Tolerance to nicotinic acid flushing.

The mechanism of tolerance to nicotinic acid flushing was determined in subjects during a 5-day course of treatment. Objective measures of skin blood flow were used to confirm the development of tolerance. Plasma levels of nicotinic acid showed marked intraindividual variability but were not decreased with the development of tolerance. However plasma levels of 9-alpha 11-beta prostaglandin F2, a stable metabolite of prostaglandin D2, became undetectable in most subjects with the development of tolerance. Thus tolerance is not associated with decreased levels of nicotinic acid or development of tolerance to the prostaglandin mediator, but with decreased levels of the mediator.

Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action?

The possibility that differences in metabolism might underly the differences in efficacy and toxicity between time-release and unmodified formulations of nicotinic acid was investigated by measuring 24-hour urinary excretion of metabolites in 10 subjects who received both forms. Nicotinic acid has two metabolic fates: formation of nicotinamide adenine dinucleotide (NAD) and formation of nicotinuric acid, the glycine conjugate of nicotinic acid. Catabolism of NAD releases nicotinamide, which is subsequently methylated and/or oxidized to form a number of metabolites, with 2-pyridone predominating. Excretion of nicotinuric acid was more than four times greater when subjects took unmodified nicotinic acid than when they took time-release nicotinic acid (78.2 and 18.8 mg, respectively). In contrast, excretion of 2-pyridone with unmodified nicotinic acid was only 30% more than with time-release nicotinic acid (171.0 and 129.9 mg, respectively). These results demonstrate a marked difference in the metabolism of unmodified and time-release nicotinic acid. It is proposed that nicotinyl coenzyme A (CoA), the metabolic intermediate in the formation of nicotinuric acid, mediates some of the hypolipidemic actions of nicotinic acid, as the acyl-CoA esters of xenobiotics, including clofibrate, have been shown to interfere with lipid metabolism.

Rate of low-density lipoprotein cholesterol and apolipoprotein B changes on initiation and discontinuation of atorvastatin treatment.

In a clinical trial, the changes in LDL cholesterol and in total apolipoprotein B with time were analyzed using a one-compartment model with constant input rate and first-order elimination rate constant after the initiation and discontinuation of treatment with atorvastatin. After initiation of treatment, input rate for total apoplipoprotein B (21 mg/dL/day) and elimination rate constants for both total apoplipoprotein B (0.36 days-1) and low-density lipoprotein (LDL) cholesterol (0.24 days-1) were similar to those reported for LDL-apolipoprotein B at steady state during treatment with other HMG-CoA reductase inhibitors. However, after discontinuation of treatment, very low elimination rate constants of 0.09 days-1 for LDL cholesterol and 0.07 days-1 for total apolipoprotein B are obtained. A likely explanation is that the model incorrectly assumes an immediate return to the pretreatment state, whereas transient stimulation of hepatic cholesterol synthesis on discontinuation of therapy with HMG-CoA reductase inhibitors is known to occur.

Atorvastatin does not produce a clinically significant effect on the pharmacokinetics of terfenadine.

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120-mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80-mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration-time curve extrapolated to infinity (AUC0-infinity), and a 2% decrease in elimination half-life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0-infinity and a 51 % increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.

Renal dysfunction does not alter the pharmacokinetics or LDL-cholesterol reduction of atorvastatin.

The objective of this study was to determine the effects of renal dysfunction on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Nineteen subjects with calculated creatinine clearances ranging from 13 mL/min to 143 mL/min were administered 10 mg atorvastatin daily for 2 weeks. Pharmacokinetic parameters and lipid responses were analyzed by regression on calculated creatinine clearance. Correlations between steady-state atorvastatin pharmacokinetic or pharmacodynamic parameters and creatinine clearance were weak and, in general, did not achieve statistical significance. Although the elimination rate constant, lambda z (0.579), was significantly correlated with creatinine clearance, neither maximum plasma concentration (Cmax, -0.361) nor oral clearance (Cl/F, 0.306) were; thus, steady-state exposure is not altered. Renal impairment has no significant effect on pharmacodynamics and pharmacokinetics of atorvastatin.

Erythromycin coadministration increases plasma atorvastatin concentrations.

The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0-infinity) increased by 37.7% and 32.5%, respectively. Mean terminal half-life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first-pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P-glycoprotein-mediated intestinal or biliary secretion.

Atorvastatin coadministration may increase digoxin concentrations by inhibition of intestinal P-glycoprotein-mediated secretion.

The effect of atovarstatin on digoxin pharmacokinetics was assessed in 24 healthy volunteers in two studies. Subjects received 0.25 mg digoxin daily for 20 days, administered alone for the first 10 days and concomitantly with 10 mg or 80 mg atorvastatin for the last 10 days. Mean steady-state plasma digoxin concentrations were unchanged by administration of 10 mg atorvastatin. Mean steady-state plasma digoxin concentrations following administration of digoxin with 80 mg atorvastatin were slightly higher than concentrations following administration of digoxin alone, resulting in 20% and 15% higher Cmax and AUC(0-24) values, respectively. Since tmax and renal clearance were not significantly affected, the results are consistent with an increase in the extent of digoxin absorption in the presence of atorvastatin. Digoxin is known to undergo intestinal secretion mediated by P-glycoprotein. Since atorvastatin is a CYP3A4 substrate and many CYP3A4 substrates are also substrates for P-glycoprotein transport, the influence of atorvastatin and its metabolites on P-glycoprotein-mediated digoxin transport in monolayers of the human colon carcinoma (Caco-2) cell line was investigated. In this model system, atorvastatin exhibited efflux or secretion kinetics with a K(m) of 110 microM. Atorvastatin (100 microM) inhibited digoxin secretion (transport from the basolateral to apical aspect of the monolayer) by 58%, equivalent to the extent of inhibition observed with verapamil, a known inhibitor of P-glycoprotein transport. Thus, the increase in steady-state digoxin concentrations produced by 80 mg atorvastatin coadministration may result from inhibition of digoxin secretion into the intestinal lumen.

Pharmacodynamics and pharmacokinetic-pharmacodynamic relationships of atorvastatin, an HMG-CoA reductase inhibitor.

The objective of this study is to determine the relationships between plasma atorvastatin concentrations, LDL (low-density lipoprotein) cholesterol reduction, and atorvastatin dose; the earliest time at which lipid levels change when atorvastatin treatment is initiated or discontinued; and alterations in LDL particle composition. Twenty-four subjects with elevated LDL-cholesterol were treated with escalating daily doses of 5, 20, and 80 mg atorvastatin for 6 weeks each. Serial plasma lipid and lipoprotein analyses were performed during the initiation and discontinuation of atorvastatin therapy, as well as at steady state. LDL-apolipoprotein B and LDL-cholesterol were measured directly after ultracentrifugation, and LDL-cholesterol also was estimated by the method of Friedewald. Steady-state atorvastatin pharmacokinetic parameters were estimated on the last day of each dosing period. LDL-cholesterol (Friedewald) reductions of 34%, 43%, and 57% were produced by atorvastatin doses of 5, 20, and 80 mg, respectively. The mean dose-response relationship was log linear, and almost all individual dose-response curves paralleled the mean curve. LDL-apolipoprotein B reductions were slightly less than those of LDL-cholesterol. Atorvastatin area under the curve (AUC(0-24) values increased proportionally with dose, while values of Cmax (maximum concentration) increased more than proportionally, and Cmin (minimum concentration) increased less than proportionally. Following initiation of dosing, statistically significant decreases in total cholesterol, LDL-cholesterol (beta quant), and LDL-apolipoprotein B were observed within 24 hours and in LDL-C (Friedewald) within 72 hours. Following discontinuation of drug dosing, statistically significant increases were observed in total cholesterol and LDL-cholesterol (Friedewald) within 48 hours and in LDL-cholesterol (beta quant) and LDL-apolipoprotein B within 72 hours. At each dose, an individual's LDL-cholesterol response was not correlated with AUC(0-24). In conclusion, atorvastatin produces marked LDL-cholesterol reductions, the mean dose-response relationship is log linear, almost all individual dose-response curves parallel the mean dose-response curve, onset and cessation of action are rapid, the estimated and measured LDL-cholesterol are the same, LDL-cholesterol and LDL-Apo B reductions are similar, and plasma concentrations are not correlated with LDL-cholesterol reduction at a given dose.

Scintigraphic cerebral spinal fluid leak study in a child with recurrent meningitis after resection of a frontal meningocele.

An In-111 DTPA cerebrospinal fluid (CSF) leak study was performed on a 3-year-old boy admitted with recurrent meningitis. He was born with a congenital encephalocele that was surgically resected at 7 days-of-age. A residual skull floor defect with a recurrent tumor of the nasal radix was clinically suspected. Computed tomography and MRI scans could not confirm or rule out the presence of a CSF leak. The scintigraphic study clearly demonstrated a leak into the left naris. A large leptomeningeal cyst extending down into the left nares was resected and a defect in the left frontal calvarium, identified as the source of the CSF leak, was repaired at surgery.

Left ventricular ejection: model solution by collocation, an approximate analytical method.

A differential equation solution method that does not utilize numerical integration is demonstrated on a physiologic model. A previously proposed model of left ventricular ejection incorporating time-varying elastance, internal resistance, aortic inductance, and a three-component windkessel is solved by collocation. Assuming internal resistance to be constant allows simplification to a third order linear differential equation in left ventricular volume. A trigonometric series is used to approximate the solution and the coefficients of the series as well as the duration of ejection and pre-ejection periods are chosen so that the governing differential equation is exactly satisfied at certain times during ejection (the collocation points), as well as the boundary conditions and steady state condition.

