摘要:

Oral hypoglycaemic drugs have widely differing pharmacokinetic properties. Possible pharmacodynamic benefits include greater efficacy and fewer adverse effects. In general, it has not been possible to demonstrate unequivocal differences in clinical efficacy between the sulphonylureas during long term use, although there are clear differences in potency.These differences have been emphasised to the extent that the term ‘second-generation’ has been used for the most potent sulphonylureas, but there is little to suggest that potency is of any therapeutic significance. Trials to study differences in efficacy have rarely been of acceptable design. They have often used fixed doses of drugs, begging the question of whether true potency ratios have been established for chronic treatment. They have rarely involved substantial numbers of patients in double-blind crossover studies with a suitable washout period. Trials which show that there is a clear relationship between drug concentrations in blood and drug effects (whether therapeutic effects or adverse effects such as severe hypoglycaemia) are generally lacking.Qualitative and semiquantitative analysis of adverse effects supports the concept that drugs with a long half-life (e.g. chlorpropamide), renally excreted active metabolites (e.g. acetohexamide) or unusual properties (e.g. glibenclamide, which accumulates progressively in islet tissue) are more likely to cause prolonged hypoglycaemia, which may be fatal. The major adverse effect of treatment with biguanides is lactic acidosis, and this probably occurs more commonly in patients treated with phenformin than those treated with metformin because of pharmacogenetic variation in phenformin metabolism.The available evidence therefore favours the use of drugs with a short elimination half-life which are extensively metabolised and which have no active metabolites.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

The ability of a wide variety of anionic, cationic, and neutral drugs to bind in a reversible manner to plasma proteins has long been recognised. Non-steroidal anti-inflammatory drugs (NSAIDs) are distinguished as a class by the high degree to which they bind to plasma protein. Plasma protein binding properties are primary determinants of the pharmacokinetic properties of the NSAIDs. Theoretical relationships are reviewed in order to define quantitatively the impact of plasma protein binding on clearance, half-life, apparent volume of distribution, and the duration and intensity of pharmacological effect. The quantitative relationships governing competitive displacement binding interactions are also presented.Experimental methods forin vitroandin vivodetermination of the degree of plasma protein binding are discussed. The more commonin vitromethods are equilibrium dialysis and ultrafiltration. Methods for characterising the degree of plasma protein bindingin vivoconsist of either measuring the concentration of drug at equilibrium in an implanted semipermeable vessel or measuring the relative drug concentrations in two body spaces with different protein content. Emphasis is given to the comparative advantages and disadvantages of experimental application of the variousin vitroandin vivomethods.Plasma protein binding is discussed as a determinant of the trans-synovial transport of NSAIDs. Trans-synovial transport of NSAIDs appears to be a diffusional process. Limited data in humans receiving ibuprofen, indomethacin, aspirin, carprofen, alclofenac, or diclofenac suggest that clearance of each of these NSAIDs from the synovium is slower than clearance from plasma.The clinical data relevant to the relationship between plasma NSAID concentration and various measures of anti-inflammatory effect are reviewed. A positive correlation between plasma NSAID concentration and anti-inflammatory effect has been observed in only one study on naproxen and one study on piroxicam. In several other studies, the lack of concentration-response correlations is generally attributed to the relatively subjective, quantitatively inexact methods used to assess anti-inflammatory effect and analgesia in arthritic patients, as well as the substantial interpatient variabilities in the fraction of unbound NSAID and the unbound plasma NSAID concentration. In view of the generally poor correlation between concentration and therapeutic response, routine therapeutic monitoring of total plasma NSAID concentration is not recommended as a means of titrating individual dosages to the desired effect in each patient.Clinical factors associated with altered plasma protein binding of NSAIDs are presented. Although competitive displacement by concurrent medications or endogenous displacers is discussed, the frequency of occurrence of clinically significant displacement interactions is apparently minimal due to avoidance of known interacting drug-drug combinations and careful monitoring of patient status. The effects of disease states on plasma protein binding of NSAIDs are considered, with particular attention to the effects of rheumatic disease, renal disease, nephrotic syndrome, and hepatic insufficiency.Finally, the effects of pregnancy, age, and haemodialysis on plasma protein binding of NSAIDs are considered.The clinical pharmacokinetic properties of future NSAIDs which emerge from the same chemical classes as currently available NSAIDs can be expected to be profoundly influenced by the extent and affinity of binding of the drugs to proteins.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

Nafimidone is a new antiepileptic drug which may be effective in partial onset seizures. We studied the pharmacokinetics of nafimidone and its metabolite, nafimidone alcohol, in 12 patients already taking phenytoin and/or carbamazepine. The half-life of nafimidone was 1.34 ± 0.48 hours after a 100mg single dose and 1.69 ± 0.91 hours after a 300mg single dose. However, the half-life of nafimidone alcohol increased from 2.84 ± 0.72 hours after a 100mg single dose to 4.22 ± 1.09 hours after a 300mg single dose (p < 0.02). The clearance of nafimidone was 43.56 ± 22.11 L/h/kg after a 100mg single dose and 35.51 ± 28.93 L/h/kg after the 300mg single dose. The respective apparent volumes of distribution of nafimidone after single 100 and 300mg doses were 80.78 ± 46.11 L/kg and 71.01 ± 36.86 L/kg. After short term (9 to 10 weeks) and long term (127 to 152 weeks) maintenance therapy on nafimidone 600mg per day the half-life of nafimidone alcohol was 2.23 ± 0.36 hours and 2.16 ± 0.60 hours, respectively. No nafimidone could be detected in urine but from 4 to 7% of the daily nafimidone dose was recovered as nafimidone alcohol. Thus, it appears that over 90% of the administered dose of nafimidone is metabolised by pathways other than glucuronidation of nafimidone alcohol and urinary excretion.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS

摘要:

A pharmacokinetic study was undertaken to determine the bioavailability of bumetanide in grossly oedematous patients. Six nephrotic patients were administered bumetanide 2mg orally (as tablets) and intravenously as single doses, in a randomised fashion. Serum bumetanide concentration-time profiles were characterised. Data were fitted to a 2-compartment model (5 patients) and a 3-compartment model (1 patient). Analysis of the areas under the curves showed a bioavailability of 0.84 ± 0.2, which is similar to that in normal individuals. It is suggested that the bioavailability of oral bumetanide in oedematous patients is not altered significantly and that the apparent resistance to diuretics in such patients may be due to another cause.

ISSN:0312-5963    

出版商:ADIS    

年代:1987

数据来源: ADIS