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1.
Summary Using a double blind, double dummy crossover design, single dose and steady state pharmacokinetics of oral controlled release (SCR) salbutamol 4 mg and 8 mg tablets b. d. has been studied in 8 Asian patients.Plasma salbutamol was measured over 12 h. In 8 patients the single dose mean Cmax was 4.2 ng·ml–1 and 7.7 ng·ml–1 after 4 and 8 mg, respectively. In 5 patients the steady state mean Cmax, Cmin and tmax were 8.1 ng·ml–1 and 4.7 ng·ml–1 and 6 h for the 4 mg tablets and 14.1 ng·ml–1 and 7.1 ng·ml–1 and 4 h for the 8 mg tablets.It is concluded that both doses of SCR show features of controlled release and that they produced a relatively constant plasma level of salbutamol in Asian patients.  相似文献   

2.
Summary Transcutaneous oxygen pressure (tcPo2), laser Doppler flux and capillary microscopy have been used to examine the forefoot skin in 5 healthy men and 8 patients with severe peripheral arterial occlusive disease in order to evaluate the dose dependent effects of iloprost on skin microcirculation. Iloprost was infused IV starting at 0.0625 ng·kg–1·min–1 and doubling the dose every 15 min up to 2 ng·kg–1·min–1.While tcPo2 at an electrode core temperature of 44°C decreased in both patients and controls, there was a significant dose dependent increase in tcPo2 (37°C) in the controls from 0.25 ng·kg–1·min–1. In the patients the reaction was variable: it was decreased in two and increased in 6, with a maximum either at 0.25–0.5 ng·kg–1·min–1 (n=3) or at the highest dose (1.0 or 2.0 ng·kg–1·min–1; n=3). Mean laser Doppler flux in both groups was increased, although the reaction was not consistent in the patients. Density of forefoot skin capillaries was reduced in 3 patients, and in the others the flow velocity was very low. During infusion of iloprost, both an increase in capillary density and blood cell velocity were observed. The effects were of variable intensity and occurred at varying doses, some appeared early and diminished as the dose was increased, and others were found only at 2 ng·kg–1·min–1.Adverse effects were numerous, extending from harmless skin flushing to mental changes and a quickly reversible attack of angina pectoris. It may be possible to divide patients into those with early effects on the microcirculation, at doses of 0.25–0.5 ng·kg–1·min–1, and those in whom the microcirculatory response is preceded and counteracted by the adverse effects.  相似文献   

3.
Summary We have studied the transfer of the analgesic ketorolac tromethamine into breast milk in ten women aged between 22 and 35 years. Ketorolac administration was started between 2 and 6 days after delivery. The breast milk was not fed to the infant because of maternal antibiotic use (6 patients) or because of jaundice of the baby.10 mg of ketorolac was given four times daily for two days. Plasma and milk samples were collected on the two dosing days and on the first day after dosing. The plasma and milk were assayed for ketorolac concentrations by HPLC; the quantification limits were 10 ng·ml–1 and 5 ng·ml–1 respectively.The maternal plasma concentrations were within established ranges for ketorolac. In four patients the concentration of ketorolac in the milk was never above 5 ng·ml–1. At 2 h after dosing on both Days 1 and 2 there were quantifiable concentrations of ketorolac in the milk. The range was 5.2 ng·ml–1 to 7.9 ng·ml–1. The ratio of breast milk: plasma concentrations of ketorolac ranged from 0.015 to 0.037.The maximum potential amount of ketorolac that an infant may be exposed to daily could range from 3.16 mg to 7.9 mg, assuming a consumption of between 400 ml and 1 l of breast milk. On a weight-adjusted basis this is equivalent to between 0.16% and 0.40% of the total daily maternal dose.Klinikum der Stadt Mannheim, Gynaecological Clinic, Mannheim, (until 1986: Krankenanstalt Rotes Kreuz, Munich)  相似文献   

4.
Summary Twelve hypertensive patients (WHO Stage I-II) were given oral verapamil (Isoptin) b.d. or t.d.s. as long-term treatment. The pharmacokinetics of verapamil and norverapamil were studied both after single and b.d. and t.d.s. doses of verapamil 240, 360 or 480 mg daily adjusted according to the blood pressure response. The apparent oral clearance of verapamil was decreased after both the twice and thrice daily dosage regimens (1.38 and 1.841/min, respectively) as compared to the single dose (4.39 l/min). The plasma half-life of verapamil was increased from 3.34 h (single dose) to 4.65 h (b.i.d.). Decreased elimination of norverapamil was also found after multiple doses of verapamil, as shown by an increase in the adjusted AUC of norverapamil (adjusted to a verapamil dose of 80 mg), namely from 574.9 h·ng·ml–1 (single dose) to 1172 h·ng·ml–1 (b.d.) and to 841 h·ng·ml–1 (t.d.s.). The plasma half-life of norverapamil increase from 5.68 h to 7.34 h during twice daily dosing. During thrice daily verapamil, no increase in plasma half-life was found either for verapamil or norverapamil, probably due to the relatively short sampling time (6 h). The plasma concentration of verapamil and the reduction in supine systolic and diastolic blood pressure were correlated. The mean decrease in supine systolic blood pressure was 5.8 mm Hg per 100 ng verapamil/ml plasma, and for diastolic pressure 2.9 mm Hg per 100 ng verapamil/ml plasma. The mean steadystate plasma concentrations of verapamil were similar after twice and thrice daily dosing regimens, which agrees with the clinical observation that blood pressure control in hypertensive patients is as good after verapamil b.d. and t.d.s.  相似文献   

5.
447C88 (N-Heptyl-N-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA:Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng·ml–1 (23 nM). It is poorly absorbed but 5 mg·kg–1·day–1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats.In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n+8) or placebo (n+4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n+8) or placebo (n+6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food.All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng·ml–1 and 9.0 ng·ml–1·h after 200 mg rising to 5.4 ng·ml–1 and 23.8 ng·ml–1·h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.  相似文献   

6.
Summary Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng·ml–1 to 170 ng·ml–1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng·ml–1 before to 336 ng·ml–1.Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitve inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.  相似文献   

7.
Summary As the pharmacokinetics of a drug may be altered in haemodynamically compromised patients, the plasma concentrations and haemodynamic effects of the calcium entry blocker nimodipine have been examined in patients resuscitated after out-of-hospital cardiac arrest.In 7 patients nimodipine was infused at increasing rates up to 30 µg·kg–1·h–1. The plasma concentrations increased with increasing dose; at the highest dose a mean steady-state plasma concentration of 22.1 ng·ml–1 was obtained, and the mean plasma clearance was 1.4 l·kg–1·h–1. There were no marked changes in mean arterial blood pressure or heart rate.In 9 other patients nimodipine was given as a bolus infusion of 10 µg·kg–1 over 3 min, followed by a continuous infusion of 30 µg·kg–1·h–1. A mean steady-state plasma concentration of 17.6 ng·ml–1 was obtained and the mean plasma clearance was 1.9 l·kg–1·h–1. Heart rate did not change significantly, but the mean arterial blood pressure fell.The data indicate that in patients resuscitated after cardiac arrest, the pharmacokinetics of nimodipine are not markedly different from patients with other conditions, e.g. subarachnoid haemorrhage. However, if a loading dose is given to obtain a steady-state concentration sooner, there will be a fall in arterial blood pressure.  相似文献   

