Rate and equilibrium constants for the epimerization of the endothelin receptor antagonist J-104,132 in aqueous solution.

The degradation of [5S-[5alpha,6beta,7alpha(R*)]]-2-butyl-5-(1,3-benzodioxol-5-yl)-7-[(2-carboxypropyl)-4-methoxyphenyl]-6-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid (J-104,132) was studied in aqueous solution as a function of temperature and pH. The degradation reaction does not proceed to completion; rather, a stable equilibrium is attained in which approximately 2% of the degradate is produced. Kinetic data for the formation of the degradate are analyzed using an integrated form of the rate law for a reversible first-order reaction, and the forward and reverse rate constants and overall equilibrium constants are presented. Isolation and spectroscopic structural determination indicate that the degradate is the C7 beta-epimer of the drug. A mechanism for the epimerization reaction involving a novel enamine-like intermediate is proposed and shown to be consistent with the kinetic data. The rate and equilibrium constants are used to predict the room temperature stability of an injectable formulation of J-104,132, and these predictions are compared to actual data from long-term stability studies. It is concluded that the preformulation kinetic studies provide essential data needed for optimum drug product development.

Selection of optimal hydrate/solvate forms of a fibrinogen receptor antagonist for solid dosage development.

The objective of this work was to compare the physicochemical properties of four crystalline forms of the fibrinogen receptor antagonist L-738,167 [2(S)-[p-toluenesulfonyl amino]-3-[[[5,6,7,8-tetrahydro-4-oxo-5-[2-(piperidin-4-yl)ethyl] -4-H-pyrazolo[1,5-a][1,4] diazepin-2-yl] carbonyl]amino]-propionic acid] to determine the best form for use in the development of oral dosage formulations. Four crystalline forms [form A (trihydrate), form B (pentahydrate), form C, and form D] were compared using x-ray powder diffractometry, thermal analysis, and moisture sorption studies. The trihydrate, form A, was demonstrated to hydrate upon exposure to relative humidity (RH) above 50% at room temperature (25 degrees C) with conversion to the pentahydrate. The pentahydrate, form B, converted to the trihydrate at room temperature when exposed to humidity levels below 25% RH. The crystalline pentahydrate was shown to be stable to dehydration upon storage at 30 degrees C/60% RH and 40 degrees C/75% RH for 3 months. The suspension of form A or form D in water resulted in conversion to form B, the stable hydrated form in an aqueous environment. Form C has a unique crystalline structure that is stable in an aqueous environment and not subject to hydration/dehydration with changes in relative humidity and thus may offer some advantages in pharmaceutical development.

A primary health care approach using Hispanic outreach workers as nurse extenders.

In an effort to improve the health of Hispanic families, particularly prenatal women and infants, the county health department instituted a program of intensified home visits using bilingual, bicultural nurse extenders within a framework of primary health care. The outreach workers offer basic health information to improve families' skills and knowledge, and to assist with linkages to community resources. Public health nurses provide assessment, establish a plan of care, evaluate progress, and supervise the workers. The program has resulted in increased numbers of individuals receiving services, more women registering earlier for prenatal care and the Women, Infants, and Children's (WIC) program, and increased numbers of infants receiving WIC services and regular medical supervision. Public health nurses report increased knowledge and positive changes in families' health behaviors. In addition, the program has strengthened relationships between the health department and Hispanic families.

Pulse oximetry and peak flow as indicators of wheezing severity in children and improvement following bronchodilator treatments.

This study examined the changes from the initial peak flows and oxygen saturations (OSAT) of wheezing children at presentation to the emergency department through their treatment in the emergency department. Data was collected prospectively on 785 patients 5 to 20 years of age during an 11-month period from November 1, 1990, to September 30, 1991. Both the initial OSAT and peak flows were correlated with the number of bronchodilator treatments required in the emergency department and with the need for hospitalization. Both the initial OSAT and the peak flows had a limited ability to predict the need for hospitalization. Oxygen saturation appears to be a valid measure of wheezing severity and is more easily obtained in children of all ages. Following bronchodilator treatment, peak flow results in a larger quantitative improvement than OSAT; however, this difference does not appear to have any significant advantage. Aerosolized albuterol and subcutaneous epinephrine resulted in a similar degree of improvement as measured by peak flow and by oxygen saturation, with clinically similar changes in heart rate.

Prevalence of hypertension risk factors among Hispanic Americans.

A program of blood pressure screening, education, and follow-up was established to meet concerns that Hispanics were at risk for hypertension and related health problems, including access to health care and information. The program provided opportunities to gather data on hypertension risk factors and general health status of the Hispanic population. Bilingual community workers provided blood pressure screening through a door-to-door survey of 3399 adults. In addition, the workers provided general and preventive hypertension education, obtained health histories, and referred identified health problems. All 203 persons identified with hypertension were assessed further and followed by public health nurses. Of these, 67 were referred to physicians for care. Referrals for other types of health problems were made for 1603 persons. Significant risk factors identified for hypertension were excessive alcohol intake, obesity, and frequent use of processed foods. A total of 871 persons reported at least one symptom of stress.