摘要:

Many antipsychotics, including perphenazine, zuclopenthixol, thioridazine, haloperidol and risperidone, are metabolised to a significant extent by the polymorphic cytochrome P450 (CYP) 2D6, which shows large interindividual variation in activity. Significant relationships between CYP2D6 genotype and steady-state concentrations have been reported for perphenazine, zuclopenthixol, risperidone and haloperidol when used in monotherapy. Other CYPs, especially CYP1A2 and CYP3A4, also contribute to the interindividual variability in the kinetics of antipsychotics and the occurrence of drug interactions. For many antipsychotics, the role of the different CYPs at therapeutic drug concentrations remains to be clarified. Some studies have suggested that poor metabolisers for CYP2D6 would be more prone to oversedation and possibly parkinsonism during treatment with classical antipsychotics, whereas other, mostly retrospective, studies have been negative or inconclusive. For the newer antipsychotics, such data are lacking. Whether phenotyping or genotyping for CYP2D6 or other CYPs can be used to predict an optimal dose range has not been studied so far. Genotyping or phenotyping can today be recommended as a complement to plasma concentration determination when aberrant metabolic capacity (poor or ultrarapid) of CYP2D6 substrates is suspected. The current rapid developments in molecular genetic methodology and pharmacogenetic knowledge can in the near future be expected to provide new tools for prediction of the activity of the various drug-metabolising enzymes. Further prospective clinical studies in well-defined patient populations and with adequate evaluation of therapeutic and adverse effects are required to establish the potential of pharmacogenetic testing in clinical psychiatry.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic β-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration.Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg.Mean peak plasma leuprorelin concentrations (Cmax) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 μg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 μg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 μg/L over 28 days after single 3.75, 7.5 or 15mg depot injections.Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours.A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a Cmaxof around 20 μg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 μg/L from day 7 until before the next injection.Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 μg/L until week 52, suggesting zero-order drug release from the implant.In general, regular or depot leuprorelin treatment is well tolerated. Local reactions are more common after application of the 3- or 4-month depot in comparison with the 1-month depot.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

β-Adrenergic blockade has provided one of the major pharmacotherapeutic advances of the 20th century. β-Blockers are first-line drugs for the management of systemic hypertension, used alone and in combination with other antihypertensive agents. Drugs in the β-blocking class have the common property of blocking the binding of catecholamines to β-adrenergic receptor sites; however, there are significant pharmacodynamic and pharmacokinetic differences between the individual agents that are of clinical importance. Among these differences are the completeness of gastrointestinal absorption, the degree of hepatic first-pass metabolism, lipid solubility, protein binding, brain penetration, concentration within the cardiac tissue, rate of hepatic biotransformation, and renal clearance of drug and/or metabolites. Long-acting formulations of existing β-blockers are currently in use, and ultra-short-acting agents are also available.Age, race, cigarette smoking and concomitant drug therapy can also influence the pharmacokinetics of β-blocking drugs. The wide interpatient variability in plasma drug concentrations observed with β-blockers makes this parameter unreliable in routine patient management. Despite the pharmacokinetic differences among β-blockers, these drugs should always be titrated to achieve the desired individual patient response.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo examine the absorption, distribution and excretion of sevelamer hydrochloride in rats and humans.ParticipantsTwelve male Sprague-Dawley rats were used in the animal study, and twenty human volunteers participated in the clinical trial.MethodsIn the animal study, six rats received a single oral dose of [3H]sevelamer and six rats were pretreated with unlabelled sevelamer in the diet for 28 days followed by a single dose of [3H]sevelamer on day 29. Total urine and faeces were collected at intervals up to 72 hours post dose, and tissues were obtained at the time of sacrifice. In the clinical trial, subjects received a single oral dose of [14C]sevelamer following 28 days of pretreatment with unlabelled sevelamer. Blood, urine and faeces samples were collected at intervals up to 96 hours.ResultsIn the rat study, no significant urinary excretion of radioactivity was observed. The average recovery of radioactivity in the faeces was 98% in the single-dose group and greater than 100% in the group pretreated with unlabelled sevelamer for 28 days. A total of less than 0.1% of the dose was found in the tissues. In the human study, no detectable amount of14C was found in the blood of any subject at any time. The majority of subjects had no detectable amounts of14C recovered in the urine. In subjects where14C was recovered in the urine, less than 0.02% was detected, a level equivalent to the free14C detected in the [14C]sevelamer preparation. On average, greater than 99% of the administered dose was recovered in the faeces of the subjects.ConclusionThese studies demonstrate that sevelamer is a non-absorbed compound.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

BackgroundAntihistamines (histamine H1receptor antagonists) are effective and convenient drugs for the treatment of allergic conjunctivitis. Because of the short duration of action generally observed for drugs administered topically to the eye, the oral route is often preferred. However, the presence of a selective barrier between blood and ocular tissues, the so-called blood-ocular barrier, does not allowa prioriassessment of the most suitable dosage for ocular therapy.ObjectiveTo investigate the tear concentrations of cetirizine, a second-generation antihistamine, over time following oral administration, and to study the relationship between plasma and tear fluid concentrations.Design and participantsPharmacokinetic study of a single oral dose of cetirizine 10mg in 40 patients treated for allergic conjunctivitis.MethodsPatients received a single oral dose of cetirizine. Samples of blood and tear fluid were taken according to predefined sampling schedules and the concentrations of cetirizine were determined by a new high performance liquid chromatography method.ResultsConcentration-time profiles for cetirizine in serum and tear fluid were similar, although the mean maximum concentration in tear fluid was reached later than in serum (90 and 30 min, respectively). However, at 60 and 120 min the cetirizine concentration in tear fluid was 98 and 92% of the mean maximum concentration, respectively, showing a plateau region and indicating that the disposition rate for the tear fluid compartment was very similar to that for the blood compartment.ConclusionOral administration of cetirizine yields therapeutically effective concentrations of the drug at the anterior surface of the eye.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS