Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous furosemide

Effects of differences in the rate and composition of intravenous fluid replacement for urine loss on the pharmacokinetics and pharmacodynamics of furosemide were evaluated using the dog as a model animal. Each of six dogs received 8-hr constant intravenous infusion of 20 mg (15 mg used in one dog) of furosemide with 0% replacement (treatment I), 50% replacement (treatment II), and 100% replacement (treatment III) with lactated Ringer's solution, as well as with 100% replacement with 5% dextrose in water (treatment IV). Most pharmacokinetic parameters, such as plasma clearance, steady-state volume of distribution, mean residence time, and terminal half-life, were essentially the same in all four treatments. Renal clearances and urinary excretion rates of the drug in treatments II–IVwere essentially the same, but about 20% higher than those in treatment I.In spite of the similarities in kinetic properties, diuretic and/or natriuretic effects from furosemide were markedly different among the four treatments. For example, mean 10-hr urine outputs were 646, 1046, 3156, and 1976 ml and mean 10-hr sodium excretions were 87.0, 142, 383, and 97.2 mmole for treatments I–IV,respectively. Except for treatment III,diuresis and/or natriuresis were found to be time-dependent, generally decreasing with time until reaching a low plateau during later hours of infusion. The present findings also showed that (1)no fluid replacement and 100% replacement with 5% dextrose solution both produced the same degree of severe acute tolerance in natriuresis, indicating the insignificance of water compensation in tolerance development; (2)in treatment II,where neutral sodium balance was achieved, the development of acute tolerance in diuresis and natriuresis can mainly be attributed to negative water balance under this special condition; (3)at steady state the hourly diuresis and natriuresis could differ up to about ten times between treatments. Some implications for the kinetic/dynamic relationship or modeling, in the clinical use, and in the bioequivalence evaluation of dosage forms are discussed.     

Molecular characteristic-based epidemiology of hepatitis B, C, and E viruses and GB virus C/hepatitis G virus in Myanmar

We carried out a molecular characteristic-based epidemiological survey of various hepatitis viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), and GB virus C (GBV-C)/hepatitis G virus (HGV), in Myanmar. The study population of 403 subjects consisted of 213 healthy individuals residing in the city of Yangon, Myanmar, and the surrounding suburbs and 190 liver disease patients (155 virus-related liver disease patients and 35 nonviral disease patients). The infection rates of the viruses among the 213 healthy subjects were as follows: 8% for HBV (16 patients), 2% for HCV (4 patients), and 8% for GBV-C/HGV (17 patients). In contrast, for 155 patients with acute hepatitis, chronic hepatitis, liver cirrhosis, or hepatocellular carcinoma, the infection rates were 30% for HBV (46 patients), 27% for HCV (41 patients), and 11% for GBV-C/HGV (17 patients). In the nonviral liver disease group of 35 patients with alcoholic liver disease, fatty liver, liver abscess, and biliary disease, the infection rates were 6% for HBV (2 patients), 20% for HCV (7 patients), and 26% for GBV-C/HGV (9 patients). The most common viral genotypes were type C of HBV (77%), type 3b of HCV (67%), and type 2 of GBV-C/HGV (67%). Moreover, testing for HEV among 371 subjects resulted in the detection of anti-HEV immunoglobulin G (IgG) in 117 patients (32%). The age prevalence of anti-HEV IgG was 3% for patients younger than 20 years and 30% or more for patients 20 years of age or older. Furthermore, a high prevalence of anti-HEV IgG (24%) was also found in swine living together with humans in Yangon. These results suggest that these hepatitis virus infections are widespread in Myanmar and have led to a high incidence of acute and chronic liver disease patients in the region.     

Concentration andpH dependent steady-state volume of distribution of methotrexate estimated by a simple physiologically based method

The effects of plasma concentration and pH on the steady-state volume of distribution, V_ss,of methotrexate (MTX) were studied in five conditioned male beagle-mongrel dogs. Steady-state plasma MTX concentrations of approximately 1, 20, and 100g/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused for the purpose of inducing plasma pH change, while the infusion of an isotonic solution of sodium chloride served as a control. Plasma and urine concentrations of MTX were quantitated by a sensitive high-performance liquid chromatographic method, and the V_ss of MTX was estimated by a recently reported physiologically based method of Chiou and Lam. Statistically significant (p<0.05) concentration and plasma pHdependent V_ss of MTX were observed. Concentration dependence of V_ss was noted in sodium chloride and ammonium chloride infused dogs, but not in bicarbonate treated dogs. There was an average 50.0 and 44.8% increase in V_ss at 1 g/ ml relative to the two higher concentrations (20 and 100 g/ ml) for dogs treated with ammonium and sodium chloride, respectively. However, V_ss of MTX at the targeted concentrations of 20 and 100 g/ml was relatively constant. Plasma pHdependence of V_ss was observed only at the plasma concentration of 1 g/ml, and on the average, ammonium chloride and sodium chloride treatments resulted in 50.0 and 31.3% higher V_ss,respectively, when compared with the bicarbonate treatment. These phenomena appear to be adequately explained by the reported tissue uptake kinetics of MTX.This research was supported in part by a grant from the National Cancer Institute, CA-29754.Abstracted from a dissertation submitted in 1984 by Chung Y. Lui to the Graduate College, University of Illinois at Chicago, in partial fulfillment of Doctor of Philosophy Degree requirements.     

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate in rabbits after intravenous administration

The pharmacokinetics of methotrexate (MTX) and 7-hydroxy-methotrexate (7-OH-MTX), a major metabolite, were investigated in rabbits after intravenous bolus injection and infusion using a specific HPLC assay. The arterial sampling (from the carotid artery) was used in all the studies since peculiar and significant arterial-venous differences in the plasma concentration of MTX and 7-OH-MTX were found following bolus administration of the drug. The disposition kinetics of MTX appeared polyexponential with a small terminal phase having a half-life of 10.2–27.5 hr. Extensive formation of 7-OH-MTX occurred at the two dose levels (15 and 50 mg/kg). Nonlinear disposition of MTX was reflected in several aspects of data analysis. A disproportionate increase in the AUC with dose was observed. An increase in dose not only reduced the mean total body clearance (7.49 vs. 4.26 ml/min/kg) and renal clearance (4.89 vs. 2.76 ml/min/kg), but also prolonged the mean residence time (26.2 vs. 43.3 min). The steady-state volume of distribution (V_ss) of MTX was estimated to range from 0.16 to 0.25 L/kg. More than 90% of the dose was excreted as MTX and 7-OH-MTX within 8 hr after dosing. Renal clearances decreased with the increasing plasma levels, suggesting active tubular secretion as one of the excretion mechanisms. A similar pattern for renal clearance of 7-OH-MTX was obtained. Infusion studies of 7-OH-MTX revealed that this metabolite had a longer residence time and a larger V_ss as compared with MTX, which were in accordance with its physicochemical properties. Essentially complete doses of 7-OH-MTX could be recovered in the rabbit urine.     

Adipose and Plasma microRNAs miR-221 and 222 Associate with Obesity,Insulin Resistance,and New Onset Diabetes after Peritoneal Dialysis

Background: The correlation between microRNA, obesity, and glycemic intolerance in patients on peritoneal dialysis (PD) is unknown. We aimed to measure the adipose and plasma miR-221 and -222 levels, and to evaluate their association with adiposity, glucose intolerance, and new onset diabetes mellitus (NODM) after the commencement of PD. Methods: We prospectively recruited incident adult PD patients. miR-221 and -222 were measured from adipose tissue and plasma obtained during PD catheter insertion. These patients were followed for 24 months, and the outcomes were changes in adiposity, insulin resistance, and NODM after PD. Results: One hundred and sixty-five patients were recruited. Patients with pre-existing DM had higher adipose miR-221 (1.1 ± 1.2 vs. 0.7 ± 0.9-fold, p = 0.02) and -222 (1.9 ± 2.0 vs. 1.2 ± 1.3-fold, p = 0.01). High adipose miR-221 and -222 levels were associated with a greater increase in waist circumference (miR-221: beta 1.82, 95% CI 0.57–3.07, p = 0.005; miR-222: beta 1.35, 95% CI 0.08–2.63, p = 0.038), Homeostatic Model Assessment for Insulin Resistance (HOMA) index (miR-221: beta 8.16, 95% CI 2.80–13.53, p = 0.003; miR-222: beta 6.59, 95% CI 1.13–12.05, p = 0.018), and insulin requirements (miR-221: beta 0.05, 95% CI 0.006–0.09, p = 0.02; miR-222: beta 0.06, 95% CI 0.02–0.11, p = 0.002) after PD. The plasma miR-222 level predicted the onset of NODM (OR 8.25, 95% CI 1.35–50.5, p = 0.02). Conclusion: miR-221 and -222 are associated with the progression of obesity, insulin resistance, and NODM after PD.     

视神经周围炎的研究进展

视神经周围炎(OPN)是指涉及视神经鞘膜的一系列病理性炎症.OPN的经典三联征包括单侧视神经病变伴随疼痛和/或视盘水肿,此病症与其它视神经病变相似,导致诊断延迟和治疗欠佳.2016年1月,我们对发表于Medline和Ovid数据库的关键词为“视神经周围炎”的各种语言的文献进行了检索,共查找到60篇文献,发表于1956-2015年.两位作者(Tai ELM和Tevaraj JMP)分别对论文摘要进行了独立筛选,并筛选出相关文章.本次综述,我们强调OPN的特点,特别是OPN和视神经炎之间的临床差异.虽然大多数OPN的病例是特发性的,但仍需进行调查以排除特异性感染和继发性OPN的炎症原因.MRI是非常重要的检查方法,由于OPN视神经周围炎症的影像学诊断.糖皮质激素治疗可使症状与体征迅速好转,长期口服糖皮质激素并慢速递减可以降低复发的风险.