ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Drug treatment of gastrointestinal diseases, which was previously limited to the use of antacids, anticholinergics, antispasmodics, cathartics and laxatives, has changed markedly over the past decade. Histamine H2-receptor antagonists (e.g. cimetidine, ranitidine and more recently famotidine and nizatidine) have revolutionised the treatment of peptic acid disorders, but their role is currently challenged by muscarinic-M1-receptor antagonists (e.g. pirenzepine), proton pump inhibitors (e.g. omeprazole), prostaglandin analogues and site-protective drugs (e.g. colloidal bismuth subcitrate and sucralfate). Newer antiemetics with prokinetic properties (e.g. metoclopramide, domperidone and cisapride) have also been introduced in the management of gastrointestinal motility disturbances, and new anti-inflammatory salicylates (e.g. olsalazine and mesalazine) have been developed for the treatment of chronic inflammatory bowel diseases. Finally, diphenoxylate and loperamide have gained wide clinical application as nonspecific antidiarrhoeal agents. The basic pharmacokinetic properties of the above agents are briefly reviewed with the main emphasis on the newer and more important drugs in current use. Furthermore, the effects of age and disease on pharmacokinetics, in addition to drug interaction potentials and pharmacokinetic-pharmacodynamic relationships, are discussed.The anti-inflammatory salicylates, nonspecific antidiarrhoeal agents, laxatives and cathartics will be dealt with in Part II.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Since many patients with a wide variety of diseases are nowadays stimulated to adopt a physically active lifestyle, the question of the influence of exercise on the pharmacokinetics of drugs has become more and more relevant. Because exercise influences a large number of physiological factors that also determine the pharmacokinetics of drugs, including haemodynamics, metabolism, pH, temperature and gastrointestinal function, it can be expected to have an effect on the pharmacokinetic parameters (absorption, distribution, elimination) of certain agents. However, only a very limited number of studies has been directed towards this issue, and only a very few drugs have been studied. Nevertheless, it is clear that exercise does influence the pharmacokinetics of certain drugs, although the magnitude and direction of the effects vary. This is not surprising in view of the widely differing physicochemical properties of drugs, the many possible - often opposing - effects of exercise on the parameters affecting drug pharmacokinetics and the different types of exercise performed.The chance of a clinically relevant effect of exercise on the pharmacokinetics of a particular drug is largest in those with a steep dose-response curve, a narrow therapeutic range, a need for continuity of therapeutic effectiveness and a relatively short half-life, in combination with intensive exercise of long duration.If untoward drug effects occur during or after exercise, a change in the pharmacokinetics of the drug related to the exercise should be seriously considered as a possible cause.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Drug interactions with this class of compounds are frequently reported and can be pharmacokinetic and/or pharmacodynamic in nature. The pharmacokinetic interactions can be divided into 3 classes: (1) drugs affecting the pharmacokinetics of an NSAID, (2) an NSAID interfering with the pharmacokinetics of another NSAID and (3) NSAIDs altering the pharmacokinetics of another drug.Although the pharmacokinetics of some NSAIDs may be significantly affected by the concurrent administration of certain other drugs (including other NSAIDs), this type of interaction only occasionally leads to serious complications. Concurrent administration of antacids or sucralfate may delay the rate of oral absorption of NSAIDs but generally has little effect on the extent. Use of antacids increases urinary pH, leading to increased renal excretion of unchanged salicylic acid and decreased plasma concentrations of this antirheumatic agent. The H2-receptor blocking agent cimetidine inhibits the oxidative metabolism of many concurrently administered drugs, including certain NSAIDs. Probenecid inhibits the renal secretion of drug glucuronides and this will lead to accumulation in plasma of those NSAIDs eliminated primarily by the formation of labile acyl glucuronides such as naproxen, ketoprofen, indomethacin, carprofen. Cholestyramine decreases the oral absorption of many concurrently administered drugs, including NSAIDs. It may also decrease plasma concentrations of those NSAIDs undergoing enterohepatic circulation (e.g. piroxicam, tenoxicam) by interrupting the enterohepatic cycle. Corticosteroids stimulate the clearance of salicylic acid, leading to low plasma salicylate concentrations. Plasma concentrations of many NSAIDs are significantly reduced when the NSAID is coadministered with aspirin. The clinical relevance of most of these interactions is not well established. However, in those cases where the interaction results in elevated plasma concentrations of the NSAID, special caution should be exercised to avoid excessive accumulation of the NSAID especially in elderly and/or very sick patients who may be more sensitive to the more serious gastroduodenal and renal side-effects of these agents.By virtue of their pharmacokinetic and pharmacodynamic properties, NSAIDs may significantly affect the disposition kinetics of a number of other drugs. They can displace other drugs from their plasma protein binding sites, inhibit their metabolism or interfere with their renal excretion. If the affected drug has a narrow therapeutic index, the interaction may be clinically significant. The pyrazole NSAIDs (phenylbutazone, oxyphenbutazone, azapropazone) inhibit the metabolism of many drugs such as the coumarin anticoagulants, oral antidiabetics and anticonvulsants such as phenytoin. Salicylates displace oral anticoagulants from their plasma protein binding sites. In addition, aspirin increases the risk of bleeding by inhibition of platelet function and by production of gastric erosions. The hypoglycaemic effect of sulfonylureas may be enhanced by large doses of salicylates through an intrinsic hypoglycaemic effect. In all these cases, alternative NSAIDs which do not interact with these agents should be used. Most, if not all, NSAIDs interfere with the renal excretion of lithium and methotrexate, which could lead to severe toxic reactions due to elevated plasma concentrations of these 2 drugs.Finally, clinically important interactions occur between NSAIDs and diuretics and antihypertensive agents. These interactions are largely pharmacodynamic in nature and in most cases seem to be the result of the prostaglandin inhibitory effects of the NSAIDs.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The pharmacokinetics of fleroxacin and its metabolites following a single oral dose of fleroxacin 400mg were examined in 6 healthy subjects and 24 patients with various degrees of renal insufficiency. Plasma and urine samples, collected at various times after administration, were assayed by high performance liquid chromatography (HPLC).In healthy subjects. Cmaxwas 6.8 ± 0.7 mg/L; tmax= about 1h, t½= 14 ± 2h, total clearance = 4.86 ± 0.72 L/h and the percentage of unchanged fleroxacin excreted in urine in 48 hours was 48 ± 4% (HPLC). Plasma concentrations of metabolites were very low and accounted for no more than 5% of the levels of unchanged fleroxacin.In uraemic patients Cmaxdid not change, whatever the degree of renal failure; tmaxwas increased in patients with a glomerular filtration rate below 0.6 L/h, and Vd/f was independent of the severity of renal failure. These data suggest that bioavailability of the drug is unchanged. In uraemic patients t½was prolonged and AUC multiplied by a factor of 2 to 3. A linear relationship was found between total and renal clearances of fleroxacin and creatinine clearance. Accumulation ofN-demethyl-fleroxacin andN-oxide-fleroxacin was very high in uraemic patients, due to slow formation of these metabolites and decreased urinary elimination.Dialysance of fleroxacin and of its metabolites was approximately 3.6 to 4.8 L/h. These findings suggest that fleroxacin dosage may need to be reduced in patients with severe renal disease; in haemodialysed patients, treated every 2 days, a single dose of fleroxacin 400mg is recommended at the end of each dialysis session.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS

摘要:

The pharmacokinetics of fleroxacin and its main metabolites,N-demethyl-fleroxacin andN-oxide-fleroxacin, were studied in 12 elderly patients aged 63 to 88 years. Plasma and urine samples collected at different times after drug administration were analysed by a specific reverse phase high performance liquid chromatography (HPLC) method.The peak plasma concentration (Cmax) of fleroxacin was 15.6 ± 1.6 mg/L, time to Cmax(tmax) was about 3h, elimination half-life (t½) was 16 ± 1h and the percentage of unchanged fleroxacin excreted in urine was 39 ± 3% of the dose. The plasma concentrations of metabolites were very low and accounted for no more than 4% of the concentration of unchanged fleroxacin.Plasma parameters were mainly correlated with age and weight; urinary parameters were correlated with creatinine clearance. Compared with results in younger normal patients, no significant change in the t½of fleroxacin or metabolites was observed. Assuming that the bioavailability (f) is complete, the apparent volume of distribution (Vd/f) was lower in elderly (0.9 ± 0.1 L/kg) than in younger patients (1.3 ± 0.1 L/kg) and a 2-fold decrease in apparent total clearance (CL/f) was noted (2.58 ± 0.42vs4.86 ± 0.72 L/h); plasma concentrations were consequently higher in elderly patients. Compared with patients with renal failure, the pharmacokinetics of fleroxacin and metabolites in the elderly were similar to those of patients with mild to moderate renal insufficiency.On the basis of the findings of this single dose study, no major dosage adjustments are needed for patients of this age range except for those with creatinine clearance < 30 ml/min.

ISSN:0312-5963    

出版商:ADIS    

年代:1990

数据来源: ADIS