摘要:

We investigated the effect of pretreatment with a prostaglandin synthetase inhibitor, ibuprofen, on the pharmacokinetics and pharmacodynamics of ethanol in six fasting subjects. Ibuprofen caused a 10% decrease in the maximum rate of elimination of ethanol. Visual memory, which is a function primarily mediated by the right cerebral hemisphere, was measured by the Benton Visual Retention test and was more impaired during combined ibuprofen and ethanol dosing than during ethanol dosing alone (P = 0.05). The auditory‐verbal memory of the subjects, which is primarily a function of the left cerebral hemisphere, was assessed by the Selective Reminding Test and showed decreased impairment during combined ibuprofen and ethanol dosing as compared with ethanol dosing alone (P = 0.04). The opposite effect of ibuprofen on ethanol‐induced cognitive impairment as measured by two lateralized functions is consistent with the reports in tissue and animal models that central nervous system effects of ethanol may be mediated at least in part by prostaglandins.Clinical Pharmacology and Therapeutics(1986)39,123–127; doi:10.1038/clpt.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.22

年代:1986

数据来源: WILEY

摘要:

We measured systemic hemodynamics, regional blood flow, and neurohormonal parameters in 13 patients with severe chronic congestive heart failure before and after 1 month of therapy with oral milrinone, a bipyridine cardiotonic agent. After milrinone there were significant reductions in pulmonary wedge pressure (27 ± 2 to 19 ± 3 mm Hg; P<0.02) and systemic vascular resistance (1866 ± 152 to 1393 ± 93 dyne · sec/cm5; P<0.05) that were associated with increases in cardiac index (1.85 ± 0.15 to 2.47 ± 0.20 L/min/m2; P<0.02). There was a marked improvement in forearm blood flow (1.98 ± 0.14 to 3.02 ± 0.16 ml/min/dl; P<0.01) and a reduction in forearm vascular resistance (45 ± 3 to 30 ± 3 U; P<0.01). Overall there was no significant change in renal blow flow, renal vascular resistance, or glomerular filtration rate. However, there was a heterogeneous response of renal blood flow and glomerular filtration rate, such that both were directly correlated with the magnitude of increase of cardiac index (r = 0.587 [P<0.05] and r = 0.721 [P<0.01], respectively). After milrinone there were no significant overall or subgroup changes in urinary sodium excretion, blood volume, plasma renin activity, urinary aldosterone levels, plasma or platelet vasopressin levels, or plasma norepinephrine levels. Thus 1 month of therapy with milrinone improves systemic and forearm hemodynamics, but its effects on renal blood flow and function were heterogeneous. These heterogeneous effects on regional blood flow may depend on the relative vasodilator and inotropic effects of milrinone.Clinical Pharmacology and Therapeutics(1986)39,128–135; doi:10.1038

ISSN:0009-9236    

DOI:10.1038/clpt.1986.23

年代:1986

数据来源: WILEY

摘要:

Pharmacokinetic studies were performed in 51 patients who received cisplatin infusions. Two treatment regimens (single‐day or daily for 5 days) and three infusion schedules (for 4 to 15 minutes, 2 to 3 hours, or 24 hours) were used. The daily dose of cisplatin varied from 20 to 120 mg/m2. The kinetics of total platinum studied up to day 5 revealed differences only during the initial period after the infusion. Peak levels were both dose and schedule dependent and initial t½values in the decay curves were only schedule dependent (mean values: 13 minutes for rapid infusions, 40.3 minutes for 2 to 3–hour infusions, and 220.5 minutes for 24‐hour infusion). The t½values between days 1 and 5 were neither dose nor schedule dependent (mean 5.0 to 7.3 days). Concentrations of free platinum declined biexponentially after the rapid and 2 to 3–hour infusions, but they declined monoexponentially after 24‐hour infusions. Final t½values ranged from 26.0 to 78.8 minutes. In patients with normal renal and hepatic function, the free platinum AUC was identical for cisplatin infusions of different duration when equal doses were given. Free platinum clearance correlated with creatinine clearance (P = 0.017). The uptake of platinum in red blood cells was rapid, and peak concentrations correlated with the free platinum AUC (P = 0.0006), independent of the infusion schedule. The decay of platinum levels in red blood cells was biphasic. The mean terminal t½for the interval between days 5 and 15 was 29.8 days. This suggests a breakdown of red blood cells that results from cisplatin dosing.Clinical Pharmacology and Therapeutics(1986)39,136–144; doi:10.1

ISSN:0009-9236    

DOI:10.1038/clpt.1986.24

年代:1986

数据来源: WILEY

摘要:

The pharmacokinetics and pharmacodynamics of BM 13.177 were investigated in eight healthy men who received a single oral dose of 800 mg on the first day and seven equal doses in 8‐hour intervals on the second to fourth days. Pharmacodynamic effects were measured ex vivo by the testing of platelet functions such as shape change, aggregation, and [3H] serotonin release. The maximum serum concentration of 6.6 or 6.7 mg/L was achieved within 1.6 hours after the first dose and within 1.5 hours after multiple doses, respectively. Afterwards, BM 13.177 was eliminated in urine with a terminal elimination t½of 0.84 or 1.0 hours after single and multiple dosing, respectively. The inhibition of platelet function showed the same close correlation with the serum concentrations of BM 13.177 after single and after multiple doses. Apparently, BM 13.177 induces neither refractoriness to BM 13.177 nor desensitization of the platelet thromboxane receptor. Because BM 13.177 was also well tolerated without subjective or objective side effects, this drug appears to be useful in evaluating the clinical benefit of thromboxane receptor blockade.Clinical Pharmacology and Therapeutics(1986)39,145–150; doi:10.1038/clpt.19

