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The relative contribution of phenotypic measures and CYP2C9-vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms to warfarin dose requirements at day 14 was determined in 132 hospitalized, heavily medicated patients. Phenotypic measures were (1) the urinary losartan metabolic ratio before the first dose of warfarin, (2) the S:R-warfarin ratio at day 1, and (3) a dose-adjusted international normalized ratio (INR) at day 4. CYP2C9 and VKORC1 genotypes were determined by gene chip analysis. In multivariate analyses, the dose-adjusted INR at day 4 explained 31% of variability observed in warfarin doses at day 14, whereas genotypic measures (CYP2C9-VKORC1) contributed 6.5%. When S:R-warfarin ratio was used, genotypes contributed more significantly (23.5%). Finally, urinary losartan metabolic ratio was of low predictive value. The best models obtained explained 51% of intersubject variability in warfarin dose requirements. Thus, combination of a phenotypic measure to CYP2C9-VKORC1 genotypes represents a useful strategy to predict warfarin doses in patients receiving multiple drugs (11+/-4 drugs/day).

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Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration-time curves from 0 to 24 hours (AUC0-24) for nicotine were 453 +/- 120 ng.hr/mL (day 2), 489 +/- 143 ng.hr/mL (day 3), and 485 +/- 143 ng.hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20-minute exercise period, nicotine plasma levels increased by 13 +/- 9% for Nicoderm and 30 +/- 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise-induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short-lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.

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Twenty-four healthy women received 2.4 mg kg-1 dolasetron mesylate (1.8 mg kg-1 dolasetron base) by a 10 min intravenous administration and by oral administration. Pharmacokinetics of dolasetron and of its active reduced metabolite MDL 74156 were monitored for 48 h in plasma. Urine was collected from 0 to 48 h, blood pressure and heart rate were measured at 0, 0.08, 1, 2, 12, 24, and 36 h, and ECGs were measured at 0, 0.08 (intravenous only), 1, 2, and 36 h after dosing. Dolasetron was widely distributed and rapidly reduced (mean t1/2 = 0.23 h) to MDL 74156 (mean t1/2 = 8.05 and 9.12 h after intravenous and oral administration respectively). MDL 74156 was extensively distributed; between 27 (oral route) and 33% (intravenous route) was eliminated unchanged in urine. Safety assessment showed mild to moderate headache, dizziness, and hot flushes after the intravenous administration and headache, abdominal cramps or pain, and constipation after oral administration. Small and clinically non-significant changes in PR, QRS, and QTc intervals were observed. We conclude that there is no obvious difference in dolasetron pharmacokinetics between healthy women and men and that dolasetron can be used as safely in women as in men.

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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.

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This study was undertaken to assess the reliability of clinical parameters and dipyridamole-thallium 201 images for predicting the occurrence of future cardiac events (nonfatal myocardial infarction or cardiac death). Dipyridamole myocardial perfusion imaging is routinely performed in patients who have possible or known coronary disease and a low exercise tolerance. A total of 753 patients underwent clinical assessment and semiquantitative dipyridamole-201TI imaging and were followed up as outpatients. Patients who underwent coronary revascularization during the follow-up period were excluded from the study because the decision to intervene would have been based at least in part on the test itself. There were 82 cardiac events and 54 noncardiac deaths, and 11 patients were lost to follow-up after a mean follow-up of 15 months. With use of a quantitative index reflecting the amount of jeopardized myocardium, patients could be stratified by dipyridamole imaging into subsets with coronary morbidity and mortality rates ranging from 1% to 89%, (p = 0.0001). When clinical and scintigraphic variables were subjected to backward stepwise logistic regression analysis, the significant predictors of cardiac events were the jeopardized myocardium index by scintigraphy (p < 0.0001), left ventricular hypertrophy on the electrocardiogram (p = 0.0009), and transient dipyridamole-induced left ventricular cavitary dilatation (p = 0.0073). Quantitative dipyridamole-201TI imaging appears to be a powerful predictor of future cardiac events in patients with coronary disease and a low exercise tolerance and is a potentially useful contributor to risk-profile assessment and to the treatment of these patients.

