摘要:

The literature reviewed herein clearly demonstrates the poor correlation between drug dosing and the ability to achieve a specific serum drug concentration and between drug dosing and clinical response, especially for drugs with a narrow therapeutic index. There is, however, a better correlation between serum drug concentration and observed clinical response. Thus, clinicians use serum drug concentrations to more accurately dose drugs.Numerous dosing methods have been developed in an attempt to improve the relationship between dosing, serum drug concentration, and response. The major hypothesis is that if dosing methods can be developed that will accurately predict serum drug concentrations, these methods would be useful in improving clinical care. Several dosing methods have been developed including use of ‘standard’ doses, population-based predictive algorithms and nomograms, pharmacokinetic equations, and Bayesian feedback. Some of these methods are accurate and useful, whereas others are not.This review evaluates the commonly used dosing methods (some of which utilise serum drug concentration feedback for dosage estimation) for 5 drugs: gentamicin, digoxin, phenytoin, theophylline, and lignocaine (lidocaine). These drugs were selected since they exhibit a representative cross section of pharmacokinetic parameters and since they have narrow therapeutic ranges. An individualised method and a Bayesian method, both using serum drug concentration feedback, appear most accurate and precise in dosing to achieve desired serum drug concentrations and, hence, response. Our bias from personal experience with this method and from published use by others is that the Bayesian method is more flexible in that any number of serum drug concentrations may be used to determine dose, instead of the 3 or more required for the individualised method.Although use of these methods would appear to be cost-effective in timely provision of health care by reduction of toxicity and hospital stay, only sparse data have been generated to support this conclusion. Thus, further examination of the cost-effectiveness of drug dosing methods is necessary to establish their place in routine patient care.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

