ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03927.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The responsibility for the regulation of pharmaceuticals is situated within the Pharmaceutical Affairs Bureau (PAB) of the Japanese Ministry of Health and Welfare. The scientific evaluation of the application is undertaken by a series of committees consisting of independent senior members of the medical and scientific community whereas all communication between them and the pharmaceutical company is conducted through PAB offices (Koseisho). As in the U.S., the Japanese drug application covers product quality, safety, and efficacy, but the actual data requirements differ between the two countries. Some of these differences have a basis in Japanese regulations whereas others emulate from demands set by senior members of the medical fraternity who carry great sway in Japan. These cause concern to international pharmaceutical companies since they may require studies to be duplicated with consequent delays. Moves toward the achievement of global harmonization of regulatory requirements with the associated benefits of reducing the numbers of animals sacrificed in the total development program and of important new medications reaching patients earlier are discussed.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03928.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The events in inflammatory and degenerative joint diseases involve major changes in the metabolic events in the articular cartilage. The effects of nonsteroidal anti‐inflammatory drugs (NSAIDs) on articular cartilage metabolism remain unclear, however. The objective of this study was to determine the effect of one commonly used NSAID, naproxen sodium, on the catabolism of proteoglycans in articular cartilage expiants maintained in culture. Release of proteoglycan from the cartilage was compared with release of neutral metalloproteinase activity. The effect of the drug also was determined on the IL‐1‐stimulated release of proteoglycan and neutral metalloproteinase activity from the expiants. At concentrations that included those present in synovial fluids of patients treated with the drug, naproxen sodium was found to suppress the release of proteoglycan and neutral metalloproteinase activity from the articular cartilage extracts. This is in contrast to the well‐documented effect of interleukin‐1 (IL‐1), which was shown to stimulate release of proteoglycan and neutral metalloproteinase activity from articular cartilage. The effect of naproxen sodium on the IL‐1‐stimulated release was to suppress, but not totally overcome, the increased release of proteoglycan and neutral metalloproteinase activity. In summary, these in vitro studies of cartilage metabolism indicate that naproxen sodium has the potential to suppress catabolic activities in articular cartilage, including those that are mo

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03929.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The pharmacodynamics of three corticosteroids were investigated after intravenous administration of the phosphate esters of methylprednisolone, dexamethasone, and triamcinolone acetonide to healthy subjects at 20, 50, and 80 mg as well as placebo. Twenty‐two different pharmacodynamic parameters were followed as a function of time for 48 hours. Statistically significant effects of the glucocorticoids were an increase in blood glucose levels, a decrease in the number of lymphocytes, eosinophils, basophils, and monocytes, and an increase in the number of granulocytes and stab cells. For the most significant pharmacodynamic effects (lymphocytes, granulocytes, and glucose) a previously derived integrated pharmacokinetic/pharmacodynamic model using plasma concentrations, protein‐binding data, and in vitro receptor‐binding affinities was used to predict the pharmacodynamic effect‐time profiles. Good agreement of predicted and measured effects was observed, confirming the validity of the model. The clinical significance of the model was demonstrated by comparison of model‐predicted maintenance doses with empirically determined clinical equivale

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03930.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Benzodiazepines are the most prescribed psychotropic drugs in the world. Comparative international data on benzodiazepine use, specifically among developed and developing countries, are unavailable. To determine the different patterns of benzodiazepine use in two representative countries, use of benzodiazepines in Chile (a developing country) and Canada (a developed country) was undertaken. Wholesale data as provided by the intercontinental Medical statistics and drug import data were used as databases. Data on trends of benzodiazepine use was determined for 5 years using the methodology recommended by the WHO for drug use research, the defined daily dose/1000 inhabitants/day. Total benzodiazepine use was similar in both countries, but Canadian use had increased slowly. Patterns of use, however, differ widely among the two countries. A linear increase of rapidly eliminated benzodiazepines was observed in Canada, whereas the reverse occurs in Chile: the slowly eliminated benzodiazepines are the ones that have increased use. Hypnotic benzodiazepines are used twice as frequently in Canada than in Chile. Striking differences in the use of individual benzodiazepines are observed. Differences in healthcare systems determine wide differences in the way these drugs are prescribed. Demographic characteristics of the two countries also may account for the differences in benzodiazepine use. The authors conclude that, although total benzodiazepine consumption is similar in the two countries, patterns of benzodiazepine use vary widely. The different patterns of use may determine differences in the morbidity rates associated with the use of these drugs.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03931.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Nine healthy subjects received 400 mg sodium valproate orally in the fasting state. Binding parameters of valproic acid to serum proteins were determined by Scatchard analysis for individual series of valproic acid data. Total and unbound (intrinsic) clearances (Cht and CLu) were calculated by dividing the dose by the appropriate area under the serum drug concentration‐time curve. Unbound clearance correlated positively with the product of association constant (Ka) and concentration of free protein ((UP)) (P<.05). Conversely, no significant correlation was found between CLt and binding parameters. The average unbound concentration correlated negatively with both CLu and ka(P) values. The result indicates an effect of CLu on Ka(P) value of valproic aci

