Evaluating Postgraduate Surgical Education Experience, Professional Satisfaction and Personal Well-Being: A Cross-Sectional Survey of Trainees in A Low-Middle Income Country in Sub-Saharan Africa.

BACKGROUND: Education at the postgraduate level is important in grooming competent specialists in different fields of surgical care. This study aimed to evaluate the training experience, professional satisfaction, and personal well-being of postgraduate surgical residents in northern Nigeria. SUBJECTS, MATERIALS AND METHODS: It was a cross-sectional survey of 157 medical doctors enrolled for a minimum of 6 months in surgical residency training in tertiary hospitals in the northern zone of the country. All participants filled a pre-tested questionnaire and their responses were analyzed using Statistical Package for the Social Sciences version 20. RESULTS: The respondents had a mean age of 34.4 ± 4.8 years. Thirty-two (20.5%) agreed that there was a balance between their training needs and rotation for clinical services. There was a marked disparity between the median time allocated for non-ward-based training activities (4.0 hours each per week) and the average time allocated for research activities (1.0 hours per week). Although 89 (57.4%) and 82 (53.3%) reported fair satisfaction in their professional role and private life respectively, a larger proportion expressed poor satisfaction with their participation in recreational (107 [68.6%]) and social activities (90 [58.4%]). One hundred and seventeen (74.5%) stated that a high level of stress was associated with their training. CONCLUSIONS: The surgical residents experienced relatively more training on patient management than on research work. Although their educational experience was associated with a high level of stress in majority of them, most of the trainees expressed fair satisfaction with activities in their professional role and private life.

Pesticide residue levels in maize samples from markets in Lagos State, Nigeria.

BACKGROUND: Pesticides are used widely in agriculture to control destructive pests and hence increase food supply. Their use inadvertently leads to residues in food crops and the environment. Pesticides, by nature are poisonous and exposure of humans to their residues may cause health hazards which include neurotoxicity and carcinogenicity among others. Evaluation of pesticide residues in food is therefore of public health importance and would help to ensure that levels are kept within safety limits. OBJECTIVE: The aim of this study was to determine the incidence and quantity of organochlorine pesticide residues in maize samples collected from various markets in Lagos State and compare values obtained with established safety values in order to highlight possible health hazards. METHODS: In this study, samples of white maize (Zea mays L.) purchased from different markets in Lagos State were analyzed for residues of organochlorine pesticides using gas chromatograph with mass spectrometric detector (GC-MS) after careful extraction and cleanup. RESULTS: The results showed that 96% of the maize samples contained residues of one or more organochlorine pesticides. Mean concentrations ranged from 7.9-52.0 microg/kg and maximum residue limits (MRLs) of some pesticides were exceeded in up to 7% of samples. The estimated total diet intakes (ETDIs) for aldrin and dieldrin exceeded their maximum permissible intakes. CONCLUSION: It is concluded that residues of organochlorine pesticides are present in maize in Lagos markets. Some exceed safety levels with possible adverse effects on human health. There is therefore a need for more stringent monitoring of the use of pesticides in agriculture and food storage in Nigeria.

Evaluation of antioxidant activity of Tetracarpidium conophorum (Müll. Arg) Hutch & Dalziel leaves.

This study evaluated the antioxidant activity as well as bioflavonoid content of the methanol and ethanol-water extracts of the fresh and dried leaves of Tetracarpidium conophorum. Antioxidant activity was determined by spectrophotometric methods using DPPH free radical, nitric oxide radical inhibition and ferric reducing antioxidant power assays. In addition, total phenolics, flavonoids and proanthocyanidin content were also determined. The ethanol: water extract of the dried leaves had the highest antioxidant activity with a 50% inhibition of DPPH at a concentration of 0.017 mg/mL compared to the standards, Vitamin C and Vitamin E with inhibition of 0.019 and 0.011 mg/mL, respectively. This extract also showed nitric oxide radical inhibition activity comparable to that of rutin, 54.45% and 55.03% for extract and rutin, respectively, at 0.1 mg/mL. Ferric reducing power was also comparable to that of ascorbic acid (281 and 287 µM Fe (11)/g, resp.) at a concentration of 1 mg/mL. The methanol extract of both the dried and the fresh leaves had higher phenolic, flavonoids and proanthocyanidin content than the ethanol:water extract. The study reveals that T. conophorum can be an interesting source of antioxidants with their potential use in different fields namely food, cosmetics and pharmaceuticals.

The physicochemical and antibacterial properties of ciprofloxacin-Mg2+ complex.

PURPOSE: Co-administration of quinolone antibiotics with cation-containing medicaments such as, antacids has been reported to influence the overall bioavailability leading to subtherapeutic plasma concentrations of these antibiotics in humans. OBJECTIVES OF THE STUDY: The present work was designed to evaluate the binding constant, binding molar ratio, influence of temperature on the binding constant of ciprofloxacin-Mg2+ and to determine the antimicrobial activity of ciprofloxacin and ciprofloxacin-Mg2+. METHODS: Job's method of continuous variation and Bonesi-Hildebrand equation were adopted to determine the molar ratio and stability constant respectively. The antibacterial activity was determined by the Agar diffusion method. RESULTS: A complexation molar ratio of 1:1 was obtained for ciprofloxacin-Mg2+ complex. The stability constants were 3.59 and 3.50 at 25 degrees C and 60 degrees C respectively. There was a significant difference between the zones of inhibition of ciprofloxacin-Mg2+ complex and that of ciprofloxacin alone against E. coli, P. aeruginosa, and S. aureus (p < 0.05). This difference showed that the complex formed was not as active as ciprofloxacin. CONCLUSION: The present studies have shown that ciprofloxacin readily complex with Mg2+ and that the stability constant was temperature dependent. The antibacterial activity of ciprofloxacin was markedly reduced in the presence of Mg2+. Concomitant administration of ciprofloxacin with Mg2. containing medicaments should be avoided to prevent resistance.

Invitro evaluation of the neutralising capacity of twenty brands of antacids in Lagos, Nigeria.

BACKGROUND: The use of substandard drugs is a great threat to the lives of people in the community. Identification of substandard drugs is important to exclude their use in clinical practice. These drugs may lead to reduced efficacy of pharmacotherapy. Antacid preparations are weakly basic and consist of metal salts, most commonly aluminium hydroxide or magnesium hydroxide. These salts dissociate to neutralise gastric acid and form neutral salts. The ultimate goal of antacid therapy is to reduce the concentration and the total load of acid in gastric juice with a pH of 1.3 to a pH between 3.5 and 5.0. OBJECTIVE: The aim of this work is to carry out an in-vitro test on the acid neutralising capacity (ANC) of commonly available antacid brands in Lagos market. METHOD: The British pharmacopoeia (BP) method of analysis of antacids was adopted. Twenty different brands of antacid suspensions and tablets were analysed. RESULT: Brand SH suspension gave the highest neutralising capacity, 101.65 ml +/- 0.15, while brand SN gave the lowest, 99.75 ml +/- 0.75. All the fourteen antacid suspensions analysed complied with the official specification and therefore passed the analysis. Brand TB tablet gave the highest acid neutralising capacity (ANC), 54.10 ml +/- 0.2 while brand TD 49.50 ml +/- 0.1 gave the lowest. All the six antacid tablet brands analysed passed the assay. The ANC of an antacid is a parameter used to measure the effectiveness of an antacid in relieving ulcer pain. CONCLUSION: The acid-neutralising capacity of the antacid brands analysed were within the BP specification. The acid neutralising capacity of antacids should be determined before administration.

Lipid peroxidation and total radical-trapping potential of the lungs of rats submitted to chronic and sub-chronic stress.

