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) greater than or equal to3.36 mmol/l (130 mg/dl) to less than or equal to6.47 mmol/l (250 mg/dl) and triglycerides less than or equal to3.95 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 tower 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. (C) 2003 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

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. Clinical Pharmacology & Therapeutics (2001) 69 , 346–355; doi: 10.1067/mcp.2001.115141

Clinical Pharmacology & Therapeutics (1999) 65, 194–194; doi:

Background: The binding of sweet-tasting compounds in a human (Mcg) Bence-Tones 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-Tones 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 tao 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-Tones dimer was verified by x-rap 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 mere observed in bleeding times after aspartame treatment, Modified template bleeding times increased at p < 0.01. Aspartame blocked the turpentine-mediated febrile rsponses 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.

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.

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.

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.