摘要:

Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) is a new antiepileptic drug developed in Japan. This compound is insoluble in water, and it is available in tablet and powder form. In experimental animals, this compound has been found to have a strong inhibitory effect on convulsions of cortical origin because it suppresses focal spiking and the spread of secondary generalized seizures. In humans, a series of double-blind, placebo-controlled studies revealed the efficacy of zonisamide for patients with refractory partial seizures and for selected patients with infantile spasms. Its antiepileptic mechanism of action remains unclear, but it is likely to involve blockade of both sodium and T-type calcium channels. Oral bioavailability of zonisamide is excellent in healthy human volunteers. Zonisamide is slowly absorbed and has a meantmaxof 5 to 6 hours. Almost 100% of it is absorbed; there is no difference in bioavailability between tablets and powder. Zonisamide concentrations are highest in erythrocytes and then in whole blood and plasma. It is approximately 40% to 60% bound to plasma proteins, primarily albumin. Its volume distribution is 0.9 to 1.4 L/kg. In adults, the elimination half-life is between 50 and 62 hours, and it takes as long as 2 weeks to reach steady state. The dose-serum level correlation is linear up to doses of 10 to 15 mg/kg per day, and the therapeutic range is 10 to 40 µg/ml. However, the relationship between serum zonisamide levels, clinical response, and adverse effects appears weak. Concurrent enzyme-inducing anticonvulsants such as phenytoin, carbamazepine, or barbiturates stimulate zonisamide metabolism and decrease serum zonisamide levels at steady state. Although zonisamide has been reported to increase the serum levels of phenytoin and carbamazepine in some patients, the interactions of zonisamide with other antiepileptic drugs seem to be of minor clinical relevance. A pilot study of zonisamide suppositories revealed that it is beneficial for patients with neurologic disorders in whom antiepileptic drugs cannot be administered by mouth.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Therapeutic drug monitoring (TDM) services, like many diagnostic services in public hospitals, have been under scrutiny over recent years as funding has decreased. The Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) sought to review clinical pharmacology departments to consider how the changes that have been implemented have affected the delivery of TDM in recent years. A questionnaire was sent to such departments and all those known to be delivering TDM services responded. The survey demonstrated that of the 11 departments contributing TDM assays, 10 had lost tests and staffing to general biochemistry departments; eight departments had been delivering research and development in TDM. The TDM tests retained in clinical pharmacology were typically the more complex chromatographic or labor-intensive toxicology tests or the more expensive immunoassays. If this direction in Australasia is typical of the situation internationally, it should be a matter of great concern to all those with a particular interest in TDM. Is the future of TDM to be one in which only rapid immunoassays will be provided, and by a staff not fully able to provide pharmacokinetic support and interpretation of such tests (i.e., to become simply number-generating services) despite all the pharmacoeconomic data that is increasingly available?

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The aim of the Multicentric Liver Transplant Spanish Study was to evaluate tacrolimus therapy at the reduced, initial oral dose of 0.1 mg/kg per day to maintain the immunosuppressive potency of the drug and to avoid toxicity. The dosage of tacrolimus (D), the trough blood concentrations (C), and the evolution of the ratio (D/C) were followed up for 2 years after transplantation in 50 adult patients (38 men, 12 women) undergoing liver allograft transplantation. A total of 1732 samples were analyzed using the IMx tacrolimus method. The overall mean ± SD concentrations were 10.84 ng/ml ± 5.32 ng/ml. During the first month, the median of the tacrolimus levels was 8.40 ng/ml, and 73.1% of the analyzed samples were within the established therapeutic range. The median oral tacrolimus dose was progressively reduced from 0.12 mg/kg per day during the first month to 0.058 mg/kg per day at the end of study period. A significant negative association was observed between the ratio of D/Cand the post-transplantation period (r= -0.3624;pCratio ranged from 0.0144 at the end of the first month to 0.0053 at 1 year. Significant declines in D/Cwere observed after the first and the third months after transplantation. The decrease in corticosteroid doses and the increase in serum albumin may explain the reduction in clearance with time.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The purpose of this study was to assess the ability of our previously constructed pharmacokinetic (PK) model to describe nitroglycerin (GTN), 1,2-dinitroglycerin (1,2-GDN), and 1,3-dinitroglycerin (1,3-GDN) plasma concentrations after a single-dose application of a GTN transdermal matrix delivery system. GTN, 1,2-GDN, and 1,3-GDN plasma concentrations were simultaneously fitted using a first-pass, mixed-order release, one-compartment PK model. Population PK parameter values were derived using an iterative two-stage methodology (IT2S). Some of the mean PK parameters estimates and their interindividual variability (CV%) were the percentage of the delivered GTN dose reaching the systemic circulation released by a first-order processA, 53% (44); the 1,2-GDN and 1,3-GDN formation rate constants,kf19 h-1(67) andkf20.5 h-1(38), respectively; the metabolite elimination rate constant,k(m) 1 h-1(27); GTN, 1,2-GDN, and 1,3-GDN volumes of distribution (Vc/F 6 L [45]),V2/F 78 L [51]), andV3/F 29 L [40]), respectively). Mean calculated elimination half-lives (t½± standard deviation[SD]) for GTN and the GDN metabolites fitted the observed plasma concentrations of GTN, 1,2-GDN, and 1,3-GDN very well. This new transdermal matrix delivery system appears to behave pharmacokinetically in the same manner as a transdermal reservior delivery system (Transderm-Nitro, Ciba-Geigy, Mississauga, Canada).

