No description available.

No description available.

No description available.

I investigated the effects of continuous administration of fluoxetine, a serotonin reuptake inhibitor, on energy expenditure, body temperature, and thyroid and catecholamine metabolism during weight reduction using a very low calorie diet (VLCD, Optifast, 1757 kJ/day) followed by a balanced deficit diet (BDD, 5016 kJ/day). Fluoxetine (60 mg/day by mouth, n = 10) or placebo (n = 10) were administered during 3 weeks of inpatient VLCD followed by 8 weeks of outpatient BDD in a double-blind, randomized design. A similar amount of weight was lost in both groups during the VLCD, but by the end of the BDD total weight loss in the fluoxetine group was significantly greater (11.0 $ pm$ 1.1 kg vs. 7.0 $ pm$ 1.0 kg, mean $ pm$ SEM, p $<$ 0.015). Resting metabolic rate (RMR) increased by 4.4 $ pm$ 1.8% (p $<$ 0.01) in the fluoxetine group but did not change in the placebo group during the first week of the VLCD, but subsequently decreased significantly in both groups as dieting continued. However, RMR remained consistently higher in the fluoxetine group for the duration of the VLCD period. No further change in RMR occurred in either group during the BDD period. The thermic effect of food did not change after VLC dieting plus fluoxetine or placebo treatment. Body temperature increased within 2 days of fluoxetine treatment by a mean of 0.3$ sp circ$C, p $<$ 0.025 and remained elevated throughout the VLCD but was unchanged in the placebo group. VLCD therapy reduced serum levels of T$ sb3$, free T$ sb3$ Index and 24-hour urinary excretion of dopamine, norepinephrine, metanephrine and normetanephrine equivalently in both groups. A thermogenic effect of fluoxetine is demonstrated in humans for the first time. The anorectic effect of fluoxetine may be related to its temperature elevating effect.

We questioned whether adrenergic amines extracted from the Seville orange Citrus Aurantium (CA) increases metabolic rate and enhance the thermic response to a 1.7MJ mixed meal (TEF) in lean and obese men and women; the latter had upper-body obesity, a condition associated with defective TEF, attributed to altered SNS. Nine lean (7M, 2F; BMI: 23 +/- 1 k g/m 2; waist circumference: 78 +/- 2 cm) and 13 obese (4M, 9F; BMI: 35 +/- 1 kg/m2; waist circumference: 105 +/- 3 cm) subjects were studied. With CA: (1) RMR increased more in men vs women (94 vs 42 kJ over 5 h), independently of body composition; (2) urinary epinephrine excretion increased in both groups and dopamine only in men. A 17% lower TEF in obese subjects was no longer significant when controlled for gender. By contrast, there was an effect of gender on TEF that remained significant when adjusted for measures of obesity. Women had a lower TEF that increased to values no longer different from men with CA. CA did not affect TEF in men. CA had no cardiovascular effects. Thus, CA ingestion increased thermogenesis by 4% above RMR and enhanced the lower TEF of women by 29% (46kJ).

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A G protein-coupled receptor with structural characteristics of a biogenic amine GPCR was cloned from Schistosoma mansoni (SmGPCR). SmGPCR was codon-optimized and double-tagged with FLAG and His epitopes at the N- and C-terminal ends, respectively. Immunofluorescence experiments targeting these epitopes revealed that the expression of codon-optimized SmGPCR was highly increased compared to wild-type in mammalian cells. These studies also demonstrated that SmGPCR has a typical GPCR topology, the N-terminus being extracellular and C-terminus intracellular. Functional assays revealed that codon-optimized SmGPCR was responsive only to histamine, which caused a dose-dependent increase in intracellular Ca2+ (EC50 = 0.54 +/- 0.05 muM), but not cAMP, consistent with a Gq pathway of signal transduction. In vitro behavioral studies showed that treatment of S. mansoni cercaria with exogenous histamine caused a dose-dependent increase in the motility of the parasite.

Several aspects of the human skin blanching assay were evaluated in an attempt to suggest improvements in the methodology of this assay. Three trials were performed in the unoccluded application mode, using two proprietary creams containing 0,1% betamethasone (as the 17-valerate). Preliminary observations of the influence of ambient temperature and relative humidity on the blanching response did not allow definite conclusions to be drawn. Studies on the number of observers required for reliable results of comparative blanching indicated that at least two trained observers should be employed. Analyses of the results of individual volunteers demonstrated the expected biological variability, and suggest that subjects selected for trials should represent a range of blanching responses. No sex-related differences in blanching responses were found, and both arms exhibited similar sensitivity to corticosteroids. Retrospective analysis of 95 040 observations of blanching responses showed that in the unoccluded application mode blanching is lowest close to the wrist, and in the occluded mode blanching is lowest close to the elbow. Studies on the method of transportation of Betnovate preparations suggest that topical formulations should not be exposed to temperature extremes during transportation. It is proposed that patients should not transport topical formulations in the holds of ships or aircraft, and that exporters and manufacturers should make use of special transportation and storage conditions. In a study of ten topical formulations from three countries it was found that there was no trend of products from one country consistently exhibiting superior blanching to products from the other two countries, or products from one country consistently exhibiting the lowest degree of blanching, although considerable differences in blanching responses were found in some cases. Interpretation of the results of these studies demonstrated the importance of employing a combination of statistical analyses, blanching profiles and AUC values when drawing conclusions regarding comparative bioavailability. A study of the blanching profiles of Betnovate cream included in all 16 trials performed during this work indicated that this preparation behaved in a similar fashion during all trials, thereby giving credence to the results of the trials

Cells experiencing a low oxygen tension show relative resistance to the lethal effects of radiation. It is believed that the effectiveness of the treatment of certain human tumors is hindered by the existence of such radioresistant cells within the tumor. The purpose of this work was to study the drug Ro-07-0582 both for its toxic effects and its ability to preferentially sensitize hypoxic cells to the lethal effects of radiation (radiosensitize). These properties were examined in vitro in two Chinese hamster cell lines, CHO and CH2B2, and also in the mouse tumour cell line EMT6. Ro-07-0582 is shown to have a chemotherapeutic potential in that it demonstrates a very selective toxicity for hypoxic cells after a few hours exposure. It is much less toxic to aerobic cells. These toxic properties were studied extensively, both in hypoxic and aerobic cell suspensions. The measured endpoint was the ability of a cell to multiply and form a colony of 50 or more cells within an allotted incubation time. Hypoxic toxicity was greater at 37°C than at 22°C and was affected by small changes (~30ppm) in 0₂ concentration in the cell suspension. The toxic effects were similar in the three cell lines. The radiosensitizing capability of Ro-07-0582 was determined by measuring the Dose Modifying Factors (DMF's) for various drug concentrations with each cell line. DMF's were calculated by comparison of survival curves for cell suspensions irradiated under hypoxia in the presence of drug with the survival curve for cell suspensions irradiated under hypoxia in the absence of drug. The DMF for the irradiation of aerobic cells in the absence of drug is called the Oxygen Enhancement Ratio (OER) and was approximately 3.0 in all three cell lines. Ro-07-0582 was found to selectively radiosensitize hypoxic cells in suspension with high efficiency. For each cell line, sensitization was observed with drug concentrations as low as 0.1mM, while concentrations of 10mM or greater yielded DMF's within the measured range of OER values. The presence of 1mM Ro-07-0582 during irradiation of hypoxic cells yields a DMF of 1.8. Introduction of the drug before or after irradiation, instead of during irradiation, had little if any effect. Radiosensitization measurements were also carried out at high cell concentrations (cell pellets), where many sensitizers are ineffective. Results showed that the 0582 radiosensitization attained in cell pellets is quite comparable with that attained in dilute suspension. The attributes of Ro-07-0582 as a potential radiosensi-tizer were considered. The sensitization achieved by Ro-07-0582 is very good, and surpasses that of metronidazole, a chemical under study for clinical use. For drug doses necessary to achieve high levels of sensitization the toxicity of Ro-07-0582 to aerobic cells is quite acceptable. The toxicity to hypoxic cells, however, is much increased over the toxicity to aerobic cells, and this may prove to be a useful adjunct to the drug's sensitizing properties in destroying hypoxic tumour cells. / Medicine, Faculty of / Medical Genetics, Department of / Graduate

No description available.