Exposure to stress induces a cluster of physiological and behavioral changes in an effort to maintain the homeostasis of the organism. Long-term exposure to stress, however, has detrimental effects on several cell functions such as the impairment of antioxidant defenses leading to oxidative damage. Oxidative stress is a central feature of many diseases. The lungs are particularly susceptible to lesions by free radicals and pulmonary antioxidant defenses are extensively distributed and include both enzymatic and non-enzymatic systems. The aim of the present study was to determine lipid peroxidation and total radical-trapping potential (TRAP) changes in lungs of rats submitted to different models of chronic stress. Adult male Wistar rats weighing 180-230 g were submitted to different stressors (variable stress, N = 7) or repeated restraint stress for 15 (N = 10) or 40 days (N = 6) and compared to control groups (N = 10 each). Lipid peroxidation levels were assessed by thiobarbituric acid reactive substances (TBARS), and TRAP was measured by the decrease in luminescence using the 2-2'-azo-bis(2-amidinopropane)-luminol system. Chronic variable stress induced a 51% increase in oxidative stress in lungs (control group: 0.037 +/- 0.002; variable stress: 0.056 +/- 0.007, P < 0.01). No difference in TBARS was observed after chronic restraint stress, but a significant 57% increase in TRAP was presented by the group repeatedly restrained for 15 days (control group: 2.48 +/- 0.42; stressed: 3.65 +/- 0.16, P < 0.05). We conclude that different stressors induce different effects on the oxidative status of the organism.

Lipid peroxidation and total radical-trapping potential of the lungs of rats submitted to chronic and sub-chronic stress

Exposure to stress induces a cluster of physiological and behavioral changes in an effort to maintain the homeostasis of the organism. Long-term exposure to stress, however, has detrimental effects on several cell functions such as the impairment of antioxidant defenses leading to oxidative damage. Oxidative stress is a central feature of many diseases. The lungs are particularly susceptible to lesions by free radicals and pulmonary antioxidant defenses are extensively distributed and include both enzymatic and non-enzymatic systems. The aim of the present study was to determine lipid peroxidation and total radical-trapping potential (TRAP) changes in lungs of rats submitted to different models of chronic stress. Adult male Wistar rats weighing 180-230 g were submitted to different stressors (variable stress, N = 7) or repeated restraint stress for 15 (N = 10) or 40 days (N = 6) and compared to control groups (N = 10 each). Lipid peroxidation levels were assessed by thiobarbituric acid reactive substances (TBARS), and TRAP was measured by the decrease in luminescence using the 2-2'-azo-bis(2-amidinopropane)-luminol system. Chronic variable stress induced a 51 percent increase in oxidative stress in lungs (control group: 0.037 ± 0.002; variable stress: 0.056 ± 0.007, P < 0.01). No difference in TBARS was observed after chronic restraint stress, but a significant 57 percent increase in TRAP was presented by the group repeatedly restrained for 15 days (control group: 2.48 ± 0.42; stressed: 3.65 ± 0.16, P < 0.05). We conclude that different stressors induce different effects on the oxidative status of the organism.

Myocardial oxidative stress and antioxidants in hypertension as a result of nitric oxide synthase inhibition.

Rats were made hypertensive by the administration of the nitric oxide synthase inhibitor nitro-L-arginine (LNA, 2.74 mmol/L) in drinking water for 7 d. Hearts from hemodynamically assessed animals were analyzed for lipid peroxidation (LPO), gamma-glutamylcysteine-synthetase (gamma-GCS), glutathione disulfide reductase (GR), glutathione peroxidase (GSHPx), catalase (CAT), superoxide dismutase (SOD), and total radical trapping potential (TRAP) activities. LNA treatment increased the mean arterial blood pressure by 46% and the heart rate by 22% without changing plasma renin activity. LNA treatment resulted in a 30% increase in LPO. gamma-GCS was reduced by 48% and GR by 36% in the cardiac tissue of hypertensive rats as compared to controls. The activity of nonselenium GSHPx was reduced by 27%, and selenium-dependent GSHPx activity in the heart was not affected by LNA treatment. In hypertensive rats, SOD activity was increased by 16%, and CAT was decreased by 46%. TRAP was lower (27%) in the myocardium of hypertensive rats than in that of controls. These data suggest that LNA-induced hypertension is associated with increased myocardial oxidative stress.

Lipid peroxidation induced by Clinostomum detruncatum in muscle of the freshwater fish Rhamdia quelen.

The effect of Clinostomum detruncatum metacercaria infection on the activities of the antioxidant enzymes superoxide dismutase and catalase in muscle of the freshwater fish Rhamdia quelen was analyzed. Tert-butyl hydroperoxide-initiated chemiluminescence, a measure of lipid peroxidation, was also investigated. Enzyme activities were similar in infected and uninfected fishes. However, the chemiluminescence was almost 2-fold higher in muscle of infected fishes than in muscle of uninfected ones. These results indicate that parasite infection induces oxidative stress and a higher level of membrane damage in the fish muscle due to an imbalance between pro-oxidants and non-enzymatic antioxidants. Our results suggest that fish response to parasite infection could involve, as in other vertebrates, reactive oxygen intermediates.

Oxidative stress in the latissimus dorsi muscle of diabetic rats

The purpose of the present study was to investigate the effects of experimental diabetes on the oxidant and antioxidant status of latissimus dorsi (LD) muscles of male Wistar rats (220 +/- 5 g, N = 11). Short-term (5 days) diabetes was induced by a single injection of streptozotocin (STZ, 50 mg/kg, iv; glycemia >300 mg/dl). LD muscle of STZ-diabetic rats presented higher levels of thiobarbituric acid reactive substances (TBARS) and chemiluminescence (0.36 +/- 0.02 nmol/mg protein and 14706 +/- 1581 cps/mg protein) than LD muscle of normal rats (0.23 +/- 0.04 nmol/mg protein and 7389 +/- 1355 cps/mg protein). Diabetes induced a 92 percent increase in catalase and a 27 percent increase in glutathione S-transferase activities in LD muscle. Glutathione peroxidase activity was reduced (58 percent) in STZ-diabetic rats and superoxide dismutase activity was similar in LD muscle of both groups. A positive correlation was obtained between catalase activity and the oxidative stress of LD, as evaluated in terms of TBARS (r = 0.78) and by chemiluminescence (r = 0.89). Catalase activity also correlated inversely with glutathione peroxidase activity (r = 0.79). These data suggest that an increased oxidative stress in LD muscle of diabetic rats may be related to skeletal muscle myopathy

Oxidative stress in the latissimus dorsi muscle of diabetic rats.

The purpose of the present study was to investigate the effects of experimental diabetes on the oxidant and antioxidant status of latissimus dorsi (LD) muscles of male Wistar rats (220 +/- 5 g, N = 11). Short-term (5 days) diabetes was induced by a single injection of streptozotocin (STZ, 50 mg/kg, iv; glycemia >300 mg/dl). LD muscle of STZ-diabetic rats presented higher levels of thiobarbituric acid reactive substances (TBARS) and chemiluminescence (0.36 +/- 0.02 nmol/mg protein and 14706 +/- 1581 cps/mg protein) than LD muscle of normal rats (0.23 +/- 0.04 nmol/mg protein and 7389 +/- 1355 cps/mg protein). Diabetes induced a 92% increase in catalase and a 27% increase in glutathione S-transferase activities in LD muscle. Glutathione peroxidase activity was reduced (58%) in STZ-diabetic rats and superoxide dismutase activity was similar in LD muscle of both groups. A positive correlation was obtained between catalase activity and the oxidative stress of LD, as evaluated in terms of TBARS (r = 0.78) and by chemiluminescence (r = 0.89). Catalase activity also correlated inversely with glutathione peroxidase activity (r = 0.79). These data suggest that an increased oxidative stress in LD muscle of diabetic rats may be related to skeletal muscle myopathy.

Circaannual changes in antioxidants and oxidative stress in the heart and liver in rats.

Reactive oxygen species are formed in physiological and pathological conditions in mammalian tissues. Because of their high reactivity, they may interact with biomolecules, inducing oxidative injury. Increases in lipid peroxidation can result in oxidative damage to cellular membranes. Protection against oxidative damage is provided by enzymatic and non-enzymatic antioxidant defenses. Antioxidant enzyme activities and lipid peroxidation, as an index of oxidative stress injury, were evaluated in different seasons over one year in the heart and liver of rats, maintained on a 12 h light and dark cycle. Glutathione peroxidase and catalase activities, in both tissues, were maximal in the summer season. Lipid peroxidation in the heart was maximal in the spring as compared to the other seasons and it did not vary in the liver during the year. These findings suggest that any study of antioxidants or oxidative stress must take into account such seasonal variations for a more precise analysis of changes due to any pathological condition.

Effects of prostaglandins and nitric oxide on rat macrophage lipid metabolism in culture: implications for arterial wall-leukocyte interplay in atherosclerosis.

Macrophages/foam cells have a pivotal role in atherogenesis although little is known about the way lipid imbalance, a hallmark of atherosclerosis, leads to lipid accumulation in these cells. Modified low-density lipoproteins are associated with macrophage lipid dysfunction in atherosclerosis, but a possible role for altered lipogenesis leading to lipid accumulation remains to be elucidated. Since endothelium-derived nitric oxide (NO) and prostaglandins (PGs) are physiological autacoids whose production may be impaired in atherosclerosis, the effects of these mediators on de novo lipid synthesis in 24-h cultured rat peritoneal macrophages is investigated. In resident (unstimulated) cells, 1 microM PGE2 and the stable analog of PGI2 carbaprostacyclin (cPGI2, 1 microM) deviated the overall [1-14C]acetate from incorporation into cholesterol, free fatty acids and triacylglycerols favoring the formation of phospholipids. In inflammatory (thioglycollate-elicited) macrophages, these eicosanoids likewise reduced 14C-incorporations into all the lipid fractions tested. Also, cPGI2 and PGE2 reduced [4-14C]cholesterol uptake from inflammatory cells but did not interfere in 14C-cholesterol export. The PGE2-derivative PGA2 (10-20 microM) reduced 14C-incorporations into all the lipids in resident cells while it enhanced phospholipid synthesis by up to 129% at the expense of reduced incorporations into the other test lipids. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1-10 microM), when added to macrophages in the presence of superoxide dismutase (SOD, to avoid the reaction of superoxide with NO), significantly reduced lipogenesis especially in inflammatory cells. These findings suggest that endothelium-derived NO and PGs may be associated with macrophage lipid accumulation by modulating lipogenesis and cholesterol uptake within these cells.

Effect of trolox C on cardiac contratucture induced by hydrogen peroxide

Hydrogen peroxide (H2O2) perfused into the aorta of the isolated rat heart induces a positive inotropic effect, with cardiac arrhythmia such as extrasystolic potentiation or cardiac contractures, depending on the dose. The last effect is similar to the "stone heart" observed in reperfusion injury and may be ascribed to lipoperoxidation (LPO) of the membrane lipids, to protein damage, to reduction of the ATP level, to enzymatic alterations and to cardioactive compounds liberated by LPO. These effects may result in calcium overload of the cardiac fibers and contracture ("stone heart"). Hearts from male Wistar rats (300-350g) were perfused at 31°C with Tyrode, 0.2 mM trolox C, 256 mM H2O2 or trolox C + H2O2. Cardiac contractures (baseline elevation of the myograms obtained) were observed when hearts were perfused with H2O2 (Tyrode: 5.9 + 3.2; H2O2: 60.5 + 13.9 percent of the initial value); perfusion with H2O2 increased the LPO of rat heart homogenates measured by chemiluminescence (Tyrode: 3,199 + 259; H2O2: 5,304 + 133 cps mg protein(-1) 60 min(-1), oxygen uptake (Tyrode: 0.44 + 0.1; H2O2: 3.2 + 0.8 nmol min(-1) mg protein(-1) and malonaldehyde (TBARS) foramtion (Tyrode: 0.12 + 0; H2O2: 0.37 + 0.1 nmol/ml). Previous perfusion with 0.2 mM trolox C reduced the LPO (Chemiluminescence: 4,098 + 531), oxygen uptake (0.51 + 0) and TBARS (0.13 + 0) bud did not prevent the H2O2-induced contractures (33.3 + 16 percent). ATP (Tyrode: 2.84 + 0; H2O2: 0.57 + 0) and glycogen levels (Tyrode: 0.46 + 0; H2O22: 0.26 + 0) were reduced by H2O2. Trolox did not prevent these effects (ATP: 0.84 + 0 and glycogen: 0.27 + 0). Trolox C is known to be more effective than alpha-tocopherol or gamma-tocopherol in reducing LPO though it lacks the phytol portion of vitamin E to be fixed to the cell membranes. Trolox C, unlike vitamin A, did not prevent the glycogen reduction induced by H2O2. Trolox C induced a positive chronotropic effect that resulted in higher energy consumption. The reduction of energy level seemed to be more important than LPO in the mechanism of H2O2-induced contracture.

