Proximal tubular function in adult rats treated neonatally with enalapril

Neonatal treatment with angiotensin-converting enzyme (ACE) inhibitors or the angiotensin II type-1 receptor antagonist losartan in rats induces irreversible renal histological abnormalities, mainly papillary atrophy, in association with an impairment in urinary concentrating ability. The aim of the present study was to assess proximal tubular function in adult rats treated neonatally with enalapril. Male Wistar rats received daily, intraperitoneal injections of either enalapril (10 mg kg^?1) or isotonic saline vehicle from 3 to 24 days of age. In 15-week-old, hydropenic rats we analysed: (i) proximal tubular iso-osmotic fluid reabsorption using the method of lithium clearance; and (ii) maximal tubular D -glucose reabsorption (Tm_G), under pentobarbital anaesthesia. The main findings were that neonatally enalapril-treated rats showed: (i) reductions in absolute (APRH₂O) and fractional (FPRH₂O) iso-osmotic fluid reabsorption in the proximal tubules (APRH₂O: 0.50 ± 0.02 vs. 0.64 ± 0.03 mL min^?1 g KW^?1, P < 0.05; FPRH₂O: 58 ± 3 vs. 68 ± 2%, P < 0.05); and (ii) a normal Tm_G. In addition, during baseline clearance measurements neonatally enalapril-treated rats showed increases in urine volume and fractional excretion rates of sodium and potassium, a reduction in urine osmolality, whereas glomerular filtration rate and effective renal plasma flow were unaltered. These results suggest that neonatal ACE inhibition produces an irreversible, but differentiated, abnormality in proximal tubular function. Thus, the development of a normal proximal tubular function in the rat seems to be dependent on an intact renin-angiotensin system, (RAS) neonatally.     

Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides

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The effect of physical conditioning on antipyrine clearance

The effects of physical conditioning on antipyrine clearance were studied in two groups of subjects. Healthy men not engaged in the systematic practice of any sport were compared with endurance runners (defined as men running >80 km/week). Studies were carried out at three different periods of the annual plan training at 4-month intervals. Antipyrine was administered orally and pharmacokinetic parameters were obtained from saliva samples by the multiple-sample method. Endurance performance, expressed in terms of the maximal oxygen uptake (V˙O_{2 max}), the ventilatory threshold and the 4-mM · l⁻¹ lactate threshold (OBLA), was higher in trained than in control subjects at each of the three periods. Antipyrine clearance was also significantly elevated and antipyrine half-life reduced in runners during all periods. No significant difference in V˙O_{2 max} or antipyrine clearance was found between the various periods in either trained or control subjects. Both ventilatory threshold and OBLA increased significantly along the training period in conditioned subjects. Significant correlations were found between antipyrine clearance and V˙O_{2 max}, ventilatory threshold and OBLA. In summary, these results indicate an association between aerobic conditioning and increased hepatic oxidative metabolism of low-clearance drugs. Accepted: 15 July 1997     

125I-白细胞介素-8在小鼠体内的分布研究

为了解白细胞介素 - 8的体内行为 ,用 Bolton- Hunter法对 IL- 8进行 1 2 5I标记 ,并测定它在小鼠体内的分布 ;得到了 1 2 5I- IL- 8在小鼠血、心、肝、肺、肾、骨、脾等脏器中的分布以及它在血液中的快相半排期 T1 /2α为 0 .3 2 h和慢相半排期 T1 /2β为 8.0 1h。1 2 5I- IL- 8主要通过肾排除     

