摘要:

Topotecan (Hycamtin®), a semisynthetic water-soluble derivative of camptothecin, is a potent inhibitor of DNA topoisomerase Iin vitroand has demonstrated encouraging antitumour activity in a wide variety of tumours, including ovarian cancer and small cell lung cancer. Now approved in the US, topotecan has completed single-agent phase I testing; phase II/III trials are ongoing.Under physiological conditions the lactone moiety of topotecan undergoes a rapid and reversible pH-dependent conversion to a carboxylated open-ring form, which lacks topoisomerase I inhibiting activity. At equilibrium at pH 7.4 the open-ring form predominates. Topotecan is stable in infusion fluids in the presence of tartaric acid (pH < 4.0), but is unstable in plasma, requiring immediate deproteinisation with cold methanol after blood sampling and storage of the extract at −30°C to preserve the lactone form.Topotecan has been administered in phase I trials in several infusion schedules ranging from 30 minutes to 21 days. The plasma decay of topotecan concentrations usually fits a 2-compartment model. Rapid hydrolysis of topotecan lactone results in plasma carboxylate levels exceeding lactone levels as early as 45 minutes after the start of a 30-minute infusion. The peak plasma concentrations and the area under the plasma concentration-versus-time curves (AUC) show linear relationship with increasing dosages. No evidence of drug accumulation is seen with daily 30-minute infusions for 5 consecutive days.Topotecan lactone is widely distributed into the peripheral space, with a mean volume of distribution (Vd) at steady-state of 75 L/m2. The mean total body clearance of the lactone form is 30 L/h/m2, with a mean elimination half-life (t½&bgr;) of 3 hours; renal clearance accounts for approximately 40% of the administered dose with a large interindividual variability.The oral bioavailability of topotecan is approximately 35%. The low bioavailability may be caused by hydrolysis of topotecan lactone in the gut, yielding substantial amounts of the open-ring form, which is poorly absorbed.Renal dysfunction may decrease topotecan plasma clearance. Creatinine clearance is significantly, but poorly, correlated with topotecan clearance. Hepatic impairment does not influence topotecan disposition.Indices of systemic exposure (steady-state concentrations and AUC) are correlated with the extent of myelotoxicity. Sigmoidal functions adequately describe the relationships between systemic exposure and the percentage decrease in neutrophils.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Famotidine, an H2receptor antagonist, has several potential advantages over cimetidine and ranitidine. These advantages include its potency, relatively longer elimination half-life, and lack of interaction with the cytochrome P450 isoforms.Eight studies addressing the use of famotidine in paediatric patients have been published. Data from these studies demonstrate that the pharmacokinetics and pharmacodynamics of intravenous famotidine appear to be similar in both children over the age of 1 year and adults. These data support a starting paediatric dosage for intravenous famotidine of 0.5 mg/kg every 8 to 12 hours.In addition, the safety and efficacy of famotidine in the treatment of peptic ulcer disease and esophagitis in paediatric patients is supported by these studies involving over 150 children.Future studies with famotidine in paediatrics should address its disposition in children under the age of 1 year and in children with compromised renal function, as well as the bioavailability of the oral formulation.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