Exercise training in aging: hemodynamic, metabolic, and oxidative stress evaluations.

The effects of exercise training on hemodynamic and metabolic parameters as well as on responses to oxidative stress in aged individuals are controversial. The aim of the present study was to investigate changes in heart hate, mean arterial pressure, vasoreactivity, and plasma levels of insulin and glucose in male aged Wistar rats submitted to exercise training for 11 weeks (1 h/d; 5 d/wk) in a treadmill. The isolated heart was perfused by H2O2, and oxidative stress was evaluated using thiobarbituric acid reactive substances. Cardiovascular functions were recorded with a data acquisition system (CODAS, 1 kHz). Trained aged rats were bradycardic as compared with sedentary aged rats (298+/-7 versus 336+/-16 bpm) but presented similar mean arterial pressure and vasoreactivity and plasma levels of insulin and of glucose, which were quantified by radioimmunoassay and colorimetric enzymatic test. Plasma levels of insulin and of glucose ratio were increased in trained aged rats (6.9+/-0.7 versus 3.5+/-0.4 in sedentary aged rats), and the response to oxidative stress was decreased (0.4+/-0.1 versus 0.7+/-0.1 nmol/mg protein in sedentary aged rats). These results showed that exercise training produced a lower resting heart rate as well as changes in metabolic and oxidative responses. This suggests a higher myocardium protection of trained than sedentary aged rats.

Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats.

Several investigators have demonstrated that streptozotocin (STZ) diabetes induces changes in the autonomic control of the cardiovascular system. Changes in cardiovascular function may be related to peripheral neuropathy. The aim of the present study was to analyze changes in heart rate (HR) and arterial pressure (AP) as well as baroreflex and chemoreflex sensitivity in STZ-induced diabetic male Wistar rats (STZ, 50 mg/kg, i.v., 15 days). Intra-arterial blood pressure signals were obtained for control and diabetic rats (N = 9, each group). Data were processed in a data acquisition system (CODAS, 1 kHz). Baroreflex sensitivity was evaluated by measuring heart rate changes induced by arterial pressure variation produced by phenylephrine and sodium nitroprusside injection. Increasing doses of potassium cyanide (KCN) were used to evaluate bradycardic and pressor responses evoked by chemoreflex activation. STZ induced hyperglycemia (447 +/- 49 vs 126 +/- 3 mg/dl), and a reduction in AP (99 +/- 3 vs 118 +/- 2 mmHg), resting HR (296 +/- 11 vs 355 +/- 16 bpm) and plasma insulin levels (16 +/- 1 vs 57 +/- 11 microU/ml). We also observed that the reflex bradycardia (-16.8 +/- 0.1 vs -12.5 +/- 0.1 bpm/mmHg, in the diabetic group) and tachycardia (-3.68 +/- 0.5 vs -1.75 +/- 0.3 bpm/mmHg, in the diabetic group) produced by vasopressor and depressor agents were impaired in the diabetic group. Bradycardia evoked by chemoreflex activation was attenuated in diabetic rats (control: -17 +/- 1, -86 +/- 19, -185 +/- 18, -208 +/- 17 vs diabetic: -7 +/- 1, -23 +/- 5, -95 +/- 13, -140 +/- 13 bpm), as also was the pressor response (control: 6 +/- 1, 30 +/- 7, 54 +/- 4, 59 +/- 5 vs diabetic: 6 +/- 1, 8 +/- 2, 33 +/- 4, 42 +/- 5 mmHg). In conclusion, the cardiovascular response evoked by baroreflex and chemoreflex activation are impaired in diabetic rats. The alterations of cardiovascular responses may be secondary to the autonomic dysfunction of cardiovascular control.

Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats

Several investigators have demonstrated that streptozotocin (STZ) diabetes induces changes in the autonomic control of the cardiovascular system. Changes in cardiovascular function may be related to peripheral neuropathy. The aim of the present study was to a changes in heart rate (HR) and arterial pressure (AP) as well as baroreflex and chemoreflex sensitivity in STZ-induced diabetic male Wistar rats (STZ, 50 mg/kg, iv, 15 days). Intra-arterial blood pressure signals were obtained for control and diabetic rats (N = 9, each group). Data were processed in a data acquisition system (CODAS, 1 kHz). Baroreflex sensitivity was evaluated by measuring heart rate changes induced by arterial pressure varíation produced by phenyiephrine and sodium nitroprusside injection. Increasing doses of potassium cyanide (KCN) were used to evaluate bradycardic and pressor responses evoked by chemoreflex activation. STZ induced hyperglycemia (447 ñ 49 vs 126 ñ 3 mg/dl), and a reduction in AP (99 + 3 vs 118 + 2mmHg), resting HR (296 ñ 11 vs 355 ñ 16 bpm) and plasma insulin levels (16 ñ 1 vs 57 + 11 muU/ml). We also observed that the reflex bradycardia (-1.68 ñ 0.1 vs -1.25 ñ 0.1 bpm/mmHg, in the diabetic group) and tachycardia (-3.68 ñ 0.5 vs -1.75 ñ 0.3 bpm/mmHg, in the diabetic group) produced by vasopressor and depressor agents were impaired in the diabetic group. Bradycardia evoked by chemoreflex activation was attenuated in diabetic rats (control: -l7 + 1,-86 + 19,-l85 ñ 18, -208 + 17 vs diabetic: -7 + 1,-23 ñ 5,-95 ñ 13, - 140 + 13 bpm), as also was the pressor response (control: 6 ñ 1,30 ñ 7,54 + 59 ñ 5 vs diabetic: 6 ñ 1,8 ñ 2,33 ñ 4,42 ñ 5 mmhg). In conclusion the cardiovascular responses evoked by baroreflex and chemoreflex activation are impaired in diabetic rats. The alterations of caradiovascular responses may be secondary to the autonomic dysfunction of cardiovascular control.

Effect of trolox C on cardiac contracture induced by hydrogen peroxide.

