The role of statins in Alzheimer’s disease: A meta-analysis

Background In Alzheimer’s disease (AD) Amyloid Beta (Aâ) is deposited in the form of extracellular plaques and previous studies have showed Aâ generation is cholesterol dependent. The use of statins in the prevention and treatment of AD is poorly explored. The aim of this work was, therefore, to perform a review of studies on the efficacy and safety of statins in the prevention as well as treatment of AD. Methods and Findings Medline and Cochrane Database of Systematic Reviews search was performed for original research articles published in English language in which participants received any type of statins for at least 6 months and evaluated for their cognitive changes. Selected articles were grouped into two, randomized controlled trials (RCTs) and observational studies, and meta-analyzed separately. Thirteen studies identified, 4 RCTs including 1153 AD patients with trial period ranging from 26 to 72 weeks and 9 observational studies including 21,819 study participants with follow up period of up to 12 years. The 4 RCTs assessed change in Alzheimer’s Disease Assessment Scale- consisting of the cognitive subscale (ADAS-Cog) and when the results of each studies were combined there was no significant difference in ADAS-Cog between the statin and placebo group [Mean difference = -0.57, 95% CI, -1.39, 0.25, p=0.17]. Four of the 9 observational studies provided computed effect sizes in the form of Hazard ratio (HR) and common HR were computed and showed that statins had significant protective effect against AD [HR=0.69, 95% confidence interval (CI), 0.542, 0.882, p=0.003]. Three of the 9 observational studies were also combined for their Odds ratio (OR) and they showed that statins were protective against AD [OR=0.447, 95% CI, 0.299, 0.668, p=000]. Treatment related adverse effects were similar between statin and placebo [OR=2.84, 95% CI, 0.41, 19.69, p=0.29]. Conclusion Though observational studies have shown statins’ protective effect against AD, there is insufficient evidence to recommend statins for the treatment of AD, as RCTs failed to show significant efficacy. Statins are generally well tolerated in AD

In vivo anti-malarial activity of hydroalcoholic extracts from Asparagus africanus Lam. in mice infected with Plasmodium berghei

Background: Malaria is a major public health problem in the world in general and developing countries in particular, causing an estimated 1-2 million deaths per year, an annual incidence of 300-500 million clinical cases and more than 2 billion people are at risk of infection from it. But it is also becoming more difficult to treat malaria due to the increasing drug resistance. Therefore, the need for alternative drugs is acute. Objective: The This study aims at investigating the in vivo antiplasmodial activity of extracts of the roots and area parts from traditionally used medicinal plant, named Asparagus africanus (Liliaceae). Methods: A rodent malaria parasite, Plasmodium berghei, which was maintained at the Ethiopian Health and Nutrition Research Institute (EHNRI) laboratory, was inoculated into Swiss albino mice. The mice were infected with 1x107 parasites intraperitoneally. The extracts were administered by an intra gastric tube daily for four days starting from the day of parasite inoculation. The control groups received the same amount of solvent (vehicle) used to suspend each dose of the herbal drug. Chloroquine was used as a standard drug, and was administered through the same route. Results: Extracts from the roots and aerial parts of A.africanus were observed to inhibit Plasmodium berghei parasitaemia in the Swiss albino mice by 46.1% and 40.7% respectively. Conclusion: The study could partly confirm the claim in Ethiopian traditional medicine that the plant has therapeutic values in human malaria. There is, thus, the need to initiate further in-depth investigation by using different experimental models. The Ethiopian Journal of Health Development Vol. 20 (2) 2006: 112-11

Invivo Antimalarial Activity of Dodonaea Angustifolia Seed Extracts Against Plasmodium Berghei in Mice Model

Dodonaea angustifolia has a wide range of therapeutic applications against various diseases including malaria. This plant is traditionally used for  treatment of malaria in different countries including Ethiopia. However, the antimalarial effect and safety of D. angustifolia are not studied. The aim of this study was to evaluate antimalarial activity of Dodonaea angustifolia in Plasmodium berghei infected mice. In the present study, aqueous and hydroalcoholic extracts as well as solvent fractions of the aqueous extract of D. angustifolia seeds were investigated for their antimalarial activity using Peters’ 4-day suppressive test method. Different concentrations of the crude extracts and the fractions of the water extract, most active  extract, were orally administered to screen for their antimalarial activities. The extracts significantly inhibited parasitemia and prevented packed cell volume reduction (p <0.05) dose-dependently. Crude extracts and fractions of the aqueous extract of D. angustifolia seeds increased the survival time of infected mice. None of the extracts, however, prevented body weight loss. The aqueous extract of D. angustifolia was found to produce 35.79% parasite suppression. From this extract, three fractions were produced by solvent fractionation technique using butanol, chloroform and water and tested in vivo against P. berghei in mice. The butanol fraction was found to be the most active producing inhibition of 48.6% at 100 mg/kg. The test substance observed to be safe with no toxicity on the mice even at 4500 mg/kg. The results of the present work supported thetraditional use of the plant against malaria and confirmed the antimalarial activity of the plant. Moreover, antimalarial compounds can be isolated from this plant and tested against human malaria parasite in the future.Keywords: Malaria; Dodonaea angustifolia; Extracts; Plasmodium berghe

Toxic effects of aqueous leaf extract of Vernonia bipontini vatke on blood, liver and kidney tissue of mice

The present paper evaluates the acute and chronic toxicity of aqueous crude leaf extract of Vernonia bipontini Vatke (V. bipontini V) in mice model. Leaves of the plant were collected from Bale, Ethiopia, dried under shade, crushed into powder and soaked in water to yield the extract. Lethal dose of aqueous leaf extract of the plant was determined using nine groups of mice to which the aqueous leaf extracts of V. bipontini V was administered at doses ranging from 1250 to 3250mg/kg. All animals were closely observed for any physical and behavioral alterations for acute toxicity evaluation. For long-term toxicity evaluation, animals were subjected to oral administration of the extract at 400 and 800mg/kg, at 24 hours intervals for 45 days. The treated animals survived for 45 days. Body weights of the mice were recorded. Blood sample was collected from experimental and control groups for hematological studies and biochemical analysis on the 46th day after anesthesia. The liver and kidney of each animal were taken and examined by light microscope for any anatomical abnormalities. The LD50 was found to be 2500.62±5.24 mg/kg. The extract had no significant effect on liver and kidney weights, hematological (RBC, WBC, platelet, Hgb, Hct, Mcv, Mcv and L) and biochemical parameters such as liver AST, ALT and ALP; and kidney urea at all doses (P>0.05). Light microscope examination of liver and kidney tissue of mice treated with 400 and 800mg/kg of the extract did not show structural abnormalities. The results suggest that the extract of this plant may be safe, even when administered at a dose of 800mg/kg for 45 days. This is in agreement with the traditional claim of the water preparation of V. bipontini Vatke leaves.Key words: V. bipontini Vatke, Swiss Albino mice, Hematological and Biochemical parameters

The Effect of Clerodendrum Myricoides Aqueous Extract on Blood, Liver and Kidney Tissues of Mice

Clerodendrum myricoides is a plant traditionally used for its medicinal value in many parts of the world including Ethiopia. Several human defects are treated in different regions of Ethiopia using the roots, leaves, twigs, fruits and root barks of Clerodendrum myricoides species. The objective of the present study is to investigate the effect of the aqueous extract of Clerodendrum myricoides root on different tissue of mice in chronic administration. The root of the plant were collected in Bale area, Ethiopia dried and crushed into powder and soaked in water to yield aqueous extract. The extract was then administered to mice at doses of 100 and 400mg/kg bw/day for six weeks and 1134mg/kg bw/day (LD50) once. The 400mg/kg bw/day and LD50 treated mice showed hypoactivity (abnormally diminished activity), grooming, prostration (submissively prone position), piloroerection (elevation of hairs) and irritation, while 100mg/kg bw/day treated mice showed no behavioral changes. The dose of 100mg/kg bw/day produced significant weight gain, while 400mg/kg bw/day produced significant weight lost in chronic administration. The extract increased only urea at the dose of 100mg/kg bw/day, whereas it increases most hematological and biochemical parameters at 400mg/kg bw/day. The extract, however did not show significant change in platelet, HGB and MCHC value at both doses. Several histopathological changes in liver and kidney were also observed at both doses of the extract. There were inflammation and hydropic degeneration of hepatocytes at both doses. The LD50 of the extract produced hemorrhages and congestion in the glomeruli of the kidney

Toxicological evaluation of methanol leaves extract of Vernonia bipontini Vatke in blood, liver and kidney tissues of mice

Background: Various medicinal plants have been studied using modern scientific approaches. These plants have a variety of properties and various biological components that can be used to treat various diseases. However, harmful effects of plants are common clinical occurrence.Objective: This study was designed to investigate toxicological assessment of acute and chronic methanol leaf extract of Vernonia bipontini Vatke (V.bipontini V) on blood, liver and kidney tissues of mice.Methods: Lethal dose (LD) at which 50% of experimental mice died and long term toxicity of methanolic leaf extract of V. bipontini V were determined. Some hematological and biochemical parameters were evaluated. Then, liver and kidney tissues of each animal were taken and processed for light microscopy.Results: Almost all mice treated with 800mg/kg methanol leaf extract of V. bipontini V showed swellings on the left part of abdominal region related to location of spleen, mild diarrhea and enlargement of spleen. The LD50 of the methanol leaf extract of V. bipontini V was 2130.6±1.5mg/kg. Treatment with 800mg/kg body weight of methanol leaf extract significantly decreased body, liver and kidney weights, red blood cells (RBC), haemoglobin (Hgb), mean cell haemoglobin (Mch), Mchc, platelet and significantly increased serum aspartate transferance (AST), vatanine tranferance (ALT) and alkaline phosphate (ALP) levels while 400mg/kg dose had no effect on these parameters. The reduced organ weights did not correlate with loss of body weight at 800mg/kg of methanol leaf extract of the plant. Light microscope observations of liver tissue of mice treated with 800mg/kg of the methanol leaf extract revealed dilated sinusoids, nuclear enlargement, lots of bi-nucleation of hepatocytes, peripheral cramped chromatin, shrinkages (single cell death) of hepatocytes, fragmentation of hepatocytes while no histopathological changes were observed in liver and kidney of mice treated at 400mg/kg. Kidney tissue sections of mice did not show significant histopathological changes at 400mg/kg. However, at 800mg/kg kidney sections showed increased cellularity of glomerulus, urinary space obliteration and enlarged macula densa.Conclusion: This study suggests that the methanol leaf extract may have been phytotoxic to liver that resulted in a rise in serum AST, ALT and ALP levels.Key words: V. bipontini Vatke, Swiss Albino mice, liver, kidney, methanol, hematological and biochemica

Early or deferred initiation of efavirenz during rifampicin‐based TB therapy has no significant effect on CYP3A induction in TB‐HIV infected patients

Background and Purpose: In TB‐HIV co‐infection, prompt initiation of TB therapy is recommended but anti‐retroviral treatment (ART) is often delayed due to potential drug–drug interactions between rifampicin and efavirenz. In a longitudinal cohort study, we evaluated the effects of efavirenz/rifampicin co‐treatment and time of ART initiation on CYP3A induction. / Experimental Approach: Treatment‐naïve TB‐HIV co‐infected patients (n = 102) were randomized to efavirenz‐based‐ART after 4 (n = 69) or 8 weeks (n = 33) of commencing rifampicin‐based anti‐TB therapy. HIV patients without TB (n = 94) receiving efavirenz‐based‐ART only were enrolled as control. Plasma 4β‐hydroxycholesterol/cholesterol (4β‐OHC/Chol) ratio, an endogenous biomarker for CYP3A activity, was determined at baseline, at 4 and 16 weeks of ART. / Key Results: In patients treated with efavirenz only, median 4β‐OHC/Chol ratios increased from baseline by 269% and 275% after 4 and 16 weeks of ART, respectively. In TB‐HIV patients, rifampicin only therapy for 4 and 8 weeks increased median 4β‐OHC/Chol ratios from baseline by 378% and 576% respectively. After efavirenz/rifampicin co‐treatment, 4β‐OHC/Chol ratios increased by 560% of baseline (4 weeks) and 456% of baseline (16 weeks). Neither time of ART initiation, sex, genotype nor efavirenz plasma concentration were significant predictors of 4β‐OHC/Chol ratios after 4 weeks of efavirenz/rifampicin co‐treatment. / Conclusion and Implications: Rifampicin induced CYP3A more potently than efavirenz, with maximum induction occurring within the first 4 weeks of rifampicin therapy. We provide pharmacological evidence that early (4 weeks) or deferred (8 weeks) ART initiation during anti‐TB therapy has no significant effect on CYP3A induction

Importance of Ethnicity, CYP2B6 and ABCB1 Genotype for Efavirenz Pharmacokinetics and Treatment Outcomes: A Parallel-group Prospective Cohort Study in two sub-Saharan Africa Populations.

We evaluated the importance of ethnicity and pharmacogenetic variations in determining efavirenz pharmacokinetics, auto-induction and immunological outcomes in two African populations. ART naïve HIV patients from Ethiopia (n = 285) and Tanzania (n = 209) were prospectively enrolled in parallel to start efavirenz based HAART. CD4+ cell counts were determined at baseline, 12, 24 and 48 weeks. Plasma and intracellular efavirenz and 8-hydroxyefvairenz concentrations were determined at week 4 and 16. Genotyping for common functional CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 variant alleles were done. Patient country, CYP2B6*6 and ABCB1 c.4036A>G (rs3842A>G) genotype were significant predictors of plasma and intracellular efavirenz concentration. CYP2B6*6 and ABCB1 c.4036A>G (rs3842) genotype were significantly associated with higher plasma efavirenz concentration and their allele frequencies were significantly higher in Tanzanians than Ethiopians. Tanzanians displayed significantly higher efavirenz plasma concentration at week 4 (p<0.0002) and week 16 (p = 0.006) compared to Ethiopians. Efavirenz plasma concentrations remained significantly higher in Tanzanians even after controlling for the effect of CYP2B6*6 and ABCB1 c.4036A>G genotype. Within country analyses indicated a significant decrease in the mean plasma efavirenz concentration by week 16 compared to week 4 in Tanzanians (p = 0.006), whereas no significant differences in plasma concentration over time was observed in Ethiopians (p = 0.84). Intracellular efavirenz concentration and patient country were significant predictors of CD4 gain during HAART. We report substantial differences in efavirenz pharmacokinetics, extent of auto-induction and immunologic recovery between Ethiopian and Tanzanian HIV patients, partly but not solely, due to pharmacogenetic variations. The observed inter-ethnic variations in efavirenz plasma exposure may possibly result in varying clinical treatment outcome or adverse event profiles between populations

Anti-Tuberculosis Therapy-Induced Hepatotoxicity among Ethiopian HIV-Positive and Negative Patients

Background: To assess and compare the prevalence, severity and prognosis of anti-TB drug induced hepatotoxicity (DIH) in HIV positive and HIV negative tuberculosis (TB) patients in Ethiopia. Methodology/Principal Findings: In this study, 103 HIV positive and 94 HIV negative TB patients were enrolled. All patients were evaluated for different risk factors and monitored biochemically and clinically for development of DIH. Sub-clinical hepatotoxicity was observed in 17.3 % of the patients and 8 out of the 197 (4.1%) developed clinical hepatotoxicity. Seven of the 8 were HIV positive and 2 were positive for HBsAg. Conclusions/Significance: Sub-clinical hepatotoxicity was significantly associated with HIV co-infection (p = 0.002), concomitant drug intake (p = 0.008), and decrease in CD4 count (p = 0.001). Stepwise restarting of anti TB treatment was also successful in almost all the patients who developed clinical DIH. We therefore conclude that anti-TB DIH is a major problem in HIV-associated TB with a decline in immune status and that there is a need for a regular biochemical and clinical follow up for those patients who are at risk