2型糖尿病肾病患者血清胱抑素C的检测及意义

目的:检测糖尿病患者血清胱抑素C浓度变化,分析其在糖尿病患者早期肾损伤中的作用。方法:根据24h尿白蛋白排泄率(UAER)的测定结果,将104例糖尿病患者分为3组:单纯糖尿病组(SDM组)、早期糖尿病肾病组(EDN组)和临床糖尿病肾病组(CDN组);46名健康者作对照组;采用颗粒增强散射免疫比浊法测定血清胱抑素C水平,常规测定内生肌酐清除率、血肌酐和UAER,并对全部患者胱抑素C血清浓度与尿UAER进行直线相关分析。结果:SDM组,EDN组及CDN组间血清胱抑素C水平均有非常显著性统计学意义(P<0.01),血清胱抑素C与UAER、内生肌酐清除率及血肌酐值有良好相关性(r值分别为0.772,-0.754,0.785,P均<0.01)。结论:血清胱抑素C水平测定有助于2型糖尿病肾病的早期诊断,优于血肌酐和内生肌酐清除率,具有临床应用价值。     

Favorable efficacy of long-term lamivudine therapy in patients with chronic hepatitis B: an 8-year follow-up study

The long-term efficacy of lamivudine therapy in patients with hepatitis B virus (HBV) infection is still not clear. In this study, 20 non-cirrhotic Japanese patients infected with HBV received lamivudine therapy for more than 1 year and were followed for a median period of 8.5 years (range, 6.7-8.7 years). The rates of HBe antigen (HbeAg) negative, HBV-DNA undetectable, and alanine aminotransferase (ALT) normal level at the start of lamivudine were 55%, 25%, and 20% and 85%, 80%, and were 80%, respectively, at the last visit, including patients who received additional treatment. The values at the last visit tended to and were significantly higher than those at the start. The values improved at the last visit regardless of the emergence of YMDD motif mutant and continuation of lamivudine. YMDD mutant and biochemical relapse with mutant virus (breakthrough hepatitis) appeared in 65% and 45% during follow-up, respectively, but severe breakthrough hepatitis occurred in only 5%. Furthermore, 80% of patients who received additional treatment for breakthrough hepatitis, regardless of continuation of lamivudine, were ALT normal level at the last visit, in contrast to 25% untreated. HBsAg clearance occurred in two patients of the discontinuous lamivudine group with non-vertical transmission, who were relatively young. One was infected with HBV genotype C with breakthrough hepatitis and the other had no YMDD mutant and was infected with genotype D, a rare type in Japan. None developed cirrhosis or hepatocellular carcinoma (HCC) during follow-up. Our results suggest that long-term lamivudine therapy improves long-term prognosis, especially when additional treatment for breakthrough hepatitis is used.     

Intracellular recordings from isolated rabbit retinal Müller (glial) cells

Müller (glial) cells were isolated from rabbit retinae by papaine and mechanical dissociation. The cells were fixed on a gelatine-covered glass slide by means of concanavalin A, and the slide was mounted in a perfusion chamber under a light microscope with modified optics. Besides the recording microelectrode, two other micropipettes could be adjusted with their tips near the cell. These micropipettes were used for application of test solutions into the environment of the cells. On application of high K⁺ solutions, the cell depolarized strongly but during prolonged application there was a marked repolarization. After the end of high K⁺ application the cells showed a hyperpolarization which was enhanced in both amplitude and duration with prolongation of the K⁺ exposure. Both repolarization and afterhyper-polarization disappeared under ouabain. Ouabain application itself caused a small reversible depolarization. Na⁺ free solution caused hyperpolarization. The results suggest the existence of an active membrane pump mechanism in our cells. This pump seems to be electrogenic under our experimental conditions and seems to be activated even in the absence of sodium. The cell membrane is demonstrated to contain a significant Na⁺ conductance.     

On the interaction between phenytoin and digoxin

Summary An open, randomized, single-blind cross over trial to investigate phenytoin-digoxin interactions at steady state was performed in 6 healthy male volunteers. Coadministration of phenytoin caused a significant reduction in the elimination half-life of digoxin from 33.9 to 23.7 h and a diminution in AUC_0–48 from 31.6 to 24.4 ng · ml^–1 · h. Renal digoxin clearance was not significantly altered from 135.7 to 120.3 ml · min^–1. Assuming no change in -acetyldigoxin absorption, the in decrease time-course the serum digoxin concentration was due to a significantly increased total digoxin clearance from 258.6 to 328.3 ml · min^–1. An insignificant reduction in the digoxin distribution volume from 749.4 to 668.0 l was also observed. No relevant change in the pharmacokinetic parameters (elimination half-life, area under the serum concentration time-curve, protein binding) of phenytoin was observed when phenytoin and digoxin were co-administered. The data suggest that with this drug combination the serum digoxin concentration should be carefully monitored and, if necessary, the daily digoxin dose should be increased.     

Correlation Between In Vivo Antipyrine Metabolite Formation and Theophylline Metabolism in Rats

Two model substrates for oxidative hepatic enzyme activity, viz. antipyrine (A) and theophylline (T), were given simultaneously to rats by iv administration. Blood concentrations of A and T were measured by a high-performance liquid chromatographic (HPLC) method. Urinary excretions of A, T, and the major metabolites arising from A—4-hydroxyantipyrine (OHA), norantipyrine (NORA), 3-hydroxymethylantipyrine (HMA), and 4,4-dihydroxyantipyrine (DOHA)—and from T—1-methyluric acid (1-MU) and 1,3-dimethyluric acid (1,3-DMU)—were also determined by HPLC. It was found that the pharmacokinetic parameters obtained after the simultaneous administration of A and T at relatively low dose levels (A, 5.0 mg; and T, 1.3 mg) were not different from those obtained after the separate administration of A or T at the same dose level. In order to investigate whether the metabolic pathways of A and T are mediated by the same or closely related forms of the cytochrome P-450 system, metabolic clearances of A (CL_A,M) and T (CL_T,M) and the clearances for production of their various metabolites, obtained in untreated rats and in rats pretreated with 3-methylcholanthrene (MC) or with MC followed by 9-hydroxyellipticine (E), were correlated. These two compounds are a selective cytochrome P-448 inducer and inhibitor, respectively. Strong correlations were found between CL_T,M and the clearances for production of OHA, NORA, and DOHA but not HMA. The best correlation, however, was observed between CL_T,M and CL_OHA, not only when all data points were taken into account (r = 0.99), but also in separate pretreatment groups (r ranging from 0.87 to 0.92). Moreover, the slopes of these correlation lines varied only slightly among groups, while the intercepts were not significantly different from zero. In the separate pretreatment groups, the correlation coefficients for the correlations between CL_T,M and the clearance for production of the other metabolites of A were considerably lower, while the slopes of the correlation lines varied substantially. Clearances for production of the metabolites of T were strongly correlated with each other (r = 0.99) and with CL_OHA (r = 0.95). It can be concluded that theophylline metabolism and formation of OHA are mediated by the same or very similar forms of cytochrome P-450, whereas formation of the other major metabolites of A is not or only partly. The study of the various pathways of metabolism after simultaneous administration of drugs is a powerful tool in the study of correlations in drug metabolism in vivo.     

Pharmacokinetics of metoprolol in healthy,elderly, non-smoking individuals after a single dose and two weeks of treatment

Summary The effect of long-term treatment on the absorption and dispsoition of metoprolol has been evaluated in 8 healthy, non-smoking, elderly individuals (mean age 74.5 years) and in a control group of 8 healthy, young individuals. Two trace doses of [³H]metoprolol were given i.v., first concomitantly with a single oral 50 mg dose of cold metoprolol, and second, with the morning dose after 2 weeks of treatment with 50 mg b.d. In the elderly, the mean AUC increased by about 45% (p<0.05) over the treatment period, while in the control group the mean AUC was 18% greater (p<0.05) on Day 14 than on Day 1. In the elderly, changes both in pre-systemic elimination and in total body clearance accounted for the elevation of the AUC, whereas reduced first-pass effect appeared to be the major cause of the increased steady-state plasma level in the control group. With the exception of the volume term, V , the pharmacokinetic parameters were not significantly different between the elderly and the young individuals. For this reason, almost identical steady-state plasma levels were attained in the two groups. The results suggest that age-related physiological changes may have some minor effects on the pharmacokinetics of metoprolol, and also that the changes do not lead to significantly altered plasma concentrations compared to those in young individuals.