摘要:

There is accumulating clinical evidence that 5-aminosalicylic acid (5-ASA) represents the therapeutc moiety of sulphasalazine in the treatment of inflammatory bowel disease.For more than 4 decades, the active metabolite, 5-ASA, has been administered in the form of the ‘prodrug’ sulphasalazine; however, in contrast to sulphasalazine, the pharmacokinetics of 5-ASA were unknown until recently. Sulphasalazine itself is poorly absorbed (3 to 12%) and its elimination half-life of about 5 to 10 hours is probably affected by the absorption process. The major part of sulphasalazine is split by bacterial azo-reduction in the colon into 5-ASA and sulphapyridine, the latter accounting for most of the adverse effects of sulphasalazine. The effective cleavage of sulphasalazine depends on an intact colon and transit time. It is markedly reduced in patients taking antibiotics and after removal of the large bowel. The formed sulphapyridine is almost completely absorbed and eliminated by hydroxylation, glucuronidation and polymorphic acetylation. Depending on the genetic phenotype, the elimination half-life and apparent oral clearance of sulphapyridine are approximately 14 hours and 40 ml/min (slow acetylators) or 6 hours and 150 ml/min (fast acetylators), respectively.Of the 5-ASA released from its ‘vehicle’ sulphapyridine in the colon, at least 25% is absorbed and after acetylation is subsequently excreted in the urine. At least 50% is eliminated in the faeces. Recently, 5-ASA has also been administered directly in the form of enemas, suppositories and oral slow-release preparations. While the elimination half-life of 5-ASA is short (0.5 to 1.5h), its major acetylated metabolite (which may be active) exhibits a half-life of 5 to 10 hours. During therapy with sulphasalazine or 5-ASA, steady-state plasma concentrations of 5-ASA are relatively low (≤ 2 &mgr;g/ml); thus its mode of action appears to be topically rather than systemically.Another approach to deliver the active 5-ASA to the gastrointestinal tract is accomplished with novel ‘prodrugs’ of 5-ASA, in which the carrier molecule sulphapyridine is replaced by 5-ASA itself (azodisalicylate) or other compounds.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

This review considers subcutaneous insulin pharmacokinetics, with emphasis on those aspects relevant to subcutaneous insulin infusion devices. These devices are in increasing use for diabetes therapy, although reliable data on subcutaneous insulin absorption is required to optimise their programming. Techniques for obtaining and interpreting pharmacokinetic data are considered. Recent studies would suggest that it is possible to simulate the major physiological fluctuations in blood insulin levels via continuous subcutaneous insulin infusion, combined with appropriate bolus insulin delivery. Most insulin infused subcutaneously will reach the systemic circulation, and in the majority of diabetics, subcutaneous insulin degradation is low. However, the absorption rate is slow and it may take 6 to 8 hours to reach a steady-state following a change in the subcutaneous infusion rate. Thus there is little to be gained from hour by hour adjustments to the basal insulin infusion rate.Basal rate supplementation, and meal insulin requirements, are best met by bolus delivery. It is particularly important to provide increased systemic delivery of insulin with the start of a meal. The most appropriate adjustment for additional exercise may be a small reduction in the preceding meal bolus, rather than a reduction in the basal rate. Studies of the pharmacokinetics of insulin are an important contributing factor to the optimisation of subcutaneous insulin infusion therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The clinical pharmacokinetics of the 4 depot antipsychotics for which plasma level studies are available (i.e. fluphenazine enanthate and decanoate, haloperidol decanoate, clopenthixol decanoate and flupenthixol decanoate) are reviewed. The proper study of these agents has been handicapped until recently by the necessity of accurately measuring subnanomolar concentrations in plasma. Their kinetic properties, the relationship of plasma concentrations to clinical effects, and conversion from oral to injectable therapy are discussed.The depot antipsychotics are synthesised by esterification of the active drug to a long chain fatty acid and the resultant compound is then dissolved in a vegetable oil. The absorption rate constant is slower than the elimination rate constant and therefore, the depot antipsychotics exhibit ‘flip-flop’ kinetics where the time to steady-state is a function of the absorption rate, and the concentration at steady-state is a function of the elimination rate.Fluphenazine is available as both an enanthate and decanoate ester (both dissolved in sesame oil), although the decanoate is more commonly used clinically. The enanthate produces peak plasma concentrations on days 2 to 3 and declines with an apparent elimination half-life (i.e. the half-time of the apparent first-order decline of plasma concentrations) of 3.5 to 4 days after a single injection. The decanoate produces an early high peak which occurs during the first day and then declines with an apparent half-life ranging from 6.8 to 9.6 days following a single injection. After multiple injections of fluphenazine decanoate, however, the mean apparent half-life increases to 14.3 days, and the time to reach steady-state is 4 to 6 weeks. Withdrawal studies with fluphenazine decanoate suggest that relapsing patients have a more rapid plasma concentration decline than non-relapsing patients, and that the plasma concentrations do not decline smoothly but may exhibit ‘lumps’ due to residual release from previous injection sites or multicompartment redistribution. Cigarette smoking has been found to be associated with a 2.33-fold increase in the clearance of fluphenazine decanoate. In 3 different studies, fluphenazine has been proposed to have a therapeutic range from < 0.15 to 0.5 ng/ml with an upper therapeutic range of 4.0 ng/ml. Plasma concentrations following the decanoate injection are generally lower than, but clinically equivalent to, those attained with the oral form of the drug.Haloperidol decanoate plasma concentrations peak on the seventh day following injection although, in some patients, this peak may occur on the first day. The apparent elimination half-life after multiple injections is approximately 3 weeks and the time to reach steady-state is approximately 3 months. The reduced metabolite of haloperidol is present in significant quantities in humans following oral therapy; however, this has not been reported in pharmacokinetic studies with the depot preparation. The therapeutic range for haloperidol has been reported to be 3 to 40 ng/ml in several studies, but these studies did not measure the reduced metabolite. It has been suggested that the presence of high concentrations of the reduced metabolite may affect the response to haloperidol.Clopenthixol is only active as the cis (Z) isomer, which is the form of the drug present in the decanoate preparation. Peak plasma concentrations are usually reached between 4 and 7 days after injection. Following multiple injections, the apparent elimination half-life is 19 days. No correlation between plasma concentrations and clinical response has been reported, but concentrations have been observed to range from 10 to 100 ng/ml following a wide range of dosages and injection intervals.Flupenthixol is available as either the palmitate or decanoate ester, although most pharmacokinetic studies have used the decanoate formulation. Like clopenthixol, flupenthixol is only active as the cis (Z) isomer which is the form present in the decanoate preparation. Peak plasma concentrations occur on approximately the seventh day following injection, and no pharmacokinetic differences have been observed between the 2% and 10% concentrations of the drug. Following a single injection, an apparent elimination half-life of 8 days was reported, whereas after multiple injections, the apparent half-life was 17 days. Following withdrawal, no statistically significant differences were noted between relapsing and non-relapsing patients, but there was a trend towards lower trough concentrations in the relapsing group. There was also a shorter apparent half-life in the relapsing group when compared with the non-relapsing patients. No correlations between plasma concentrations and clinical response were found.Most methods for converting oral preparations to depot injections have been empirically developed. One study that did examine plasma concentrations and clinical effects during conversion of oral fluphenazine to the decanoate found that 1.2 to 2.5 times the oral dose (mg/day) given weekly resulted in a smooth transition between dosage forms. Fluphenazine plasma concentrations on the decanoate were lower during the first 3 weeks in comparison with oral fluphenazine therapy. It is recommended that the initially effective dose be reduced or the injection interval increased after 4 to 6 weeks to prevent possible accumulation of drugs as plasma concentrations approach steady-state. The recommended dose of haloperidol decanoate is 20 times that of the daily oral dose (mg/day) given monthly, but this should be reduced to a factor of 15 in geriatric patients. Flupenthixol 10mg given orally daily is proposed to be equivalent to 25mg of the decanoate given weekly. The use of the mean conversion ratios as a starting point for an individual patient's conversion is appropriate, but wide interindividual variations in pharmacokinetics require plasma level monitoring and careful clinical observation of the patient.Adverse effects from depot antipsychotics are relatively rare, except for extrapyramidal system reactions. The most serious (albeit very rare) problem that can occur with a long acting antipsychotic is the neuroleptic malignant syndrome. Due to their long apparent half-lives after injection, effective treatment of this syndrome following administration of depot antipsychotics can be difficult.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

Ergotamine has been in use for the treatment of migraine for a century and is still considered to be the most effective therapeutic agent for acute attacks. Only during the last few years have assays been developed, enabling its pharmacokinetics to be studied. Appropriate assays for determining ergotamine concentrations in plasma are radioimmunoassay and high-performance liquid chromatography.There is great interindividual variation in absorption of ergotamine in both patients and normal volunteers. Bioavailability is of the order of 5% or less by oral or rectal administration. After intramuscular or intravenous administration, plasma concentrations decay in a biexponential fashion. The elimination of half-life is 2 to 2.5 hours and clearance is about 0.68 L/h/kg. As yet, formal pharmacokinetics following oral dosing have not been determined. There is some evidence that ergotamine enters the cerebrospinal fluid. Metabolism occurs in the liver, and the primary route of excretion is biliary.Up to 90% of migraine patients experience complete or partial symptom relief after ergotamine, providing the drug is given as early in their attack as possible. Efficacy is greatest after parenteral administration, although adverse effects may make the rectal or inhaled routes preferable. There is some evidence to suggest that good responses are associated with plasma concentrations of 0.2 ng/ml or above within one hour of administration.The mode of action of ergotamine in migraine may be by means of selective arterial vasoconstriction on certain cranial vessel beds or, alternatively, by depression of central serotonergic neurons mediating pain transmission or circulatory regulation.Principal adverse effects of ergotamine include nausea, vomiting, weakness, muscle pains, paraesthesiae and coldness of the extremities. Ergotamine dependence is not uncommon, resulting in an exacerbation of the above symptoms. Dosage must therefore be limited to no more than 10mg per week to minimise toxicity.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The oral pharmacokinetics of aminoglutethimide were determined in 17 patients receiving the drug therapeutically. The absorption of aminoglutethimide after oral intake was almost complete as judged by recovery of radio-labelled drug in the urine. The plasma half-life of the drug was markedly reduced (mean 43%) during multiple-dose administration as compared with a single dose, but only a moderate increase in total clearance (mean 26.9%) was observed. This finding was consistent with a significant reduction (mean 29.2%) in apparent volume of distribution (Vd) occurring during prolonged treatment.These alterations in drug distribution could also be demonstrated after a drug-free interval of 96 hours during treatment. The reduction in apparent volume of distribution could not be explained by altered plasma protein binding of aminoglutethimide, as evaluated by equilibrium dialysis experiments.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

During therapeutic use of doxepin, we have often observed unexpectedly low doxepin plasma concentrations in patients on moderate dosages, e.g. 100 to 200mg daily. While non-compliance seemed the most likely explanation, we present the data for 6 patients in whom we considered non-compliance unlikely. The data can be explained by hypothesising that in some patients, there is not a linear dosage-plasma concentration relationship and that on a steady dosage, plasma concentrations are not always maintained. If these phenomena can be more carefully documented they may assume clinical importance; indeed for 2 of the patients studied the falling plasma concentrations on a steady dosage were associated with a recurrence of depression.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS