摘要:

Current approaches to the development of drug delivery systems are based typically on the premise that the relationship between the plasma concentration and therapeutic effect of a drug is invariant with time. Release kinetics from these systems are, therefore, usually engineered to be either zero-order or a simple function of time. It has been recognised for some time, however, that this approach may not be appropriate for certain drugs and it has been suggested that therapeutic efficacy may be improved by the utilisation of triggered, pulsed and programmed delivery systems. This article considers an approach to the development of responsive drug delivery system based on the utilisation of functional polymers, which aim to improve therapeutic efficacy by varying drug release in accordance with a patients's varying requirements.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Bambuterol, a biscarbamate ester prodrug of the &bgr;2 adrenergic agonist terbutaline, has been approved for the treatment of asthma in 28 countries. It is available in 10 and 20mg (25 and 50 μmol) tablets as the hydrochloride salt.Bambuterol is stable to presystemic elimination and is concentrated by lung tissue after absorption from the gastrointestinal tract. The prodrug is hydrolysed to terbutaline primarily by butyrylcholinesterase, and lung tissue is capable of this metabolic pathway. It is also oxidatively metabolised to products which can be hydrolysed to terbutaline.Peak terbutaline plasma concentrations occur 3.9 to 6.8 hours after bambuterol ingestion, and the peak : trough terbutaline concentration ratio is lower than that after ingestion of terbutaline. Older patients have a greater area under the plasma concentration-time curve for terbutaline over a dose interval at steady-state.Whether genetic variations in the expression of butyrylcholinesterase alter therapeutic response remains to be determined. The efficacy of bambuterol has been demonstrated to last for 24 hours after ingestion; once-daily administration in the evening is recommended. Maximum therapeutic benefit requires more than 1 week of treatment.Except for the suppression of plasma butyrylcholinesterase, the adverse effect profile of bambuterol is essentially that of a &bgr;2 agonist and is best correlated with circulating terbutaline concentration in plasma. Plasma butyrylcholinesterase activity returns to control values approximately 2 weeks after discontinuation of treatment with bambuterol.This new drug provides oral &bgr;2 agonist therapy in a more convenient form than was available previously, and may have a better therapeutic : toxic ratio than terbutaline.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

This paper presents the current state of knowledge on chloroquine disposition, with special emphasis on stereoselectivity and microsomal metabolism. In addition, the impact of the patient's physiopathological status and ethnic origin on chloroquine pharmacokinetics is discussed.In humans, chloroquine concentrations decline multiexponentially. The drug is extensively distributed, with a volume of distribution of 200 to 800 L/kg when calculated from plasma concentrations and 200 L/kg when estimated from whole blood data (concentrations being 5 to 10 times higher).Chloroquine is 60% bound to plasma proteins and equally cleared by the kidney and liver. Following administration chloroquine is rapidly dealkylated via cytochrome P450 enzymes (CYP) into the pharmacologically active desethylchloroquine and bisdesethylchloroquine. Desethylchloroquine and bisdesethylchloroquine concentrations reach 40 and 10% of chloroquine concentrations, respectively; both chloroquine and desethylchloroquine concentrations decline slowly, with elimination half-lives of 20 to 60 days. Both parent drug and metabolite can be detected in urine months after a single dose.In vitroandin vivo,chloroquine and desethylchloroquine competitively inhibit CYP2D 1/6-mediated reactions. Limitedin vitrostudies and preliminary data from clinical experiments and observations point to CYP3A and CYP2D6 as the 2 major isoforms affected by or involved in chloroquine metabolism.In vitroefficacy studies did not detect any difference in potency between chloroquine enantiomers but,in vivoin rats,S(+)-chloroquine had a lower dose that elicited 50% of the maximal effect (ED950) than that ofR(−)-chloroquine. Stereoselectivity in chloroquine body disposition could be responsible for this discrepancy. Chloroquine binding to plasma proteins is stereoselective, favouringS(+)-chloroquine (67%vs35% for theR-enantiomer). Hence, unbound plasma concentrations are higher forR(−)-chloroquine. Following separate administration of the individual enantiomers,R(−)-chloroquine reached higher and more sustained blood concentrations. The shorter half-life ofS(+)-chloroquine appears secondary to its faster clearance. Blood concentrations of theS(+)-forms of desethylchloroquine always exceeded those of theR(−)-forms, pointing to a preferential metabolism ofS(+)-chloroquine.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Alfentanil, fentanyl and sufentanil are synthetic opioid analgesics acting at specific opioid receptors. These opioids are widely used as analgesics to supplement general anaesthesia for various surgical procedures or as primary anaesthetic agents in very high doses during cardiac surgery. Fentanyl and sufentanil especially are administered via infusion for long term analgesia and sedation in intensive care patients.Opioid analgesics are mainly administered using the intravenous route. However, other techniques of administration, including epidural, intrathecal, transdermal and intranasal applications, have been demonstrated.Important pharmacokinetic differences between alfentanil, fentanyl and sufentanil have been shown in many reports. Alfentanil has the most rapid analgesic onset and time to peak effect as well as the shortest distribution and elimination half-lives. The volume of distribution and total body clearance of this agent are smaller when compared with those of fentanyl and sufentanil.The pharmacokinetics of the opioid analgesics can be affected by several factors including patient age, plasma protein content, acid-base status and cardiopulmonary bypass, but not significantly by renal insufficiency or compensated hepatic dysfuntion. In addition, pharmacokinetic properties can be influenced by changes in hepatic blood flow and administration of drug combinations which compete for the same plasma protein carrier or metabolising pathway.Although comparing specific pharmacokinetic parameters such as half-lives is deeply entrenched in the literature and clinical practice, simply comparing half-lives is not a rational way to select an opioid for specific requirements. Using pharmacokinetic-pharmacodynamic models, computer simulations based on changes in the effect site opioid concentration or context-sensitive half-times seem to be extremely useful for selecting an opioid on a more rational basis.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Peritoneal dialysis (PD) has gained recognition worldwide as an alternative to haemodialysis in the management of patients with end-stage renal disease. Because the peritoneal catheter provides direct access to the peritoneum, intraperitoneal drug administration has become widely used for the administration of certain drugs. The instillation and drainage of PD fluids contribute to the total body clearance of drugs given by other routes. For most drugs, peritoneal clearance is low.This paper provides an updated review of recently published pharmacokinetic studies involving the administration of selected drugs to patients receiving PD. Antibiotics continue to be extensively studied and administered in PD patients because of the frequent occurrence of infections. Epoetin (recombinant human erythropoietin) has become widely used and is the subject of ongoing pharmacokinetic investigation. Intraperitoneal insulin has become accepted for the treatment of patients with diabetes receiving PD; the pharmacokinetics of vitamin D analogues in PD patients continue to be explored.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS

摘要:

Therapy with traditional antiepileptic drugs is associated with a wide range of pharmacokinetic drug-drug interactions. In particular, enzyme induction, enzyme inhibition and displacement from protein binding may result in important changes in serum concentrations of antiepileptics. Relevant interactions have also been described for some new antiepileptics.Felbamate increases serum concentrations of phenytoin, phenobarbital and valproic acid (sodium valproate). On the other hand, it reduces concentrations of carbamazepine and increases concentrations of its metabolite carbamazepine-10, 11-epoxide. Concentrations of felbamate itself are reduced by phenytoin and carbamazepine. Concentrations of lamotrigine are considerably increased by valproic acid and decreased by phenytoin, carbamazepine and phenobarbital (phenobarbitone). Vigabatrin reduces serum concentrations of phenytoin by approximately 20%.On the other hand, some new antiepileptics have the important advantage of not interfering with the metabolism of other antiepileptics; this is the case for gabapentin, lamotrigine and oxcarbazepine. Furthermore, the pharmacokinetics of gabapentin, oxcarbazepine and vigabatrin are independent of concomitant drugs. These aspects are especially important as, until now, new antiepileptics have been most often utilised as add-on therapy.

ISSN:0312-5963    

出版商:ADIS    

年代:1996

数据来源: ADIS