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STUDY OBJECTIVE: A validation study was conducted first to test assumptions about the effect of saturated and unsaturated dietary fat supplements. The second study was conducted to determine the effect on blood cholesterol levels of saturated and unsaturated fat supplements in patients who followed a low-fat diet and were administered lovastatin. DESIGN: Randomized, crossover design, with three periods in the first study and four in the second study, each lasting 6 weeks. SETTING: Cholesterol Research Center. PATIENTS: The first study evaluated adults with total cholesterol levels between 200 and 280 mg/dl (5.172 and 7.241 mmol/L). The second study included adults with low-density lipoprotein (LDL) cholesterol levels above 160 mg/dl (4.138 mmol/L). INTERVENTIONS: Fat supplements with either coconut or canola oil were delivered to patients in oatmeal-raisin cookies. MEASUREMENTS AND MAIN RESULTS: In the validation study, patients' mean prerandomization total cholesterol level of 222 mg/dl was reduced to 213 mg/dl with canola oil and increased to 233 mg/dl with coconut oil cookies (p = 0.0038). In the second study the mean prerandomization total cholesterol level of 214 mg/dl was decreased to 199 mg/dl with canola oil and to 208 mg/dl with coconut oil cookies (p = 0.2342). The LDL cholesterol levels changed in a similar fashion in both studies. CONCLUSIONS: Changes in total and LDL cholesterol levels in the validation study were expected based on established effects of saturated and unsaturated fatty acids, but changes in these levels in lovastatin-cookie study were not expected. They could have occurred because lovastatin reversed the effect of saturated fats and enhanced the effect of unsaturated fats. Alternatively, they may have been due to enhanced bioavailability of lovastatin when administered with a high-fat diet. These findings must be confirmed.

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OBJECTIVE: To compare escalating doses of immediate-release (IR) and sustained-release (SR) niacin for effectiveness in reducing levels of low-density lipoprotein cholesterol and triglycerides and increasing levels of high-density lipoprotein cholesterol, and for the occurrence of adverse reactions, especially hepatotoxicity. DESIGN: Randomized, double-blind, parallel comparison of IR and SR niacin administered sequentially at 500, 1000, 1500, 2000, and 3000 mg/d, each for 6 weeks. SETTING: Cholesterol research center. PATIENTS: Forty-six adults, 23 in each group, with low-density lipoprotein cholesterol levels greater than 4.14 mmol/L (160 mg/dL) after 1 month of a step 1 National Cholesterol Education Program diet. OUTCOME MEASURES: Fourteen-hour fasting lipid and lipoprotein cholesterol levels, results of clinical laboratory tests, a symptom questionnaire, and withdrawal rates. RESULTS: The SR niacin lowered low-density lipoprotein cholesterol levels significantly more than IR niacin did at the dosage of 1500 mg/d and above, while IR niacin increased high-density lipoprotein cholesterol levels significantly more than SR niacin did at all dosage levels. The reduction in triglyceride levels was similar with IR and SR niacin. Nine (39%) of the 23 patients assigned to the IR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were vasodilatory symptoms, fatigue, and acanthosis nigricans. Eighteen (78%) of the 23 patients assigned to the SR dosage form withdrew before completing the 3000-mg daily dose; the most common reasons for withdrawal were gastrointestinal tract symptoms, fatigue, and increases in levels of liver aminotransferases, often with symptoms of hepatic dysfunction. None of the patients taking IR niacin developed hepatotoxic effects, while 12 (52%) of the 23 patients taking SR niacin did. CONCLUSION: The SR form of niacin is hepatotoxic and should be restricted from use. The IR niacin is preferred for the management of hypercholesterolemia but can also cause significant adverse effects and should be given only to patients who can be carefully monitored by experienced health professionals.

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BACKGROUND: A number of relatively inexpensive compact analyzers are available for use in physician offices and outpatient clinics to measure total cholesterol and, more recently, high-density lipoprotein (HDL) cholesterol and triglycerides. This study was designed to document the analytical performance of two of them, the Abbott Vision and the Kodak Ektachem DT60, for assays of total cholesterol, HDL cholesterol, triglycerides, and calculated low-density lipoprotein (LDL) cholesterol. METHODS: Lipid profiles were measured from venous blood samples of 70 subjects with each test device, and results were compared with those from a laboratory standardized to the Centers for Disease Control. Coefficient of variation (CV) of multiple measurements from three pools of human serum (ie, precision), mean percent difference between device and standard laboratory results (ie, accuracy or bias), and 95% tolerance intervals (total error) were determined. The correct classification of patients into risk categories with device results was compared with the standardized laboratory results. RESULTS: The average CVs for total cholesterol, triglycerides, and HDL cholesterol with the Vision analyzer were 3.6%, 4.4%, and 10.5%, respectively, and with the DT60, 5.0%, 4.1%, and 6.8%, respectively. The average percent biases for the same analytes with the Vision analyzer were 0.2%, 4.0%, and -2.3%, respectively, and with the DT60, -2.1%, 12.1%, and 0.1%, respectively. Total error assessments indicated that total and HDL cholesterol measurements in individual patients met the guidelines of the National Cholesterol Education Program with both devices, but that triglycerides and LDL cholesterol measurements did not. Classification of subjects into risk groups based on total or LDL cholesterol gave clinically satisfactory results with either device. CONCLUSIONS: More precise measurement technology for LDL cholesterol is needed. Physicians and others who rely on compact analyzer results for diagnosis and treatment decisions should consider the degree of inaccuracy and imprecision in these values.

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The effect of hydrochlorothiazide, propranolol, and enalapril on cognitive and motor function and quality of life (QOL) in hypertensive patients was studied. Patients > or = 55 years of age with asymptomatic essential hypertension were included in a randomized, double-blind, placebo-controlled, crossover study. Subjects discontinued their previous antihypertensive agents and started hydrochlorothiazide 25 mg, extended-release propranolol hydrochloride 120 mg, enalapril maleate 10 mg, or placebo. One capsule was taken for three days and then the dosage was doubled for the remainder of a four-week period. Subsequent crossover treatments were begun without a washout period. In each treatment phase, a battery of psychometric tests was used to assess cognitive and motor function and quality of life; all tests but one were self-administered via computer terminal. Pulse rate and blood pressure were recorded, and compliance was monitored by capsule count. Sixteen of 30 patients interviewed completed the trials; one additional patient was evaluated after receiving all treatments except hydrochlorothiazide. Mean +/- S.D. age of the subjects was 66 +/- 6.1 years; 10 were black and 7 white; 9 were men. Except for the hydrochlorothiazide group, blood pressure in the active treatment groups did not differ significantly from placebo; hydrochlorothiazide significantly reduced systolic but not diastolic blood pressure compared with placebo. Compared with placebo, hydrochlorothiazide was associated with fewer incorrect responses in a test of complex reaction time and with greater discriminant reaction time response rates; otherwise, no difference between groups was noted in cognitive or motor performance. There were no significant differences between active treatments and placebo on individual QOL measures.(ABSTRACT TRUNCATED AT 250 WORDS)

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This multicenter, double-blind, placebo-controlled study was conducted to evaluate dose-response effects and safety of once-daily administration of pravastatin, a new inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Pravastatin 5, 10, 20, 40 mg or placebo was administered at bedtime to 150 patients with primary hypercholesterolemia inadequately controlled on a low-fat, low-cholesterol (AHA Phase I) diet. After 8 weeks of treatment, pravastatin produced dose-dependent reductions in low-density lipoprotein (LDL) cholesterol of 19.2 to 34.1% (p less than or equal to .001 vs. baseline and placebo) and reductions in total cholesterol of 14.3 to 25.1% (p less than or equal to .01 to p less than or equal to .001 vs. placebo and p less than or equal to .001 vs. baseline). The relationship between the loge dose of pravastatin and decrease in LDL cholesterol was linear (p less than 0.002). High-density-lipoprotein cholesterol increased up to 11.7% and triglycerides decreased by as much as 23.9%. Pravastatin was well tolerated; no patient withdrew from the study as a consequence of treatment-related adverse events. Despite its relatively short serum half-life of approximately 2 h, once-daily administration of pravastatin provides a safe and effective means of reducing elevated LDL and total cholesterol.

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In two experiments, we examined the acquisition and retention of a letter-detection skill with a consistent-mapping procedure. In Experiment 1, subjects were trained from 0 to 4 sessions at detecting the letter H in displays containing random letters, and retesting occurred after a 1-month delay. Performance improved and in some cases became more automatic, and the performance level was maintained over the retention interval. When tested with a prose passage, the high error rate on the word THE was eliminated after training and after the retention interval, regardless of the amount of training. In Experiment 2, two subjects were given 12 sessions of training followed by a retention test 6 months later. For 1 subject there was also a retention test 15 months after acquisition. Performance improved dramatically with training, and substantial but not complete automaticity was achieved. Performance on the retention tests was close to the final acquisition level. The surprising lack of forgetting in this study was contrasted with the substantial forgetting typically found in studies of verbal learning.

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The steady-state pharmacokinetics and renal clearance of guanfacine were studied in patients with renal insufficiency. Apparent total body and renal clearances of guanfacine, as well as apparent volume of distribution, decreased in parallel with the decline in renal function. Higher plasma levels of guanfacine were observed in patients with GFR less than 30 ml/min. The steady state t 1/2 of guanfacine in the presence of renal insufficiency was insignificantly prolonged relative to that observed in the presence of normal renal function and appeared to be independent of the degree of renal insufficiency.

