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Abstract As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Cholesta-5,7,9(11)-trien-3β-ol and its oleate ester were incorporated into human low-density lipoprotein and reconstituted high-density lipoprotein. The unesterified sterol was more efficient than its ester in quenching tryptophan fluorescence, especially in low-density lipoprotein. The results, which indicate that in such lipoproteins unesterified sterols are more closely associated with peptide than are esterified sterols, are used to assess possible structures for the lipoproteins.

1. Liver biopsies were performed in healthy control subjects and in subjects with alcoholic and non-alcoholic liver disease in order to examine alcohol dehydrogenase (ADH; EC 1.1.1.1) and aldehyde dehydrogenase [ALDH; aldehyde dehydrogenase (NAD+); EC 1. 2. 1. 3] activities. Erythrocyte ALDH and ethanol metabolism were also investigated in the same subjects. 2. Fifteen per cent of the subjects studied (seven of 48 subjects tested) presented atypical ADH activity, characterized by elevated activity at pH 7.4 or 8.8 compared with that found in subjects with the usual ADH form. However, the ethanol elimination curves obtained in two subjects with atypical ADH were indistinguishable from the kinetics of the group with normal ADH. Subjects displaying atypical ADH activity showed normal liver and erythrocyte ALDH activities. 3. Considering only the subjects with the normal ADH form, hepatic ADH activity was unaltered in subjects with non-alcoholic liver disease (chronic hepatitis or cirrhosis) and in those with alcoholic steatosis. Subjects with alcoholic hepatitis or alcoholic cirrhosis showed a lower ADH activity compared with the healthy control group. 4. In spite of the changes detected in subjects with alcoholic liver disease, curves of blood ethanol concentration after oral administration of 0.4 g of ethanol/kg were indistinguishable between the alcoholic hepatitis group and the control group. 5. Hepatic ALDH activity, assayed at 300 μmol/l acetaldehyde, was found to be diminished in all liver pathologies investigated, regardless of their aetiology. Nevertheless, erythrocyte ALDH activity was not modified in subjects with non-alcoholic or alcoholic liver disease. As a result of these findings, no relationship was found between hepatic and erythrocyte ALDH. 6. In summary, our data demonstrate that (a) marked modifications in ADH activity, as found in patients with atypical ADH or in subjects with alcoholic liver disease, are not accompanied by parallel alterations in the kinetics of ethanol disappearance, suggesting that ADH activity per se does not limit ethanol metabolism in vivo, (b) hepatic high-Km ALDH activity is decreased in patients with liver disease independent of alcoholism, and therefore decreased ALDH activity cannot be considered as a primary defect in alcoholism but as a consequence of liver damage, and (c) erythrocyte ALDH does not reflect hepatic high-Km ALDH.

Abstract: Five groups of NMRI mice were fed ethanol or sucrose in a nutritionally adequate liquid diet for 9 days. The dietary fat consisted of olive oil with the fatty acid composition 18:1 77%, 18:2 10%, 18:0 and 16:0 12%. The ethanol treated groups received 5% w/v ethanol (E) or isocaloric sucrose (S). Two groups (S‐ and E‐) received the diet without supplement. In two groups (S+ and E +) 7% of the fat was exchanged for arachidonic acid (20:4). In a fifth group (IE +) treated with ethanol and arachidonic acid the diet also contained indomethacin (10 mg/1). The mean intake of ethanol was about 20 g/kg/day. After 9 days animals were killed and liver lipids analyzed after Folch extraction. The post mortem accumulation of prostaglandin E2 in the kidney was measured by GC‐MS. Dietary 20:4 was found to protect mice against fatty liver caused both by a high fat diet alone and in combination with ethanol. The liver triglycerides were 30.7 + 4.3 (S ‐), 46.1+6.9 (E ‐), 6.8 + 0.4 (S +) and 19.4 ±1.8 (E +). Prostaglandin levels in the kidney were depressed by ethanol treatment. Indomethacin gave variable degrees of PG synthesis inhibition. The degree of liver triglyceride accumulation in the IE+ group was inversely propotional to the degree of PG synthesis. The data suggest a role for liver 20:4 cyclooxyganase metabolites in fatty liver caused by high fat diets and ethanol.

AbstractObjectives:  Little is known about the clinical significance of acute ethanol coingestion around the time of acetaminophen (paracetamol) overdose. This study prospectively examined the effect of acute ethanol coingestion on risk of hepatotoxicity among patients admitted to hospital for N‐acetylcysteine (NAC) therapy after deliberate acetaminophen overdose.Methods:  This was a prospective observational study and included sequential patients who presented within 24 hours of acute acetaminophen ingestion and required NAC therapy. Significant hepatotoxicity was defined by alanine transaminase > 1,000 U/L or the international normalized ratio > 1.3 after a standardized intravenous administration of 300 mg/kg NAC.Results:  There were 362 patients, including 178 (49.2%) who coingested ethanol acutely. The prevalence of hepatotoxicity was 5.1% (95% CI = 2.6% to 9.5%) in those who ingested ethanol, compared to 15.2% (95% CI = 10.7% to 21.2%) in those who did not (p = 0.0027 by chi‐square proportional test). Acute ethanol intake conferred a lower risk of hepatotoxicity in patients who had acetaminophen concentrations above or below the “200‐line” and was independent of the interval between ingestion and assessment.Conclusions:  Acute ethanol intake is associated with a lower risk of hepatotoxicity after acetaminophen overdose. This apparent protective effect cannot be explained solely by lower exposure to acetaminophen in this group, nor differences in the interval between ingestion and initiation of treatment. Further work is required to establish mechanisms by which ethanol might confer protection against hepatotoxicity, so as to identify novel strategies for reducing risk after acute acetaminophen ingestion.

Abstract Background Mulberry leaf as a traditional Chinese medicine is able to treat obesity, diabetes, and dyslipidemia. It is well known that diabetes leads to intestinal microbiota dysbiosis. It is also recently discovered that liver glycogen structure is impaired in diabetic animals. Since mulberry leaves are able to improve the diabetic conditions through reducing blood glucose level, it would be interesting to investigate whether they have any positive effects on intestinal microbiota and liver glycogen structure. Methods In this study, we first determined the bioactive components of ethanol extract of mulberry leaves via high-performance liquid chromatography (HPLC) and liquid chromatography/mass spectrometry (LC/MS). Murine animal models were divided into three groups, normal Sprague-Dawley (SD) rats, high-fat diet (HFD) and streptozotocin (STZ) induced type 2 diabetic rats, and HFD/STZ-induced rats administered with ethanol extract of mulberry leaves (200 mg/kg/day). Composition of intestinal microbiota was analyzed via metagenomics by sequencing the V3-V4 region of 16S rDNAs. Liver glycogen structure was characterized through size exclusion chromatography (SEC). Both Student’s t-test and Tukey’s test were used for statistical analysis. Results A group of type 2 diabetic rat models were successfully established. Intestinal microbiota analysis showed that ethanol extract of mulberry leaves could partially change intestinal microbiota back to normal conditions. In addition, liver glycogen was restored from fragile state to stable state through administration of ethanol extract of mulberry leaves. Conclusions This study confirms that the ethanol extract of mulberry leaves (MLE) ameliorates intestinal microbiota dysbiosis and strengthens liver glycogen fragility in diabetic rats. These finding can be helpful in discovering the novel therapeutic targets with the help of further investigations.

Salaspuro, M. P. & Kesaniemi, Y. A. Intravenous galactose elimination tests with and without ethanol loading in various clinical conditions. Scand. J. Gastroent. 1973, 8, 681-686.Intravenous galact...

At present, Artemisia annua L. is the major source of artemisinin production. To control the outbreaks of malaria, artemisinin combination therapies (ACTs) are recommended, and hence an ample amount of artemisinin is required for ACTs manufacture to save millions of lives. The low yield of this antimalarial drug in A. annua L. plants (0.01-1.1%) ensues its short supply and high cost, thus making it a topic of scrutiny worldwide. In this study, the effects of root endophyte, Piriformospora indica strain DSM 11827 and nitrogen fixing bacterium, Azotobacter chroococcum strain W-5, either singly and/or in combination for artemisinin production in A. annua L. plants have been studied under poly house conditions. The plant growth was monitored by measuring parameters like height of plant, total dry weight and leaf yield with an increase of 63.51, 52.61 and 79.70% respectively, for treatment with dual biological consortium, as compared to that of control plants. This significant improvement in biomass was associated with higher total chlorophyll content (59.29%) and enhanced nutrition (especially nitrogen and phosphorus, 55.75 and 86.21% respectively). The concentration of artemisinin along with expression patterns of artemisinin biosynthesis genes were appreciably higher in dual treatment, which showed positive correlation. The study suggested the potential use of the consortium P. indica strain DSM 11827 and A. chroococcum strain W-5 in A. annua L. plants for increased overall productivity and sustainable agriculture.