Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia.

AIMS: This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of ezetimibe 10 mg/day in patients with primary hypercholesterolemia. METHODS AND RESULTS: Following dietary stabilization, a 2-12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) > or =3.36 mmol/l (130 mg/dl) to < or =6.47 mmol/l (250 mg/dl) and triglycerides < or =3.95 mmol/l (350 mg/dl) were randomized 3:1 to receive ezetimibe 10 mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo (P<0.01). Response to ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein(2)-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo. CONCLUSIONS: Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.

Aspartame effect in sickle cell anemia.

OBJECTIVE: To examine the in vitro and in vivo attributes of aspartame and to determine its efficacy for treating sickle cell anemia. RATIONALE: Aspartame (l-aspartyl-l-phenylalanine methyl ester) binds with 2 human Bence Jones proteins. The proteins (Mcg and Sea) showed phenylalanine penetrating into hydrophobic binding sites. This aspartame property suggested a potential to interfere with sickle hemoglobin fibril formation. METHODS: For the in vitro studies, blood from 20 subjects monitored for sickle cell anemia was collected in heparinized tubes. Specimens were divided in thirds and aspartame was added to 2 tubes to yield a 1 mg/mL or 2 mg/mL concentration. Sickled cells that were present after a drop from each aliquot was added to a fresh 2% metabisulfite solution were counted 3 times. For the in vivo studies, 23 subjects from the Sickle Cell Clinic (University of Oklahoma Health Sciences Center, Oklahoma City, Okla) consented to participate in a randomized single-dose administration of 1.5, 3.0, or 6 mg/kg aspartame. Heparinized blood was obtained at 0, 30, 60, 120, 240, 480, and 1440 minutes after aspartame administration. Specimens were counted in a blinded manner by means of the technique used for the in vitro method, but a photomicrograph of 1 field from each triplicate count was made. The pictures were marked and were computer counted. RESULTS: For the in vitro studies, sickled cells decreased from 28% to < 14% when 1 mg/mL aspartame was added and decreased further with 2 mg/mL. For the in vivo studies, a decreased number of sickled cells in homozygous blood (HbSS) were observed after oral administration of aspartame. Sickling was inhibited by 6 mg/kg aspartame for at least 6 hours in 15 subjects with HbSS anemia. CONCLUSIONS: Further evaluations of the efficacy of aspartame for sickle crisis and crisis prevention appears to be warranted.

Treatment of osteoarthritis with aspartame.

OBJECTIVE: The binding of sweet-tasting compounds in a human (Mcg) Bence-Jones dimer has been characterized by x-ray crystallography. Aspartame binding in this immunoglobulin fragment is remarkable. Unexpected pain relief noted by A.B.E., a crystallographer with diagnosed osteoarthritis, suggested that the accommodation of aspartame in the active site of the dimer may represent surrogate binding by other proteins, with analgesia as the outcome. METHODS: X-ray analysis of the complex of aspartame and the Bence-Jones dimer was conducted with crystalline Mcg protein and pure aspartame. A single-blind (n = 1) study to confirm analgesia was completed by administration of aspartame to A.B.E. A controlled double-blind trial was performed in patients with x-ray-documented osteoarthritis. Pain and performance changes were evaluated with use of two doses of placebo and two doses of aspartame. Effects on bleeding time were then evaluated by determination of template bleeding times in 34 normal volunteers. Finally, antipyretic effects were studied in Sprague-Dawley rats given intramuscular turpentine injections. RESULTS: Aspartame binding in the Bence-Jones dimer was verified by x-ray crystallography. Improvements in performance and pain relief were observed in A.B.E. at p < 0.001. Decreased pain and improved performance were also observed in patients with osteoarthritis (p < 0.001). Mild antihemostatic responses were observed in bleeding times after aspartame treatment. Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile responses in the treated rats (p < 0.01). CONCLUSIONS: L-Aspartyl-L-phenylalanine methyl ester is biologically active and appears to relieve pain, induce mild antithrombotic effects in humans, and decrease fever in animals.

Cardiovascular effects of coffee and caffeine.

This study evaluated the cardiovascular effects and elimination kinetics of coffee and caffeine in 54 volunteers selected according to 3 gradations of daily caffeine consumption, cigarette smoking status and the presence of caffeine intolerance. After 24 hours of caffeine abstinence, subjects received coffee and 2.2 mg/kg of caffeine (equivalent to 2 cups of coffee). Blood pressure, heart rate, systolic time intervals and plasma concentrations of caffeine were measured before and at timed intervals after coffee and caffeine. There were no differences in response to coffee and caffeine. The average systolic/diastolic blood pressure increased 9/10 mm Hg. The maximal decrease in heart rate averaged 10 beats/min, and there were small increases in the systolic time intervals. There were no cardiovascular differences among the various groups. Caffeine in the smokers and heavy caffeine users had a shorter half-life (3.2 and 4.1 hours) than that in nonsmokers and nonusers (5.1 and 5.3 hours). In the caffeine-intolerant group it had a longer half-life, while the cardiovascular effects were similar to those of the other groups. Thus, irrespective of the amount of daily caffeine consumption, smoking status or caffeine intolerance, the cardiovascular responses were similar and tolerance, if present, was gone by 24 hours.

Comparison of the beta 1 and beta 2 adrenoceptor blocking properties of acebutolol and propranolol.

The purposes of this study were to evaluate the beta 1 and beta 2 adrenoceptor blocking properties of acebutolol and propranolol and measure the plasma levels of acebutolol, its acetylated metabolite and propranolol. Ten patients with reversible obstructive airways disease and hypertension received two separate dose levels of acebutolol and propranolol for five days each. Cardioselective properties were assessed by determining the beta 1 and beta 2 adrenergic-stimulating effects of terbutaline 5 mg before and at the end of each five-day treatment period. Both acebutolol and propranolol were clinically well tolerated. Following study drug there was a 100 percent inhibition of the beta 1 terbutaline effect, and an approximate 83 percent inhibition of the beta 2 terbutaline effect. There were no clinically significant differences between acebutolol and propranolol. The acetylated acebutolol metabolite accumulated levels two to three times higher than the parent compound, and its effects may have destroyed the cardioselectivity of acebutolol. Thus, acebutolol did not demonstrate clinically relevant cardioselectivity.

Effect of fiber on breath hydrogen response and symptoms after oral lactose in lactose malabsorbers.

The effect of ingesting cellulose, pectin, and psyllium with orally administered lactose in water or milk was tested in six lactose malabsorbers. Breath hydrogen tests were used to evaluate lactose malabsorption and mouth-to-cecum transit times. Addition of psyllium significantly reduced the breath hydrogen response, and symptoms in each subject; whereas, less diminution of expired hydrogen was seen after cellulose or pectin was added. The effect of each fiber on gastric emptying rates of an equal volume liquid meal was evaluated in three volunteers. Pectin had no effect, while the cellulose and psyllium modestly delayed emptying at approximately 30 min.

The use of diethyl-IDA Tc 99m clearance curves in the differentiation of biliary atresia from other forms of neonatal jaundice.

A family of isotope elimination curves that reflects changes in the biodistribution of diethyl-IDA Tc 99m in neonatal cholestatic jaundice and biliary atresia is defined. Time/activity curves generated from equal areas over the heart and liver were evaluated separately and in conjunction with the scintigraphic data. Patients without scintigraphic evidence of significant hepatic uptake and with a hepatic curve that resembled the cardiac curve were found to have neonatal hepatitis. Good hepatic uptake and a hepatic curve with a terminal portion that appeared to be parallel to or divergent from the cardiac curve were associated with biliary atresia. Apparently converging hepatic and cardiac curves were associated with biliary patency. Although preliminary, these results provide further documentation that diethyl-IDA Tc 99m is useful in discriminating biliary atresia from other causes of cholestatic jaundice, while reducing radiation exposure and the need for pharmacologic intervention.

Effect of psyllium hydrophilic mucilloid on oral glucose tolerance and breath hydrogen in postgastrectomy patients.

Twenty postgastrectomy patients ingested glucose solutions with or without psyllium hydrophilic mucilloid to determine its effects on their blood glucose and breath hydrogen excretion. On the basis of the breath hydrogen tests following glucose alone, 15 had various degrees of glucose malabsorption which the addition of psyllium markedly reduced. In all 20 patients, psyllium significantly lowered peak blood glucose and prolonged its rate of fall. However, areas under the glucose concentration time curves were similar with and without psyllium, suggesting that total glucose absorption was unaltered by psyllium. In vitro, centrifuged psyllium-water-glucose slurries released glucose over 3 hr into water. Although the mechanisms of the psyllium alteration of the blood glucose and breath hydrogen responses are probably multifactorial, our studies suggest that release from the psyllium-glucose slurry results in a slower and more complete glucose absorption.

Differentiation of cholestatic jaundice in infants. Utility of diethyl-IDA.

Time-activity curves of technetium-labeled diethyl-IDA were used to evaluate 31 patients in an effort to differentiate infants with cholestatic jaundice. Results can be obtained rapidly with minimal radiation exposure and no known secondary effects. The combination of diethyl-IDA time-activity curves and gamma glutamyl transferase activity was found to discriminate biliary atresia from neonatal hepatitis. The group with neonatal hepatitis was characterized by abnormal, yet lower, gamma glutamyl transferase activities and diethyl-IDA time-activity curves which peaked within 1 minute of injection, yet decayed in a manner similar to cardiac activity. The group with biliary atresia was characterized by elevated gamma glutamyl transferase activities, hepatic peaks at 8 minutes and markedly delayed decay. In that early operative intervention is associated with increased survival in biliary atresia, prompt differentiation should improve prognosis.

Effectiveness of milk products in dietary management of lactose malabsorption.

Eleven lactose malabsorbers were studied to compare the effectiveness of commercially available products recommended for dietary treatment of lactose malabsorption. One product, a commercial lactase preparation, is added to milk for lactose hydrolysis before consumption. The other is a commercial milk product containing lactose-hydrolyzing, nonpathogenic bacteria, Lactobacillus acidophilus. Both of these products are presently recommended for management of lactose malabsorption, although such recommendations have not been validated by controlled studies. Lactose malabsorption was determined by breath H2 analyses after subjects drank four different test doses on 4 different days. The first test dose was 480 ml of low fat milk; the second was 480 ml of milk treated with a commercial lactase preparation; the third was 480 ml of a commercial L. acidophilus-containing milk; and the fourth was 480 ml of the L. acidophilus-containing milk after 1 wk of gastrointestinal exposure to this commercial bacteria-containing milk. The mean breath H2 response to the lactase-treated milk was significantly lower (p less than 0.001) than the mean response to regular milk. However, the mean breath H2 response to either of the test doses of the L. acidophilus-containing milk were not significantly different than responses to regular milk. It is concluded that the lactase-treated milk reduces breath H2 responses and symptomatic discomfort from malabsorption while the L. acidophilus-containing milk does not.

Cardiac, pulmonary and neuromuscular effects of clenbuterol and terbutaline compared with placebo.

1 Cardiac, neuromuscular (tremor) and pulmonary effects of multiple single oral doses of clenbuterol (40, 60 and 80 micrograms) and terbutaline (2.5 and 5 mg) were compared with placebo in thirteen patients with reversible obstructive airways disease. 2 The percent change in the bronchodilator and neuromuscular effects of clenbuterol and terbutaline were greater than that of the cardiac activity. 3 Both drugs decreased T wave amplitude and occasionally caused J point ST segment depression. These changes were considered typical of this class of drugs and clinically insignificant. 4 While these drugs had comparable cardiac, pulmonary and neuromuscular effects, clenbuterol, at larger doses, had a higher incidence of transient headaches and nervousness.

Assessment of hepatic function after hepato-porto-enterostomy for biliary atresia using Tc-diethyl-IDA.

A quantifiable biliary function index has been developed from analysis of hepatic time--activity curves. Diethyl-IDA, a technetium-labeled iminodiacetic acid was given intravenously 27 times in 11 patients with proven biliary atresia. An estimated bile bilirubin clearance index derived from the inscribed hepatic absorption and elimination curves appears to be a reliable indicator of bile bilirubin clearance. The actual bile bilirubin clearance, previously shown to be a major determinant of survival, was clinically correlated in five patients studied before and after surgery and confirms the experimental findings. The clearance index should allow objective assessment of the efficacy of surgery for biliary atresia.

Pharmacokinetics of moxalactam in patients with renal insufficiency.

Moxalactam pharmacokinetics were determined in 18 patients with renal insufficiency (creatinine clearance, 0 to 99 ml/min). Each patient was given 0.5 g of moxalactam intramuscularly. Drug half-life ranged from 4.1 to 49.1 h and correlated inversely with creatinine clearance (r = -0.97). Total body drug clearance ranged from 0 to 88 ml/min, and renal clearance ranged from 0 to 57 ml/min. In four patients studied during hemodialysis, drug half-life was 21.7 +/- 7.5 h (mean +/- standard error) between dialyses and 4.4 +/- 0.5 h during dialysis. Moxalactam dialysance averaged 44 +/- 2 ml/min per m2 of dialyzer surface area, and approximately 50% of the drug was removed during a single hemodialysis. We confirmed that moxalactam is eliminated from the body primarily by renal excretion. Recommendations are given for dosage adjustment in patients with renal insufficiency.

Tocainide conjugation in humans: novel biotransformation pathway for a primary amine.

The metabolism of tocainide, an experimental antiarrhythmic drug, was studied in humans. Urinary excretion of unchanged drug was 28-55% in 24 hr after oral dosing. Urine hydrolysis with hydrochloric acid or beta-glucuronidase increased tocainide recovery to 55-79%. Saccharo-1,4-lactone inhibited the beta-glucuronidase-mediated tocainide recovery increase. Adjustment of urine to pH 13 produced a compound identified as 3-(2,6-xylyl)-5-methylhydantoin. Evidence suggests that it was derived from the same metabolite that formed the additional tocainide after acid or beta-glucuronidase treatment. Tocainide carbamoyl O-beta-D-glucuronide is the structure proposed for the metabolite. The suggested pathway for its formation involves the addition of carbon dioxide to the amino nitrogen of tocainide followed by uridine diphosphate-glucuronic acid conjugation.

Systemic and renal hemodynamic effects of trimazosin: a new vasodilator.

Trimazosin was administered for 2 days in doses-ranging from 50 to 200 mg to 16 patients with essential hypertension. The patients were randomized on the third day and received either the active drug in a single dose of 300 mg or a placebo. Systemic hemodynamic studies in both the supine and 50 degrees upright tilt position, including the Valsalva maneuver and a 1 min sustained handgrip test at 30% maximal voluntary contraction, were performed during control and 0, 1, 2, and 3 hr after drug administration. Renal function studies including plasma renin activity (PRA) were performed during control period and 3 hr after drug administration. Trimazosin reduced arterial pressure and peripheral vascular and renal vascular resistances, increased heart rate, cardiac output, and renal blood flow, and had no effect on glomerular filtration rate or PRA. Placebo had no effect on any of the above-mentioned parameters. The increase in renal blood flow was independent of cardiac output. We conclude that trimazosin lowers arterial pressure through a direct arteriolar dilation and reduction in peripheral vascular resistance. Its direct renal effects would make it a useful agent in the treatment of hypertension associated with renal function impairment.

A comparative trial of clofibrate and nicotinyl alcohol tartrate in hyperlipoproteinemic patients.

The effects of nicotinyl alcohol tartrate (Roniacol) and clofibrate (Atromid-S) on plasma cholesterol, triglycerides and lipoprotein cholesterol concentrations were compared in 19 patients with hyperlipoproteinemia in a 32-week, double-blind, crossover trial. Determination of serum clofibric acid concentrations, used to check compliance, allowed us to detect an error in the order in which the drugs were dispensed. Both drugs decreased (p less than 0.01) plasma cholesterol approximately 17% in patients with type II hyperlipoproteinemia. Nicotinyl alcohol reduced plasma triglycerides by 20% in six and clofibrate in eight of the nine patients with type IV hyperlipoproteinemia, although the mean effect was not statistically significant due to the large variance. Both drugs decreased (p less than 0.02) very low density lipoprotein (VLDL) cholesterol in the type IV patients; however, clofibrate increased (p less than 0.05) low density lipoprotein (LDL) cholesterol, whereas nicotinyl alcohol did not. Neither drug altered high density lipoprotein (HDL) levels significantly. In future studies, the effect of hypolipidemic drugs on the major classes of plasma lipoproteins should be determined in addition to the response of plasma lipids.