Determination of order parameters and correlation times in proteins: a comparison between Bayesian, Monte Carlo and simple graphical methods.

We describe a novel approach to deducing order parameters and correlation times in proteins using a Bayesian statistical method, and show how likelihood contours, P(tau,S), and confidence levels can be obtained. These results are then compared with those obtained from a simple graphical method, as well as those from Monte Carlo simulations. The Bayes approach has the advantage that it is simple and accurate. Unlike Monte Carlo methods, it gives useful contour plots of probability (also not provided by the simple graphical method), and provides likelihood/confidence information. In addition, the Bayesian approach gives results in very good agreement with those obtained from Monte Carlo simulations, and as such use of Bayesian statistical methods appears to have a promising future for studies of order and dynamics in macromolecules.

Prospective comparison of patient tolerance to enteric-coated vs nonenteric-coated erythromycin.

Erythromycin base and its salts are frequently used in clinical practice. The most frequent side effects of oral erythromycin preparations are gastrointestinal. Various salts and enteric coatings have been developed without adequate comparison in regard to gastrointestinal side effects. The overall incidence of gastrointestinal side effects (abdominal pain and cramps, nausea, vomiting, diarrhea, and gas) of two common erythromycin base formulations, Erythromycin Base Filmtab (Abbott), a nonenteric-coated base tablet, and Eryc (Parke-Davis), a pelletized, encapsulated, enteric-coated base capsule, were compared in 368 adults at two dosage levels (1 g/d and 2 g/d). Minimal differences were found when target symptoms were compared by preparation coating. In contrast, subjects receiving erythromycin at the 2-g/d dosage level reported higher incidence rates for each of the target symptoms, regardless of product coating, than did those patients treated at the 1-g/d dosage level. Enteric coating of erythromycin base offers little protection from the common dose-related gastrointestinal adverse effects of oral erythromycin.

Haemodynamic and pharmacokinetic evaluation of alfuzosin in man. A dose ranging study and comparison with prazosin.

In an open dose ranging study with random inclusion of placebo, alfuzosin (alpha 1-adrenoceptor antagonist) 1, 2.5 and 5 mg was administered to 6 healthy volunteers, 3 of the volunteers received 10 mg alfuzosin. Supine systolic blood (SBP) pressure was not reduced by alfuzosin although significant increases occurred in supine heart rate (HR) after 2.5 and 5 mg. In the standing position, SBP was reduced at 2 and 4 h with 5 mg alfuzosin; significant increases in HR occurred following 1, 2.5 and 5 mg at 2, 4, 6 and 8 h after administration. Exercise SBP was not reduced; diastolic blood pressure was significantly reduced at 4 and 6 h with 5 mg alfuzosin. More marked effects were seen in the 3 subjects who received 10 mg alfuzosin. After 1 and 5 mg, tmax ranged from 1-2 h; Cmax (4.1 to 20.8 ng.ml-1; AUC (0-24) 20 to 132 ng.ml-1.h (1 and 5 mg respectively) increased progressively with dose indicating dose dependent kinetics; no significant changes occurred in the visual analogue scale for sedation. A comparison of alfuzosin 5 mg, prazosin 1 mg and placebo each administered for 4 days, indicated that alfuzosin did not significantly reduce standing SBP on either Day 1 or Day 4; prazosin reduced SBP at 2 and 4 h on Day 1 and 6 h on Day 4 compared to placebo. Standing HR was increased by alfuzosin at 2 h on Day 1 and Day 4; increases occurred with prazosin at 2, 4, 6 and 8 h on Day 1 and 6 h on Day 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil (Isoptin, Knoll; Calan, Searle).

Verapamil is a calcium antagonist that is pharmacologically different from other currently marketed antiarrhythmics. It is used for the acute treatment of PSVT and atrial fibrillation and flutter. It appears to be more effective than beta-adrenergic blocking agents in the treatment of PSVT. Approximately 80 percent of patients with PSVT will convert to normal sinus rhythm after verapamil 0.075-0.15 mg/kg. Atrial fibrillation and flutter seldom convert to sinus rhythm with verapamil, but it successfully reduces the ventricular rate in 90 percent of these patients. Verapamil is useful for the rapid conversion of PSVT to normal sinus rhythm and for the rapid control of ventricular rate in atrial fibrillation and flutter before other antiarrhythmics have taken effect. Because of its short plasma half-life, other agents or cardioversion can be used if verapamil is unsuccessful. The use of verapamil in the treatment of classical and variant angina, hypertrophic cardiomyopathy, and hypertension is being evaluated. Mild reduction in blood pressure and heart rate may occur with verapamil therapy. Caution must be exercised when verapamil is administered to patients with sinus node disease, advanced AV block, concomitant beta-adrenergic blocking agents, and digitalis intoxication.

Diagnosis and treatment of Prinzmetal's variant angina.

The presentation, diagnosis (including provocative testing), and therapy of Prinzmetal's variant angina are reviewed. Prinzmetal's variant angina (PVA) is a form of angina caused by coronary-artery vasospasm (CAS) and is not associated with exertion. It is diagnosed by history, electrocardiogram, or coronary-artery angiography. Provocative tests, such as the cold-pressor test or intravenous ergonovine maleate, are sometimes used to aid diagnosis of PVA. Nitrates, adrenergic - blocking agents, and calcium-channel blocking agents can be used in treating PVA. Nitroglycerin and isosorbide dinitrate effectively relieve CAS. However, long-term prospective studies on the use of these drugs for PVA are lacking in the literature. Studies on treating PVA with adrenergic-blocking agents have been equivocol, with some studies reporting improvement and some reporting worsening. Calcium-channel blocking agents are promising drugs for PVA. Nifedipine is generally considered the prototype of this class for antianginal activity. It is administered orally in PVA patients and is effective. Side effects are mild and do not usually require termination of therapy. Verapamil hydrochloride, the prototype calcium-channel blocking agent for arrhythmias, is effective for PVA, but only 10-20% of an orally administered dose reaches systemic circulation because of the first-pass effect. Other calcium-channel blockers, including perhexilene maleate, diltiazem hydrochloride, prenylamine, and lidoflazine, have been tested in a few CAS patients with some success; adverse effects and toxicities limit the use of some of them, especially perhexilene. Therapy, using combinations of nitrates, adrenergic-blocking agents, and calcium-channel blocking agents, is needed in some patients. Dosing guidelines for all drugs are given in the paper. Treatment of PVA should begin with oral nitrates. Calcium-channel blocking agents are indicated in the patient who has failed to respond or is intolerant to maximum doses of nitrates given in various forms.