The influence of time of administration on the pharmacokinetics of a once-a-day diltiazem formulation: morning against bedtime.

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08:00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD) = 47 center dot 2 (25 center dot 8) against 39 center dot 6 (21 center dot 1) ng mL-1, p = 0 center dot 038), AUC0-24 (2008 (814) against 1754 (714) ng h mL-1, p = 0 center dot 024), and AUC0-48 (2662 (1244) against 2395 (238) ng h mL-1, p = 0 center dot 034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage.

Bioavailability of metformin in tablet form using a new high pressure liquid chromatography assay method.

Twenty-four young healthy volunteers received a single dose of metformin 500 mg (Glucophage, Nordic Laboratories, Canada) in tablet form. Plasma concentrations were determined by HPLC in samples collected prior to and 0.33, 0.66, 1, 1.33, 1.66, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18, 24, and 30 h after dosing. Mean (+/- SD) Cmax was 682.1 (160.6) ng ml-1 at a mean (+/- SD) tmax of 2.4 (0.93) h. Overall elimination was monoexponential with a mean (+/- SD) half-life of 3.16 (0.47) h. We conclude that metformin is rapidly absorbed from this formulation and is also rapidly eliminated. Extrapolation to steady state predicts that equilibrium will be reached within 24 h.

RECPAM: a computer program for recursive partition and amalgamation for survival data and other situations frequently occurring in biostatistics. III. Classification according to a multivariate construct. Application to data on Haemophilus influenzae type b meningitis.

The methodology of RECursive Partition and AMalgamation (RECPAM) previously presented in Parts I and II (A. Ciampi et al., Computer. Methods Progr. Biomed. 26 (1988) 239-256 and 30 (1989) 283-296) pursues its development with an application to predict long-term effects of a disease given a set of clinical information measured at the time of illness. This paper illustrates how RECPAM deals with a situation typical in Medical Informatics applied to data on Haemophilus influenzae type b meningitis.

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses.

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.

Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses.

In young healthy volunteers diltiazem does not have linear kinetics between single and multiple doses. Elimination half-life increases and gives AUC's and Cmax higher than those predicted from single dose data. Kinetics of diltiazem were assessed in 16 healthy elderly after a single 60 mg dose and in 24 healthy elderly after 60 mg every 8 h for 7 days. Thirteen participants completed both studies. Elimination half-life, AUC0-24, AUC0-infinity, and Cmax were (mean +/- SE) 7.4 (1.2) h, 349 (34) ng/ml.h, 392 (44) ng/ml.h, and 43 (5) ng/ml respectively after a single dose. After multiple doses elimination half-life, AUC0-48, AUC0-infinity, Cmax and Cmin were respectively 5.7 (0.3) h, 974 (107) ng/ml.h, 1022 (108) ng/ml.h, 102 (7) ng/ml and 43 (5) ng/ml. Exploratory statistics on the 13 volunteers common to both studies showed that the ratio of AUC desacetyl-diltiazem (DAD)/AUC diltiazem rose between single and multiple doses while elimination half-life of both diltiazem and N-desmethyl-diltiazem (MA), tmax, and AUC MA/AUC diltiazem were not affected. The conclusion of this study is that elimination half-life of diltiazem does not increase in elderly between single and multiple doses, possibly due to an increased biotransformation into DAD.

Cluster analysis of an insulin-dependent diabetic cohort towards the definition of clinical subtypes.

Clinical and biochemical data on 111 consecutive insulin-dependent diabetic children enrolled in a longitudinal prospective study were analyzed to determine if more than one clinical expression of Type I diabetes exists. Use of multivariate statistical methods, including Correspondence Analysis, kappa-means clustering and RECPAM (RECursive Partition and AMalgamation), show that there are two well differentiated clinical expressions of IDDM each characterized by a cluster. One is characterized by later age, less severe onset, longer symptom duration, less beta-cell disappearance after 12 months, more females; the other by earlier age, more sudden and severe onset, DR 3/4, earlier disappearance of beta-cell function and more males. RECPAM analysis provides further insight into the structure of the two clusters. An other RECPAM tree identifies low, medium and high risk groups of disappearance of beta-cell function at 12 months after diagnosis.

RECPAM: a computer program for recursive partition amalgamation for censored survival data and other situations frequently occurring in biostatistics. II. Applications to data on small cell carcinoma of the lung (SCCL).

The RECPAM methodology previously presented in part I (A. Ciampi et al., Comput. Methods Programs Biomed. 26 (1988) 239-256) is applied to the analysis of survival data on small cell carcinoma of the lung (SCCL). It is shown how RECPAM can help answer the following questions which occur frequently in the analysis of clinical data: Is it possible to find a classification of patients with a certain disease into distinct prognostic groups? Given a covariate of special interest, does it have an independent prognostic significance even after confounding is taken into account? Does the prognostic significance of a covariate of special interest vary across patient subgroups? For the SCCL data, a prognostic classification is obtained and the tumor marker LDH is treated as a variable of special interest. Many features of RECPAM are illustrated, including, among others, Forward and Backward (Pruning) Stopping Rules, treatment of missing data, and use of several dissimilarity measures.

GENCOV: a Fortran program that generates randomly censored survival data with covariates.

We present a Fortran program for simulating censored survival data with covariates under the assumption of random censoring. The program generates times distributed according to the uniform distribution, the generalized Gamma distribution, the log-normal distribution and Pettitt's generalized logistic distribution with Box-Cox transformation of the time variable. Covariates can be introduced in the definition of the survival time, resulting in the generalized log-gamma, log-normal and Pettitt's regression models. Thereby the program provides the means for generating censored survival data according to parametric versions of three common regression models for censored survival data: the Accelerated Failure Time, the Proportional Hazards and the Proportional Odds models.

RECPAM: a computer program for recursive partition and amalgamation for censored survival data and other situations frequently occurring in biostatistics. I. Methods and program features.

The methodology of recursive partition and amalgamation in biostatistics is presented and a FORTRAN program for its implementation, RECPAM, is described. RECPAM can be used to obtain classifications of patients according to several criteria commonly occurring in clinical biostatistics: an example is prognostic classification based on survival data. Classes are defined by simple statements, expressed in clinical terms, about predictor variables (e.g. prognostic factors). Special features of RECPAM are: the possibility of implementing a variety of classification criteria, the integration of recursive partition and amalgamation, and the availability of several strategies for constructing classification trees. A simple example to illustrate input and output features is given. The scope and flexibility of RECPAM will be illustrated in greater detail in a subsequent paper.