Effect of food on the pharmacodynamics and pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase.

The pharmacodynamics and pharmacokinetics of atorvastatin, an HMG-CoA reductase inhibitor, were characterized in 16 healthy subjects following administration of 10 mg atorvastatin tablets with, or 3 h after, evening meals for 15 days in an open-label, randomized, 2-way crossover study. Atorvastatin was well tolerated. Atorvastatin administration with evening meals resulted in 25.2% lower mean Cmax and 29.8% longer mean tmax values relative to administration after meals. The mean AUC(0-24) value was 8.6% lower for atorvastatin administration with meals compared to after meals. In contrast to the effect of food on pharmacokinetics, LDL-C reductions were similar after atorvastatin administration with or after evening meals. Average reductions from baseline were 24.4% for total cholesterol, 39.6% for LDL-C and 10% for triglycerides. Therefore, atorvastatin may be administered with or without food.

Medication use in training cases: a survey.

Though the introduction of psychotropic medication for the treatment of depression and anxiety was first greeted by the psychoanalytic community with overt opposition, in recent years the belief that medication and psychoanalysis are incompatible is being reconsidered. A study at the Columbia University Center for Psychoanalytic Training and Research showed that in 29% of candidate training cases medication was used in combination with psychoanalysis. In most cases the indication for medication was a diagnosis of depression, and an antidepressant was prescribed. The implication of these data with respect to the impact of medication on analytic process and candidate training is discussed.

Strain distribution and linkage relationship of a mouse embryonic hemoglobin variant.

Search for structural variants of three globin chains (x, y, z), synthesized only during mouse embryonic hematopoiesis, was carried out by electrophoretic analysis of blood from 12-day embryos, all with C57BL/6 mothers, and fathers from 115 inbred stocks selected for their diverse genetic origins. Structure of the beta-chains of adult hemoglobins differed among the tested strains, with 57 carrying the Hbbs allele, 56 the Hbbd allele, and two the Hbbp allele. The search revealed no x- or z-chain variants but confirmed and extended knowledge of a previously described y-chain variant. Blood of all embryos sired by males from the 57 Hbbs strains contained only y'-chains, while blood of au embryos sired by Hbbd or Hbbp males contained y2-chains as well as the y1-chains inherited from their C57BL/6 mother. The locus controlling structure of the y-chain of mouse embryonic hemoglobins is thus extremely closely linked to the locus controlling structure of adult hemoglobin beta-chain, with maximum possible recombination frequency less than 0.019.

Filter replicas and permanent collections of recombinant DNA plasmids.

A permanent, ordered collection of 23,000 recombinant DNA plasmids containing Drosophila melanogaster DNA has been established. Simple and practical methods for storing and manipulating this collection were developed. In addition, an improved, simple and inexpensive method for making paper filter replicas of such an ordered collection and of a high density (10,000 colonies/petri dish) unordered collection was developed. These filter replicas are suitable for nucleic acid hybridization screens of recombinant DNA colinies and each filter replica can be used for many (greater than 5) successive screens. The kinetics of this hybridization reaction were examined and allow design of experiments that detect colony complementarity to a nucleic acid that is 0.5% of the hybridization probe.

Cimetidine does not alter atorvastatin pharmacokinetics or LDL-cholesterol reduction.

OBJECTIVE: To determine the effects of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of atorvastatin, a 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS: Twelve healthy subjects participated in a randomized two-way crossover study. Each subject received atorvastatin 10 mg every morning for 2 weeks and atorvastatin 10 mg every morning with cimetidine 300 mg four times a day for 2 weeks, separated by a 4-week washout period. Steady-state pharmacokinetic parameters (based on an enzyme inhibition assay) and lipid responses were compared. RESULTS: Pharmacokinetic parameters and lipid responses were similar following administration of atorvastatin alone and atorvastatin with cimetidine. Mean values for Cmax (the maximum concentration) were 5.11 ng eq.ml(-1) and 4.54 ng eq.ml(-1), for tmax (the time to reach maximum concentration) 2.2 h and 1.3 h, for AUC0-24 (area under the concentration-time curve from time 0 h to 24 h) 58.6 ng eq.h.ml(-1) and 58.5 ng eq.h.ml(-1), and for t1/2 (terminal half-life) 10.1 h and 17.0 h, respectively, following administration of atorvastatin alone and atorvastatin with cimetidine. Following treatment with atorvastatin alone and atorvastatin with cimetidine, mean values for the percentage change from baseline for total cholesterol were -29.5% and -29.9%, for low-density lipoprotein (LDL) cholesterol -41.0% and -42.6%, for high-density lipoprotein (HDL) cholesterol 6.3% and 5.8%, and for triglycerides -33.8% and -25.8%, respectively. CONCLUSIONS: The rate and extent of atorvastatin absorption and the effects of atorvastatin on LDL-cholesterol responses are not influenced by coadministration of cimetidine.