Analysis of paralytic shellfish poisoning toxin congeners by a sodium channel receptor binding assay

This study was carried out to characterize the detection and quantitation of several paralytic shellfish poisoning (PSP) toxin congeners using a receptor binding assay (RBA). This involved competitive binding of the toxin congeners against tritiumlabeled STX for receptor sites on rat brain sodium channels. Competitive binding curves were described by a four-parameter logistic equation. Half-saturation values (EC50) ranged from 4.38 nM for STX to 142 nM for GTX5. Receptor binding affinity was in the order STX . GTX1/4 . neoSTX . GTX2/3 . dcSTX . GTX5, and this was similar to the order of mouse toxicity of these congeners. Predicted toxin concentrations from observed STXeq values and EC50 ratios relative to STX were within 20% or better of the actual concentrations used in the assay. In contrast predicted toxin concentrations using mouse toxicity ratios relative to STX did not provide a good match to actual concentrations, except for GTX1/4. This study has shown that the rat brain sodium channel RBA will provide a reliable integration of total toxicity of various PSP toxin congeners present in a sample

Vitamin B₁₂ and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation

Background & Aims Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH. Methods We examined the effects of HHcy on NASH progression, metabolism, and autophagy in dietary and genetic mouse models, patients, and primates. We employed vitamin B12 (B12) and folate (Fol) to reverse NASH features in mice and cell culture. Results Serum Hcy correlated with hepatic inflammation and fibrosis in NASH. Elevated hepatic Hcy induced and exacerbated NASH. Gene expression of hepatic Hcy-metabolizing enzymes was downregulated in NASH. Surprisingly, we found increased homocysteinylation (Hcy-lation) and ubiquitination of multiple hepatic proteins in NASH including the key autophagosome/lysosome fusion protein, Syntaxin 17 (Stx17). This protein was Hcy-lated and ubiquitinated, and its degradation led to a block in autophagy. Genetic manipulation of Stx17 revealed its critical role in regulating autophagy, inflammation and fibrosis during HHcy. Remarkably, dietary B12/Fol, which promotes enzymatic conversion of Hcy to methionine, decreased HHcy and hepatic Hcy-lated protein levels, restored Stx17 expression and autophagy, stimulated β -oxidation of fatty acids, and improved hepatic histology in mice with pre-established NASH. Conclusions HHcy plays a key role in the pathogenesis of NASH via Stx17 homocysteinylation. B12/folate also may represent a novel first-line therapy for NASH. Lay summary The incidence of non-alcoholic steatohepatitis, for which there are no approved pharmacological therapies, is increasing, posing a significant healthcare challenge. Herein, based on studies in mice, primates and humans, we found that dietary supplementation with vitamin B12 and folate could have therapeutic potential for the prevention or treatment of non-alcoholic steatohepatitis

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

Toxin profile and relative toxicity of three paralytic shellfish poisoning toxin- producing dinoflagellates from Malaysia

This study was carried out to determine the toxin profile and toxin content of Alexandrium minutum, Alexandrium tamiyavanichii and Pyrodinium bahamense var. compressum. These are three of the paralytic shellfish poisoning (PSP) toxin-producing marine dinoflagellates present in Malaysian waters. PSP toxins were analysed using an isocratic, post-column derivatization HPLC method with fluorescence detection. The three species differed significantly in toxin profile. A. minutum contained only GTX1, GTX2, ..

Tribological behaviour of different diamond-like carbon materials

This paper comparatively studies the tribological behaviour of different types of diamond-like carbon (DLC) coatings in a reciprocating sliding wear test. The results are interpreted in terms of structure and surface morphological characteristics. At the beginning of each reciprocating sliding wear test, the higher coefficient of friction of the DLC coatings reflects the original surface conditions of contacting counterfaces, whereas the low coefficient of friction achieved under the steady regime is linked to the presence of wear debris and an enlarged real contact area. sp(2) carbon bonding has been related to the occurrence of a higher coefficient of friction and surface damage of DLC materials compared to bulk diamond. The a-C coatings and ta-C films have a lower coefficient of friction at the steady regime than the a-C:H coatings, possibly due to a significant amount of hydrogen in the a-C:H coatings. (C) 1998 Elsevier Science S.A.status: publishe