ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Most of the currently available psychotropic drugs form 1 or more active metabolites duringin vivobiotransformation in humans and/or animals. In some cases these metabolites are rapidly conjugated and excreted, but in others they attain blood and/or brain concentrations within the same range as, or even higher than, those of the parent drug, thus being potential biologically active compounds.The formation of metabolites with their own biological activity in addition to that of the parent compound may result in a complex situation where different chemical species participate in the final effects. These chemical species may have different pharmacokinetic properties of distribution and clearance. They may act by similar mechanisms, by different mechanisms or even antagonistically. The formation of active metabolites may be important not only for the therapeutic outcome but also for explaining the toxicity of particular drugs.The examples given, although limited, provide evidence that studies on drug metabolites are essential for an understanding of the mechanism of action of psychotropic drugs, and for extrapolating pharmacological and toxicological findings from animals to humans. The development of any new psychotropic agent requires knowledge of the pharmacology and toxicology of all active species as well as their pharmacokinetic profile, including the extent to which they reach the central nervous system.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Part I of this article, which appeared in the previous issue of the Journal, covered the physical properties, pharmacology, toxicology and pharmacokinetics of furosemide (frusemide). In part II the authors examine the pharmacodynamics of the drug, and suggest various areas for future study.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Oral contraceptive steroids are used by an estimated 60 to 70 million women worldwide. Over the past 20 years there have been both case reports and clinical studies on the topic of drug interactions with these agents. Some of the interactions are of definite therapeutic relevance, whereas others can be discounted as being of no clinical significance. Pharmacological interactions between oral contraceptive steroids and other compounds may be of 2 kinds: (a) drugs may impair the efficacy of oral contraceptive steroids, leading to breakthrough bleeding and pregnancy (in a few cases, the activity of the contraceptive is enhanced); (b) oral contraceptive steroids may interfere with the metabolism of other drugs.A number of anticonvulsants (phenobarbital, phenytoin, carbamazepine) are enzyme-inducing agents and thereby increase the clearance of the oral contraceptive steroids. Valproic acid has no enzyme-inducing properties, and thus women on this anticonvulsant can rely on their low dose oral contraceptive steroids for contraceptive protection. Researchers are now beginning to unravel the molecular basis of this interaction, with evidence of specific forms of cytochrome P450 (P450IIC and IIIA gene families) being induced by phenobarbital. Rifampicin, the antituberculous drug, also induces a cytochrome P450 which is a product of the P450IIIA gene subfamily. This isozyme is one of the major forms involved in 2-hydroxylation of ethinylestradiol.Broad spectrum antibiotics have been implicated in causing pill failure; case reports document the interaction, and general practitioners are convinced that it is real. The problem remains that there is still no firm clinical pharmacokinetic evidence which indicates that blood concentrations of oral contraceptive steroids are altered by antibiotics. However, perhaps this should not be a surprise, given that the incidence of the interaction may be very low. It is suggested that an individual at risk will have a low bioavailability of ethinylestradiol, a large enterohepatic recirculation and gut flora particularly susceptible to the antibiotic being used.Two drugs, ascorbic acid (vitamin C) and paracetamol (acetaminophen), give rise to increased blood concentrations of ethinylestradiol due to competition for sulphation. The interactions could have some significance to women on oral contraceptive steroids who regularly take high doses of either drug. Although on theoretical grounds adsorbents (e.g. magnesium trisilicate, aluminium hydroxide, activated charcoal and kaolin) could be expected to interfere with oral contraceptive efficacy, there is no firm evidence that this is the case. Similarly, there is no evidence that smoking alters the pharmacokinetics of oral contraceptive steroids.These agents are now well documented as being able to alter the pharmacokinetics of other concomitantly administered drugs. The clearance of a number of benzodiazepines undergoing oxidation (chlordiazepoxide, alprazolam, diazepam) and nitro reduction (nitrazepam), theophylline, prednisolone, caffeine and cyclosporin, is reduced in oral contraceptive steroid users. The clearance of some drugs undergoing glucuronidation (temazepam, salicylic acid, paracetamol, morphine, clofibric acid) is apparently increased.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

This article reports on a study of the disposition of loading doses (1g and 15 mg/kg) of vancomycin given intraperitoneally to 6 patients on continuous ambulatory peritoneal dialysis with Gram-positive peritonitis. Dialysate samples were collected every 30 minutes during the first dwell, and serum samples were collected after the first 5 exchanges and after 7 or 14 days. The dialysate concentration/time data were fitted to a monoexponential curve for 4 patients and to a biexponential curve for 2 others. Dialysis clearance was 0.73 ± 0.04 L/h (1g dose) and 0.70 ± 0.23 L/h (15 mg/kg dose). Total body clearance was 0.51 ± 0.36 L/h. Serum concentrations reached 14 to 18 mg/L (15 mg/kg dose) and 6.75 to 24 mg/L (1g dose) at the end of the first dwell. The half-life of equilibration of vancomycin across the peritoneal membrane was 2.5 ± 2.3 hours. Intraperitoneal loading doses of vancomycin produce concomitant serum concentrations in excess of the minimum inhibitory concentrations for susceptible organisms. Administration on a milligram per kilogram basis produces more consistent serum concentrations than using a standard loading dose which is not based on bodyweight.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The pharmacokinetics of fluconazole given orally (100mg) or intraperitoneally (50 and 150mg) were determined in 15 patients with chronic renal failure who were undergoing continuous ambulatory peritoneal dialysis. The half-life (72 to 85 hours) was intermediate between values obtained in healthy volunteers and in patients with renal insufficiency studied during an interhaemodialysis period. The peritoneal clearance, 0.26 to 0.33 L/h, led to an 18% recovery of administered drug in the dialysates after 48 hours. The peritoneal absorption was slow (time to peak plasma concentration 7 hours) but the peritoneal bioavailability was excellent at 87 ± 5%. The mean concentrations of fluconazole up to 24 hours were 770 and 1900 μg/L after single intraperitoneal doses of 50 and 150mg, respectively. The volume of distribution (40 to 60L) did not differ from that determined in patients with normal renal function. In the case of fungal peritonitis essentially attributed toCandidaspp., a 6-hour intraperitoneal infusion of fluconazole 150mg every 2 days appears to be a good regimen to rapidly exceed minimum inhibitory concentrations and treat infection without risk of systemic dissemination of fungi or toxicity.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS