Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists.

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.

Hepatitis-B surface antigen and VDRL in healthy blood donors of Brunei Darussalam.

We screened 3276 voluntary blood donors for Hepatitis-B surface antigen (HBsAg) and VDRL. The results were analysed to assess the prevalence and the possible relation to age, sex, race and blood group. Our present study was done in Belait District of Brunei Darussalam where we have a mixed population of various racial groups namely Malays, Chinese, Ibans, Dusuns, Kelabits, Kadazans, Nepalese, Filipinos, Thais, Koreans, Eurasians, Indians, British, Dutch, Americans, Africans and Australians. Our findings suggest that the prevalence of HBsAg is 4.71% and that of VDRL is 0.64% of the donor population. HBsAg positivity rate among various blood groups is found to be not statistically significant (p greater than 0.05). However, this rate is found to be highly significant among racial groups (p less than 0.001) and the rate of positivity of VDRL is also found to be significantly different among racial groups (p less than 0.01), with the highest percentage of both being in the Ibans.

Prevalence of hepatitis-B surface antigen in the pregnant women of Brunei Darussalam.

In view of the high incidence of mother-to-child transmission of hepatitis B virus (HBV), routine screening of pregnant at antenatal clinic and vaccination of the newborn has become a common practice throughout the world. The prevalence of HBsAg in pregnant women of Brunei Darussalam was assessed. Of 1,267 pregnant women who attended the antenatal clinic of Suri Seri Begawan Hospital, Kuala Belait, the overall prevalence of HBsAg was 3.2% with significant differences in various ethnic groups (p less than 0.05). Malays, who form the major ethnic group had the lowest rate of 1.9%.

Pattern of acute myocardial infarction in a district hospital in Brunei Darussalam--a pilot study.

The objective of the authors was to study the pattern of presentation, risk factors, and natural course of acute myocardial infarction in the general population of Belait District in Brunei Darussalam. A prospective study was done of 100 consecutive cases of acute myocardial infarction admitted to the coronary care beds of a District General Hospital. The patients were followed up to 12 weeks after admission to hospital. There were three times more males than females (75 males, 25 females). Nine cases out of 75 males were below the age of 40 years, 3 being below 30 years. The mean age of the male denominator was 57.4 years while that of the female counterpart was 67.48 years showing a mean difference of 10.08 years. There were significant association with hypertension (31%), smoking (30%) and diabetes mellitus (27%). The majority of the patients had prodromal symptoms, the most common presenting symptoms were chest pain (63%) and shortness of breath (27%). Only 4% of the patients had silent infarction. Acute myocardial infarction is common in Brunei forming 2.6% of all the patients admitted to the medical wards and the relative rate is 3 times higher in males than in females. There is significant association of IHD with 3 main risk factors namely hypertension, smoking and diabetes mellitus.

Beneficial effects of ACE inhibitors in severe mitral stenosis.

There are several reports of beneficial effects of ACE inhibitors in both primary and secondary pulmonary hypertension. However the effect of ACE inhibitors in mitral stenosis is not documented. The authors report three patients with severe mitral stenosis in whom surgery was delayed. They had initial symptomatic improvement with diuretics and sodium restriction, but had recurrence of their symptoms while on treatment. Enalapril not only relieved their symptoms in particular exertional dyspnoea and haemoptysis but prevented recurrence and improved their effort tolerance without causing excessive fall of blood pressure or impairment of renal function.

Subserosal appendicular stripping.

Appendicectomy in patients with recurrent appendicitis can be difficult due to an adherent and inflamed appendix. We describe the technique and results of subserosal appendicular stripping (SAA). Over a four-year period, 49 patients who were diagnosed with recurrent appendicitis required SAA. They had prior admission for acute appendicitis which resolved with antibiotic treatment. Persistent symptoms necessitated surgery. SAA was necessary in these patients due to an inflamed, adherent appendix with extensive serosal adhesions. The appendix was delivered out from the serosa following retrograde ligation of the appendicular base. The adherent serosa was left intact. Average patient age was 23 years. All had persistent symptoms for more than one week with a history of one or more previous attacks. No surgical complications were observed except transient serosal bleeding in the first case managed by gentle diathermy. We advocate SAA as a modification of appendicectomy in patients with recurrent appendicitis where the appendix is inflamed and adherent.

Mebendazole retention enema for severe Trichuris trichiura (whipworm) infection: a case report.

The authors report a case of massive Trichuris trichiura infection, resulting in severe anaemia and congestive cardiac failure in a 9-year-old Iban boy, who was resistant to the usual oral anthelmintic treatment, but promptly responded to mebendazole retention enema. This patient also had an associated Entamoeba histolytica infection.

Tattooing and hepatitis B infection.

To determine the prevalence of HBV carrier status in tattooed persons, 200 healthy, tattooed volunteers and 200 non-tattooed volunteers to match the first group for age, sex and ethnic group were screened. Prevalence of HBsAg in tattooed and non-tattooed volunteers was 19.5 and 9% respectively, which was a statistically significant difference (P less than 0.01). There was no difference in the prevalence in various age groups, ethnic groups, or sex, between the two groups.