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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.

The carbohydrate chains of the bronchial-mucus glycoproteins of six cystic fibrosis patients with blood group O were released by alkaline borohydride treatment. Low-molecular-mass, monosialyl oligosaccharide-alditols were isolated by anion-exchange chromatography and fractionated by high-performance liquid chromatography. Structural characterization was performed by 500-MHz 1H-NMR spectroscopy in combination with quantitative sugar analysis. The established structures range in size from tetra- up to heptasaccharides. They are all sialyl analogs of neutral oligosaccharides that were characterized previously [Lamblin G., Boersma A., Lhermitte M., Roussel P., Mutsaers J. H. G. M., Van Halbeek H. & Vliegenthart J. F. G. (1984) Eur. J. Biochem. 143, 227-236]. The NeuAc residue was found to occur either in alpha (2----3)-linkage to Gal, or in alpha (2----6)-linkage to GalNAc-ol or Gal.

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.

The substrate specificity, pH activity curves, inhibition characteristics and in vitro stabilities of the human ADH isozymes characteristic of the structural loci, ADH1, ADH2 and ADH3, have been investigated using crude tissue extracts and partially purified material. Alcohol substrates: Seventeen different alcohols were tested. The products of the three loci showed differences in their relative activities with the different substrates. Thus ADH1 isozymes were most active with ethanol, allyl alcohol, sec propanol and cyclohexanol; the 'usual' ADH2 were most active with ethanol, butanol, octanol and sec butanol; the 'atypical' ADH2 isozymes were most active with ethanol and octanol, but showed relatively low activity with butanol and Ronicol; the ADH3 isozymes were relatively very active with long straight chain primary alcohols. Aldehyde substrates: Six different aldehydes were tested. No significant differences between the isozyme products of the three loci were detected except in the case of chloral hydrate. The ADH1 and 'usual' ADH2 isozymes showed activity with chloral hydrate but this was a very poor substrate for the ADH3 and 'atypical' ADH2 isozymes. pH activity profiles: With ethanol as substrate the pH optimum for the ADH1, 'usual' ADH2 and the ADH3 isozymes was around pH 11.5 and for the 'atypical' ADH2 isozymes was about pH 8.8. With acetaldehyde as substrate the pH optima for the ADH1, 'usual' ADH2, 'atypical' ADH2 and ADH3 isozymes were about pH 8.8, 6.0, 7.0-7.5 and 6.5, resp. Inhibitors: Trichloroethanol was found to be a potent inhibitor of the ADH1 isozymes; isobutyramide an inhibitor of ADH3; and pyrazole and thiourea were shown to be powerful inhibitors of the 'atypical' ADH2 isozymes. In vitro stability: The ADH1 isozymes appeared to be relatively less stable than the 'usual' ADH2 and ADH3 isozymes. The 'atypical' ADH2 isozymes were found to be relatively very labile and particularly susceptible to freezing and thawing or storage at 10° C. The ADH 1;3 and ADH 2;3 isozymes were not demonstrably different in the properties tested.

Naegleria fowleri causes an uncommon but deadly disease called primary amoebic meningoencephalitis (PAM). There has been an increase of reported PAM cases, particularly since 2000. Although water is the dominant route of transmission of PAM, infection through soil/dust is a possible alternative route. We have observed differences in epidemiology between the southern states in the USA and the Indian subcontinent (ISC). The patient age range is greater in the ISC than in the USA, and there are more infections in the ISC which are not water-associated. We show that PAM is under-reported and argue that climate change will increase the incidence of PAM, and that the geographic range of N. fowleri will spread polewards.

Green tea catechins mixed with caffeine have been proposed as adjuvants for maintaining or enhancing energy expenditure and for increasing fat oxidation, in the context of prevention and treatment of obesity. These catechins-caffeine mixtures seem to counteract the decrease in metabolic rate that occurs during weight loss. Their effects are of particular importance during weight maintenance after weight loss. Other metabolic targets may be fat absorption and the gut microbiota composition, but these effects still need further investigation in combination with weight loss. Limitations for the effects of green tea catechins are moderating factors such as genetic predisposition related to COMT-activity, habitual caffeine intake, and ingestion combined with dietary protein. In conclusion, a mixture of green tea catechins and caffeine has a beneficial effect on body-weight management, especially by sustained energy expenditure, fat oxidation, and preservation of fat free body-mass, after energy restriction induced body-weight loss, when taking the limitations into account.