout patients in whom other treatments have failed, and to assess the pharmacokinetics and safety of pegloticase. Methods Forty-one patients were randomized to undergo 12,14 weeks of treatment with pegloticase at 1 of 4 dosage levels: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and antipegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded. Results The mean plasma urate level was reduced to ,6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%. Gout flares occurred in 88% of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Antipegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients. Conclusion Pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at ,6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication. [source] The Ototoxic Effects Induced in Rats by Treatment for 12 Weeks with 2-Butenenitrile, 3-Butenenitrile and cis-2-PentenenitrileBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2001François Gagnaire The rats were given, by gastric intubation, doses of 10, 20 and 40 mg ,· ,kg,1 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg ,· ,kg,1 of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile >cis-2-pentenenitrile >cis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea. [source] Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphateBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2010Wei Yin Abstract The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25,mg/m2, n=14) or oral (40,mg/m2, n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23,h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (±SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3±4.0 vs 9.7±2.0,h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25,mg/m2 IV and 40,mg/m2 oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes. Copyright © 2009 John Wiley & Sons, Ltd. [source] Comparison of self-administered vaginal misoprostol versus placebo for cervical ripening prior to operative hysteroscopy using a sequential trial design,BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 5 2008KS Oppegaard Objective, To compare the impact of 1000 micrograms of self-administered vaginal misoprostol versus self-administered vaginal placebo at home on preoperative cervical ripening in both premenopausal and postmenopausal women before operative hysteroscopy. Design, Two separate but identical parallel, randomised, double-blind, placebo-controlled sequential trials, one in premenopausal women and one in postmenopausal women. The boundaries for the sequential trials were calculated on the primary outcomes of a difference of cervical dilatation ,1 mm, with the assumption of a type 1 error of 0.05 and a power of 0.95. Setting, Norwegian university teaching hospital. Sample, Eighty-six women referred to outpatient operative hysteroscopy. Methods, The women were randomised to either 1000 micrograms of self-administered vaginal misoprostol or self-administered vaginal placebo the evening before outpatient operative hysteroscopy. Main outcome measures, Preoperative cervical dilatation (primary outcome), number of women who achieve a preoperative cervical dilatation ,5 mm, acceptability, complications and adverse effects (secondary outcomes). Results, In premenopausal women, the mean cervical dilatation was 6.4 mm (SD 2.4) in the misoprostol group and 4.8 mm (SD 2.0) in the placebo group, the mean difference in cervical dilatation being 1.6 mm (95% CI 0.5,2.7). Among the premenopausal women receiving misoprostol, 88% achieved a cervical dilatation of ,5 mm compared with 65% in the placebo group. Twelve percent of the women who received misoprostol were difficult to dilate compared with 32% who received placebo. Dilatation was also quicker in the misoprostol group. Misoprostol had no effect on cervical ripening in postmenopausal women compared with placebo, and 43% of the women were difficult to dilate. The trials were terminated after analysis of 21 postmenopausal women and 65 premenopausal women after reaching a conclusion on the primary outcome with only 28% of the number of women needed in a fixed sample size trial. Three of 45 women who received misoprostol experienced severe lower abdominal pain, and there was an increased occurrence of light preoperative bleeding in the misoprostol group. Most women did not experience misoprostol-related adverse effects. The majority (83% of premenopausal and 76% of postmenopausal women) found self-administered vaginal misoprostol at home to be acceptable. There were two serious complications in the premenopausal misoprostol group: uterine perforation with subsequent peritonitis and heavy postoperative bleeding requiring blood transfusion, but these were not judged to be misoprostol related. Complications were otherwise comparatively minor and distributed equally between the two dosage groups. Conclusions, One thousand micrograms of self-administered vaginal misoprostol 12 hours prior to operative hysteroscopy has a significant cervical ripening effect compared with placebo in premenopausal but not in postmenopausal women. Self-administered vaginal misoprostol of 1000 micrograms at home the evening before operative hysteroscopy is safe and highly acceptable, although a small proportion of women experienced severe lower abdominal pain. There is a risk of lower abdominal pain and light preoperative bleeding with this regimen, which is very cheap and easy to use. [source] Fertility control: Oral versus self-administered vaginal misoprostol at home before surgical termination of pregnancy: a randomised controlled trialBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 1 2006Kevin Sunde Oppegaard Objective, To compare the impact of 400 ,g oral versus self-administered vaginal misoprostol at home on pre-operative cervical priming in both primigravid and multigravid women prior to first trimester surgical abortion. Design, Randomised controlled trial. Setting, Norwegian University Teaching Hospital. Sample, Three hundred and thirty-eight women undergoing surgical abortion between 7 and 12 weeks of gestation. Methods, The women were randomised to either 400 ,g of oral misoprostol the evening before or 400-,g of self-administered vaginal misoprostol at home the same day as vacuum aspiration. Main outcome measures, Pre-operative cervical dilatation, complications and acceptability. Results, The median cervical dilatation was 6.2 mm (range 0,11 mm) for the women in the 400 ,g oral misoprostol and 6.5 mm (range 0,11 mm) in the 400-,g vaginal misoprostol groups. The median pre-operative dilatation was larger in multigravidae (6.4 and 6.7 mm for the oral and vaginal routes, respectively) than in primigravidae (5.8 and 6.0 mm, respectively). In primigravidae, 19% achieved a pre-operative dilatation of ,7 mm, with no significant difference between oral and vaginal dosage. In multigravidae, 52% achieved a pre-operative dilatation of ,7 mm with vaginal dosage, compared with 36% with oral dosage (P= 0.03). There was no difference between non-immigrant versus immigrant women in pre-operative cervical dilatation. The 400-,g oral dosage group had a higher risk of bleeding, compared with the group receiving 400-,g vaginal misoprostol [odds ratio (OR) = 10.4; confidence interval (CI) 5.2,20.8]. There was no difference between non-immigrant and immigrant women in acceptability of self-administered vaginal misoprostol; almost all women found this administration route acceptable. Complications were minor and were distributed equally between the two dosage groups. Conclusions, The vaginal route will result in a satisfactory dilatation in about half of multigravidae but is much less effective in primigravidae. The oral route does not lead to satisfactory dilatation in either group and is associated with a higher occurrence of pre-operative bleeding. Self-administered vaginal misoprostol at home is highly acceptable. [source] Morphine-related apnoea in CPAP-treated preterm neonatesACTA PAEDIATRICA, Issue 9 2006Jan Enders Abstract Background: Morphine can be used to treat pain in preterm neonates with CPAP because of its analgetic potency; however, it is known to induce apnoea. Aim: To evaluate this risk of apnoea. Methods: We retrospectively analysed 91 preterm neonates with CPAP who received morphine intravenously. The incidence of apnoea 4 h before and after morphine administration was compared. The data were analysed for three dosage groups (<0.01, 0.01,0.03 and 0.03 mg/kg) and according to the incidence of apnoea before morphine application. Results: In the whole group (gestational age 29.1±2.9 wk, morphine dosage 0.017±0.01 mg/kg) we did not find differences in apnoea before and after morphine (0.9±1.8 vs 1.1±1.8 apnoea). The only significant increase in apnoea was seen in the subgroup of patients receiving,>,0.03 mg/kg (0.3±0.67 vs 1.5±2.5 apnoea). Interestingly, we found a significantly delayed increase in apnoea in the fourth hour. Conclusion: Morphine in preterm infants with CPAP is not widely accepted practice until further randomized studies evaluate efficacy and safety. Morphine in a low dosage (,0.03 mg/kg) did not significantly increase the apnoea rate in CPAP-treated preterm infants. For clinical work, it is very important to note that morphine-related apnoea may appear with a delay of approximately 4 h. [source] Absence of hypoglycemia in response to varying doses of recombinant human insulin-like growth factor-I (rhIGF-I) in children and adolescents with low serum concentrations of IGF-IACTA PAEDIATRICA, Issue 2 2006Jaime Guevara-Aguirre Abstract Aim: To determine whether recombinant human insulin-like growth factor-I (rhIGF-I) administration to children with low IGF-I and relatively low insulin-like growth factor binding protein-3 (IGFBP3) serum concentrations would result in hypoglycemia. Methods: Eighteen children age 11,19 y with serum levels of IGF-I,<,,,2 SDS and IGFBP3,<,0 SDS were randomly assigned to receive rhIGF-I at 80 µg/kg body weight daily (n=6), 40 µg/kg twice daily (n=6), or 80 µg/kg twice daily (n=6). After a 10-d dose escalation and 15 d of treatment at the specified dosage, a 25-h pharmacokinetic/pharmacodynamic profile was obtained, which included 22 blood glucose measurements. Regular meals and snacks were provided. Results: No signs or symptoms of hypoglycemia were noted throughout the study. There were no differences in mean blood glucose concentrations among the three dosage groups. The lowest glucose value recorded, 3.44 mmol/l, was 15 min after a morning injection of 80 µg/kg IGF-I, and promptly rose. Although subjects were selected on the basis of low concentrations of IGF-I to represent proposed candidates for rhIGF-I therapy, the mean and range of SDS for height were not different from those of previously studied normal Ecuadorian controls. Conclusion: In normal individuals with low serum concentrations of IGF-I and relatively low concentrations of IGFBP3, the administration of therapeutic doses of rhIGF-I, while maintaining reasonable food intake, does not result in hypoglycemia. [source] | ||||||||||