摘要:

The product label, or package insert, is the ‘manual’ for the safe and effective use of a drug. Important pharmacokinetic and pharmacodynamic properties of a drug product should appear in the label under specific sections, as required in the Code of Federal Regulations (CFR), using a format and language recommended by the Food and Drug Administration (FDA) in various guidances to the industry. The relevant regulations and guidance documents impacting on how this information is conveyed to the healthcare professional are discussed, with special emphasis on how the new proposed rule will impact upon how information is to be conveyed. With the availability of new clinical pharmacology information not available at the time of approval, package inserts for older drugs should be updated to reflect the new data and recommend the proper dosage regimen, enabling prescribers to optimise drug therapy and minimise possible adverse events.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. The current concept is that inadequate drug delivery is a major factor that explains the unsatisfactory response of chemosensitive brain tumours. Various strategies have been devised to circumvent the BBB in order to increase drug delivery to the CNS. The various approaches can be categorised as those that attempt to increase delivery of intravascularly administered drugs, and those that attempt to increase delivery by local drug administration. Strategies that increase delivery of intravascularly injected drugs can manipulate either the drugs or the capillary permeability of the various barriers (BBB or blood-tumour barrier), or may attempt to increase plasma concentration or the fraction of the drug reaching the tumour (high-dose chemotherapy, intra-arterial injection). Neurotoxicity is a major concern with increased penetration of drugs into the CNS or when local delivery is practised. Systemic toxicity remains the limiting factor for most methods that use intravascular delivery.This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Tirofiban is a nonpeptide tyrosine derivative that antagonises platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptors. It is one of three GP IIb/IIIa antagonists approved by the US Food and Drug Administration for the treatment of patients with acute coronary syndromes. The clinical effect of tirofiban has been shown in large studies such as PRISM (Platelet Receptor Inhibition for Ischemic Syndrome Management), PRISM-PLUS (PRISM − Patients Limited by Unstable Signs and Symptoms) and RESTORE (Randomised Efficacy Study of Tirofiban for Outcomes and Restenosis).Tirofiban is administered as an intravenous infusion. Volume of distribution ranges from 21 to 87L, and binding to human plasma proteins is modest at 64%. Metabolism in humans is negligible, and most drug is excreted renally with systemic clearance ranging from 4.8 to 25.8 L/h. Renal function may influence the excretion of tirofiban, but concurrent disease or other drugs generally used in patients with ischaemia seem not to do so.This review updates what is known about the pharmacokinetics of tirofiban in humans, especially in comparison with the monoclonal antibody against the IIb/IIIa receptor, abciximab.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Dorzolamide is a carbonic anhydrase inhibitor for topical ophthalmic application. It is used in the treatment of glaucoma to lower the intraocular pressure. After absorption via the cornea and stroma, it inhibits carbonic anhydrase in the ciliary process, which leads to a reduction of aqueous humour production and therefore to the desired therapeutic effect. In the systemic circulation, dorzolamide is bound mainly to carbonic anhydrase in red blood cells. It is slowly metabolised toN-de-ethyldorzolamide, which in turn is also stored in red blood cells. The very slow elimination (half-life >4 months) of both substances takes place via the renal route. However, the inhibition of carbonic anhydrase in red blood cells is moderate in the course of a topical treatment, avoiding systemic adverse effects.This review summarises the pharmacokinetic and pharmacodynamic properties of dorzolamide and its metabolite in eye tissues and in the systemic circulation.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update.All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (tmax) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals.The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin.Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and β-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes.ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

ObjectiveTo investigate the bioavailability of rivastigmine, an approved therapy for patients with mild to moderate dementia of the Alzheimer’s type, at the highest approved single dose of 6mg.Design and settingRandomised, two-period crossover, single-centre, non-blinded, inpatient study.Patients and participantsEleven patients (five females and six males) with mean age 69.5 years.MethodsThe 6mg oral dose was compared with a 2mg intravenous dose of rivastigmine infused over a 1-hour period. Plasma concentrations of rivastigmine and its metabolite NAP 226-90 were measured with a gas chromatographic/mass spectrometric method.ResultsFollowing oral administration of a single 6mg capsule, rivastigmine is rapidly absorbed with an average time to peak plasma concentration of about 1 hour and an average peak concentration of about 25.6 μg/L. By a noncompartmental approach, the absolute bioavailability of the 6mg oral dose of rivastigmine was 71.7% when compared with a 2mg intravenous infusion normalised for dose. By using a population pharmacokinetic model with Michaelis-Menten elimination, absolute bioavailability was estimated at 60.2%. The average terminal elimination half-life of rivastigmine ranged from 1.4 to 1.7 hours for both treatments. Plasma concentrations of the major metabolite, NAP 226-90, formed by the hydrolysis of rivastigmine by cholinesterase are lower than those of the parent compound following oral and intravenous administration.ConclusionA noncompartmental approach and a compartmental approach based on a population pharmacokinetic model with Michaelis-Menten elimination yielded comparable values, 71.7% and 60.2% respectively, for the absolute bioavailability of a single 6mg oral dose of rivastigmine. Comparison with previous studies confirmed that the oral form of the drug exhibits increased bioavailability with increasing dose, consistent with its nonlinear pharmacokinetics.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS