Mutagenicity evaluation of azaperone in the Salmonella/microsome test

Azaperone was evaluated for its mutagenic potential by the Salmonella/microsome test. No mutagenic activity towards six S. typhimurium strains could be evidenced with azaperone at doses up to 2,000 micrograms/plate, either without or with metabolic activation at usual test conditions. Higher concentrations of liver post-mitochondrial fraction from Aroclor 1254 (ARO)-pretreated rats did not reveal any increase in the number of revertants towards S. typhimurium strains TA1537, TA1538 and TA98. Moreover, a plate-incorporation test with liver post-mitochondrial fractions from mice pretreated with phenobarbital (PB) and a liquid preincubation test with liver post-mitochondrial fractions from rats pretreated with ARO also failed to reveal any mutagenic action of azaperone towards S. typhimurium strain TA98. Thus, none of the tests used provided any indication of azaperone having a mutagenic action.     

Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study

Abstract

Objective:

Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes.     

Increase of 2,3-epoxybutane mutagenicity by glutathione-S-transferases

The mutagenicity of 2,3-epoxybutane (2,3-EB) towards Salmonella typhimurium TA1530 is increased by rat liver S9 mix. This enhancement can be induced by Aroclor 1254 (ARO) or phenobarbitone (PB) pretreatment. Comparative assays with purified subcellular liver fractions demonstrated that cytosol is the most active in increasing the mutagenic effect of 2,3-EB. Addition of reduced glutathione (GSH) to metabolic activating mixtures containing S9 or cytosol, strengthened this effect. From these results it is suggested that 2,3-EB is stabilized through enzymic conjugation with GSH.     

Centralized Pan-European survey on the under-treatment of hypercholesterolaemia (CEPHEUS): overall findings from eight countries

Abstract

Background:

Surveys evaluating plasma lipid goal attainment in patients with coronary heart disease have shown that hypercholesterolaemia is inadequately treated. Limited data account for the reasons behind this. The aim of the CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) survey was to evaluate the current use and efficacy of lipid-lowering drugs (LLD), and to identify possible patient/physician characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets recommended by the 2003 European guidelines (Third Joint Task Force).     

Evaluation of the safety of the dietary antioxidant ergothioneine using the bacterial reverse mutation assay

The dietary antioxidant l-(+)-ergothioneine was tested for its potential mutagenic activity using the bacterial reverse mutation assay. The experiments were carried out using histidine-requiring auxotrophic strains of Salmonella typhimurium (Salmonella typhimurium TA98, TA100, TA1535 and TA1537), and the tryptophan-requiring auxotrophic strain of Escherichia coli (Escherichia coli WP2 uvrA) in the presence and absence of a post-mitochondrial supernatant (S9) prepared from livers of phenobarbital/β-naphthoflavone-induced rats. The revertant colony numbers of vehicle control plates with and without S9 Mix were within the corresponding historical control data ranges. The reference mutagen treatments (positive controls) showed the expected, biologically relevant increases in induced revertant colonies in all experimental phases in all tester strains. No biologically relevant increases were observed in revertant colony numbers of any of the five test strains following treatment with l-(+)-ergothioneine at any concentration level, either in the presence or absence of metabolic activation (S9 Mix) in the performed experiments. On the basis of the data reported, it can be concluded that l-(+)-ergothioneine did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used. Thus l-(+)-ergothioneine has no mutagenic activity on the applied bacteria tester strains under the test conditions used in this study. Research is continuing to define the role of l-(+)-ergothioneine in disease pathophysiology. Further studies on its safety are suggested.     

Slaframine and Swainsonine,Mycotoxins from Rhizoctonia Leguminicola

Abstract

The mold, Rhizoctonia leguminicola, parasitizes certain legumes, e.g. red clover, in wide areas of the U.S. Consumption of such moldy forage may cause several syndromes of varying severity including excessive salivation, lacrimation, diarrhea, and even death. 1-Acetoxy-6-aminooctahydroindolizine (slaframine, SF) a parasympathomimetic, and 1,2,8-trihydroxyoctahydroindolizine (swainsonine, SW) a potent a-mannosidase inhibitor, are produced in pure R. leguminicola cultures and were also isolated directly from moldy red clover hay which had caused a severe slobbers outbreak. SW when compared with locoweed was found to produce similar effects on tissue glycosidases and oligosaccharides of the pig indicating that SW is the principal toxin responsible for the induction of locoism. Our research presently focuses on aspects of SW as a mycotoxin e.g. the possibility that SW may enter the human food chain via milk from diary cattle consuming moldy forage is being considered. Additionally we are interested in the biogenesis of SF and SW from lysine in R. leguminicola enzyme systems and if such pathways of secondary nitrogen metabolism are subject to conventional regulatory mechanisms of microbial pathways.     

Effects of Panax Ginseng Extract on the Benzo(a)Pyrene Metabolizing Enzyime System

ABSTRACT

Ethanol extract of Panax ginseng C. A. Meyer, which has been used for centuries as a tonic in Asian countries, exhibited a selective induction of epoxide hydratase and cytosolic glutathione transferase activity without the concurrent induction of aryl hydrocarbon hydroxylase activity. Thus, Panax ginseng appears to have the potential to alter the metabolic patterns of benzo(a)pyrene and its reactive metabolites.     

Surface Lipids of Seeds Support Both Aspergillus Parasiticus Growth and Aflatoxin Production

Abstract

Seed surface lipids (SSL) play a key role in supporting aflatoxin (AFT) output in oily and starchy seeds following infection with Aspergillus parasiticus. On oily seeds, fungal growth and AFT production occur when the levels of SSL are higher than 0.15% of total oil content of seeds, with a ratio between triglycerides and free fatty acids (TG/FFA) of SSL > 1. If FFA prevail over TG, growth can be inhibited because of the toxicity towards Aspergillus of unsaturated FFA of SSL. Defatted meals of sunflower seeds support a reduced AFT biosynthesis. On starchy seeds, A. parasiticus proliferates in the germ region, the area richest in lipids.     

Outcomes from the International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) project

Aims: The International Survey Informing Greater Insights in Opioid Dependence Treatment (INSIGHT) study evaluated the implementation of opioid dependence treatment across different countries to assess treatment delivery, quality of care and outcomes. Methods: A questionnaire-based survey was used to gather data in nine countries across Central and Eastern Europe, South Africa and South-East Asia, from patients with opioid dependence receiving medication-assisted treatment (MAT), healthcare professionals (HCPs) who cared for opioid-dependent patients and opioid users not receiving MAT. Findings: There was substantial variation between countries, but overall results suggest that several aspects of MAT can be improved, such as access to treatment (conditions to start or remain in treatment), quality of care (availability/awareness of treatment options and appropriate medication dosing) and treatment outcomes (on-top use, misuse and diversion). Conclusions: This analysis highlights key priorities that should improve the quality of opioid dependence care and access to treatment. These priorities include: acknowledging opioid dependence as a chronic medical condition requiring long-term treatment; recognition by policymakers of the cost-effectiveness of treatment; making available, to those who want them, psychosocial interventions and educating HCPs to prescribe the safest, least divertible forms of medications available at optimal doses in order to reduce opioid use, misuse and diversion.     

The Significance of Isomerism and Stereospecificity to the Chemistry of Plant Teratogens

Abstract

Among the stereochemical relationships which may be relevant to the biological properties of four types of teratogenic plant alkaloids are: (a) rotational isomerism about the C-20, C-22 bond of 22,26-epiminocholestenes, (b) nitrogen inversion and/or preferential ring F opening of 22α-N spirosolanes, (c) conformational or configurational interconversions of solanidanes, and (d) atropisomerism of colchicine and its analogs.     

Sphingomyelinase of Bacillus Cereusas a Bacterial Hemolysin

Abstract

The enzymatic, toxic and molecular properties of sphingomyelinase from Bacillus cereuswere described in relation to other bacterial sphingomyelinases such as β-toxin of Staphylococcus aureus. The complete amino acid sequences of B. cereussphingomyelinase, determined from its chromosmal DNA, were examined in relation to other phospholipases C from B. cereusand Clostridium perfringens. The gene of B. cereussphingomyelinase codes 27 amino acid residues of signal peptide and 306 residues of mature protein. Both the genes of sphingomyelinase and phosphatidylcholine-hydrolyzing phospholipase C of B. cereusformed a gene cluster. According to the prediction of secondary structure of sphingomyelinase, almost half of the total amino acid residues might participate in loop or turn structure, while one-fifth and one-fourth of amino acid residues might be involved in α-helix and β-structure, respectively. The helical content determined by circular dichroism (CD) spectra indicated 0–5%. The enzyme specifically hydrolyzes sphingomyelin in the intact erythrocyte membranes as well as in the micelles and liposomes, causing the hemolysis of erythrocytes. The enzyme is specifically adsorbed onto the surface of membranes of erythrocytes and liposomes. The hydrolysis of sphingomyelin and the adsorptive properties were influenced by the divalent metal ions such as Mg²⁺, Ca²⁺and Mn²⁺. Selective modfication of amino acid residues in the molecule of sphingomyelinase suggested that acidic amino acid residues such as Asp and Glu would be involved in the catalytic center and adsorptive sites in the sphingomyelinase molecule. Also, the effects of membrane-perturbing agents were described.     

Mutagenicity of Mouriri pusa Gardner and Mouriri elliptica Martius

Mouriri pusa Gardner and Mouriri elliptica Martius are fruit-bearing plants of the Melastomataceae family, popularly known in Brazil as puçá-preto or jaboticaba-do-cerrado, and they are used in folk medicine for the treatment of gastric ulcers. In this study, we employ the Ames test to assess the mutagenicity of compounds obtained from the leaves of these species. The methanol extract of the M. pusa was mutagenic to the Salmonella typhimurium strains TA98, TA97a and TA100, with or without metabolic activation. The methanol extract of M. elliptica induced mutagenic activity in TA98 when metabolized with S9 fraction and TA97a with and without S9, but with lower mutagenicity index (MI) and potencies values than those for M. pusa. Enriched fractions of flavonoids and tannins of M. pusa were also evaluated and they demonstrated positive mutagenicity. The highest values of MI and potency were obtained with the flavonoid fraction, which contains large amounts of quercetin, quercetin glycosides and myricetin. These compounds are probably related to the mutagenicity observed in the Ames test. The dichloromethane extract was not mutagenic in any of the test conditions employed.     

Studies on Glutathione S-Transferases of Aspergillus Flavus Group in Relation to Aflatoxin Production

Abstract

Aflatoxin synthesis in the mycelia of Aspergillus is positively correlated with the activity of cellular glutathione (GSH) S-transferases (Saxena, Manju, Mukerji, K.G., Raj, H.G. 1988, Biochem. J. 254, 567-570). This finding is further extended to the action of inducer and inhibitor of aflatoxin synthesis upon A. flavus GSH S-transferase. Phenobarbitone (PB) a known inducer of aflatoxin formation increases GST activity in toxigenic strain alone as compared to non-toxigenic strains. Tinaderm (Tolnaftate) an antifungal drug specifically inhibit aflatoxin synthesis. Tinaderm - treated A. flavus mycelium was found to have significantly diminished GSH S-transferase activity coupled with reduce levels of aflatoxin. These observations point out clearly that theendogenous aflatoxin is the main factor effecting specific induction of A. flavus GSH S-transferase. The inducing effect of aflatoxin appears to be different from phenobarbital pattern of induction of GSH S-transferase. In this connection, a direct interaction of aflatoxin with A. flavus genome similar to the action of TCDD is suggested.     

Evaluation, using Salmonella typhimurium, of the mutagenicity of seven chemicals found in cosmetics

Six chemicals used as ingredients in cosmetics were evaluated for mutagenic activity in Salmonella typhimurium. Two of these ingredients, trans-4-phenyl-3-butene-2-one and 2,2′,4,4′-tetrahydroxybenzophenone, were mutagenic in the presence of rat liver S-9 towards strains TA100 and TA1537 respectively. An impurity found in some cosmetic products, N-nitrosodiethanolamine, was mutagenic to S. typhimurium stains TA1535 and TA100 in the presence of hamster-liver S-9 but not rat-liver S-9.     

Differences in the in vivo and in vitro Effects of the Carbamate Insecticide,Carbaryl on rat Hepatic Monooxygenases

ABSTRACT

The effects of one of the most widely used insecticides, carbaryl, on the hepatic cytochrome P-450—dependent monooxygenases were determined. Addition of carbaryl to liver microsomes from untreated or phenobarbital (PB)-pretreated rats resulted in a weak Type I binding spectrum. A much stronger spectral Type I interaction was observed when microsomes from 3-methylcholanthrene(3—MC)-treated rats were used. In vitro, carbaryl caused marked inhibition of ethylmorphine and benzphetamine N-demethylases, benzo(a)pyrene hydro-xylase, 7-ethoxycoumarin and 7-ethoxyresorufin 0-deethylases in liver microsomes. Kinetic studies demonstrated that carbaryl was a competitive inhibitor of ethylmorphine N-demethylase activity. Daily administration of carbaryl for 4 days by gavage or intra-peritoneally resulted in no significant alterations in hepatic cytochrome P-450 levels, ethylmorphine N-demethylase or benzo(a)-pyrene hydroxylase activities. The lack of effect of carbaryl in vivo may be due to the rapid metabolism of the insecticide, such that the insecticide may not be present in the liver endoplasmic reticulum to cause the inhibitory effects observed in vitro.     

Therapist Rotation—A New Element in the Outpatient Treatment of Alcoholism

For nine years, the so-called “therapist rotation” has been a central part of OLITA, the Outpatient Longterm Intensive Therapy for Alcoholics. Thus far, the participation of several equally responsible therapists in the treatment of a patient has rarely been seen as a specific therapeutic approach. The present article analyzes the therapist rotation from a theoretical and clinical perspective. Articles concerned with the therapeutic alliance in the treatment of substance use disorders are reviewed. Furthermore, the literature on multiple psychotherapy, which may be seen as the precedent of the therapist rotation is surveyed. Based on the efficacy of multiple psychotherapy and the importance of the therapeutic alliance in the treatment of substance use disorders, the present work discusses the therapist rotation as an essential factor for the success of OLITA. It considers both potential advantages and disadvantages for patients and therapists and tries to identify conditions under which this approach appears to promote therapeutic interactions. Finally, the implementation of therapist rotation into OLITA is described, including the theoretical background of the program itself and the treatment procedure. New areas of application for the therapist rotation are discussed.     

Ames mutagenicity tests of products from a heated potato-starch system

A charred sample was prepared from potato starch heated with ammonium carbonate at 600°C in a flask under a nitrogen stream. The water produced was collected and extracted with methylene chloride. The basic fraction obtained from the extract exhibited strong mutagenicity in Ames assays using Salmonella typhimurium strains TA98 or TA100 with metabolic activation (rat-liver S-9 mix). The basic fraction was further fractionated by silica gel column chromatography and subsequently by Scphadex column chromatography. Some of the resulting fractions exhibited strong mutagenic activities in S. typhimurium strain TA98 with S-9 mix.     

Aflatoxin Related Occupational Hazards Among Rice Mill Workers

Abstract

Present study has been designed to find out the airborne mycoflora of the work environment of rice mills where workers are occupationally exposed to these environmental flora with a special reference to isolation and identification of aflatoxin positive Aspergillus strain from the work environment. The study covered altogether three rice mills located at Bawla town in Ahmedabad district (India). Of all the isolates, 27.39 were Aspergillus of which 6.64; were A. flavus. Quantitative evaluation showed the maximum number of isolates recovered from work place (P<0.01) in comparison to office (control). Strains of A. flavus were subcultured onto various qualitative media for identification of toxigenic strain, but none of the strains showed positive result indicating that all the eight strains were non-toxigenic.     

The Direct Actinc α-Fibrin(Ogen)Olytic Enzymes from Snake Venoms

Abstract

A variety of α-fibrin(ogen)olytic enzymes have been found in snake venoms. More than 15 α-fibrin(ogen)ases have been isolated and characterized. Most work has been done with the venom of snakes belonging to a few species from the Agkistrodon, Crotalus, Trimeresurus, Bothrops, and Vipera. Only one α-fibrin(ogen)olytic enzyme is characterized from Elapidae snake venoms. The enzymatic properties of these proteinases are described in relation to action on fibrinogen, fibrin, and casein. The fibrinolytic enzymes act directly on fibrin and do not activate plasminogen. The proteolytic activity of these metalloproteinases is inhibited by EDTA. Most thoroughly investigated snake venom fibrinolytic enzymes are fibrolase from Agkistrodon contortrix contortrix venom, atroxase from Crotalus atrox venom and cerastase from Cerastes cerastes venom. Antibodies to fibrolase were prepared and their cross-reactions with other fibrinolytic components from several snake venoms have been detected. These antibodies were successfully used for purification of fibrolase from crude southern copperhead venom. Fibrolase and atroxase have no hemorrhagic activity, and they effectively solubilize artificial thrombi. Research in this area has a chance to provide new therapeutic agents for dissolving thrombi.     

Comparison of Efficacy of Ginger with Various Antimotion Sickness Drugs

Abstract

Ginger and several other medications were compared with scopolamine and d-amphetamine for effectiveness in prevention of motion sickness. Methods: Double-blind techniques were used. The subjects were given the medications two hours before they were rotated in a chair making head movements until a synptun total short of vomiting was reached. Standardized N.A.S.A. techniques were used for speed of rotation and end-point of motion sickness. Results: The three doses of ginger were all at the placebo level of efficacy. Amitriptyline, ethopropazine and trihexyphenidyl increased the tolerated head movements but the increase was not statistically significant. Significant levels of protection were produced by dimenhydrinate, promethazine, scopolmine and d-amphetamine. Protection was further increased by combination of these latter drugs with d-amphetamine. Efficacy was greatest as the dose was increased. Conclusions: The medication of choice in this study was scopolamine 0.6 mg with d-amphetamine 10 mg. This combination provided good protection with acceptable side effects.