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In three experiments we examined aspects of the word inferiority effect and word frequency disadvantage for letter detection. In Experiment 1 we tested a prediction derived from a hypothesis based solely on attentional factors. Adult subjects performed one of two secondary detection tasks while reading for comprehension. The inferiority effects were obtained only when the secondary task was letter detection, not when nonletter targets were used in the secondary task. This finding is inconsistent with the attentional hypothesis, but is consistent with the unitization hypothesis of Healy and Drewnowski (1983). In Experiments 2 and 3 we found that manipulation of the need to read for comprehension had little influence on the letter-detection inferiority effects, but a strong influence on the effects involving the detection of nonletter targets. These results are discussed in terms of their implications concerning processing system flexibility.

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Previous studies have obtained conflicting evidence regarding the effect of probe modality when a secondary probe task is used to measure attentional demands of a primary letter-matching task. The present experiments found no difference in the shape of the probe reaction time functions for auditory and visual probes as long as probe modality was known. When probes "unexpectedly" occurred in the modality that was different from the majority of the probes, differences were obtained. Only the unexpected auditory function changed, shape relative to the others, with reaction time to probes that occurred early in the matching task sequence being increased. The results are interpreted as supporting a role of attentional capacity in the activation of structures that accept relevant sensory input.

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Apomorphine-induced vomiting is often used for preclinical efficacy testing of putative antiemetics in normal volunteers. The usual technique of individual intravenous titration for finding the threshold emitic dose of apomorphine in each subject is slow and tedious. We used a uniform dose of 0.05 mg/kg apomorphine given subcutaneously to test the antiemetic action of metoclopramide and votracon in ten healthy, young male volunteers. All ten subjects vomited in response to this dose of apomorphine when pretreated with placebo. Pretreatment with metoclopramide prevented vomiting in all subjects, and votracon prevented vomiting in two. Apomorphine, 0.05 mg/kg, subcutaneously appears to be an appropriate challenge dose for testing compounds for antiemetic activity in normal human volunteers.

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A familiarity effect in these experiments is defined as a subject's ability to respond more rapidly to a familiar stimulus than to an unfamiliar stimulus. In the first experiment, responding faster to familiar letters (upright) than to unfamiliar letters (inverted) occurred only when the two stimulus types were presented in a random order. These results were interpreted in terms of the effects of processing strategy changes. The second experiment compared the responding of Japanese and American subjects to Japanese and English letters. American subjects responded faster to English letters and Japanese subjects responded faster to Japanese letters. This familiarity effect was obtained even when stimulus presentation was organized by letter type and subjects knew which letter type to expect. The final experiment compared English and Japanese letters in a memory search task. The rate of search for Japanese letters was slower than for English letters. However, no zero-intercept difference was obtained. The evidence indicates that familiarity does not affect an initial encoding process, but it can affect a comparison process.

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Blood levels and urinary excretion rates of bethanidine were determined in three normal human subjects following oral administration of a single dose of the drug. The postabsorptive decline of blood concentration with time was noticeably slower than the corresponding decline in the urinary excretion rate. The discrepancy can be attributed to a continual decrease in the renal clearance of bethanidine throughout the study. Therefore, pharmacokinetic modeling of urinary excretion data alone would lead to erroneous conclusions concerning the persistence of drug in the blood.

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The antiarrhythmic activity of diphenidol, an antiemetic, has been demonstrated both in electrophysiologic studies of patiens and in experimental arrhythmias in animals. Accordingly, 18 patients with tachyarrhythmias were treated with intravenous diphenidol in doses of 0.5 to 1.5 mg/kg. In six patients with atrial arrhythmias, there was no notable effect. Similarly, 12 patients with premature ventricular contractions were treated and studied. In six of them, ectopic beats were abolished, at least transiently; in three the number of ventricular premature contractions decreased; in two there was no effect; and in one, the number of premature beats was increased. Of the total number of 18 patients, 14 suffered adverse effects related to the central nervous system. These adverse effects were of such severity as to suggest that further studies with diphenidol as an antiarrhythmic are not warranted.

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Resting human muscle blood flow (MBF) was determined simultaneously in the usual intramuscular injection sites to resolve whether variance in MBF could account for differences in drug absorption. Three pairs of muscles (gluteus maximus, vastus lateralis, and deltoid) were studied in each of 20 adult subjects. Use of dual, matched linear rate meters allowed two muscles to be studied simultaneously, with the order of injection random within an incomplete block design. MBF was calculated from the 133xenon washout rate using a single exponential that the computer found to best fit the data. Deltoid MBF (11.6 ml/100 gm/min plus or minus 0.5) was significantly (p smaller than 0.05) greater than gluteus MBF (9.6 plus or minus 0.5), with vastus or between right and left sides for each muscle. These data indicate that there are consistent differencies in resting MBF among specific muscle groups of sufficient magnitude (19%) to affect the rate of absorption and peak serum levels following intramuscular administration of drugs.

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