摘要:

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p > 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p > 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p 0.05). We conclude from these new observations that the KC-induced decrease in CsA C1(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5–10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of Cs

ISSN:0031-7012    

DOI:10.1159/000138850

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The influence of the mode of intravenous (i.v.) administration (bolus injection or continuous infusion) on the tissue penetration of ceftazidime was studied in the rat. The antibiotic concentration was monitored in serum, pleural exudate, vitreous humor, kidney, liver, lung, testicles and epididymal fat tissue. Administration as a bolus resulted in a significantly higher AUC in pleural exudate and in higher peak levels in serum, liver and lung than continuous infusion, which produced a higher peak concentration in kidney than a bolus. No differences in AUC and peak concentrations between the two methods of administration were observed in the other tissues or fluids. With either method of administration the highest antibiotic accumulation was observed in kidney.

ISSN:0031-7012    

DOI:10.1159/000138851

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Rilopirox is a synthetic, fungicidal antimycotic agent with hydrophobic characteristics. Its chemical name is 6-[4-(4-chlorophenoxy)-phenoxymethyl]-1-hydroxy-4-methyl-2-pyridone and it has a molecular weight of 357.79. Rilopirox is very soluble in dimethyl sulfoxide (DMSO) and dimethylformamide (DMF) but poorly soluble in water. The amount of antimycotic agent remaining in the solution is dependent on the final concentration of the solvent and the amount of rilopirox used. Complexometric studies show that rilopirox has a high affinity for iron ions [unpubl. data]. Catalase, an iron-containing enzyme, is inhibited by the chelating agent rilopirox. Studies on yeast mitochondria and submitochondrial particles show that rilopirox inhibits the respiratory chain. Complex I (NADH-ubiquinone oxidoreductase) contains iron-sulfur proteins and is the main system which is inhibited.

ISSN:0031-7012    

DOI:10.1159/000138852

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The analgesic and thermic responses to morphine (5 and 10 mg/kg) injected intravenously to 8- and 24-week-old male Sprague-Dawley rats were determined. Greater analgesic and lower hyperthermic responses to morphine in 24-week-old rats in comparison to 8-week-old rats were observed. The pharmacokinetic parameters of morphine administered intravenously were also determined. Cmax for 5 and 10 mg/kg doses of morphine were smaller in 24-week-old rats in comparison to 8-week-old rats; however, AUC0→∞ was smaller only for 5 mg/kg dose. For 10 mg/kg dose, mean residence time (MRT) and the apparent steady state volume of distribution (Vss) for the older rats were higher than for the younger ones, but for 5 mg/kg dose the values did not differ. The enhanced responses to morphine in older age group of rats for 5 mg/kg dose cannot be explained solely on the basis of pharmacokinetics. However, for 10 mg/kg dose of morphine, the greater responses in 24-week-old rats could probably be related to increases in MRT and Vss. Factors other than serum kinetics, like kinetics of morphine in the brain as well as the brain opiate receptors, may also be involved in the differential effects of morphine in rats of different a

ISSN:0031-7012    

DOI:10.1159/000138853

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Serotonergic receptors are involved in many vascular functions, but only a few studies have been made in human vessels. Thus, this study aimed to characterize these receptors in the human uterine artery without endothelium. The pD2 value of serotonin (5-HT) was 5.96, but the intrinsic activity was 59% of that of noradrenaline. Spiperone and ketanserin shifted the concentration-response curves of 5-HT to the right (pA2 = 8.56 and 9.76; slopes = 0.98 and 0.83, respectively). Propranolol, yohimbine, prazosin and atropine did not significantly shift the concentration-response curves to 5-HT. Phentolamine inhibited the 5-HT response (pA2 = 6.69), and previous treatment of the vascular strips with 6-hydroxydopamine only partially reduced such an effect. The results demonstrate the existence, in the human uterine artery, of 5-HT2 receptors which are blocked by high concentrations of phentolamine. In this tissue, 5-HT does not release noradrenaline from perivascular nerves.

ISSN:0031-7012    

DOI:10.1159/000138854

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The in vitro effects of a calcium channel antagonist (nifedipine) and agonist (BAY K8644) on the neurogenic responses of the streptozotocin-induced diabetic rat bladder were investigated. The bladder body and bladder base were studied separately. There were no significant differences in neurogenic responses in diabetic bladder body compared to control body, but the diabetic bladder base demonstrated an increased contractile response at each frequency compared to control base. The rate of contractile response was similar in controls and diabetics but was significantly different between body and base. Although declining with time, contractile responses in the diabetic bladder body and base were increased from control in the absence of extracellular calcium. Differences were found in effects upon maximum responses between diabetic and control tissues treated with nifedipine and BAY K8644. BAY K8644 did not completely reverse the effect of nifedipine on the neurogenic responses in the diabetic bladder body. Effects of diabetes on the bladder body and base are associated with changes in calcium channel activity of bladder smooth muscle.

ISSN:0031-7012    

DOI:10.1159/000138855

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The influence of dietary sodium and saralasin on the natriuretic and diuretic response to furosemide (5 mg/kg i.v.) was studied in three groups of conscious rabbits maintained for 4 weeks on either a normal sodium diet (NSD), or a low sodium diet (LSD) or a high sodium diet (HSD). Neither the sodium content in the diet nor saralasin affected glomerular filtration rate or renal plasma flow. Compared to the NSD, an LSD did not affect the furosemide-induced increment in urinary excretion of sodium (dUNaV) but increased the increment in urinary excretion (dUV) (p < 0.05). An HSD reduced the furosemide-induced dUNaV and dUV (p < 0.05). Plasma renin activity (PRA) increased following furosemide administration in animals on an NSD and an LSD, but not in those on an HSD. Independent of diet, a positive correlation occurred between the increment in PRA and the dUNaV (p < 0.001). Saralasin increased PRA and decreased baseline urinary excretion of sodium (UNaV). In addition, in rabbits on an LSD, saralasin reduced the furosemide-induced dUNaV and dUV by 34 and 27% (p < 0.05), respectively. It is concluded that furosemide-induced diuresis is increased in rabbits on an LSD and decreased in rabbits on an HSD. In animals on an LSD, the increase in furosemide response appears to be associated with changes in the activity of the renin-angiotensin system and in rabbits on an HSD, the decrease in furosemide effect is probably the net result of several factors.

ISSN:0031-7012    

DOI:10.1159/000138856

出版商:S. Karger AG    

年代:1991

数据来源: Karger

ISSN:0031-7012    

DOI:10.1159/000138857

出版商:S. Karger AG    

年代:1991

数据来源: Karger