Discovery of liver-targeted inhibitors of stearoyl-CoA desaturase (SCD1).

Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.

SCH 412499: biodistribution and safety of an adenovirus containing P21(WAF-1/CIP-1) following subconjunctival injection in Cynomolgus monkeys.

Monkey studies were conducted for the preclinical safety assessment of SCH 412499, an adenovirus encoding p21, administered by subconjunctival injection prior to trabeculectomy for postoperative maintenance of the surgical opening. Biodistribution of SCH 412499 was minimal and there was no systemic toxicity. Findings included swollen, partially closed or shut eye(s) and transient congestion in the conjunctiva. A mononuclear cell infiltrate was present in the conjunctiva, choroid and other ocular tissues, but completely or partially resolved over time. Electroretinograms and visual evoked potentials revealed no adverse findings. Thus, the findings are not expected to preclude the clinical investigation of SCH 412499.

Incidental mononuclear cell infiltrate in the uvea of cynomolgus monkeys.

Mononuclear cell infiltrate (MCI) in the uvea was observed in naïve, untreated (control group) cynomolgus monkeys in approximately 25% of drug safety evaluation studies. The total incidence of MCI in the choroid and the ciliary body was 29% of 342 males and 25% of 306 female monkeys. In the studies in which MCI was present in the ciliary body or choroid, the incidence was as high as 75%. There were no other ocular histopathologic findings in these monkeys. All monkeys were clinically healthy and the eyes were not remarkable when examined ophthalmoscopically.

Nutrition Made Simpe, 4th Edition

[Preface]. This is the fourth edition of Nutrition Made Simple. In the 1980 edition specific articles from the weekly Nyam News series were put together as a basic nutrition resource. It was well received, used primarily by people working in health and education, and others involved in public education programmes. The emphasis then was on malnourished children. Their plight has greatly improved. Presently, obesity (fatness) and diseases like diabetes, high blood pressure, heart attack, stroke and cancer in adults have taken our region like a storm. These diseases, we now understand, also have direct connections with the way we eat. Once inflicted, they carry very grave consequences. Thus, "an ounce of prevention is better than a pound of cure". Many of these diseases are preventable through sound dietary practices.

Food, nutrition and health in the Caribbean: a time for re-examination Part 1 - abstract

Today the countries of the English-speaking Carribean are at a crossroads. While the old problem of malnutrition in children has declined sharply, a large proportion of adults suffer from obesity. Estimates, according to Caribbean experts, are that 30 percent of the population above 35 years of age are suffering from high blood pressure and 10-12 percent from diabetes. The report "Health of the Americas" by the Pan American Health Organization shows that the countries are threatened with a massive epidemic of diabetes, hypertension, heart attack, stroke and cancer among adults, as these diseases are among the first five principal causes of deaths (AU)

Food, nutrition and health in the Caribbean: a time for re-examination Part 1 - abstract

Today the countries of the English-speaking Carribean are at a crossroads. While the old problem of malnutrition in children has declined sharply, a large proportion of adults suffer from obesity. Estimates, according to Caribbean experts, are that 30 per cent of the population above 35 years of age are suffering from high blood pressure and 10-12 per cent from diabetes. The report "Health of the Americas" by the Pan American Health Organization shows that the countries are threatened with a massive epidemic of diabetes, hypertension, heart attack, stroke and cancer among adults, as these diseases are among the first five principal causes of deaths

Project lifestyle: developing positive health lifestyles for schoolchildren in Antigua

Countries of the English-speaking Caribbean are in epidemiological transition. Following 30 years of socioeconomic change, obesity and chronic diseases have almost replaced malnutrition and infectious diseases as major health problems. Major risk factors for this modern epidemic are lifestyle-related. Project Lifestyle seeks to develop positive health lifestyles in schoolchildren gradually, sequentially, and systematically from grades 1-12 and throughout the school system on the island of Antigua. The four health habits addressed include weighing right, eating right, doing daily physical exercise, and having a positive self-concept. Since risk interventions with schoolchildren have produced positive results in several developed countries, this project developed an intervention methodology in the Caribbean context (AU)

Diet as a risk factor for diabetes

Diabetes is not a single disease entity. It is a heterogenous group of disorders characterized by metabolic abnormalities primarily of glucose but also of lipid and protein, and long-term complications involving multiple organs. Not all forms of diabetes have a relationship with diet. Among the major forms, diet has not been to be an underlying cause of Insulin-dependent and Gestational Diabetes Mellitus. In a small percentage of cases which are classified as malnutrition-related diabetes, protein-energy malnutrition is suspected to be causally related. The majority of cases of diabetes (80-90 percent) are of the noninsulin-dependent type. Diet has been suspected as a risk factor since the disease was recognized hundreds of years ago but it has been diffucult to prove even now. Contrary to the long held belief, there is no evidence that excess consumption of carbohydrate, particularly simple sugar causes diabetes. On the contrary vegetarians appear to have a lower risk of diabetes. Among the nutrients, fat particularly saturated fat still remains a suspect. A high fat diet also assumes added importance because of the higher incidence of diseases such as coronary artery disease, hypertension, stroke and peripheral vascular disease in individuals with diabetes. While no specific nutrient has been shown as a definite risk factor for diabetes, there is little doubt that obesity, particularly upper body obesity, is causally related to diabetes. A defect in insulin receptors in the cell membrane as well as post receptor events associated with obesity are the most likely causes of insulin's ineffectiveness. Thus the reduction of obesity through proper diet and regular physical exercise is the best preventive measure for reducing the incidence of diabetes. Physical activity, in addition to being a potent method of reducing obesity, helps regulate glucose metabolism. Because diabetes is associated with several other chronic diseases, the diet recommended for the control of other chronic diseases is suitable for the prevention of diabetes as well. It has been recommended, that such a diet should derive 60-70 percent of calories from complex carbohydrate, less than 30 percent from fat and not more than 10 percent from saturated fat. Increase in the consumption of fruits, vegetables, grains and legumes and decrease in meat, particularly red meat, and fat appear to meet this dietary goal. (Summary)

Bioelectrical-impedence analysis as a measure of body composition in a West Indian population

Percent body fat (percent BF) was estimated in 50 males and 50 females aged 8-21 y by using hydrodensitometry (percent BF) and a bioelectrical-impedance analyzer (percent BF-BIA). The sample population was racially heterogenous, though predominantly of African origin. Percent body fat was computed from density by using an equation derived specifically for blacks. The BIA predicted percent BF with r2 = 0.77 (SEE = 3.7 percent BF), underestimating by a mean of 1.7 percent BF. Residuals ( percent BFd - percent BF-BIA) were normally distributed but were significantly correlated with age (P less than 0.01), although this effect was small. The theoretical bases for impedance analysis and for hydrodensitometry would appear for different reasons to impair applicability of these techniques to the present population and age group. However, for our population sample the BIA estimated percent BF as precisely as other simple techniques applied to other populations. (AU)