Lenalidomide enhancement of human T cell functions in human immunodeficiency virus (HIV)-infected and HIV-negative CD4 T lymphocytopenic patients.

Suppressed T cell functions in human immunodeficiency virus (HIV) infection were identified and corrected by lenalidomide in middle-aged HIV-infected patients. Chemotaxis of T cells from HIV-infected men (n = 6, mean 43 years) to sphingosine 1-phosphate (S1P) and CCL21 was significantly lower than that of HIV-negative men (n = 6, mean 41 years), and was enhanced significantly up to control levels by 100 and 1000 nM lenalidomide. Generation of interleukin (IL)-2, but not interferon (IFN)-γ, by T cells of middle-aged HIV-infected men was significantly lower than that for controls and was increased significantly by 10-1000 nM lenalidomide up to a maximum of more than 300%. CD4 and CD8 T cells isolated from healthy middle-aged men and reconstituted in vitro at a low CD4 : CD8 ratio typical of HIV infection had depressed chemotaxis to S1P, but not CCL21, and generation of IL-2, but not IFN-γ. Significant enhancement of chemotaxis to S1P and CCL21 was induced by 100-1000 nM lenalidomide only for normal T cells at a low CD4 : CD8 ratio. T cells from HIV-negative middle-aged CD4 T lymphocytopenic patients (n = 3), with a CD4 : CD8 ratio as low as that of HIV-infected patients, had similarly diminished chemotaxis to S1P and CCL21, and depressed generation of IL-2, but not IFN-γ. Lenalidomide at 30-1000 nM significantly enhanced chemotaxis to S1P and IL-2 generation for T cells from HIV-negative CD4 T lymphocytopenic patients as from HIV-infected patients, with less effect on CCL21-elicited chemotaxis and none for IFN-γ generation. Defects in functions of T cells from middle-aged HIV-infected men are partially attributable to CD4 T lymphocytopenia and are corrected by lenalidomide.

Effects of testosterone on the Q-T interval in older men and older women with chronic heart failure.

The Q-Tc interval duration on the electrocardiogram is recognized to differ between the sexes. In vitro data and data from humans before and after puberty and menopause suggest that sex hormones play a role in the longer Q-Tc intervals in women, or conversely, the shorter Q-Tc intervals in men. Direct investigations of sex hormone effects on the Q-Tc interval in humans, however, are limited and reach conflicting conclusions. Our objective was to determine effects of testosterone on ECG Q-T intervals of older men and older women. ECG's from 84 older men and older women in double-blind placebo-controlled investigations of testosterone supplementation for the treatment of chronic heart failure (CHF) were analysed. Thirty men received 1000mg intramuscular long-acting testosterone undecanoate and 28 men received saline at 0, 6 and 12weeks. ECG's were recorded at baseline and 12weeks. Sixteen women received transdermal testosterone (33µg) and 10 women received matching placebo twice weekly for 24 weeks with ECG's at baseline and after 24weeks. Testosterone, but not placebo, shortened Q-T and Q-Tc intervals without heart rate changes. Q-T intervals decreased from 385±28 (mean±SD) to 382±28 ms (p<0.002) and Q-Tc intervals decreased from 398±26 to 392±27 (p<0.006) in men on testosterone. In women, Q-T intervals decreased from 400±25 to 397±23ms (p=0.06) and Q-Tc intervals from 415±26 to 409±27ms (p=0.3) on testosterone. Q-T intervals were longer in women compared with men under all conditions (p<0.03). The data support a direct effect of testosterone to shorten Q-T intervals in older men and older women in the absence of HR changes or hypogonadal status. Mean decreases are small and unlikely to affect risks of arrhythmic events in patients receiving Q-T prolonging medications.

The current state of knowledge on age, sex, and their interactions on clinical pharmacology.

Pharmacokinetic and pharmacodynamic changes occur with increasing age. Sex differences in pharmacokinetics and pharmacodynamics exist and persist at older age. The issue for the clinician is how to best treat the older patient with currently available knowledge. This communication highlights age- and sex-related differences in pharmacokinetics that should influence clinical practice and prescribing guidelines to optimize clinical responses. The most compelling data for sex-specific medication dosing guidelines for older patients are related to volume of distribution differences, or size differences, between the sexes and to differences in glomerular filtration rates.

The ACC professional life survey: career decisions of women and men in cardiology. A report of the Committee on Women in Cardiology. American College of Cardiology.

OBJECTIVES: This survey was conducted to learn how the career decisions of women and men in cardiology influenced their professional and personal lives. BACKGROUND: Women represent only 5% of practicing adult cardiologists and 10% of trainees. Yet, women and men now enter medical school at nearly equal numbers. The factors that contribute to career satisfaction in cardiology should be identified to permit the development of future strategies to ensure that the best possible candidates are attracted to the profession. METHODS: A questionnaire developed by the Ad Hoc Committee on Women in Cardiology of the American College of Cardiology (ACC) was mailed in March 1996 to all 964 female ACC members and an age-matched sample of 1,199 male members who had completed cardiovascular training. RESULTS: Women were more likely to describe their primary or secondary role as a clinical/noninvasive than invasive cardiologist (p < 0.0001 women vs. men). Men and women both reported a high level of satisfaction with family life, but women were less satisfied with their work as cardiologists (88% vs. 92%, p < 0.01) and with their level of financial compensation. Compared with men, women expressed less overall satisfaction (69% vs. 84%) and more dissatisfaction with their ability to achieve professional goals (21% vs. 9%). These differences were most pronounced for women in academic practice. Women reported greater family responsibilities, which may limit their opportunities for career advancement. Women were more likely to alter training or practice focus to avoid radiation. A majority of women (71%) reported gender discrimination, whereas only 21% of men reported any discrimination, largely due to race, religion or foreign origin. CONCLUSIONS: Women cardiologists report overall lower satisfaction with work and advancement, particularly within academic practice. They report more discrimination, more concerns about radiation and more limitations due to family responsibilities, which may ultimately explain the low percentage of women in cardiology. Attention to these issues may result in programs to improve professional satisfaction and attract the best candidates into cardiology in the future.

Effect of nifedipine on serum digoxin concentration and renal digoxin clearance.

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady-state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5 +/- 4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (+/- SD) digoxin concentrations of 0.74 +/- 0.20 and 0.75 +/- 0.25 ng/ml on placebo were not altered by nifedipine (0.77 +/- 0.23 ng/ml). Digoxin clearance was 2.2 +/- 0.6 and 2.7 +/- 0.8 ml/kg/min on placebo and 2.5 +/- 0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.

Verapamil stereoisomers during racemic verapamil administration: effects of aging and comparisons to administration of individual stereoisomers.

Aging decreases elimination of racemic verapamil but reports vary regarding effects of aging on clearance of individual verapamil enantiomers. To determine effects of aging on elimination of S- and R-verapamil, racemic verapamil was infused to steady-state concentrations of approximately 30, 60, and 120 ng/ml in 27 healthy subjects ranging in age from 23 to 81 years (young, 20 to 39 years; middle aged, 40 to 59 years; old, 60 to 81 years), and enantiomer concentrations were measured at each steady-state and after infusions. S-Verapamil clearance was greater than R-verapamil clearance in all age groups (p < 0.001), and aging decreased S-verapamil (p < 0.05) and R-verapamil (p < 0.008) clearance (average +/- SD, S-verapamil clearance was 14.3 +/- 4.7, 13.4 +/- 5.2, and 11.7 +/- 5.2 ml/min/kg; R-verapamil clearance was 6.5 +/- 3.3, 5.6 +/- 2.8, and 4.5 +/- 1.6 ml/min/kg in young, middle-aged, and older subjects, respectively). Enantiomer clearance was not effected by verapamil concentration. A trend toward an age effect on elimination half-lives was seen (S-verapamil half-life, 281 +/- 116 versus 234 +/- 89 minutes in elderly versus young; R-verapamil half-life, 253 +/- 56 versus 199 +/- 58 minutes in elderly versus young, p = 0.08). R- but not S-verapamil clearance during multistage infusions of racemic verapamil was lower than previously reported clearance after single intravenous enantiomer doses (p < 0.0001). In summary, aging decreases clearance of both S- and R-verapamil during steady-state intravenous dosing of racemic verapamil with preserved stereoselective clearance of verapamil with aging.

Aging of women alters S-verapamil pharmacokinetics and pharmacodynamics.

Pharmacokinetics and pharmacodynamics of S-verapamil were studied in 25 healthy nonsmoking women ranging in age from 23 to 33 years (young) and from 63 to 79 years (elderly) after 15-minute intravenous infusions of 0.10 to 0.11 mg/kg. S-Verapamil clearance decreased in an age-related manner (15.7 +/- 3.5 ml/min/kg in young women versus 12 +/- 1.5 ml/min/kg in elderly women; p < 0.0004) and elimination half-life values increased in an age-related manner from 347 +/- 97 minutes in young women to 453 +/- 153 minutes in elderly women (p < 0.05). Neither volume of distribution beta, steady-state volume of distribution, nor protein binding were altered by age. S-Verapamil decreased blood pressure (p < 0.0001), increased PR intervals during sinus rhythm (p < 0.0001), and transiently increased heart rate (p < 0.0001) in both young and elderly subjects. Age-related differences in responses were seen for mean (p < 0.03) and systolic blood pressure (p < 0.002) (greater decreases in the elderly), heart rate (less increase in the elderly; p < 0.0001), and PR intervals during sinus rhythm (less prolongation in the elderly; p < 0.0001). In summary, aging alters S-verapamil pharmacokinetics and pharmacodynamics in women.

Lack of interaction between verapamil and cimetidine.

Nine healthy normal subjects received verapamil, 10 mg iv, before (control) and during cimetidine dosing (300 mg every 6 hours), and verapamil, 120 mg po, twice in the same manner. After intravenous doses, the t1/2 (means +/- SE: control, 3.60 +/- 0.40 hours; cimetidine trial, 4.30 +/- 0.60 hours), volume of distribution (5.8 +/- 0.6 vs. 6.6 +/- 0.9 L/kg), and total clearance (19.2 +/- 1.5 vs. 18.4 +/- 1.6 ml/min/kg) did not change during cimetidine dosing. After oral doses, the t1/2 (4.25 +/- 0.57 vs. 4.60 +/- 0.70 hours), plasma AUC (585 +/- 113 vs. 506 +/- 82 ng/ml X hr) and absolute bioavailability (35% +/- 7% vs. 30% +/- 5%) did not differ between control and cimetidine trials, respectively. Five of the subjects also received lidocaine, 25 mg iv, once in the control state and once during the cimetidine regimen described above. Lidocaine clearance fell (665 +/- 216 vs. 527 +/- 134 ml/min; P less than 0.05) during cimetidine therapy, resulting in a trend toward a longer t1/2 (1.81 +/- 0.41 vs. 2.44 +/- 0.42 hours; 0.1 greater than P greater than 0.05) with no change in volume of distribution (1.77 +/- 0.66 vs. 1.99 +/- 0.81 L/kg). Verapamil pharmacodynamics (ECG PR interval, blood pressure, and heart rate) were evaluated after intravenous doses. A decrease in mean arterial pressure (8 +/- 1 vs. 9 +/- 2 mm Hg) and a reflex increase in heart rate (14 +/- 3 vs. 17 +/- 2 bpm) were no different in the control and cimetidine trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of cimetidine or ranitidine administration on nifedipine pharmacokinetics and pharmacodynamics.

The effect of cimetidine or ranitidine administration on responses to single and multiple doses of nifedipine were studied in 11 subjects who received cimetidine (300 mg q.i.d.) and 12 who received ranitidine (150 mg b.i.d.) in combination with nifedipine. After single doses of nifedipine, cimetidine decreased apparent oral clearance (dose/AUC) from 66 +/- 32 L/hr to 33 +/- 14 L/hr (p less than 0.01); elimination half-life increased from 4.0 +/- 2.2 to 4.9 +/- 2.9 hours (p less than 0.07). Increases in heart rate were greater (26 +/- 13 vs 13 +/- 11 beats/min standing; 19 +/- 11 vs 9 +/- 9 beats/min supine) and lasted longer than after nifedipine alone. Hypotensive effects were similar (10 +/- 7 mm Hg decrease vs 9 +/- 9 mm Hg). During nifedipine multiple-dose administration, cimetidine decreased the apparent oral clearance from 76 +/- 39 to 43 +/- 20 L/hr (p less than 0.01). Blood pressure responses were not altered by cimetidine but heart rate increased more (18 +/- 9 vs 9 +/- 9 beats/min supine; 18 +/- 13 vs 13 +/- 14 beats/min standing). Ranitidine coadministration did not alter nifedipine elimination or dynamic responses. During administration of nifedipine alone, the ratio of oral clearances (multiple to single doses) was 1.1 +/- 0.5. Thus (1) cimetidine but not ranitidine alters responses to nifedipine and (2) nifedipine kinetics do not differ between single- vs multiple-dose conditions.

Faster clearance of sustained release verapamil in men versus women: continuing observations on sex-specific differences after oral administration of verapamil.

Pharmacokinetic studies after administration of 120 mg oral sustained- and regular-release racemic verapamil were performed in 13 healthy subjects (seven men, age 74 +/- 4 years [mean +/- SD], weight 69.9 +/- 5.4 kg, and body mass index 24.6 +/- 2.2]; and six women, age 65 +/- 13 years, weight 65 +/- 9.9 kg, and body mass index 25.3 +/- 3). Verapamil was measured by HPLC, concentration versus time data analyzed by noncompartmental models, and statistical analyses performed by ANOVA for repeated measurements. The area under the concentration versus time curve (AUC) after administration of sustained-release verapamil was 48,951 +/- 18,079 ng/mL x min(-1) in women compared with 25,595 +/- 10,245 in men and lower than after administration of regular-release verapamil (63,055 +/- 24,411 for women and 34,686 +/- 25,279 in men; P = .05 for sex-related effect and P < .02 for formulation effect). AUC ratios of norverapamil (N-demethylated metabolite) to verapamil after administration of sustained-release verapamil were 1.43 +/- 0.26 in women compared with 1.74 +/- 0.41 in men and 1.43 +/- 0.26 in women compared with 1.78 +/- 0.37 in men after administration of regular-release verapamil (P = .1 for sex-related effect and P = .9 for formulation effect). Apparent oral clearance was 43 +/- 15 mL/min/kg in women compared with 75 +/- 29 in men after administration of sustained-release verapamil and 35 +/- 16 mL/min/kg in women compared with 65 +/- 31 in men after administration of regular-release verapamil (P < .05 for sex-related effect and P < .02 for formulation effect). Apparent oral clearance of both regular- and sustained-release formulations of verapamil was faster in men compared with women in contrast to findings after intravenous administration of verapamil, suggesting that intestinal processes are a factor in sex-specific difference in drug clearance. Greater verapamil and norverapamil bioavailability after administration of regular- compared with sustained-release verapamil also suggests saturable processes at the intestinal level.

Race and sex influence clearance of nifedipine: results of a population study.

OBJECTIVE: To estimate oral clearance of nifedipine and to determine demographic and clinical covariates that affect nifedipine clearance in a clinical population. METHODS: Apparent oral clearance of nifedipine and protein binding were measured in 226 patients receiving sustained-release nifedipine formulations for hypertension and coronary artery disease (black men, n = 111; black women, n = 27; white men, n = 64; white women, n = 24). Mean age +/- SD was 71 +/- 11 years, and mean weight was 86 +/- 17 kg. Nifedipine concentrations were analyzed by HPLC, protein binding was measured by equilibrium dialysis, clearance and covariate effects were estimated by a nonlinear mixed effects population model, and statistical analyses were performed by a nonlinear mixed-effects model (clearance) and ANOVA (protein binding). RESULTS: Clearance was significantly slower in black subjects (8.9 +/- 0.7 mL/min/kg; mean +/- SE) compared with white subjects (11.6 +/- 0.8 mL/min/kg; P = .00004) and in men compared with women (9.3 +/- 0.6 versus 12.1 +/- 1.5 mL/min/kg; P = .0021). Reported alcohol use (alcohol, 8.6 +/- 1.1 versus no alcohol, 10.8 +/- 0.6 mL/min/kg; P = .0002) and smoking status (smoker, 8.8 +/- 2.0 versus nonsmoker, 10.2 +/- 0.6 mL/min/kg; P = .0362) also affected nifedipine clearance. Race and sex had no effect on protein binding of nifedipine (P = .29 and P = .44, respectively). No effects of age, stable coronary artery disease, or reported intake of beta-blockers on nifedipine clearance were detected in this primarily elderly population with hypertension. CONCLUSIONS: The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.