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The population pharmacokinetic profile of vancomycin (VCM) in Japanese pediatric patients infected with methicillin-resistantStaphylococcus aureuswas analyzed using 181 samples of serum concentration data from 49 patients obtained in routine drug monitoring. The one-compartment linear model was adopted, where the VCM clearance (CL) and the distribution volume (Vd) were correlated with covariates such as postnatal age (AGE) and body weight (BWT). The population pharmacokinetic analysis program NONMEM with the first-order conditional estimation method was used. The results showed that the population mean clearance normalized by BWT increases with AGE up to 1 year of age [CL(L/hour per kg) = 0.119 + 0.0619 · (AGE - 1)] and decreases with age over 1 year old [CL(L/hour per kg) = 0.119 + 0.00508 · (1 - AGE)]. The population mean of the distribution volume normalized by BWT was independent of AGE (Vd(L/kg) = 0.522). The interindividual variability of CL was 39.6%, and that of Vdwas 18.8%. The intraindividual, residual variability was 34.6%. These results were compared with those in other articles, and a guideline for dosage adjustment in VCM therapy is discussed.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The free fraction of phenytoin (PHT) in serum increases considerably in combination with valproic acid (VPA), depending on the VPA concentration. Equations to predict the free PHT concentration (PTHf) from the total PHT concentration (PHTt) and from the VPA concentration were developed by Haidukewych and colleagues. (equation 1: PHTf = 0.095 × PHTt + 0.001 × VPA × PHTt) and May and colleagues (equation 2: PHTf = 0.0792 × PHTt + 0.000636 × VPA × PHTt]; in both equations, PHTf, PHTt, and VPA are given in µg/ml. Obviously, the equations give different predictions. The aim of this study was to investigate whether different methods for the determination of PHTt and PHTf were responsible for the differences; equation 1 was calculated from standard TDx measurements and equation 2 from high-performance liquid chromatography (HPLC) values. A total of 52 samples from patients with VPA (n = 26) or without VPA (n = 26) were analyzed using HPLC and TDx. The concentrations measured by HPLC and TDx were highly correlated but TDx yields significantly higher PHTt (Y = 0.98 × X + 2.46; X = HPLC, Y = TDx,r2= 0.957) and, in particular, higher PHTf concentrations (Y = 1.03 × X + 0.30; X = HPLC, Y = TDx,r2= 0.919), compared with our HPLC method. The accuracy of the predictive equations depends on the method used for the determination of PHTt and PHTf. The best predictions of PHTf were obtained if equation 2 and HPLC measurements were used. However, the differences in the predicted PHTf could only partly be explained by the different methods of determination.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The authors' goal was to study the biologic availability and pharmacokinetics of two different formulations of controlled-release (CR) tablets of albuterol. A two-way, cross-over biologic availability study was performed with 20 healthy male volunteers to evaluate the relative biologic availability of two CR tablets of albuterol versus two different formulations of immediate-release (IR) albuterol tablets. Albuterol concentrations in plasma were measured using an HPLC procedure. Each patient subject received a 4.8-mg CR tablet every 12 hours for 6 days and a 4.8-mg IR tablet every 8 hours for 6 days. Tests of single doses and steady state were assayed for CR and IR albuterol tablets. The meanCmaxandtmaxfor two CR tablets given after a single dose were 7.3 ± 1.5, 7.9 ± 1.4 µg · L-1and 4.6 ± 0.8, 4.8 ± 0.5 hours, respectively. TheCmaxandtmaxfor two IR tablets given after a single dose were 12.5 ± 1.3, 15.3 ± 2.3 µg · L-1and 1.3 ± 0.4 hours, respectively. The relative biologic availability of two CR albuterol tablets were 106.0 ± 6.2% and 109.8 ± 9.0%, respectively. Administration of CR albuterol twice a day provides an alternative to administration of IR albuterol three or four times a day.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n = 7), and in control patients treated with clozapine alone (n = 15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232 ± 104 versus 356 ± ng/ml; mean, SD,ppp

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In a phase I-II study, the authors evaluated the intracellular pharmacokinetics, toxicity, and efficiency of a high dose of mitoxantrone given as first induction in acute non-lymphocytic leukemia. Twenty-two patients with previously untreated de novo ANLL were included and received 30 or 40 mg/m2mitoxantrone on day 1 by intravenous infusion over 1 hour and 500 mg/m2ara-C twice a day for 5 days. If there was no complete remission (CR), a second induction with ara-C, etoposide, and amsacrine was given. The CR rate after two courses with this regimen was 77%. Median duration of severe neutropenia was 18 days in the 30-mg/m2group and 25 days in the 40-mg/m2group. Two patients had fatal lung complications probably unrelated to mitoxantrone. A third patient had a possible mitoxantrone-induced reversible lung complication. In the leukemic cells, we found a high accumulation of mitoxantrone which, in contrast to the plasma concentration, remained stable during the 48 hours studied. Compared with previous results with 12 mg/m2mitoxantrone, the AUC for intracellular concentrations versus time for the first 20 hours studied was increased by 150% to 0.638 nmol/mg cell protein × hour with 30 mg/m2mitoxantrone and by 260% to 1.103 nmol/mg cell protein × hour with 40 mg/m2mitoxantrone. In conclusion, a high dose of mitoxantrone results in a high intracellular exposure of the leukemic cells, which may be an advantage in improving survival of these patients.

ISSN:0163-4356    

出版商:OVID    

年代:1998

数据来源: OVID