8.
Summary The pharmacokinetics and pharmacodynamics of thiazinamium (Multergan) were studied after intravenous and intramuscular administration to 7 males with chronic reversible airways obstruction.Disposition after i.v. administration was described by a clearance of 0.54 l·min–1, central compartment volume of 14.8 l, distribution rate constant 0.092 min–1, and an elimination rate constant of 0.0044 min–1. The corresponding estimates after i.m. administration were 0.324 l·min–1, 34.1 l, 0.035 min–1, and 0.0018 min–1. The bronchodilator response (expressed as % predicted FEV1) after i.v. administration was characterized by maximum increase in FEV1 of 33.9%, with an EC50 of 12.8 ng·ml–1 and an equilibration half-time of 11 min. Corresponding parameter estimates after i.m. administration were 32.2%, 18.8 ng·ml–1, and 9 min.Anticholinergic activity, measured by the change in heart rate after i.v. administration, showed maximum increase of 76 beats·min–1, with an EC50 of 176 ng·ml–1 and an equilibration half-time of 1.3 min. After i.m. administration the corresponding values were 120 beats·min–1, 250 ng·ml–1, and 3 min.The optimal plasma concentration of thiazinamium was about 100 ng·ml–1, which should give a near maximal bronchodilator response (over 80% of predicted normal) and a heart rate of about 100 beats·min–1.  相似文献   

9.
The aim of this study was to evaluate the effects of the new anti-allergic drug, N-acetyl-aspartyl-glutamate (ZY15106), on allergen-induced nasal symptoms and mediator release. Fifteen outpatients suffering from seasonal allergic rhinitis due to grass pollen were included in the study. A nasal antigen challenge followed by evaluation of symptoms was performed in basal conditions. Ten of the 15 patients underwent sequential nasal lavages in order to evaluate allergen-induced mediator release. The study was performed in winter, when the patients were symptom free, and was a randomized single-blind crossover trial of a 6 % solution of ZY15106 (daily dosage: 48 mg) versus placebo (lactose). The drug and the placebo were administered intranasally q.i.d. for 1 week, with a 2-week interval between the two treatments. Treatment with ZY15106, but not with placebo, caused a significant reduction in nasal obstruction in the first 30 min after challenge and at 60 min and itching in the first 10 min after challenge, but did not reduce sneezing and rhinorrhoea. Moreover, ZY15106 significantly reduced the histamine release in 5 min postchallenge lavage (4.5 ng·ml–1 after placebo administration vs 2.5 ng·ml–1, after treatment with ZY15106). A reduction in immunoreactive LTC4 release in the 5 and 10 min post-challenge lavages was observed after ZY15106 administration (placebo vs active treatment: at 5 min 2.9 ng·ml–1 vs 1.4 ng·ml–1; at 10 min: 2.25 ng·ml–1 vs 0.9 ng·ml–1). These results indicate that 1-week treatment with ZY15106 can reduce antigen-induced nasal obstruction and itching, and mediator release in human nasal airways. The clinical activity of ZY15106 in the treatment of allergic rhinitis may be related to its ability to inhibit mediator release.  相似文献   

10.
Summary The total and free steady-state plasma levels of nifedipine in patients with renal failure have been compared with those in subjects with normal renal function. Studies were done after administration of nifedipine 10 mg t.d.s. p.o. for 5 days, after i.v. infusion of 4·4 mg, and after a single 10 mg oral dose.The systemic clearance of nifedipine after a single i.v.-dose was higher in subjects with renal insufficiency (854 ml/min) than in those with normal renal function (468 ml/min). After the single oral dose the AUC (6100 ng·min·ml–1) and maximum plasma concentration (75.0 ng·ml–1) were lower than in subjects with normal renal function (19300 ng·ml–1; 122 ng·ml–1). The plasma protein binding of nifedipine averaged 95.5% in normal subjects and 94.8% in patients with renal failure.Although free and total steady-state plasma levels of nifedipine tended to be somewhat lower than normal in renal failure, the changes in pharmacokinetics and decreased protein binding of nifedipine did not result in a significantly different steady-state plasma level of the drug. The blood pressure response to a given plasma nifedipine level appeared to be enhanced in renal failure.  相似文献   

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