In vivo comparison of putative probes of CYP3A4/5 activity: erythromycin, dextromethorphan, and verapamil.

OBJECTIVES: Multiple in vivo CYP3A4/5 probes have been proposed. We compared verapamil clearance measures (CYP3A4/5 substrate) to the erythromycin breath test (ERBT) and the cumulative urinary dextromethorphan/3-methoxymorphinan test. METHODS: Clearance of intravenous and oral racemic verapamil and the area under the plasma concentration versus time curve (AUC) ratio of norverapamil (N-demethylated metabolite) to verapamil after oral verapamil dosing, the ERBT, and the dextromethorphan urinary metabolite ratios were measured in 84 healthy nonsmoking subjects (42 men and 42 women; age, 47 +/- 23 (mean +/- SD) years; weight, 69 +/- 11 kg). Relationships between putative CYP3A4/5 probes were assessed by linear regression. RESULTS: The strongest correlation was between intravenous and oral verapamil clearance (r2 = 0.26; P = .0001). Relationships between cumulative urinary dextromethorphan/3-methoxymorphinan and (1) intravenous verapamil clearance (r2 = 0.073; P = .024), (2) oral verapamil clearance (r2 = 0.144; P = .001), and (3) plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil (r2 = 0.10; P = .01) were also detected. The ERBT and intravenous verapamil clearance were weakly related (r2 = 0.04; P = .067). No relationship was detected between ERBT and dextromethorphan/3-methoxymorphinan ratios (r2 = 0.00006; P = .945), oral verapamil clearance (r2 = 0.00006; P = .94), or plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil (r2 = 0.0002; P = .9). CONCLUSIONS: Intravenous and oral verapamil clearance values were significantly correlated, and cumulative dextromethorphan/3-methoxymorphinan urinary ratios correlated with both plasma AUC(norverapamil)/AUC(verapamil) after oral verapamil dosing and with oral and intravenous verapamil clearance. The ERBT correlated only weakly with intravenous verapamil clearance. Results with verapamil are comparable to results with other intravenous and oral CYP3A4/5 probes. Lack of correlation between putative CYP3A4/5 probe results may be attributable to the route of administration; probe characteristics; and intersubject, intrasubject, between-day, and testing measurement variability.

Pharmacokinetics of calcium antagonists under development.

Calcium antagonist drugs under clinical development are of the Type I (verapamil, diltiazem-like) and Type II (nifedipine-like) classes. Tiapamil, the only Type I drug currently available, is a high clearance, widely distributed drug which undergoes extensive presystemic elimination. Pharmacokinetically it is quite similar to verapamil; however, it does have increased biliary excretion and decreased binding to plasma proteins. Eight Type II (dihydropyridine) drugs are reviewed. Seven of these drugs (felodipine, isradipine, nicardipine, nilvadipine, nimodipine, nisoldipine and nitrendipine) are pharmacokinetically similar to nifedipine, with high clearance, extensive distribution, and significant presystemic elimination. Amlodipine has lower clearance, even greater peripheral distribution, and greatly decreased presystemic elimination. Three of the 8 dihydropyridines have been reported to have plasma protein binding greater than 90%. Unlike nifedipine, each dihydropyridine drug under development has an asymmetric centre; therefore each in fact is a racemic mixture. Human pharmacokinetic and pharmacodynamic data have not been reported for any of the racemates. Each of the drugs has been studied in patients with hepatic and renal disease. Predictably, patients with severe hepatic disease have decreased presystemic clearance and, in some cases decreased clearance after intravenous administration of the dihydropyridines, although renal failure has little influence on their pharmacokinetics. Unfortunately, disease-drug interaction studies of this class of drugs do not generally report plasma protein binding. The effect of age on the disposition of 2 of the dihydropyridines has been reported; however, only for nicardipine can a conclusion be drawn, namely that volume of distribution may increase with age and clearance may remain unchanged. A variety of potential drug-drug interactions have been evaluated, most commonly the effect of these drugs on cardiac glycoside disposition and effect, and the effect of cimetidine on the disposition of dihydropyridines. Tiapamil, like verapamil, impairs digoxin clearance significantly. Among the dihydropyridines, although minor pharmacokinetic effects have in some cases been reported, the magnitude of the interactions suggest they have limited clinical importance. From drugs currently under development, it is clear that a large number of calcium antagonists will soon be introduced into clinical use. Only 1 of the newer drugs, amlodipine, has significant pharmacokinetic differences from the agents currently in use, although possible pharmacodynamic differences among the drugs have been suggested.(ABSTRACT TRUNCATED AT 400 WORDS)

Digoxin and nifedipine.