Etretinate, isotretinoin (13-cis-retinoic acid), and tretinoin (all-trans-retinoic acid) are retinoic acid analogues comprising a group of compounds known as the retinoids. However, they exhibit distinct and important differences with regard to their therapeutic and toxicological profiles. Tretinoin, due to a low oral therapeutic index, is limited almost exclusively to topical application, whereas etretinate and isotretinoin are therapeutically effective when given systemically by the oral route.Clinical doses of isotretinoin range from 0.5 to 8 mg/kg/day, with acute side effects appearing following doses of 1 mg/kg/day or greater. Plasma concentrations of isotretinoin following single and multiple doses peak between 2 to 4 hours and exhibit elimination half-lives of 10 to 20 hours. Isotretinoin blood concentration-time curves following a singleor multiple-dose regimen are well described by a linear model with biphasic disposition characteristics.Etretinate, which possesses a narrower therapeutic concentration range than isotretinoin, is used clinically at doses between 0.5 to 1.5 mg/kg/day; acute side effects appear following doses of 0.5 mg/kg/day or more.In most conditions, the retinoids produce a maximal effect in about 8 weeks (at the highest tolerated dose), with a slow recurrence of symptoms usually occurring within several weeks following cessation of treatment - except in the treatment of cystic acne with isotretinoin. Maintenance or intermittent dosing usually results in a prolongation of remission.Pharmacokinetically, the major difference between isotretinoin and etretinate is the much longer elimination half-life (120 days) of etretinate following long term administration. Recently, however, blood concentrationversustime curves from day 1 to day 180 of etretinate therapy have been fitted by a single polyexponential pharmacokinetic equation without the need to invoke non-linearity in the kinetics. The observed lengthening of the elimination half-life with multiple dosing may thus be due to a lack of assay sensitivity at drug concentrations seen after single-dose administration, rather than to time-related alterations in the pharmacokinetics of etretinate.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The macrolide antibiotics erythromycin and triacetyloleandomycin (troleandomycin) are prescribed for many types of infections. As such they are often added to other preexisting drug therapy. Thus, there are frequent opportunities for the interaction of these antibiotics with other drugs.Both erythromycin and triacetyloleandomycin appear to have the potential to inhibit drug metabolism in the liver and also drug metabolism by micro-organisms in the gut, either through their antibiotic effect or through complex formation and inactivation of microsomal drug oxidising enzymes. Of the two agents, triacetyloleandomycin appears to be the more potent inhibitor of microsomal drug metabolism. Published studies indicate that triacetyloleandomycin can significantly decrease the metabolism of methylprednisolone, theophylline and carbamazepine. Its ability to cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in patients on oral contraceptives may also be related to its inhibitory effect on drug metabolism.Erythromycin appears to be a much weaker inhibitor of drug metabolism. There are numerous reports describing apparent interactions of erythromycin with theophylline and a lesser number of reports dealing with carbamazepine, warfarin methylprednisolone and digoxin. There are sufficient data to suggest that erythromycin can, in some individuals, inhibit the elimination of methylprednisolone, theophylline, carbamazepine and warfarin. The mean change in drug clearance is about 20 to 25% in most cases, with some patients having a much larger change than others. Like tetracycline, erythromycin also appears to have the potential for increasing the bioavailability of digoxin in patients who excrete high amounts of reduced digoxin metabolites, apparently through destruction of the gut flora that form these compounds.Concurrent administration of triacetyloleandomycin with drugs whose metabolism is known to be affected or that could potentially be affected should be avoided unless appropriate adjustments in dosage are made. Coadministration of erythromycin with drugs believed to interact should be undertaken with caution and with appropriate patient monitoring.Among the other macrolide antibiotics, josamycin has seldom been involved in causing drug interactions, while midecamycin and the older derivative spiramycin have not so far been incriminated.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The metabolism of carbamazepine (CBZ) was studied in 3 groups of subjects: (1) 6 healthy volunteers given a single dose of 200mg carbamazepine; (2) 4 epileptic patients on carbamazepine monotherapy; and (3) 5 patients receiving carbamazepine in combination with other anticonvulsants. Carbamazepine kinetics in the patients were investigated by use of15N-CBZ. The mean plasma clearances of carbamazepine were 19.8, 54.6 and 113.3 ml/h/kg in groups 1, 2 and 3, respectively. The increased clearance in the patients was mainly due to an induction of the epoxide-diol pathway, as reflected by an increased urinary excretion of the trans-CBZ-diol metabolite. The urinary excretion (as a percentage of the administered dose) of 9-hydroxymethyl-10-carbamoyl-acridan (9-OH-CBZ) was also increased, whereas the excretion of 2-OH-CBZ and 3-OH-CBZ in groups 2 and 3 were decreased in comparison with group 1.As it has been suggested that 9-OH-CBZ is formed from carbamazepine-10,11-epoxide (CBZ-E) or trans-CBZ-diol, the formation of 9-OH-CBZ was investigated in 3 patients with trigeminal neuralgia treated with carbamazepine or CBZ-E as monotherapy on separate occasions. The urinary excretion of 9-OH-CBZ was 1.9, 3.3 and 4.0% of the trans-CBZ-diol excretion during CBZ-E therapy and 23, 32 and 24%, respectively, during carbamazepine administration. Thus only a minor part of the 9-OH-CBZ excreted in urine during carbamazepine therapy is formed via the epoxide-diol pathway.Data on plasma concentrations of carbamazepine and CBZ-E, and on urinary excretion of trans-CBZ-diol from 4 patients on carbamazepine therapy were used to calculate the plasma clearance of CBZ-E. The hydration of CBZ-E during carbamazepine therapy was found to be induced, but to a lesser extent than the epoxidation of carbamazepine.The interrelationship between carbamazepine-epoxidation and oxidative metabolic reactions of some other drugs was also studied in 8 healthy volunteers. Carbamazepine-epoxidation was not correlated to 4-hydroxylation of debrisoquine, oxidation of sparteine, 3- and 4-hydroxylation and demethylation of antipyrine, demethylation of amitriptyline, or total metabolism of theophylline.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS

摘要:

The elimination kinetics of aztreonam (SQ 26, 776), a new, completely synthetic, monocyclic &bgr;-lactam antibiotic, were studied after the administration of a single 1g intra-venous dose. Five healthy volunteers and 20 patients with various degrees of renal insufficiency were enrolled in this study. Concentrations of aztreonam in serum and urine were determined by both microbiological and high pressure liquid chromatography (HPLC) assays.The pharmacokinetic parameters for aztreonam were calculated on the basis of a 2-compartment open model. Serum concentrations of aztreonam at 10 minutes after administration were approximately 100 &mgr;g/ml in all subjects, regardless of renal function (HPLC assay). The mean serum half-life during the &agr;-phase showed no important variation with renal function. The mean serum half-life during the &bgr;-phase was 1.8 hours in normal subjects and 8.4 hours in haemodialysis patients (HPLC assay). There was a linear correlation between the serum clearance of aztreonam and creatinine clearance.The mean cumulative urinary recovery of aztreonam in 48 hours was 60 to 70% of the administered dose in normal subjects but this was reduced in the presence of renal insufficiency. SQ 26,992, the microbiologically inactive metabolite of aztreonam resulting from hydrolytic opening of the &bgr;-lactam ring, was undetectable in the serum of normal subjects but was found in low levels in uraemic patients. Half of a 1g intravenous dose of aztreonam was eliminated during 4 hours of haemodialysis.Guidelines for administration of aztreonam in the presence of renal failure are given.

ISSN:0312-5963    

出版商:ADIS    

年代:1985

数据来源: ADIS