Influence of nicorandil on the pharmacodynamics and pharmacokinetics of gliclazide in rats and rabbits

Chronic diabetes precipitates ischaemic heart disease (IHD) and many other disorders. IHD inturn is shown in the form of angina initially. According to EUROPA study, the incidence of angina is high in type II diabetics. Gliclazide, a second generation sulphonylurea derivative is widely used in the treatment of type-II diabetes and is known to release insulin by K⁺ channel inhibition. Nicorandil, a newer antianginal drug widely used now a days acts by opening potassium channels in the cardiac muscle cell and also by releasing nitric oxide. However its action on pancreatic cell K⁺ channel is not known. Since there is possibility for drug interaction leading to decreased activity of gliclazide the present study was conducted to evaluate the effect of the combination.Studies in normal and alloxan induced diabetic rats were conducted with oral doses of 2 mg/kg bd. wt. of gliclazide, 1.8 mg/kg bd. wt. of nicorandil and their combination with adequate washout periods in between treatments. Studies in normal rabbits were conducted with 5.6 mg/1.5 kg bd. wt. of gliclazide, 1.4 mg/1.5 kg bd. wt. of nicorandil and their combination given orally. Blood samples were collected in rats from retro orbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h and by marginal ear vein puncture in rabbits at 0, 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 h. All the blood samples were analysed for glucose by GOD/POD method. The blood samples of rabbits were analysed by HPLC for gliclazide.Gliclazide produced hypoglycaemic/antidiabetic activity in normal and diabetic rats with peak activity at 1 h and 8 h and hypoglycaemic activity in normal rabbits at 3 h, while nicorandil alone produced significant hyperglycaemia at 4 h and reduced the effect of gliclazide with no significant change in pharmacokinetics when administered in combination. The interaction observed appears to be pharmacodynamic at the receptor level as expected.     

Time-kill assay of itraconazole against Malassezia species

The in vitro pharmacodynamic activity of itraconazole against Malassezia was determined by time-kill methods. Itraconazole showed fungistatic activity at concentrations greater than 2x minimum inhibitory concentration (MIC) for each of the isolates of all nine Malassezia species associated with humans. A concentration exceeding 4x MIC decreased the growth to less than the inoculum amount (1 x 10(5) cells/ml).     

Data-Derived Uncertainty Factors: Boric Acid (BA) as a Case Study

There is growing support for the use of data-derived uncertainty factors. In recent years, risk assessments of boric acid have been performed by several well-respected organizations, including IEHR, ECETOC, IPCS, and WHO. For each, the pivotal study was a developmental toxicity study in rats with a no-observed-adverse-effect level (NOAEL) of 55 mg BA/kg/day. These risk assessments employed reduced uncertainty factors in the range of 25 to 60 for boric acid, because available pharmacokinetic data for boric acid reduced uncertainty in evaluating the overall data base with this compound. However, a limitation of previous risk assessments was the absence of specific data on the renal clearance of boric acid in pregnant rats and pregnant women. New data has demonstrated that when renal clearance was normalized to body weight (ml/min/kg), pregnant rats cleared boric acid at a rate roughly three times greater than pregnant women. In addition, the boric acid specific allometric relationship was determined from the log-log plot of clearance vs. body weight. Based on the new renal clearance data, it was estimated that pregnant women and rats would have the same AUC when pregnant women are given 30% of the boric acid dose given to pregnant rats. In addition, the renal clearance of boric acid among pregnant women varied by a factor of about 2. Therefore, boric acid-specific data on renal clearance in pregnant women and rats supports reduced interspecies and intraspecies pharmacokinetic uncertainty factors of approximately 3 and 2, respectively. Further, growing evidence of the essentiality in animals, combined with consistency of effects among species in toxicity studies, suggests a reduced pharmacodynamic uncertainty factor is appropriate for boric acid. Total uncertainty factors in the range of 22 to 44 are scientifically justified for this compound. An acceptable daily intake of 1.25 to 2.5 mg BA/kg/day is estimated by applying an uncertainty factor of 22 to 44 to the NOAEL of 55 mg BA/kg/day. Data-derived uncertainty factors should be used whenever possible, and they should be determined and applied in a consistent manner. Ultimately, estimates based on target tissue dose-adjusted relationships should offer a better approach to risk assessment.     

Current evidence on the circadian-time-dependent effects of hypertension medications and their combinations in relation to findings of MAPEC and Hygia Chronotherapy Trial

ABSTRACT

The main purpose of this commentary is to update, based on our extensive review of the published literature of the past 45 yrs, the differential therapeutic effects of hypertension medications of various classes and their combinations when ingested in the evening/at-bedtime versus in the morning/upon-awakening. Interestingly, revision of the currently available evidence on the differential circadian-time-dependent effects of hypertension medications of six different classes and their combinations indicates among the 137 published hypertension medication trials that evaluated blood pressure (BP)-lowering efficacy according to treatment-time, 112 (81.75%) documented significant better benefits by evening/bedtime compared to morning/awakening-scheduled therapy. The remaining 25 published trials found no treatment-time difference in effects; indeed, no single study has reported better benefits of the still conventional, but scientifically unjustified, morning than evening/at-bedtime treatment scheme.     

Development and validation of a quantitative method for thymidine phosphorylase activity in peripheral blood mononuclear cells

Abstract

The enzyme thymidine phosphorylase (TP) is important for activation of capecitabine and 5-fluorouracil. Assessment of TP phenotype might be suitable for identification of patients at risk of fluoropyrimidine-induced toxicity. In this paper, we describe the development and validation an assay for TP activity in peripheral blood mononuclear cells (PBMCs). The assay was based on ex vivo conversion of the TP substrate thymidine to thymine. The amount of thymine formed was determined by high-performance liquid chromatography – ultraviolet detection (HPLC-UV) with 5-bromouracil as internal standard. Lymphocytes and monocytes were purified from isolated PBMCs to examine cell-specific TP activity. TP activity in PBMCs demonstrated Michaelis-Menten kinetics. The lower limit of quantification was 2.3?µg PBMC protein and assay linearity was demonstrated up to 22.7?µg PBMC protein. Within-day and between-day precisions were ≤9.2% and ≤6.0%, respectively. Adequate stability TP activity was demonstrated after long-term storage of PBMC dry pellets and lysates at ?80?°C. In monocytes, TP activity was approximately 3 times higher than in lymphocytes. Clinical applicability was demonstrated in samples that were collected from five cancer patients. A simple, precise and sensitive HPLC-UV assay for quantification of TP activity in PBMCs was developed that can be applied for clinical research.     

中药炭药的临床应用及作用机理研究

制炭是将净药材用武火炒至表面焦黑,内部焦黄的一种中药炮制方法.不同的中药炒炭标准略有差异,炒制程度不同,药效不同.本文从炭药的临床应用、中药炒炭前后药性和功效的改变、制炭对中药品质的影响以及与炭药药效作用相关的作用机理研究等角度,分析和总结了炒炭类中药的研究现状,探讨了炒炭类中药的发展思路,为指导炭药在临床上的合理应用,建立炒炭类中药规范的炮制工艺、科学完善的检验标准提供参考.     

泊沙康唑药动学-药效学及其治疗药物监测研究进展

泊沙康唑为新一代三唑类广谱抗真菌药,临床主要用于侵袭性曲霉菌病、念珠菌病的预防和难治性口咽念珠菌病的治疗,具有抗菌 活性高、耐受性好、不良反应少等特点,但其口服后生物利用度具有较大的个体差异。综述泊沙康唑混悬液的药动学影响因素、不同患者 人群的药动学特征以及群体药动学特征、药动学 / 药效学特性、治疗药物监测对临床疗效和不良反应的重要影响,以指导临床个体化用药, 提高用药的有效性和安全性。     

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (?)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration–effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley-Liss, Inc.     

藏药西藏棱子芹抗炎镇痛药效学研究

本文采用二甲苯致小鼠耳廓肿胀法、棉球致小鼠肉芽肿法观察藏药西藏棱子芹的抗炎作用,采用热板法、醋酸扭体法观察藏药西藏棱子芹的镇痛作用。结果表明藏药西藏棱子芹能明显抑制二甲苯所致小鼠耳廓肿胀和棉球所致小鼠肉芽肿;能提高小鼠对热板疼痛的阈值,减少小鼠扭体反应的次数,延长醋酸所致小鼠扭体反应的潜伏时间。藏药西藏棱子芹具有显著的抗炎镇痛作用,值得开发研究。     

Single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties

Bispecific antibody production using single host cells has been a new advancement in the antibody engineering field. We previously showed comparable in vitro biological activity and in vivo mouse pharmacokinetics (PK) for two novel single cell variants (v10 and v11) and one traditional dual cell in vitro-assembled anti-human epidermal growth factor receptor 2/CD3 T-cell dependent bispecific (TDB) antibodies. Here, we extended our previous work to assess single cell-produced bispecific variants of a novel TDB against FcRH5, a B-cell lineage marker expressed on multiple myeloma (MM) tumor cells. An in vitro-assembled anti- FcRH5/CD3 TDB antibody was previously developed as a potential treatment option for MM. Two bispecific antibody variants (designs v10 and v11) for manufacturing anti-FcRH5/CD3 TDB in single cells were compared to in vitro-assembled TDB in a dual-cell process to understand whether differences in antibody design and production led to any major differences in their in vitro biological activity, in vivo mouse PK, and PK/pharmacodynamics (PD) or immunogenicity in cynomolgus monkeys (cynos). The binding, in vitro potencies, in vitro pharmacological activities and in vivo PK in mice and cynos of these single cell TDBs were comparable to those of the in vitro-assembled TDB. In addition, the single cell and in vitro-assembled TDBs exhibited robust PD activity and comparable immunogenicity in cynos. Overall, these studies demonstrate that single cell-produced and in vitro-assembled anti-FcRH5/CD3 T-cell dependent bispecific antibodies have similar in vitro and in vivo properties, and support further development of single-cell production method for anti-FcRH5/CD3 TDBs and other single-cell bispecifics.