Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists

OBJECTIVE AND DESIGN: Elevated blood pressure and insulin resistance are strongly associated in patients. We explored the potential for the anti-hypertensive angiotensin II type 1-receptor (ATR(1)) antagonists to improve insulin sensitivity through modulation of the nuclear receptor PPARgamma, in vitro and in vivo compared to the potent insulin sensitizer, rosiglitazone. METHODS: PPARgamma modulation by ATR(1) antagonists was measured first by direct recruitment of PGC-1, followed by trans-activation reporter assays in cells, and promotion of adipogenesis in fibroblast and pre-adipocyte cell lines. Improvement of insulin sensitivity was measured as changes in levels of glucose, insulin, and adiponectin in ob/ob mice. RESULTS: Telmisartan, candesartan, irbesartan, and losartan (but not valsartan or olmesartan) each served as bona fide PPARgamma ligands in vitro, with EC(50) values between 3 and 5 micro mol/l. However, only telmisartan, and to a lesser extent candesartan, resulted in significant PPARgamma agonism in cells. In vivo, although rosiglitazone significantly lowered both glucose (33%, p<0.01) and insulin (61%, p<0.01) levels and increased expression of adiponectin (74%, p<0.001), sartan treatment had no effect. CONCLUSIONS: Many members of the sartan family of ATR(1) antagonists are PPARgamma ligands in cell-free assays but their modulation of PPARgamma in cells is relatively weak. Furthermore, none appear to improve insulin sensitivity in a rodent model under conditions where other insulin sensitizers, including rosiglitazone, do. These results question whether reported effects of sartans on insulin sensitivity may be through other means, and should guide further efforts to develop dual agents to treat hypertension and insulin resistance.     

Our experience in the management of neonatal jaundice

Summary Two hundred (200) cases of neonatal jaundice were treated in this hospital (CH CC) with phenobarbitone and phototherapy as a single agent and with a combination of phototherapy and phenobarbitone. Phenobarbitone was given in a dosage of 5 mg 8 hourly in normal weight (birth weight more than 2.5 kg) and 6 mg/kg per day 8 hourly in low birth weight babies (birth weight less than 2.5 kg) in group A. Phototherapy was used as a single agent in 6 hours on and 2 hours off around the clock in group B. In group C phototherapy was used in combination with phenobarbitone. The study has shown no significant advantage of phenobarbitone over phototherapy as a single agent and vice-versa. But it has definitely shown the advantage of photobarb over phototherapy or phenobarbitone as a single agent. From the Department of Paediatrics and Medicine CH (CC) Lucknow.     

Hypoglycemic effects of Citrullus colocynthis roots

The aim of this study was to examine the effect of root of C. colocynthis on the biochemical parameters of normal and alloxan-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal (120 mg/kg b.w.) injection of alloxan monohydrate for three days and the animals showing blood glucose level in the range of 175-300 mg/dL were selected for study. The blood glucose concentrations of the animals were measured at the beginning of the study and the measurements were repeated on 3rd, 5th and 7th day after the start of the experiment. On day 7, blood was collected by cardiac puncture under mild ether anesthesia. Aqueous extract of roots of Citrullus colocynthis showed significant reduction in blood sugar level (58.70%) when compared with chloroform (34.72%) and ethanol extracts (36.60%) (p < 0.01). The aqueous extracts showed improvement in parameters like body weight, serum creatinine, serum urea and serum protein as well as lipid profile and also restored the serum level of bilirubin total, conjugated bilirubin, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transminase (SGPT) and alkaline phosphatase (ALP).     

Video-assisted thoracic surgery for hemothorax following coronary artery bypass

A 56-year-old man complained of dyspnea and cough 9 days after coronary artery bypass grafting. Chest radiography showed opacity and left lung collapse. Following removal of clots from the pleural cavity by videothoracoscopy, he recovered without further incident. Video-assisted thoracic surgery is a feasible and safe option in the management of early hemothorax.     

The latest trends in the taste assessment of pharmaceuticals

To date, the most widely used method for measuring the taste characteristics of pharmaceutical preparations is psychophysical evaluation by a taste panel. However, conventional chemical analyses, on the basis of release studies, have been shown to be useful subsidiary methods. More recently, novel in vitro taste assessment apparatus and methodologies have been developed for high-throughput taste screening and quality control. Biomimetic taste sensing systems (BMTSSs), such as multichannel taste sensors or electronic tongues with global selectivity, have been welcomed by both pharmaceutical scientists and the industry as a whole. As we discuss here, the emerging in vitro approaches for assessing taste characteristics of taste masked drug and drug products will result in a decreased reliance on human panel tests.     

Preclinical pharmacology of a nonsteroidal ligand for androgen receptor-mediated imaging of prostate cancer

Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and approximately 25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (K(i) = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (K(i) = 32.9 nM) and dihydrotestosterone (K(i) = 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.     

Insulin-dependent diabetes loci Idd5 and Idd9 increase sensitivity to experimental autoimmune encephalomyelitis

The spontaneous development of autoimmune diabetes in NOD mice suggests that they are unable to establish and maintain immunologic self-tolerance. Congenic NOD mice expressing B10-derived alleles are protected from pancreatic beta cell destruction and autoimmune diabetes. To determine if the B10 alleles in loci Idd5 and Idd9 could influence susceptibility to autoimmunity in other organs, we compared MOG35-55-induced EAE in NOD mice to that of diabetes-resistant NOD.B10.Idd5 and NOD.B10.Idd9 mice. Surprisingly, the severity and chronicity of EAE were enhanced in the diabetes-resistant congenic mice. Our findings indicate that some alleles may influence susceptibility to immune-mediated damage in an organ or tissue-specific fashion, and highlight the necessity of disease-specific investigations.     

A method for solvent-free fabrication of porous polymer using solid-state foaming and ultrasound for tissue engineering applications

Most of the existing fabrication techniques for tissue engineering scaffolds require the use of organic solvents that may never be fully removed even after long leaching hours. The residues of these organic solvents reduce the ability of biological cells to form new tissue. This paper presents an approach toward solvent-free fabrication of tissue engineering scaffolds. Interconnected porous structures were created using solid-state foaming and ultrasound. The material used in this study was polylactic acid (PLA) and the blowing agent was CO(2). In order to determine suitable process conditions, saturation and foaming studies were first conducted. Selected foam samples were then processed using pulsed ultrasound. The microstructures before and after the ultrasound processing were compared. It was shown that the inter-pore connectivity of the solid-state foams was substantially enhanced. The combined solid-state foaming and ultrasound processing provide a way to fabricate porous polymer for potential tissue engineering applications.