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03932.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The metabolic effects of ethanol on treadmill performance were determined in four trained runners. Ethanol in doses of 25 mL in 150 mL of grapefruit juice (total volume) or grapefruit juice was randomly administered 10 minutes before and at 30 minutes of a 60‐minute treadmill run. The speed and grade of the treadmill was adjusted to elicit an average oxygen consumption (VO2) of 80 to 85% of the subjects' VO2max. Three of the four subjects could not complete the treadmill run after the administration of ethanol. Administration of ethanol resulted in significant increases in the heart rate responses to treadmill running above those for the placebo grapefruit treatment. VO2was higher after ethanol administration than the placebo grapefruit juice treatment, but these values were not significant. Blood glucose content rose significantly between 0 and 30 minutes of treadmill running for both the ethanol and placebo grapefruit juice treatments. Between 30 minutes of treadmill running and the termination of the exercise, the blood glucose level decreased significantly by 24% after the second ethanol treatment at 30 minutes of exercise. Plasma fatty acid, triglyceride, creatine phosphokinase, and renin contents followed expected exercise changes. It was concluded that the administration of ethanol adversely influenced treadmill exercise performance by eliciting a hypoglycemic effect between 30 minutes and the termination of the exercis

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03933.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Nifedipine disposition varies among populations. Reports on oral nifedipine pharmacokinetics show that peak plasma levels and AVC values are higher in Mexican and Japanese than in European and North American subjects. Increased nifedipine bioavailability in the nonwhite populations is likely due to nutritional habits. Certain flavonoids that inhibit the first‐pass metabolism of dihydropyridines are present in the diets of both Mexican and Japanese. Differences in phenotypes may play a role in interethnic variabilit

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03934.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The influence of chronic perindopril treatment on digoxin pharmacokinetics was investigated in 10 patients with mild chronic heart failure under stable diuretic and digitalis treatment and normal renal function. Digoxin was administered at a dose of 0.125 mg/day (n = 2) or 0.250 mg/day (n = 8). The 24‐hour steady‐state digoxin profile was assessed before and after concomitant administration of perindopril for 1 month at doses of 2 mg once a day for the first 8 days and 4 mg once a day for the remaining 21 days. Chronic treatment with perindopril produced no significant effect on mean (± standard deviation) digoxin serum area under the curve for 24 hours (17.9 ± 7.4 versus 16.3 ± 4.4 ng/mL · h), peak digoxin concentration (1.3 ± 0.54 versus 1.2 ± 0.36 ng/mL), time to peak concentration (3 versus 4 hours), and apparent oral clearance of digoxin (237.7 ± 109.6 versus 237.4 ± 79.5 mL/min). Clinical and biologic tolerance of perindopril was good throughout the study. Chronic administration of perindopril did not alter steady‐state digoxin kinetics in patients with mild chronic heart failure and normal renal function, indicating that no adaptation of the digoxin dose is required during co‐prescription with perindopril i

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03935.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Parenteral compounds present special drug delivery challenges. This open‐label study evaluated a portable infusion pump as a means to deliver intravenous ciprostene, a stable prostacyclin analog. Ten patients with peripheral vascular disease and claudication received ciprostene (titrated to 120 ng/kg/min) infused over 8 hours 1 day per week for 4 consecutive weeks. Patients successfully maintained the pump strapped to the waist. The mean ± standard deviation delivery error, with volumes of 6 to 10 mL over 8 hours, was −0.895 ± 3.177%. Accordingly, the pump performed well with a potent drug under these clinical conditions. Headache, flushing, and infusion site irritation during infusion were the most frequent side effects. Blood pressure remained unchanged during infusion; however, heart rate increased significantly (P<.05, maximum increase was 13.9 ± 2.1 beats per minute [mean ± standard error of the mean]. Mean (± standard error of the mean) relative claudication times on treadmill remained unchanged; however, absolute claudication times increased (P<.05) from 6.6 ± 1.8 to 10.0 ± 2.2 minutes. Ciprostene inhibited adenosine diphosphate‐induced platelet aggregation by 56.0 ± 12.7% (mean ± standard error of the mean). Mean template bleeding times and plasma concentrations of platelet‐specific proteins (beta‐thromboglobulin, platelet factor

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb03936.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY