New potent alpha-glucohydrolase inhibitor MDL 73945 with long duration of action in rats.

Inhibition of intestinal alpha-glucohydrolase activity is one approach for reducing the glycemic response from dietary carbohydrate and may prove useful for the treatment of diabetes mellitus. In this article, we describe the pharmacological properties of a time-dependent intestinal alpha-glucohydrolase inhibitor, MDL 73945. When preincubated 2 h with a rat intestinal mucosa preparation before substrate addition, MDL 73945 was a potent inhibitor of sucrase, maltase, glucoamylase, and isomaltase activities (MDL 73945 concentrations required to cause a 50% decrease in enzyme activity, 2 x 10(-7), 1 x 10(-6), 5 x 10(-6), and 8 x 10(-6) M, respectively); without preincubation, it was 10- to 500-fold less potent. In rats, a single oral dose of MDL 73945 administered simultaneously with 2 g/kg body wt sucrose resulted in a dose-dependent reduction in the area under the 0- to 3-h glycemic response curve, which was significant at 1 (45% reduction) and 3 (65% reduction) mg/kg. When administered 1 h before sucrose, the compound was more potent, with 0.3 mg/kg MDL 73945 significantly reducing the glycemic response to sucrose by 62%. A reduction in the glycemic response to sucrose was accompanied by reduced insulin secretion. MDL 73945 was slightly less effective against a starch load, with 3 and 10 mg/kg MDL 73945 administered 0.5 h before starch reducing the glycemic response by 39 and 52%, respectively. MDL 73945 was more effective against a sucrose load in streptozocin-administered rats than in control rats and was as effective after 16 daily doses as after a single dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombotic activity of a novel C-terminal hirudin analog in experimental animals.

A synthetic hirudin55-65 C-terminal fragment analog was evaluated for anticoagulant activity and in models of experimental thrombosis in mice and rats. Intravenous injection caused dose-related inhibition of thrombin and anticoagulation in rat blood samples, protection from thromboembolism in mice and inhibition of stasis-induced venous thrombosis in rats. Antithrombotic effectiveness corresponded with anticoagulant activity. Anephric animals exhibited longer duration of activity than normal animals suggesting the kidney as a major route of elimination.

Synthesis and cardiotonic activity of novel biimidazoles.

A series of substituted 2,2'-bi-1H-imidazoles and related analogues was synthesized and evaluated for inotropic activity. Structure-activity relationship studies based on a nonclassical bioisosteric approach indicated the necessity of a cyano group on one of the imidazole rings to obtain the desired pharmacological profile. 4(5)-Cyano-2,2'-bi-1H-imidazole (15a) was the most potent inotropic agent in the series. It produced a 25% increase in left ventricular dP/dt at 0.16 mg/kg iv (ED25% = 0.16 mg/kg) and increased left ventricular contractile force 60% at 1 mg/kg iv in anesthetized dogs. Compound 15a is a good inhibitor of type IV cyclic nucleotide phosphodiesterase isolated from dog heart having a potency similar to that of amrinone. Neither 5'-cyano-2,4'-bi-1H-imidazole (44) nor 4-cyano-2,4'-bi-1H-imidazole (48) demonstrated inotropic activity. In addition, the two possible 1,1'-dimethylcyano-2,2'-bi-1H-imidazoles (24 and 25) were inactive, indicating that an acidic NH as well as a cyano group are essential for inotropic activity.

A retrospective review of maternal and child health services at the Albert Schweitzer Hospital in rural Haiti.

PIP: For the past 25 years the Albert Schweitzer Hospital in Deschapelles, Haiti has been providing a wide range of maternal and child health services to the people of its rural district. Numerous special services for mothers and children have been added over the years, but these began to realize considerably greater potential with the creation of the hospital's Community Health Department in 1967. This department has carried out numerous preventive health programs and services designed to accommodate these groups' special health needs. Attention is directed to neonatal tetanus control; surveillance, treatment, and prevention of malnutrition; and other maternal and child health services (school programs, immunization activities, prenatal and postnatal care, family planning, the midwives' program, the "cord-cut" unit, the low birth weight project, and dispensaries and health agents). In 1967 the hospital began to develop programs especially designed to control neonatal tetanus. Communities were immunized systematically. By establishing outdoor immunization clinics at the hospital and at major marketplaces in the district and by working with traditional midwives, these programs were responsible for a sharp decline in the incidence of neonatal tetanus. Malnutrition has remained the most frequently occurring health problem among children in the hospital district. Several services and programs have been established throughout the years to meet the identified needs. These include the following which are described: the nutrition clinic; courtyard education; "weigh-ins;" nutrition recovery centers; the 3-day center at Deschapelles; nutrition intervention and case follow-up program; and malnutrition treatment. The hospital's family planning program has gradually increased its use of community education to reach the population and to try to gain acceptance of the need to space and limit births. This community education has been disseminated by dispensaries, mobile health team workers, public health nurses, and physicians. Implementation of immunization, health surveillance, health education, and improved tuberculosis control activities have produced gratifying reductions in overall maternal and child morbidity and mortality in the Schweitzer hospital district.^ieng

Tetanus in Haiti.

In 1958-72, 985 cases of tetanus (excluding tetanus of the newborn) were admitted to a hospital in Haiti. Mortality was 22%, and in later years (1966-72) mortality fell. During this period the dosage of tetanus antitoxin was lowered to 10,000 units and, for sedation, diazepam has satisfactorily replaced multiple-drug regimens used in earlier years. However, good nursing, including close attention to breathing, is probably the most important item in treatment. As a result of a programme of maternal immunisation, admissions for neonatal tetanus have fallen, and mortality for this condition has been reduced to 26%.