Hydrogen peroxide (H2O2) perfused into the aorta of the isolated rat heart induces a positive inotropic effect, with cardiac arrhythmia such as extrasystolic potentiation or cardiac contractures, depending on the dose. The last effect is similar to the "stone heart" observed in reperfusion injury and may be ascribed to lipoperoxidation (LPO) of the membrane lipids, to protein damage, to reduction of the ATP level, to enzymatic alterations and to cardioactive compounds liberated by LPO. These effects may result in calcium overload of the cardiac fibers and contracture ("stone heart"). Hearts from male Wistar rats (300-350 g) were perfused at 31 degrees C with Tyrode, 0.2 mM trolox C, 256 mM H2O2 or trolox C + H2O2. Cardiac contractures (baseline elevation of the myograms obtained) were observed when hearts were perfused with H2O2 (Tyrode: 5.9 +/- 3.2; H2O2: 60.5 +/- 13.9% of the initial value); perfusion with H2O2 increased the LPO of rat heart homogenates measured by chemiluminescence (Tyrode: 3,199 +/- 259; H2O2: 5,304 +/- 133 cps mg protein-1 60 min-1), oxygen uptake (Tyrode: 0.44 +/- 0.1; H2O2: 3.2 +/- 0.8 nmol min-1 mg protein-1) and malonaldehyde (TBARS) formation (Tyrode: 0.12 +/- 0; H2O2: 0.37 +/- 0.1 nmol/ml). Previous perfusion with 0.2 mM trolox C reduced the LPO (chemiluminescence: 4,098 +/- 531), oxygen uptake (0.51 +/- 0) and TBARS (0.13 +/- 0) but did not prevent the H2O2-induced contractures (33.3 +/- 16%). ATP (Tyrode: 2.84 +/- 0; H2O2: 0.57 +/- 0) and glycogen levels (Tyrode: 0.46 +/- 0; H2O2: 0.26 +/- 0) were reduced by H2O2. Trolox did not prevent these effects (ATP: 0.84 +/- 0 and glycogen: 0.27 +/- 0). Trolox C is known to be more effective than alpha-tocopherol or gamma-tocopherol in reducing LPO though it lacks the phytol portion of vitamin E to be fixed to the cell membranes. Trolox C, unlike vitamin A, did not prevent the glycogen reduction induced by H2O2. Trolox C induced a positive chronotropic effect that resulted in higher energy consumption. The reduction of energy level seemed to be more important than LPO in the mechanism of H2O2-induced contracture.

An in vivo method for estimating the concentration of crotamine in a solution

A very sensitive method for estimating the concentration of crotamine in a solution was developed. This method was based on the based on the time required for the appearance of permanent hyperextension of the rear legs of mice as a function of the dose administered. This method can be used to determine toxin doses as low as 0.32 mg/kg(-1). Its high specificity for crotamine means that it can be used to measure toxin concentrations in the presence of other proteins and polypeptides.

RP 64477: a potent inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase with low systemic bioavailability.

RP 64477 (N-butyl-3-(p-decyloxybenzamido)-4-(methylthio)benzamide) has been shown to be a potent inhibitor of the cholesterol esterifying enzyme Acyl-coenzyme A:cholesterol O-acyltransferase (EC 2.3.1.26; ACAT) in intestinal, hepatic, adrenal, and arterial tissue preparations obtained from a range of animal species. Drug concentrations producing 50% inhibition of enzyme activity (IC50 values) ranged from 14-283 nM. Inhibition by RP 64477 in a rabbit intestinal enzyme preparation was shown to be non-competitive with respect to the substrate oleoyl-CoA. In whole cell assays using human intestinal (CaCo-2), hepatic HepG2) and monocytic (THP-1) cell lines, RP 64477 inhibited ACAT activity with IC50s of 113, 503, and 180 nM, respectively. RP 64477 (0.03% w/w by diet) reduced significantly cholesterol absorption in cholesterol/cholic acid-fed rats from 94+/- 8% to 65 +/- 4%. In cholesterol-fed rabbits, cholesterol absorption was reduced from 72 +/- 5% to 50 +/-5% and 44 +/- 5% at dose levels of 10 and 30 mg kg-1 b.i.d., respectively. Plasma cholesterol levels were reduced dose-dependently in both cholesterol/cholic-acid-fed rats and cholesterol-fed rabbits. Neither cholesterol absorption nor plasma cholesterol levels were reduced significantly in animals maintained on standard laboratory diets. Pharmacokinetic studies indicated that RP 64477 were very poorly absorbed following oral administration to rats. Plasma levels of drug were < 2 ng mL-1 following a dose of 2000 mg kg-1 p.o.. When radiolabelled RP 64477 was administered orally, limited absorption was indicated by the overwhelming elimination of radioactivity in the faces (96.4% of administered material) coupled with low renal clearance (0.6% of dose) and biliary excretion (0.05% of dose). In conclusion, this work shows that RP 64477 is a potent inhibitor of ACAT obtained from a range of animal species and man. Inhibition of cholesterol absorption and hypocholesterolaemic activity has been demonstrated in rats and rabbits maintained on diets supplemented with cholesterol. Pharmacokinetic studies indicate low systemic exposure to RP 64477 as a result of limited absorption of this drug.