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Biomedical subjects

N C Sambol

Publications and source records attributed to N C Sambol.

5 recordsLinked to original sources
PubMed1992

Variational analysis of the transdermal delivery rate from two prototypical ethanol-water nitroglycerin TTS devices and Transderm-Nitro 10 in the normal population.

The performance of two prototypical ethanol-water flux-enhanced transdermal therapeutic systems were compared to the performance of commercial Transderm-Nitro 10. This was a single-center, open-label, three-treatment, randomized crossover study in six healthy subjects who completed the study. Concurrent with each transdermal treatment, an infusion of the stable isotope [15N]3-nitroglycerin was administered. The use of double isotope methodology was incorporated into this study to minimize the variation introduced by fixed-effect error on the evaluation of transdermal flux. The objectives of this study were to isolate experimentally and characterize the average flux enhancement of each prototype, to determine the temporal profile of delivery, and to evaluate the components of variance of drug delivery from each transdermal system. The results of this study showed that the two flux-enhanced transdermal systems with different fill volumes both produced flux enhancement factors of 2 to 3 relative to Transderm-Nitro 10. Prototype B demonstrated a 57% reduction in intersubject variation relative to Transderm-Nitro 10 indicative of enhanced control of drug permeation across a subject population. Prototype A, while reducing intersubject variations, was less than optimal. Both prototypes demonstrated comparable intrasubject variation relative to Transderm-Nitro 10, indicating similar stability for within-subject transdermal drug delivery. The flux enhancement and variational properties of Prototype B were consistent with those intended based on mechanistic considerations of mutual nitroglycerin and ethanol-coupled transdermal delivery.

Administration, Cutaneous↗
PubMed1991

Population dose versus response of betaxolol and atenolol: a comparison of potency and variability.

The dose-response curves of betaxolol and atenolol were compared in 140 patients with mild to moderate essential hypertension. Patients with a supine diastolic blood pressure of 95 to 115 mm Hg at the end of a 4-week single-blind placebo washout phase were randomized (double-blind) to receive either betaxolol or atenolol in a dose-escalation manner. The dose (5 mg, 10 mg, and 20 mg betaxolol; 25 mg, 50 mg, and 100 mg atenolol) was increased if the supine diastolic blood pressure remained greater than 90 mm Hg after 4 weeks at each level. The final dose in the escalation phase was continued for an additional 12 weeks and then followed by a 2-week placebo phase. The data were analyzed with a population model using the program NONMEM (nonlinear mixed effects model). Atenolol exhibited a graded dose-response curve, whereas the lowest dose of betaxolol produced maximum or near-maximum effect. The estimated maximum effect (drug plus possibly unmeasured placebo effect) was similar for both treatments, about 13 mm Hg (95% confidence interval, 10 to 15 mm Hg). A trend toward less interindividual variability (coefficient of variation) was apparent for betaxolol compared to atenolol, 19% (95% confidence interval, 0% to 29%) versus 31% (95% confidence interval, 0% to 47%). The intraindividual variability (standard deviation) in supine diastolic blood pressure, 5.9 mm Hg (95% confidence interval, 5.2 to 6.5 mm Hg), did not differ significantly between drugs despite significantly greater intraindividual variability (coefficient of variation) in atenolol concentrations, 62% (95% confidence interval, 48% to 73%) versus 26% (95% confidence interval, 22% to 29%) for betaxolol.

Adolescent↗
PubMed1989

Study designs for dose-ranging.

Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.

Analysis of Variance↗
PubMed1989

A comparison of the influence of famotidine and cimetidine on phenytoin elimination and hepatic blood flow.

The H2-receptor antagonist cimetidine has been reported to decrease the hepatic clearance of numerous drugs by inhibiting cytochrome P-450 metabolism, decreasing liver blood flow or both. In this open-label, randomized crossover study we determined whether therapeutic doses of famotidine, a newer H2-receptor antagonist, has similar effects. Ten healthy subjects received single doses of both phenytoin 100 mg orally and indocyanine green intravenously without other treatment, and then again during treatment with famotidine or cimetidine. After a drug-free period, this sequence was repeated with the alternate H2-receptor antagonist. Cimetidine decreased the plasma clearance of phenytoin by 16% +/- 14% (mean +/- s.d.), but was not found to have a significant influence on phenytoin volume of distribution or terminal elimination rate constant nor on blood clearance of indocyanine green. Famotidine was not found to alter either phenytoin or indocyanine green kinetics.

Cimetidine↗