摘要:

Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30−50mg (0.53 mg/kg bodyweight) over 5−10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase.Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17−24 minutes, and the mean terminal half-life was 65−132 min. Over the clinically relevant dose range of 30−50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V1was 4.2−6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1−9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V1. Total bodyweight explained 19% of the variability in CL and 11% of the variability in V1, and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL.The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC2−90exceeded 320 μg • min/ml, corresponding to an average plasma concentration of 3.6 μg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30−50mg was higher than for alteplase 100mg.Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Sertraline is a naphthalenamine derivative with the predominant pharmacological action of inhibiting presynaptic reuptake of serotonin from the synaptic cleft. It was initially marketed for the treatment of major depressive disorder and is now approved for the management of panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder.Sertraline is slowly absorbed following oral administration and undergoes extensive first-pass oxidation to formN-desmethyl-sertraline, a weakly active metabolite that accumulates to a greater concentration in plasma than the parent drug at steady state. Sertraline is eliminated from the body by other metabolic pathways to form a ketone and an alcohol, which are largely excreted renally as conjugates. The elimination half-life of sertraline ranges from 22−36 hours, and once-daily administration is therapeutically effective. Steady-state plasma concentrations vary widely, up to 15-fold, in patients receiving usual antidepressant dosages between 50 and 150 mg/day. However, only sparse data have been published that support useful correlations between sertraline plasma concentrations and therapeutic or adverse effects to justify therapeutic drug monitoring.Sertraline has minimal inhibitory effects on the major cytochrome P450 enzymes, and few drug-drug interactions of clinical significance have been documented. Like other selective serotonin reuptake inhibitors, sertraline is well tolerated in therapeutic dosages and relatively safe in overdosage.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

A number of programmable rate-controlled drug delivery technologies have been developed during the last two decades with the aim of regulating the rate of drug delivery, sustaining the duration of therapeutic action and/or targeting the delivery of drug to a specific tissue. As a result, several therapeutically beneficial outcomes can be achieved, such as:controlled delivery of a therapeutic dose at a desirable rate of delivery;maintenance of drug concentrations within an optimal therapeutic range for prolonged duration of treatment;maximisation of efficacy-dose relationship;reduction of adverse effects;minimisation of the need for frequent dose intake; andenhancement of patient compliance. The treatment of illness can thus be optimised.To gain a better understanding of how to optimise the treatment of illnesses by applying programmable rate-controlled drug delivery technologies, this article reviews the scientific concepts and technical principles behind the development of various programmable rate-controlled drug delivery systems that have been marketed or are under active development. Finally, the roles of these technologies in optimising therapeutic outcomes in nine therapeutic areas are discussed.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo compare the effects of two different formulations of glibenclamide (glyburide) combined with metformin on postprandial glucose excursions, and to assess their pharmacokinetics. The formulations were a combination glibenclamide/metformin tablet (Glucovance™; controlled−particle-size glibenclamide and metformin) versus glibenclamide (Micronase®) and metformin (Glucophage®) coadministered separately.DesignA randomised, double-blind, two-way crossover study in which patients with type 2 diabetes received either glibenclamide/metformin 2.5/500mg tablets or glibenclamide 2.5mg with metformin 500mg twice daily for 14 days. After a 2-week washout, patients were crossed over to the other treatment for 14 days. Patients consumed standardised meals on the days when pharmacokinetic and pharmacodynamic evaluations were performed.ParticipantsForty patients with type 2 diabetes were enrolled; 37 were randomised (18 men, 19 women) and 35 completed the study. Mean age was 58 years; mean body mass index was 31 kg/m2. The baseline glycated haemoglobin (HbA1c) was 9.3% for both treatment groups.Main outcome measureTwo-hour postprandial glucose excursion (PPGE) was used to assess postprandial glucose dynamics.ResultsTreatment with glibenclamide/metformin resulted in a significantly smaller mean PPGE than was attained by treatment with glibenclamide plus metformin, according to measurements taken after the day 14 afternoon standardised meal (89.5 vs 117.4 mg/dl, p = 0.011). The mean glibenclamide peak concentration (Cmax) was significantly greater (~16%) after glibenclamide/metformin treatment on both days 1 and 14. Glibenclamide/metformin treatment was associated with a 2-fold greater area under the concentration-time curve to 3 hours for glibenclamide (AUC3) [p < 0.001], although the AUC over the administration interval was equivalent for both formulations.ConclusionIn patients with type 2 diabetes, glibenclamide/metformin resulted in lower PPGE, suggesting that the higher glibenclamide AUC3observed with this formulation may contribute to better postprandial glycaemic control than is attained by glibenclamide plus metformin separately.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS