International journal of clinical pharmacology, therapy, and toxicology最新文献

The influence of cimetidine on the natriuretic and diuretic responses to furosemide was studied in 10 patients with hepatic cirrhosis. After four days on a low sodium diet, the patients were given 40 mg of furosemide i.v. and from the sixth to the eleventh day they received 400 mg of cimetidine p.o. every 6 h and a second dose of furosemide with the last 6 h dose. Ten healthy subjects received the same dose of furosemide. Multiple blood and urine samples from both groups were analyzed for furosemide, sodium and creatinine. Furosemide kinetics were not affected in patients with hepatic cirrhosis but the effect was lower than in the controls: urinary excretion of sodium (0.47 +/- 0.07 vs 1.59 +/- 0.10 mmol/min, p < 0.05) and urine excretion (4.86 +/- 0.57 vs 9.16 +/- 0.85 ml/min, p < 0.05). The predicted maximal effect of furosemide (Emax) and the furosemide urinary rate of excretion needed to elicit 50% of Emax for the cirrhotic patients and the controls were 1.85 +/- 0.21 and 3.22 +/- 0.41 mmol/min (p < 0.05) and 137 +/- 15 and 99 +/- 12 micrograms/min (p < 0.05), respectively. The amounts of sodium filtered (FNa) and reabsorbed in response to the injection of furosemide were lower in the cirrhotic patients than in the controls, however, relative to the FNa, the cirrhotic patients reabsorbed more sodium than the controls. The administration of cimetidine did not affect the kinetics of furosemide nor its natriuretic or diuretic responses.(ABSTRACT TRUNCATED AT 250 WORDS)

When certain drugs are taken concomitantly with an oral contraceptive, the efficacy of the contraceptive may be obtunded, and pregnancy may ensue. Since the function of oral contraceptives is to suppress ovulation, the risk of ovulation is an important parameter in clinical studies investigating interactions between drugs and oral contraceptives. The purpose of this paper is to compare a crossover design, and a new study design used for assessing a possible interaction between a drug and an oral contraceptive, and to discuss the statistical issues involved in the planning and evaluation of the results of such studies.

Triazolam is an effective hypnotic that can cause amnesia and psychomotor performance decrements, particularly after a 0.5 mg dose. Previous pharmacodynamic studies suggested a relationship between these effects and triazolam plasma concentration. A novel dual release bilayer tablet was designed to mimic the onset of action of a 0.25 mg dose and to maintain the duration of a 0.5 mg dose without the side effects associated with the 0.5 mg dose. The immediate release component of the bilayer tablet contained 0.25 mg triazolam while the sustained release component contained 0.15 mg triazolam. Two prototype formulations of the bilayer tablet, differing in rate of release in the sustained release component, were tested against a conventional 0.5 mg triazolam compressed tablet and placebo in a single-dose, double-blind, four-way crossover study in healthy male subjects. Triazolam plasma concentration time profile was obtained over 12 hours following single administration of each treatment. Effects of triazolam on central nervous system function were evaluated using psychomotor performance tests, immediate and delayed recall tests and rating of sedation. The triazolam plasma concentrations were not significantly different among the active drug treatments, although the dual release tablets did give the expected profiles. There were significant differences in triazolam effects on memory and psychomotor performance. The slowest releasing dual-release tablet showed significantly less psychomotor impairment and memory deficit than the conventional tablet. There was no difference in sedation among the active drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of tobacco has resulted in major health related problems worldwide. Nicotine replacement is one of the most promising strategies in smoking cessation. The in vivo delivery rate and the pharmacokinetic properties of a recently developed transdermal nicotine system (TNS) was investigated in three separate studies. Two sizes (16 cm2 and 24 cm2) of the patches were tested. Mean daily nicotine delivery, expressed by a first order kinetic, varied between 0.9 and 1.0 mg/cm2 patch. The different sizes of the patches led to linearly dose-related nicotine plasma Cmax- and AUC-values. The nicotine levels achieved were in the same range with those of other nicotine patches and the chewing gum. As a result of multiple dose kinetic, no significant accumulation of nicotine was observed. Mean elimination half-life of nicotine after removal of the patches (3.5 +/- 1.8 h for the larger patch and 4.5 +/- 1.9 h for the smaller patch) was longer than reported values after i.v. administration, which was reported to vary between 40 and 120 min.

In the present study, the consumption of several drugs on the territories of the former GDR and FRG was compared using 200,000 prescriptions and the defined daily doses (DDD). Furthermore, for the two parts of Germany, the 20 most frequently prescribed drugs were evaluated. Calcium antagonists and the beta-blockers prevailed in East Germany, while cardiac glycosides, vasodilators, reserpin-containing antihypertensives, bronchodilators (beta-adrenoceptor agonists), neuroleptics, tricyclic antidepressants, antacids, H2-receptor blockers, chondroprotectives were used 1.5 to 5 times more frequently in West Germany. Because in East Germany, a shortage of drugs was no longer observed in 1991, several other reasons for the "over-prescription" of drugs for the patients in West Germany must be mentioned.

A 57-year-old schizoaffective disorder patient was placed on chlorpromazine because of its sedative properties and low profile for extrapyramidal side effects. After two years of treatment, the patient developed photosensitivity and blue-gray pigmentation of the skin of the face, neck and dorsum of hands. Significant pigment deposits were also observed in eye lens and cornea. An oval translucent lesion lateral to the left angle of the mouth was removed and the biopsy showed a basal cell carcinoma. The cutaneous and eye pigmentation were only partially reversible after the discontinuation of chlorpromazine. There has been no recurrence of basal cell carcinoma.

The dextromethorphan (DMP) O-demethylation and the dextrorphan (DRP) glucuronidation distributions were studied in 120 French Caucasian subjects. After a single 25 mg DMP oral administration, DMP, free and total DRP concentrations were measured in 8h-urine collection, using an HPLC technique with fluorescent detection. The DMP and free DRP concentrations ratio, in log form, was used to estimate the oxidative demethylation phenotype of the subjects. Two different populations were found. The first one consisted of the extensive metabolizers (90.8%, 95% confidence interval from 85.6 to 95.9%) and the second one consisted of poor metabolizers (9.2%, 95% confidence interval from 4.0 to 14.4%). The antimode value of the distribution was estimated at approximately 0.7 corresponding to a ratio of 5. Moreover, this ratio was compared to the DMP and total DRP concentrations ratio, usually defined to DMP O-demethylation phenotyping. On the other hand, the glucuronide DRP concentration was calculated by subtracting the free DRP concentration from the total DRP concentration. Consequently, the free DRP and glucuronide DRP concentrations ratio was also used to estimate the DRP glucuronidation in the present population. This ratio in log form reflected the UDP-glucuronyltransferase(s) capacity(ies). This log ratio appeared to be normally distributed in the population studied. These results show that log DMP/free DRP ratio can be used, as well as log DMP/total DRP ratio, to determine the oxidative phenotype of subjects and that the DRP conjugation does not exhibit any apparent genetic polymorphism.

A single dose comparative bioavailability study and an in vitro evaluation were conducted on two sustained-release formulations of diclofenac sodium (Voltaren "V" and Diclogesic "D"). The two products were found similar in weight and content uniformity. The in vitro dissolution, however, revealed that product D has a significantly faster rate of drug release compared to product V. The bioavailability study was carried out on 15 healthy male volunteers, who received a single oral dose (100 mg tablet) of each product according to a randomized crossover design. Blood samples were obtained over a 12 h period, and drug concentrations were determined by an HPLC assay. The two products were not found to be statistically different with respect to the lag time between dosing and appearance of the drug in the serum (0.8 +/- 0.2 and 0.6 +/- 0.1 h for V and D, respectively), or in the time needed to attain the peak concentrations (4.5 +/- 0.8 and 4.1 +/- 0.9 h for V and D, respectively). The two products, however, varied in the peak serum concentration (736 +/- 125 and 536 +/- 63 ng.ml-1 for V and D, respectively), but this difference was not statistically significance. In terms of the extent of absorption, assessed by estimating the area under the concentration-time curve over 12 h, the two products were not significantly different (3,340 +/- 270 and 3,045 +/- 294 ng.h.ml-1 for V and D, respectively). These in vitro and in vivo findings indicate that Diclogesic is characterized by sustained-release properties which are comparable to Voltaren.

A comparative study between two dopaminergic antagonists: metoclopramide and domperidone, was undertaken in nineteen (19) hypertensive patients at the Vargas Hospital, Caracas. The patients were pretreated with labetalol, 800-1,200 mg/day, orally, over a period of one week, after which they were divided into two groups: group A, a total of eleven patients were intravenously infused with dopamine hydrochloride 0.5-3 micrograms/kg/min, before and after treatment with metoclopramide (10 mg, i.v. as a bolus); group B (n = 8), was pretreated with domperidone, 20 mg b.i.d., p.o. over a period of one week and intravenously infused with dopamine hydrochloride, 0.5-3 micrograms/kg/min. In group A, dopamine induced a decrease of blood pressure from 171.9 +/- 6.35/103.6 +/- 3.12 to 152.7 +/- 7.55/93.8 +/- 2.97 mmHg (p < 0.001) without altering heart rate, and it increased plasma insulin levels from 8.29 +/- 0.70 microunits/ml to 12.09 +/- 1.83 microunits/ml (p < 0.01). Metoclopramide caused no changes of blood pressure or plasma insulin levels. However, hypotensive responses and plasma insulin rises due to dopamine were blocked by metoclopramide. In group B, domperidone also blocked dopamine-induced antihypertensive effect (from 170.0 +/- 9.23/102.8 +/- 3.80 to 160.2 +/- 9.84/95.5 +/- 2.50 mmHg) although it was less effective than metoclopramide. Domperidone also blocked dopamine-induced increase of plasma insulin levels from 9.65 +/- 4.50 microunits/ml to 11.78 microunits/ml. We conclude that a dopaminergic receptor may be involved in some cardiovascular responses and in modulating insulin secretion in man.

Ataprost alfadex [5(E),-6,9-deoxa-6,9 alpha-methylene-15-cyclopentyl-16,17,18,19,20-pentanor- PGI2 alpha-cyclodextrin clathrate] is a novel PGI2 derivative. From animal studies, it is expected to be a more potent inhibitor of platelet aggregation and less hypotensive than PGI2. The pharmacokinetics of ataprost were studied in 9 healthy male volunteers during and after i.v. infusion for 2 hours at the rates of 2.5 (n = 5) and 10 ng/kg/min (n = 4). Both treatments were well tolerated by the subjects. At the end of the infusion, plasma levels of 191 +/- 76 (mean +/- SD) and 645 +/- 191 pg/ml were reached, declining rapidly with half-lives of 6.7 +/- 3.0 and 5.5 +/- 0.84 minutes at the lower and higher infusion rates, respectively. The area under the plasma concentration-time curve extrapolated to infinity increased with the dose as follows: 28.7 +/- 9.8 and 80.9 +/- 24.8 ng.min/ml. The unchanged drug was not detected in urine but a metabolite was recovered in it, reaching up to 6.0 +/- 0.85% of the total dose within the first 24 hours, the most part of which was recovered within the first 4 hours.