This paper reviews the effects of renal insufficiency on the pharmacokinetics of oral antidiabetic drugs. Of the 3 groups of drugs currently available for the treatment of non-insulin-dependent diabetes mellitus (NIDDM), the sulphonylureas and metformin are, in general, well-tolerated and generally safe. In patients with chronic renal insufficiency, however, care must be exercised in the use of many of these drugs, as accumulation, either of the active drug or of active metabolites, can lead to serious adverse effects such as hypoglycaemia or, with metformin, lactic acidosis.The sulphonylurea drugs, to a greater or lesser degree, are metabolised in the liver to a variety of active or inactive compounds which, in general, are excreted by the kidneys. In addition, varying amounts of parent compound may depend on renal elimination. As a result, sulphonylurea drugs such as tolazamide, acetohexamide, chlorpropamide and glibenclamide (glyburide) are more likely to cause significant hypoglycaemia, as the metabolism of these drugs, compared with other commonly prescribed sulphonylureas, can lead to the accumulation of either the parent drug or the active metabolite in the presence of renal insufficiency. Tolbutamide, glipizide, gliclazide and gliquidone are much less likely to cause hypoglycaemia as their metabolites are either inactive or have minimal hypoglycaemic potency.Metformin is dependent on renal excretion and is not significantly metabolised. As a result, caution is required when treating patients with renal insufficiency where metformin accumulation can occur, with the danger of lactic acidosis. Although the correlation between creatinine clearance (CLCR) and total oral clearance of drug is weaker than the correlation between CLCRand renal clearance (CLR) of metformin, it is clear that renal insufficiency is associated with most cases of metformin-induced lactic acidosis. For this reason, clinicians in general would regard a raised plasma creatinine as a contraindication to metformin treatment.Acarbose, an &agr;-glucosidase inhibitor, and a relatively new agent for treating NIDDM, is likely to be safe in patients with impaired renal function, as the drug is not significantly absorbed from the gut, but data on this subject are lacking.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The ability to measure the serum concentrations of antiepileptic drugs, and the widespread use of this procedure, has markedly improved the treatment given to patients with epilepsy during the past 3 decades. The monitoring of antiepileptic drug concentrations in serum is necessary for the optimal drug therapy of seizures, because the therapeutic and toxic effects of these drugs are better related to serum concentration than to administered dosage. Monitoring appeared to have a major impact on improving the effectiveness and safety of antiepileptic drug therapy.The age-related variability of pharmacokinetic parameters may also require the individualisation of therapy, with subsequent re-evaluation as the person grows older. Monitoring serum concentrations of antiepileptic drugs may help to optimise the dose. A drug concentration, however, can only be regarded as a guide around which to alter the dosage according to the patient's clinical condition.Serum drug concentration monitoring is particularly useful to ensure compliance and in helping to manage combinations of antiepileptic drugs that invariably interact. The addition or deletion of other antiepileptic drugs may change dosage requirements. Therefore, routine monitoring of antiepileptic drug serum concentrations would be extremely useful, especially in the paediatric population, and in patients who require associated antiepileptic medication.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

The hepatitis B virus (HBV) is the world's most important chronic virus infection. The immunomodulator interferon-&agr; (IFN&agr;) is the only clinically applied drug available, despite its low response rate (approximately 30%) even in highly selected chronic carriers. Antiviral nucleoside analogues have proven to be potent inhibitors of viral replicationin vitro,but their significant adverse effects which are, at least partially, due to their nonspecific body distribution, have forced the cessation of their clinical development in the past. For example, vidarabine causes severe neuromuscular toxicity, and fialuridine has caused fatal cases of liver and kidney failure in a recent clinical trial. Furthermore, the potential clinical application of (modified) antisense oligodeoxynucleotides, which are very specific inhibitors of viral replication, is hampered by their nonspecific body distribution, instability in serum and poor cell penetration.As infection and replication of HBV mainly occur in liver parenchymal cells, selective targeting of antiviral nucleoside analogues as well as antisense oligodeoxynucleotides to the liver would theoretically improve therapeutic efficacy. At present, conjugates of vidarabine and neoglycoproteins have entered clinical trials, and initial data suggest that therapeutic concentrations are achieved at lower dosages with minor adverse effects. These data have stimulated preclinical research on other liver-specific drug carriers for the selective delivery of HBV-active drugs such as glycosylated polymers and neolipoproteins: these approaches are outlined in this paper.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Early diagnosis and treatment of septic arthritis improves the potential for a favourable outcome. Optimal treatment includes the prompt and judicious use of effective antimicrobial agents coupled with prompt drainage of the affected joint. Adequate drainage may be accomplished by means of repeated closed large-bore needle aspiration, arthroscopy, or an open surgical procedure.The purpose of this article is to describe optimal antimicrobial therapy based upon available pharmacokinetic data. The host-dependent vulnerability to specific pathogens, local antibacterial susceptibility patterns and knowledge of antibacterial activity at the site of infection must all be taken into account when planning appropriate treatment. This article does not address arthritis secondary to human and animal bites, diabetic foot infections, mycobacteria, fungi, Lyme spirochaete, or other nonbacterial causes of septic arthritis.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS