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Dose Requirements (dose + requirement)
Selected AbstractsSpeed of induction of anaesthesia in dogs administered halothane, isoflurane, sevoflurane or propofol in a clinical settingAUSTRALIAN VETERINARY JOURNAL, Issue 1-2 2008RG Pottie Objective To compare the speed and quality of induction of general anaesthesia using three different inhalant agents and one intravenous agent, in healthy dogs undergoing desexing surgery. Materials and methods Less excitable dogs were not premedicated; others were premedicated with intramuscular acepromazine and morphine. Anaesthesia induction protocol was randomly assigned, with halothane, isoflurane or sevoflurane delivered by mask, or propofol delivered intravenously. Maximum vaporiser settings were used for inhalant inductions. Induction of anaesthesia was considered complete at the time of endotracheal intubation. Quality of induction was scored by the administering veterinarian. Results Seventy-one dogs were enrolled. Twenty-four received no premedication and 47 received premedication. Isoflurane inductions were significantly faster than halothane inductions (2.86 ± 0.25 vs 3.71 ± 0.22 min; mean ± SE, P = 0.013). Sevoflurane inductions (3.29 ± 0.24 min) were not significantly different from either halothane (3.71 ± 0.22 min, P = 0.202) or isoflurane inductions (2.86 ± 0.25 min, P = 0.217). Induction with propofol (1.43 ± 0.13 min) was significantly faster than inhalant induction (P < 0.001 in each case). Premedication decreased the dose requirement and time to induction for dogs induced with propofol, but did not significantly change the time to intubation for inhalant inductions. Dogs administered propofol and/or premedication were significantly more likely to have an excellent quality of induction, but there was no difference between inhalant agents in terms of induction quality. Conclusion Sevoflurane possesses chemical properties that should produce a more rapid induction of anaesthesia in comparison to halothane or isoflurane. However, in clinical practice patient related factors outweigh this improvement. [source] Maternal hypothyroidism in early and late gestation: effects on neonatal and obstetric outcomeCLINICAL ENDOCRINOLOGY, Issue 5 2005Iskandar Idris Summary Background, Maternal hypothyroidism may be associated with a variety of adverse neonatal and obstetric outcomes. Whether these outcomes are affected by maternal thyroid status at initial presentation or in late gestation specifically within a dedicated antenatal endocrine clinic remains unclear. The effects of thyroxine dose requirement during pregnancy and serum concentrations of TSH within such clinic settings are still not known. Objectives, We investigated these outcomes in patients with hypothyroidism during early and late gestation. TSH levels and thyroxine dose requirement during early and late gestation were also evaluated. Methods, We performed a retrospective study of data from 167 pregnancies managed in the antenatal endocrine clinic. Analysis of outcomes was linked to TSH at first presentation and in the third trimester. Outcome variables included: rate of caesarean section, pre-eclampsia, neonatal unit admission, neonatal weight and gestational age. Controlled TSH was defined as mothers with TSH between 0·1 and 2 with normal free thyroid hormone levels. Results, The caesarean section (CS) rates were higher in the study cohort (H) compared with the local (C) rate (H = 28·7%, C = 18%). The higher rate in our patient cohort was not due to a higher rate of emergency section nor to a lower threshold for performing elective caesarean section. The infant birthweight (IBW) from mothers with TSH > 5·5 (H1) and mothers with TSH between 0·1 and 5·5 at presentation (H2) was [median (range)] 3·38 (1·73,4·70) vs. 3·45 (1·36,4·76); P = ns. The prevalence of low-birthweight (LBW) infants (< 2·5 g) in groups H1 and H2 was 15% and 4·8%, respectively [odds ratio (OR) = 3·55, 95% confidence interval (95% CI) = 0·96,10·31]. IBW from mothers with TSH > 2 (H3) and mothers with controlled TSH in the third trimester (H4) were similar [3·38 (1·78,4·4) vs. 3·46 (1·36,4·76); P = ns]. The prevalence of LBW in groups H3 and H4 was 9% and 4·9%, respectively (OR = 1·95, 95% CI = 0·52,7·26). The median thyroxine dose (µg) increased significantly during pregnancy (first trimester: 100; second trimester: 125, P < 0·001; and third trimester: 150, P < 0·001) associated with appropriate suppression of TSH levels in the second and third trimesters. Rates of pre-eclampsia or admissions to neonatal units were negligible. Conclusion, Thyroxine dose requirement increases during pregnancy and thus close monitoring of thyroid function with appropriate adjustment of thyroxine dose to maintain a normal serum TSH level is necessary throughout gestation. Within a joint endocrine,obstetric clinic, maternal hypothyroidism at presentation and in the third trimester may increase the risk of low birthweight and the likelihood for caesarean section. The latter observation was not due to a higher rate of emergency caesarean section nor to a lower threshold for performing elective caesarean section. A larger study with adjustments made for the various confounders is required to confirm this observation. [source] Commercial manufacturing scale formulation and analytical characterization of therapeutic recombinant antibodiesDRUG DEVELOPMENT RESEARCH, Issue 3 2004Reed J. Harris Abstract Stable therapeutic antibody dosage forms present production technology challenges, particularly when high-concentration formulations are needed to meet the elevated dose requirements that are generally required for successful antibody therapy. Solid dosage forms, such as lyophilized powders, are generally more stable than liquid formulations. High-concentration drug products can be achieved by reconstitution of the lyophilisate in a smaller volume than its initial (pre-lyophilization) volume, but requires a significant vial overfill. High-concentration liquid formulations are becoming feasible as new techniques and technologies become available. Analytical methods to detect subtle molecular variations have been developed to demonstrate manufacturing consistency. Some molecular heterogeneity is contributed by conserved sites, such as Asn297 glycosylation and the loss of heavy chain C-terminal Lys residues. Characteristics that affect potency, stability, or immunogenicity must be elucidated for each therapeutic antibody. Drug Dev. Res. 61:137,154, 2004. © 2004 Wiley-Liss, Inc. [source] Effect of vascular injury on inhibition of venous thrombosis with ZK-807834, a direct inhibitor of factor XaJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2003D. R. Abendschein Summary., Inhibition of factor Xa with the small molecule inhibitor ZK-807834 (Mr 527 Da, Ki 0.11 nM) attenuates progression of thrombosis, but the ED50 is substantially lower for venous compared with arterial thrombosis in experimental animals. To determine whether this reflects differences in the extent of vascular injury, we compared the dose,response of ZK-807834 for inhibition of venous thrombosis induced with a cotton thread and copper wire device in the presence and absence of balloon catheter-induced injury to the vena cava in rabbits. ZK-807834 administration over 2 h (total dosages of 0.0023,2.3 µmol kg,1, n = 6/group) resulted in dose-dependent reductions in clot weight compared with vehicle controls, but the ED50 was 0.03 µmol kg,1 for non-injured veins and 0.42 µmol kg,1 for injured veins. We conclude that vascular injury invokes a tissue factor-mediated response that increases the dose requirements for inhibition of venous thrombosis with ZK-807834. [source] Utility of azathioprine metabolite measurements in post-transplant recurrent autoimmune and immune-mediated hepatitisPEDIATRIC TRANSPLANTATION, Issue 6 2004Carolina Rumbo Abstract:, Patients with post-transplant immune-mediated hepatitis (IMH) and recurrent autoimmune hepatitis (RAIH) have a poor outcome and a higher need for retransplantation. Azathioprine (AZA) is used as adjunctive immunosuppression after transplantation; optimizing its dose may be a key point in preserving graft function. Complications of high AZA dosing make dose escalation potentially problematic. Our aim was to correlate AZA metabolite levels with therapeutic effects, toxicity, and adherence to medication in children with IMH and RAIH. Charts of 14 patients were retrospectively reviewed. The post-transplant diagnosis was based on liver biopsy and autoimmune markers. AZA was prescribed after establishing the post-transplant diagnosis. AZA was started at 1.1 (1.0,1.8) mg/kg/day. Routine biochemical studies, tacrolimus levels, 6-thioguanine (6-TG) and 6-methylmercaptopurine levels were assessed every 8 wk. AZA dose was routinely adjusted to achieve 6-TG levels between 235 and 450 pmol per 8 × 108 RBC. A total of 92 samples from 14 patients were reviewed. Four patients were excluded because of non-adherence. AZA dose was increased by 245% resulting in eight of 10 patients in the target range; no hepatic or bone marrow toxicity was observed. ALT levels and steroid requirements were significantly reduced (p < 0.05). The AZA dose required to achieve target 6-TG levels was significantly greater in children <10 yr. AZA metabolite testing in children post-liver transplant is useful in assessing adherence to medication and it is potentially helpful in optimizing medication dosing. In younger children the AZA dose requirements were two to four times higher than previously reported standard doses. [source] COMT genotypes and use of antipsychotic medication: linking population-based prescription database to the HUNT study,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 4 2008Dr Knut Hagen Abstract Purpose The aim of this prospective study was to evaluate the impact of codon 158 polymorphism at the catechol- O -methyltransferase (COMT) gene on prescription of antipsychotic medication in a general population. Methods The sample comprised 2623 non-diabetic individuals who participated in the Nord-Trøndelag Health Study (HUNT) in the period 1995,97 and who were alive 1 January 2004. The subjects were followed up with respect to prescription of antipsychotic medication based on data obtained from the Norwegian prescription database. Results Among the group of 76 individuals who had been prescribed antipsychotic medication the distribution did not differ between genotypes and alleles when compared to a control group. For 47 individuals with at least three prescriptions a correlation between median total defined daily doses (DDDs) and genotype groups was found (Spearman's rho, ,0.40, p,=,0.01), being highest for the Met/Met genotype (250), intermediate for the Met/Val genotype (126) and lowest for the Val/Val genotype (47) (p,=,0.03). Conclusion In this population-based cohort of 2623 adults, the Val158Met polymorphism at the COMT gene had no major impact on number of individuals who had been prescribed antipsychotic medication. However, linkage to the prescription database may in an indirect way indicate an association between the COMT Val158Met polymorphism and treatment response or dose requirements of antipsychotic medication. Copyright © 2008 John Wiley & Sons, Ltd. [source] Changes in prescribed drug doses after market introductionPHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 6 2002Eibert R. Heerdink PhD Abstract Purpose The establishment of recommended dosing regimens has always been a difficult aspect of drug development. This paper examines the extent to which postmarketing prescribing deviates from initially recommended dosing regimens. We used the World Health Organization's (WHO) periodically updated compilation of the ,Defined Daily Dose' (DDD) to reflect prevailing patterns of prescribing in national markets. The aim of this study was to evaluate DDD changes over time (1982,2000) and to identify possible determinants of these changes. Methods Data on DDD changes were obtained from the WHO's Oslo Collaborating Centre. We performed a case,control analysis in which we compared drugs with (cases) and without (controls) postmarketing changes in DDD on possible determinants associated with DDD change. Results We found 115 instances of a change of DDD in the period 1982,2000 (45 (39.1%) increases and 70 (60.9%) decreases). Antibiotics showed the greatest number of changes in DDD: predominantly increases in the 1980s, while the 1990s were dominated by decreases in DDD of mostly cardiovascular drugs. Conclusion Changes in DDD reflect the outcome of a melange of forces, including misconceptions of dose requirements during pre-market development of drug and postmarketing changes in pharmacotherapeutic knowledge, clinical concepts, economic forces, and, in the case of anti-infective agents, changing patterns of resistance/sensitivity of target microorganisms to the anti-infective agent(s) in question. Copyright © 2002 John Wiley & Sons, Ltd. [source] Trilostane treatment in dogs with pituitary-dependent hyperadreno-corticismAUSTRALIAN VETERINARY JOURNAL, Issue 10 2003JA BRADDOCK Objective To evaluate the efficacy of trilostane in treating dogs with pituitary-dependent hyperadrenocorticism. Design Prospective clinical trial using client-owned dogs with pituitary-dependent hyperadrenocorticism treated at University Veterinary Centre, Sydney from September 1999 to July 2001. Procedure Thirty dogs with pituitary-dependent hyperadrenocorticism treated with trilostane, a competitive inhibitor ,-HSD, were monitored at days 10, 30 and 90 then 3-monthly by clinical examination, tetracosactrin stimulation testing, urinary corticoid:creatinine ratio measurement and by client questionnaire. Results Twenty-nine of 30 dogs were successfully treated with trilostane (median dose 16.7 mg/kg; range 5.3 to 50 mg/kg, administered once daily); one responded favourably but died of unrelated disease before full control was achieved. Conclusion Trilostane administration controlled pituitary-dependent hyperadrenocorticism in these dogs. It was safe, effective and free of side-effects at the doses used. Most dogs were initially quite sensitive to the drug for 10 to 30 days, then required higher doses until a prolonged phase of stable dose requirements occurred. Urinary corticoid:creatinine ratio was useful in assessing duration of drug effect. Some dogs treated for more than 2 years required reduction or temporary cessation of drug because of iatrogenic hypoadrenocorticism. [source] Technological progresses in monoclonal antibody production systemsBIOTECHNOLOGY PROGRESS, Issue 2 2010Maria Elisa Rodrigues Abstract Monoclonal antibodies (mAbs) have become vitally important to modern medicine and are currently one of the major biopharmaceutical products in development. However, the high clinical dose requirements of mAbs demand a greater biomanufacturing capacity, leading to the development of new technologies for their large-scale production, with mammalian cell culture dominating the scenario. Although some companies have tried to meet these demands by creating bioreactors of increased capacity, the optimization of cell culture productivity in normal bioreactors appears as a better strategy. This review describes the main technological progresses made with this intent, presenting the advantages and limitations of each production system, as well as suggestions for improvements. New and upgraded bioreactors have emerged both for adherent and suspension cell culture, with disposable reactors attracting increased interest in the last years. Furthermore, the strategies and technologies used to control culture parameters are in constant evolution, aiming at the on-line multiparameter monitoring and considering now parameters not seen as relevant for process optimization in the past. All progresses being made have as primary goal the development of highly productive and economic mAb manufacturing processes that will allow the rapid introduction of the product in the biopharmaceutical market at more accessible prices. © 2010 American Institute of Chemical Engineers Biotechnol. Prog., 2010 [source] Apparent low absorbers of cyclosporine microemulsion have higher requirements for tacrolimus in renal transplantationCLINICAL TRANSPLANTATION, Issue 4 2007Andrew A. House Abstract:, Bioavailability and exposure of cyclosporine microemulsion and tacrolimus in renal transplantation are governed by many complex factors. Failure to achieve therapeutic two-h post-dose (C2) levels despite adequate doses of cyclosporine ("low absorbers") may merit conversion to tacrolimus. We compared tacrolimus dose requirements in "low absorbers" (n = 15) with a random control group of de novo tacrolimus patients (n = 14). Low absorbers failed to reach target C2 despite increasing dose from 10.1 to 16.2 mg/kg/d. At conversion the mean C2 was 969 ng/mL (95% CI: 684,1255; target 1700 ng/mL). Low absorbers tended to be younger, heavier, and diabetic. Despite a similar initial tacrolimus dose (0.17,0.18 mg/kg/d), low absorbers required a much higher daily dose to achieve target; 0.25 vs. 0.16 mg/kg/d (p = 0.016). Furthermore, daily maintenance tacrolimus remained much higher in low absorbers at three wk (0.22 vs. 0.13 mg/kg/d, p = 0.012). Although not statistically significant, this group experienced an acute rejection rate of 33%, compared with 21% in the control group. Patients treated with cyclosporine as initial immunosuppression who fail to reach target C2 levels in a timely fashion are at risk for impaired bioavailability of tacrolimus. Based on our data, a starting dose of 0.25 mg/kg/d in divided doses may be warranted for low absorbers converting to tacrolimus; however, we encourage larger studies with formal pharmacokinetic analysis in this population. [source] Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantationCLINICAL TRANSPLANTATION, Issue 5 2005Xin Zhang Abstract:, Objective:, Tacrolimus is an immunosuppressive drug with a narrow therapeutic range and wide interindividual variation in its pharmacokinetics. Cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp, encoded by MDR1) play an important role in the absorption and metabolism of tacrolimus. The objective of this study was to evaluate whether or not CYP3A5*1/*3 or MDR1 C3435T polymorphisms are associated with the tacrolimus concentration per dose. Methods:, CYP3A5 and MDR1 genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism analysis in 118 Chinese renal transplant patients receiving tacrolimus. Whole blood trough tacrolimus concentration was measured by enzyme-linked immunosorbent assay and dose-adjusted concentration (ng/mL per mg/kg/d) was calculated at 1 wk, 1 month, and 3 months after transplantation. Results:, The dose-adjusted concentration of CYP3A5*1/*1 and *1/*3 patients was significantly lower than *3/*3 patients (32.8 ± 17.7 and 41.6 ± 15.8 vs. 102.3 ± 51.2 at 1 wk; 33.1 ± 7.5 and 46.4 ± 12.9 vs. 103 ± 47.5 at 1 month; 35.3 ± 20.9 and 59.0 ± 20.6 vs. 150 ± 85.3 at 3 months after transplantation respectively). At 1 wk, 46% of the CYP3A5*1 allele carriers had a tacrolimus concentration lower than 5 ng/mL and 77% lower than 8 ng/mL, whereas 20% of the *3/*3 patients had a concentration higher than 20 ng/mL. There was a mild difference between *1/*1 homozygotes and *1/*3 heterozygotes at 1 and 3 months after transplantation. No difference was found among the MDR1 genotypes. Conclusion:, CYP3A5*1/*3 polymorphisms are associated with tacrolimus pharmacokinetics and dose requirements in renal transplant recipients. Pharmacogenetic methods could be employed prospectively to help initial dose selection and to individualize immunosuppressive therapy. [source] | |||||||||||||||||||