ISSN:0009-9236    

DOI:10.1038/clpt.1986.25

年代:1986

数据来源: WILEY

摘要:

Recent studies have demonstrated a cytoprotective effect of sucralfate on gastric mucosa in patients receiving aspirin. The potential drug interaction between sucralfate and aspirin was evaluated in a randomized crossover manner in 12 healthy men. Subjects were initially given a single dose of aspirin alone or in combination with sucralfate for 2 days. The drug dosing schedule was then reversed after 1 week. Sixteen blood samples were drawn after each aspirin dose for HPLC assay of aspirin and its metabolites. Pharmacokinetic parameters were calculated for aspirin, salicylic acid, and salicyluric acid. None of these parameters demonstrated any statistically significant differences between the two treatment groups. The combined use of sucralfate and aspirin is therefore not likely to result in a clinically significant pharmacokinetic drug interaction. The systemic therapeutic effect of aspirin is not expected to be altered when sucralfate is used concurrently in patients receiving chronic aspirin therapy.Clinical Pharmacology and Therapeutics(1986)39,151–155; doi:10.1038/clpt.1986.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.26

年代:1986

数据来源: WILEY

摘要:

The analgesic and antidepressive effects of amitriptyline (AT) in relation to its kinetics and metabolism were studied in 19 outpatients with chronic pain who received a daily dose of 75 mg AT for at least 6 weeks. Riboflavin was added to the medication to check compliance. On days 0, 4, and 8 and weeks 3, 6, 9, and 12 after the start of dosing, blood samples were drawn from the patients 10 ± 1 hours after the first morning dose and a sample of the first morning urine was taken to check riboflavin. Serum levels of AT and its metabolites, especially nortriptyline (NT) andE‐10‐hydroxy‐nortriptyline (E‐10‐OH‐NT), were measured by HPLC. On day 0 and at 3, 6, and 12 weeks the severity of depression was scored by means of a self‐rating depression scale and pain intensity scores were measured. In addition, after 6 weeks of dosing patients estimated their percentage of pain in comparison with baseline. Mean (± SD) steady‐state concentrations of AT, NT, and E‐10‐OH‐NT were 36 ± 23.5, 28 ± 14.9, and 52 ± 23.7 μg/L, respectively, in male patients (n = 8; age 45 ± 7.4 years) and 34 ± 14.6,45 ± 25.1, and 40 ±15.6 μg/L, respectively, in female patients (n = 11; age 46 ± 6.8 years). There was a significant sex‐related difference in the NT/AT ratio, which was higher in women. After 6 weeks of treatment, neither the improvement in the depression score nor the improvement in pain intensity score in comparison with baseline scores correlated significantly with steady‐state levels of AT, NT, and E‐10‐OH‐NT and the NT/AT ratio.Clinical Pharmacology and Therapeuti

ISSN:0009-9236    

DOI:10.1038/clpt.1986.27

年代:1986

数据来源: WILEY

摘要:

Prednisolone pharmacokinetics were compared in seven patients with asthma managed by alternate‐day prednisone therapy and in seven patients with asthma requiring daily doses of prednisone. Steroid requirements of these patients were carefully characterized and had been stable for at least 12 months. Prednisolone volume of distribution, elimination clearance, and elimination t½averaged 0.606 ± 0.061 and 0.553 ± 0.162 L/kg, 2.28 ± 0.43 and 1.93 ± 0.54 ml/min/kg, and 204 ± 44 and 214 ± 19 minutes in patients receiving alternate‐day or daily prednisone therapy, respectively. These results indicate that differences in these pharmacokinetic parameters do not account for the well‐established clinical observation that some patients require daily prednisone doses and that their disease cannot be managed with alternate‐day steroid therapy.Clinical Pharmacology and Therapeutics(1986)39,163–168; doi:10.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.28

年代:1986

数据来源: WILEY

摘要:

Central α2‐adrenoceptor stimulation decreases blood pressure, whereas stimulation of postjunctional peripheral adrenoceptors induces a pressor response. The net blood pressure response during multiple dosing is the sum of these effects and is dependent on drug kinetics, receptor affinity, and receptor occupancy. Guanfacine (2 to 6 mg/day), a selective α2‐adrenoceptor agonist, decreased blood pressure in patients with hypertension. At a dose>6 mg/day the antihypertensive response deteriorated. Steady‐state kinetics were linear but there was a tendency for a decrease in clearance after the highest dose. These results have practical implications for the therapeutic handling of the drug: Low doses for maximal therapeutic effect and longer dosage intervals at high‐dosage schedules are indicated.Clinical Pharmacology and Therapeutics(1986)39,169–172; doi:10.1038/

ISSN:0009-9236    

DOI:10.1038/clpt.1986.29

年代:1986

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1986)39,173–174; doi:10.1038/clpt.1986.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.30

年代:1986

数据来源: WILEY

摘要:

Clinical Pharmacology and Therapeutics(1986)39,175–175; doi:10.1038/clpt.1986.

ISSN:0009-9236    

DOI:10.1038/clpt.1986.31

年代:1986

数据来源: WILEY