Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Knowledge, attitudes and beliefs about the health hazards of biomass smoke exposure amongst commercial food vendors in Nigeria.

BACKGROUND: Exposure to biomass smoke is a major cause of morbidity and mortality in Africa. Commercial food vendors in Nigeria and elsewhere in Africa are commonly exposed to biomass smoke from open fire cooking both at work and home. Little is known about the knowledge, attitudes and beliefs of food vendors about the health hazards of biomass smoke exposure in Nigeria. METHODS: We did a descriptive cross sectional survey of the knowledge, attitudes and beliefs of commercial food vendors in the cities of Benin and Calabar in Nigeria. We recruited respondents using a multi-stage approach. Structured interviewer-administered questionnaires were used for data collection. RESULTS: We recruited 308 participants (164, 53.2% female). The majority 185(60.2%) were married and had post-primary education 206(67.4%). The average monthly income was <30,000 Naira (US$150). Most 198(64.4%) were not aware that biomass smoke exposure is harmful to human health. About three-quarters (221; 71.8%) were unconcerned as to the effect of exposure to fumes from biomass fuels on their health. Less than half of respondents (110, 41.6%) believed biomass smoke was harmful to health. Male gender, being single, having post-primary education and preferring electricity or gas fuels were associated with good knowledge of the adverse health effects of biomass smoke exposure whilst female gender and having good knowledge of the adverse health effects of biomass smoke were associated with positive attitudes towards preventing exposure. CONCLUSION: Commercial food vendors in our study had limited knowledge about the adverse health effects of biomass smoke exposure and negative attitudes towards preventing these adverse health effects. We suggest an educational intervention is needed to improve this knowledge.

Evaluation of various static and dynamic modeling methods to predict clinical CYP3A induction using in vitro CYP3A4 mRNA induction data.

Several drug-drug interaction (DDI) prediction models were evaluated for their ability to identify drugs with cytochrome P450 (CYP)3A induction liability based on in vitro mRNA data. The drug interaction magnitudes of CYP3A substrates from 28 clinical trials were predicted using (i) correlation approaches (ratio of the in vivo peak plasma concentration (Cmax) to in vitro half-maximal effective concentration (EC50); and relative induction score), (ii) a basic static model (calculated R3 value), (iii) a mechanistic static model (net effect), and (iv) mechanistic dynamic (physiologically based pharmacokinetic) modeling. All models performed with high fidelity and predicted few false negatives or false positives. The correlation approaches and basic static model resulted in no false negatives when total Cmax was incorporated; these models may be sufficient to conservatively identify clinical CYP3A induction liability. Mechanistic models that include CYP inactivation in addition to induction resulted in DDI predictions with less accuracy, likely due to an overprediction of the inactivation effect.

Evaluation of various static in vitro-in vivo extrapolation models for risk assessment of the CYP3A inhibition potential of an investigational drug.

Nine static models (seven basic and two mechanistic) and their respective cutoff values used for predicting cytochrome P450 3A (CYP3A) inhibition, as recommended by the US Food and Drug Administration and the European Medicines Agency, were evaluated using data from 119 clinical studies with orally administered midazolam as a substrate. Positive predictive error (PPE) and negative predictive error (NPE) rates were used to assess model performance, based on a cutoff of 1.25-fold change in midazolam area under the curve (AUC) by inhibitor. For reversible inhibition, basic models using total or unbound systemic inhibitor concentration [I] had high NPE rates (46-47%), whereas those using intestinal luminal ([I]gut) values had no NPE but a higher PPE. All basic models for time-dependent inhibition had no NPE and reasonable PPE rates (15-18%). Mechanistic static models that incorporate all interaction mechanisms and organ specific [I] values (enterocyte and hepatic inlet) provided a higher predictive precision, a slightly increased NPE, and a reasonable PPE. Various cutoffs for predicting the likelihood of CYP3A inhibition were evaluated for mechanistic models, and a cutoff of 1.25-fold change in midazolam AUC appears appropriate.

Breast diseases in Southern Yemen.

OBJECTIVE: To investigate the magnitude of breast diseases, and its frequency distribution in different age groups in Hadramout, Yemen. METHODS: This is a prospective study conducted at the Central Laboratory of Ibn-Sinna Hospital, Hadramout, Yemen from January 2006 to December 2009. Patients attending surgical units for breast problems were eligible. Patients were assessed clinically and referred to the laboratory center to confirm the diagnosis by histopathology. The data were collected from the patients and referral sheets. RESULTS: A total of 635 cases of breast disease were diagnosed. This includes 604 female and 31 male patients. Benign breast diseases (BBD) was the most common lesion found in this study comprising 493 cases (77.6%), and 142 (22.4%) comprised malignant cases. Among BBD, the most common lesion was fibroadenoma (40.5%) followed by fibrocystic changes (16%), other benign breast lesions (10%), and inflammatory lesion (8%). The age groups affected by BBD were: 20-29 years for fibroadenoma; 30-39 years for fibrocystic change; 20-29 years for other benign breast lesions; and 30-39 for inflammatory lesions, and carcinoma of the breast was common in the 40-49 age group. The left breast was affected in 331 (52%) cases, the right in 283 (45%), while in 3%, both breasts were affected. CONCLUSION: Fibroadenoma was the most frequently diagnosed benign breast lesion in Hadramout. An educational program is needed to alert patients of the significance of breast masses.

Preoperative use of analgesia in appendicitis.

OBJECTIVE: To determine the influence of diclofenac sodium (DS) on masking the diagnosis of acute appendicitis. METHODS: A prospective, experimental study was carried out in Ibn Sinna General Hospital, Mukalla, Hadramout Governorate, Yemen from November 2006 to March 2007. The data were collected using a well designed questionnaire, with observation during the period of admission, prior to the operation. RESULTS: This study includes 80 patients (40 as cases, and 40 as controls), and the results revealed that most of the symptoms (fever, anorexia, nausea, and vomiting), and signs (tenderness, obturator and psoas signs, local guarding, and rigidity), were not hidden by DS (p>0.05), while other symptoms (pain), and signs (rebound tenderness, Rovsing's, and pointing) had been hindered by the use of DS. The most common presenting symptom in the placebo and DS group was pain (100%), which showed a marked decrease in severity in those who received DS as analgesia (72.2%). CONCLUSION: Some of the symptoms, and signs of acute appendicitis were masked by the use of analgesia, while others were not. In summary, DS did not influence the diagnosis or management of acute appendicitis.