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Diltiazem is a calcium antagonist used in angina pectoris and hypertension. There is little information concerning the slow-release (SR) formulation in the literature. The pharmacokinetics of diltiazem SR (120 mg) have been assessed over a 36h period in healthy volunteers after single- (SD) and multiple-dose (MD) administrations. Cmax, AUC0-36, and AUC0-infinity were significantly increased at steady state compared to the extrapolated SD values, suggesting accumulation of the drug. Renal and cardiovascular parameters have also been assessed at intervals of 3-6h during baseline (B) and following single and multiple doses of diltiazem SR. Diuresis over a 24 h period was increased, but not significantly, by the administration of diltiazem SR i.e. 1782 ml (MD) and 1915 ml (SD), versus 1626 ml (B). Natriuresis and creatinine clearance were slightly decreased by diltiazem SR, compared to B values; this might be due to the relatively short period over which steady state was maintained (five days) and the effects of norepinephrine and angiotensine II on renal vasculature and the pharmacokinetics of diltiazem SR. No increase in the systolic blood pressure occurred after the administration of diltiazem SR; diastolic blood pressure and PR interval were decreased and increased respectively by diltiazem SR. These results do not appear to be clinically significant. Finally, no relation was found between the pharmacokinetics and pharmacodynamics of diltiazem. This may be attributed to the absence of clinically significant effects in healthy volunteers, the presence of active metabolites, the pharmacokinetics of the SR formulation and/or the accumulation of the drug at steady state.

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Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.

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Pharmacokinetic and pharmacodynamic interactions of alcohol and nifedipine were assessed in 10 healthy human volunteers. Doses of 20 mg (2 x 10-mg capsules) of nifedipine were administered with either 150 ml of orange juice or 75 ml of alcohol (94%) in 75 ml of orange juice according to a crossover randomized design. Plasma nifedipine levels were monitored for 16 hr after each dosing, along with pulse rate and blood pressure. The relative bioavailability of nifedipine, measured as AUC, was increased by 54% (533 vs 346 ng.hr/ml) after the dose of alcohol (P less than 0.0002). However, there were no significant differences between treatments in Cmax, tmax, or t1/2. Although there was no difference in the systolic and diastolic blood pressure and pulse rate between the two treatment groups, the time to reach peak heart rate was significantly faster in the group treated with alcohol (1.4 vs 2.2 hr). This study shows that ethanol increases the bioavailability of nifedipine and decreases the time for onset of increased heart rate.

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Nitrates continue to play a key role in the treatment of heart disease. Tolerance can be prevented if treatment is interrupted for periods of eight to 14 hours. Because patients respond differently to nitrate therapy, consideration must be given to individual response, the risk of tolerance, and the method of administration.

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The efficacy of continuous and intermittent nitroglycerin patches (10 mg/day) was compared in a randomized, placebo-controlled trial in 36 patients with stable angina and reproducible, exercise-induced ST depression. Intermittent treatment was administered either 18 or 14 h/day with an intermission of 6 h or 10 h, respectively. Exercise tests were performed during the last 2 h of patch application. Compared with placebo, neither continuous nitroglycerin nor the two intermittent regimens prolonged total treadmill time or time to 1 mm ST depression. No treatment eliminated exercise-induced ST depression in greater than 1 of the 36 patients. Time to angina was prolonged (by 40 +/- 66 s) only during the "10 h off" treatment (p = 0.001); time to angina increased by greater than or equal to 20% in 13 patients. Responders to treatment could be predicted by a short history of angina (p less than 0.05) and a time to angina less than or equal to 250 s during the placebo test. For each treatment, greater than or equal to 25 of the patients reported headache; 4 additional patients dropped out because of severe headache and 2 others because of a coronary event in a washout period. Thus, in most patients with stable angina, side effects outweight any benefit demonstrable with this therapy.

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To determine if an occupational work evaluation could shorten the time to return to work, 201 employed men aged 49 +/- 7 years who were recovering from uncomplicated myocardial infarction were randomized to usual care (n = 102) or to an occupational work evaluation (n = 99). The occupational work evaluation consisted of a symptom-limited treadmill test performed 23 +/- 3 days after myocardial infarction and a formal recommendation to the patient and primary physician that the patient return to work within the next two weeks. The groups did not differ in age, medical status, comorbid disease, occupation type, or years on the job. At six months, 92% of patients receiving the intervention and 88% of patients receiving usual care were working either full- or part-time. Return to full-time work occurred at a median of 51 days in patients receiving the intervention and 75 days in patients receiving usual care. This 32% reduction in the convalescence period was associated with +2102 of additional earned salary per intervention patient in the six months after myocardial infarction. One or more recurrent cardiac events occurred in 14 intervention patients (one death, one nonfatal myocardial infarction, three angioplasties, and nine coronary surgeries) and in 13 usual-care patients (two deaths, three nonfatal myocardial infarctions, six angioplasties, and seven coronary surgeries) in the six months after myocardial infarction. The early return to work of low-risk patients based on an occupational work evaluation is associated with important economic benefits.

