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.

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)

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)

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

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)

Knowledge, attitudes, and practices of Jamaican secondary school students regarding health and fitness - abstract

Improvements in lifestyles, particularly weight control, dietary practices, exercise habits and self esteem in youth have been found to lessen the probability of obesity, diabetes mellitus, hypertension and heart attack in adulthood. A school-based project is being implemented to test this in the Caribbean. Baseline data on knowledge, attitudes, and practice of 2,910 students were collected from 2 intervention and 2 Secondary/High Schools. Sixteen (16) percent of the children thought that they were too thin while 13 percent thought they were too fat. Only 44 percent said that they knew how to accurately measure their weight and height. However, 82 percent wanted to know how to maintain desirable weights. Seventy-one (71) percent thought that weighing was related to health. Forty-nine (49) percent believed that weighing right is healthy while 51 percent and 36 percent thought that being too fat and too thin, respectively, can lead to ill health. Sixty-one (61) percent of the sample thought that eating right meant having the right type and amount of food. Fifty (50) percent usually had three (3) meals per day while 32 percent ate as many times as possible. Sixty-seven (67) percent, 62 percent and 53 percent of the students said that sweet, greasy and salty foods, respectively, are unhealthy. Thirty (30) percent of the sample usually add salt ot prepared food while 33 percent did so occasionally. Ninety-one (91) percent of the sample thought it important for everyone to exercise. However, only 28 percent exercised regularly. Sixty-three (63) percent of the students belonged to groups either at school or in their communities. Ninety-five (95) percent thought it was all right to feel good about themselves, and 71 percent considered themselves worthwhile. These results are useful not only in determining the nature of the intervention needed to facilitate the desired changes in lifestyles, but also in identifying variables which may serve as bases for future evaluations (AU)

Food availability and nutritional status in Guyana, 1980-1986 - abstract

The deterioration of the Guyana economy started in the late 1970s and continued into the '80s: 1983 was the lowest ebb. Gross domestic product (GDP) declined steadily from 1980 to 1983 due to a reduction in output from most sectors, mining and agriculture in particular. Some slight recovery was experienced in 1984, but this was not enough to offset the effects of the previous years. Expenditure on consumer food imports was cut by 87 percent, and on intermediate food stuffs by 78 percent in keeping with the Government's policy of promoting self-sufficiency in food. Research into the current food and nutrition situation in Guyana was conducted during July and August, 1987. Data were collected from relevant Government Ministries, the CARICOM Secretariat and the local office of the Pan American Health Organisation. The data showed that overall Guyana is not short of food. However, the quality, affordability and distribution would also influence nutritional outcome. The food/beverage/tobacco price index rose by 110.6 percent from 1982 to 1986. Dairy products, meat and wheat flour were among the items in short supply and thus very expensive. The cheapest and more abundant foods were the staples - rice, starchy roots/tubers and sugar. Hospital clinic records revealed high prevalences of still-births and low-birth-weight babies. These, together with the high infant and toddler mortality rates, are indicative of nutritional status. While the level of malnutrition increased between 1982 and 1984, there was some improvement in 1985 and 1986. Gastroenteritis, the principal cause of paediatric admission to the Georgetown Hospital, and malnutrition, were the leading causes of death among children (AU)