Many investigators have studied the potential interactions between calcium-channel antagonists and digoxin. Digoxin is usually well absorbed, and its excretion is dependent on renal mechanisms, primarily glomerular filtration. Several studies have reported a decrease in digoxin clearance and an increase of approximately 50% in digoxin levels when verapamil was added to digoxin therapy. Because renal digoxin clearance was decreased but no concomitant change in creatinine clearance was shown, the presumed major mechanism for decreased renal digoxin clearance is an alteration in renal tubular secretion of digoxin. Although an early report described a digoxin-nifedipine interaction, several subsequent studies have shown no significant changes in digoxin kinetics during nifedipine administration. Four studies found no significant decrease in creatinine clearance of digoxin during nifedipine administration. Thus significant changes in glomerular filtration are unlikely. Physiologic endpoints were measured by 2 groups describing a digoxin-nifedipine interaction and, although there was an increase in serum digoxin concentration, no changes were found in electrophysiologic correlates. Thus, if a digoxin-nifedipine interaction does exist, steady-state digoxin levels might increase from 24 to 45% when nifedipine therapy is added. Studies to date have involved small numbers of subjects with and without cardiac disease and have used different study protocols. Nonetheless, little evidence exists for any clinically significant increase in physiologic effects and no adverse effects have been found in patients receiving combined nifedipine and digoxin.

Responses to intravenous and oral diltiazem in elderly and younger patients with systemic hypertension.

Diltiazem concentrations and blood pressure, heart rate, PR interval and forearm vascular resistance responses to intravenous (25 and 50 mg) and oral (120 mg) diltiazem were compared in 13 elderly persons (mean age 68 +/- 4 years) and 10 young persons (mean 30 +/- 5 years) with essential hypertension. Diltiazem elimination was slower in the elderly. After a dose of 25 mg, clearance was 13 +/- 4 ml/min/kg in the elderly and 23 +/- 7 in the young (p less than 0.05); after 50 mg, 16 +/- 6 and 21 +/- 12 ml/min/kg (p less than 0.05); and after oral administration, 22 +/- 9 and 35 +/- 14 ml/kg/min (p less than 0.02). No age-related differences in volume of distribution (by model or area methods) were seen. Elimination half-lives were 4.5 +/- 2.2 hours in the elderly and 3.8 +/- 0.7 hour in the young persons (p less than 0.01); 4.5 +/- 1.6 and 3.3 +/- 0.7 hours (p = 0.10); and 4.7 +/- 1.5 and 3.3 +/- 1.8 hours (p = 0.08) after 50, 25 and 120 mg. Maximal decreases in mean blood pressure were from 113 +/- 14 to 91 +/- 12 mm Hg (19%) in the elderly patients and from 108 +/- 8 to 99 +/- 9 mm Hg in the younger patients (8%) after 50 mg; from 106 +/- 13 to 93 +/- 14 mm Hg and from 109 +/- 11 to 99 +/- 13 mm Hg, respectively, after 25 mg; and from 113 +/- 10 to 97 +/- 10 mm Hg and from 109 +/- 11 to 97 +/- 8 after 120 mg orally.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison in young and elderly patients of pharmacodynamics and disposition of labetalol in systemic hypertension.

Pharmacodynamics and pharmacokinetics of labetalol, a combined alpha- and beta-adrenoceptor antagonist drug, were studied in elderly and young hypertensive patients. After receiving intravenous labetalol, elderly patients had a greater maximal mean decrease in systolic blood pressure (BP) (39 +/- 8 vs 25 +/- 13 mm Hg, p less than 0.02); however, maximal decrease in diastolic BP was similar in elderly (18 +/- 10 mm Hg) and young (17 +/- 6 mm Hg) patients. After receiving oral labetalol, elderly patients had a greater maximal decrease in standing systolic BP (41 +/- 16 vs 16 +/- 14 mm Hg, p less than 0.001) and similar decreases in standing diastolic BP (21 +/- 7 vs 17 +/- 9 mm Hg). Sitting maximal BP decreases after oral labetalol treatment were similar in elderly and young patients (12 +/- 16 vs 17 +/- 7 mm Hg systolic and 24 +/- 6 vs 12 +/- 7 diastolic). The decrease in heart rate was greater in young patients after intravenous labetalol administration. To evaluate labetalol pharmacodynamics, a linear model was used. Slope of labetalol concentration vs systolic BP for elderly vs young patients was 0.928 +/- 1.05 vs 0.326 +/- 0.490 ng/ml X mm Hg-1 (difference not significant). The slope of labetalol concentration vs heart rate for elderly vs young patients was 0.176 +/- 0.063 vs 0.406 +/- 0.303 ng/ml X beats/min-1 (p less than 0.05), with 2 elderly patients showing no decrease in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age and gender on the QT response to exercise.

Although gender differences in resting corrected QT intervals have been well documented, the effects of age and exercise on gender differences in QT have not been well characterized. Data were analyzed from 91 healthy volunteers (47 women). Forty-five young subjects (aged 20 to 39 years) and 46 older subjects (61 to 84 years) were recruited. All underwent Bruce protocol stress testing. QT offset and QT peak were measured at exercise stages and during recovery. In a heart rate (HR)-independent analysis, data were divided into HR bins of 10 beats/min. In a HR-dependent analysis, 6 models were used to approximate the QT-RR relation; the best were used to analyze age and gender effects. Women had longer QT intervals than men at a HR < 100 beats/min for QT offset and < 110 beats/min for QT peak. At faster HRs, no significant differences were found. Older subjects had slightly longer QT intervals than the younger group, with a mean difference of 2 ms for QT offset and 9 ms for QT peak. Women had increased constant and slope coefficients. The QT increase in the elderly was relatively small. Gender differences in QT disappear at faster HRs, whereas age differences are smaller but are present throughout exercise, with no significant age-gender interaction. A natural logarithmic model provides the best approximation of the QT-RR relation with exercise, is simple to implement, and should become the preferred method of QT correction.

Gender effects in pharmacokinetics and pharmacodynamics.

There are a number of examples of sex differences in drug pharmacokinetics and pharmacodynamics. Recent advances in the characterisation of specific isozymes involved in drug metabolism now allow for the preliminary identification of enzyme systems that are affected by sex. While current data are somewhat limited and not in complete agreement, the majority of studies show that apparent cytochrome P450 (CYP) 3A4 activity is higher in women than in men, whereas the activity of many other systems involved in drug metabolism may be higher in men than in women. Women and men also show different pharmacodynamic responses to a variety of drugs. While the clinical significance of these sex differences remains to be determined, we anticipate that they will be most important in the administration of drugs that have a narrow therapeutic range. In addition, sex differences in drug metabolism may be involved in the higher incidence of adverse reactions to drugs in women compared with men. Further research is needed to determine the scope and significance of these sex differences. Female-specific issues such as pregnancy, menopause, oral contraceptive use and menstruation may also have profound effects on drug metabolism. These effects can often be clinically important. Pregnancy may increase the elimination of antiepileptic agents, reducing their efficacy. Oral contraceptive use can interfere with the metabolism of many drugs and, conversely, certain drugs can impair contraceptive efficacy. More research is needed to determine the impact of menopause, hormone replacement and menstruation on drug therapy.

Early experience with dobutamine stress testing and cardiac cine-tomographic imaging in the elderly: antianginal effects of nifedipine-GITS.

OBJECTIVE: To determine the effects of nifedipine-GITS (GITS = gastrointestinal transport system) on angina and cardiovascular responses to stress-dobutamine infusion, we used ultrafast cine-computed tomography (CT) to assess regional wall motion, myocardial perfusion, and indices of ventricular filling and emptying. DESIGN: Randomized, double-blind placebo-controlled efficacy study after an open-label dose titration phase. SETTING: University of California, San Francisco. PATIENTS: Elderly patients (> 60 years; n = 9:8 male, 1 female) with coronary artery disease by history and diagnostic treadmill or coronary angiography. INTERVENTION: After a 3-week open-label dose-titration phase, eight subjects were randomized to receive either placebo or nifedipine-GITS at the highest tolerated dose for 2 weeks, followed by a crossover to the alternate therapy for 2 weeks. One declined because of singulus in the open-label period. MAIN OUTCOME MEASURES: Symptomatic angina relief (frequency and nitroglycerin consumption), dobutamine stress responses (time to ischemia during dobutamine infusions, cardiac output, cardiac ejection fraction, ventricular segmental wall motion, and perfusion as measured by ultrafast cine-CT), and reported adverse effects. RESULTS: When compared with placebo, nifedipine-GITS administration was associated with less frequent angina and nitroglycerin consumption (NS) and significantly decreased systolic blood pressure. Nifedipine-GITS administration also increased resting supine heart rates. Dobutamine infusions increased heart rate, cardiac output, cardiac ejection fraction, and stroke volume and induced angina symptoms. Neither double product at angina nor systolic indices of cardiac function in response to dobutamine differed between nifedipine-GITS and placebo, although heart rate responses were greater during nifedipine. A trend toward increased peak filling rates was seen during dobutamine stress in the nifedipine-administration period. In most subjects (6/8), perfusion and regional wall motion abnormalities were not visualized on regional wall motion abnormalities were not visualized on either rest or stress cine-CT studies. Edema without congestive heart failure occurred frequently during nifedipine-GITS administration. CONCLUSIONS: These data suggest that (1) dobutamine stress can be used to induce cardiac ischemia in elderly patients with coronary artery disease, (2) nifedipine-GITS provides symptomatic angina relief in elderly patients, (3) peripheral edema is frequent in elderly patients on nifedipine-GITS, and (4) ultrafast computed cine-tomography testing can be used to assess ventricular performance, but current methodology may not detect perfusion or wall motion abnormalities during angina.

Dopaminergic responses in the Fischer 344 rat heart: preserved chronotropic and dromotropic responses with aging.

BACKGROUND: Marked decreases in cardiac responses to beta-adrenergic stimuli have been found in cellular, animal, and human models of physiologic aging. As another probe of receptor-regulated cardiovascular changes with aging, responses to dopamine were studied. Responses were studied with and without depletion of myocardial catecholamines to eliminate effects secondary to myocardial catecholamine release. METHODS: Responses of heart rate (A-A intervals), atrioventricular conduction (AV intervals and AV Wenckebach block cycle length) to 0-50 microM dopamine were studied in Langendorff perfused hearts from 10 mature (6.2 +/- 0.8 mo, mean +/- SD) and 9 senescent (23.6 +/- 0.7 mo) Fischer 344 rats and in hearts from 10 mature (5.3 +/- 0.4 mo) and 8 senescent (23.9 +/- 0.8) Fischer 344 rats after myocardial catecholamine depletion by reserpine (0.25 mg/kg i.p. x 5 days). RESULTS: Dopamine decreased A-A (p < .0001) and AV conduction intervals (p < .0001) and increased peak developed pressure (p < .0001) and dP/dt (p < .001) in hearts from nonreserpine treated mature and senescent rats. Greater decreases in A-A intervals and AV conduction were seen in senescent compared to mature hearts (p < .0001). Contractile responses were greater in mature hearts (p < .001). After reserpine, A-A interval and paced AV conduction dose vs response relationships shifted rightward (p < .0001), but peak responses and age-related differences in responses were not significantly affected. In contrast, increases in peak developed pressure were greatly reduced in mature hearts (p < .0001) and age-related differences in contractile responses to dopamine were eliminated in hearts from reserpine-treated rats. CONCLUSIONS: (a) A-A interval and AV conduction responses to dopamine were greater in senescent hearts even after catecholamine depletion, suggesting age-related differences in sinus and AV nodal responses to direct dopaminergic stimuli exist. (b) Age-related differences in contractile responses to dopamine were eliminated by reserpine suggesting basal age-related differences in response were secondary to age-related differences in responses to myocardial catecholamine release.