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In this experiment, we tested for opioid and nonopioid mechanisms of pain control through cognitive means and the relation of opioid involvement to perceived coping efficacy. Subjects were taught cognitive methods of pain control, were administered a placebo, or received no intervention. Their pain tolerance was then measured at periodic intervals after they were administered either a saline solution or naloxone, an opiate antagonist that blocks the effects of endogenous opiates. Training in cognitive control strengthened perceived self-efficacy both to withstand and to reduce pain; placebo medication enhanced perceived efficacy to withstand pain but not reductive efficacy; and neither form of perceived self-efficacy changed without any intervention. Regardless of condition, the stronger the perceived self-efficacy to withstand pain, the longer subjects endured mounting pain stimulation. The findings provide evidence that attenuation of the impact of pain stimulation through cognitive control is mediated by both opioid and nonopioid mechanisms. Cognitive copers administered naloxone were less able to tolerate pain stimulation than were their saline counterparts. The stronger the perceived self-efficacy to reduce pain, the greater was the opioid activation. Cognitive copers were also able to achieve some increase in pain tolerance even when opioid mechanisms were blocked by naloxone, which is in keeping with a nonopioid component in cognitive pain control. We found suggestive evidence that placebo medication may also activate some opioid involvement. Because placebos do not impart pain reduction skills, it was perceived self-efficacy to endure pain that predicted degree of opioid activation.

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Ten patients with panic disorder or agoraphobia with panic attacks and 10 normal controls received infusions of normal saline (placebo) and sodium lactate in a single-blind design. The time course of changes in the dependent variables was closely monitored, and expectancy biases and demand characteristics were minimized. Lactate increased self-reported anxiety and heart rate equally in patients and controls. The only variables showing statistically different responses between the groups were systolic and diastolic blood pressure. Overall, in both groups, the effects of lactate were quite similar to states of natural panic or anxiety for both self-report measures and heart rate. Patients had a tendency to endorse somatic symptoms indiscriminately. Our data do not support response to lactate as a biological marker of proneness to panic attacks.

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Of 33 "panic" attacks reported by patients wearing an ambulatory solid-state heart rate/activity monitor for 6 days, 19 (58%) occurred at heart rates disproportionate to activity levels and different enough from surrounding heart rates to indicate a distinct physiologic state. Intense panic attacks with three or more symptoms were the most readily identified. ECG monitoring found the elevated heart rates to be sinus tachycardias. Heart rate elevation did not occur during anticipatory anxiety episodes. Ambulatory heart rate recordings confirm the presence of major physiologic changes during self-reported panic attacks.

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A portable solid-state recorder-display system was used to measure and analyze heart rate during the waking hours of 3 consecutive days in free-living sedentary normal middle-aged men who were randomized to undergo 3 regimens of physical activity during a 12-week period: low-intensity exercise training at home (n = 21), high-intensity exercise training at home (n = 23) and customary activity (n = 20). This was done to determine whether the system could detect changes in heart rate and, indirectly, in physical activity within the 3 groups. In both training groups the percentage of total recorded time spent within the prescribed high or low heart rate range recorded at 6 or 12 weeks increased significantly (p less than 0.05), whereas control subjects showed no increase above baseline values. Peak oxygen consumption increased by 8% and 17% in men undergoing low- and high-intensity training, whereas in control subjects it did not change. This solid-state system reliably measures prescribed increases in heart rate and provides an indirect measure of physical activity in normal sedentary men undergoing exercise training at home.

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The effects of 12 weeks of home-based exercise training on peak oxygen consumption (VO2 max) in healthy sedentary middle-aged men, mean age 49 +/- 6 years, were evaluated. Twenty-one men trained at low intensity, 23 trained at high intensity and 20 were control subjects. Individually prescribed low- and high-intensity training was performed 5 times per week within a range of 42 to 60% and 63 to 81% of baseline VO2 max, corresponding to average heart rates of 102 to 122 and 128 to 148 beats/min, respectively. Caloric expenditure per training session approximated 350 kcal in both groups; adherence was at least 90% in both groups. VO2 max increased 8% in patients who trained at low intensity, 17% in those who trained at high intensity (both p less than 0.001), and not at all in control subjects. Low-intensity exercise training at home significantly augments functional capacity in healthy sedentary middle-aged men.

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Subungueal splinter hemorrhage (S.U.S.H.) has been reported in various conditions and may herald a serious systemic disease. It has been related to miscellaneous conditions such as: subacute bacterial endocarditis, severe rheumatoid arthritis, uninfected mitral stenosis, trichinosis, peptic ulcer, hypertension, neoplasm, trauma, and in some cases, is considered idiopathic. Some dermatologic conditions such as psoriasis, dermatitis, and fungal infections may also produce S.U.S.H. It consists of "a homogeneous mass of blood in a layer of squamous cells, adherent to the under surface of the nail, considered to be of embolic origin." In a brief review of pertinent medical literature on thromboangiitis obliterans, we were unable to find a description of its occurrence in this disease. The earliest lesions described in this condition are "painful vesicles on the pulp of digits with intense hyperemia and hypersensitivity of the surrounding skin." It is our opinion that S.U.S.H. is an earlier and quite useful sign of arterial involvement as seen in the following cases observed in our vascular disease section.

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