Chlorophyll a fluorescence and ultrastructural changes in chloroplast of water hyacinth as indicators of environmental stress

Chlorophyll a fluorescence parameters and transmission electron microscopy (TEM) were used to assess the stress conditions in water hyacinth along the Paraiba do Sul River (PSR), an important River in southeastern Brazil. The data were obtained at the end of the dry season of 2005 and at the end of the wet season of 2006. Changes in F-o and F-m parameters were observed as differentiated responses, depending on the season. Non-photochemical dissipation (qN and NPQ) from plants was greater in the most industrialized region of the PSR in both seasons. However, F-v/F-m for all samples ranged between 0.77 and 0.81, showing that high maximum quantum yield was maintained. Although the F-v/F-m suggests that the plants were exhibiting normal photochemical activities, ultrastructural changes in chloroplasts showed thylakoids disorganization. Plants from the most industrialized region showed non-stacking grana thylakoids disposition. In spite of these alterations, the membrane integrity was maintained, suggesting an adaptation to adjustment to adverse environmental conditions. (C) 2008 Elsevier B.V. All rights reserved.

Statin regulation of CYP3A4 and CYP3A5 expression

CYP3A4 and CYP3A5 are cytochrome P450 enzymes that are highly expressed in the liver and gut and metabolize endogenous compounds and xenobiotics. Statins are cholesterol-lowering drugs that are extensively metabolized by CYP3A4 and CYP3A5. The bioavailability of statins is affected by CYP3A4 and CYP3A5 and glucuronidases metabolism as well as uptake and efflux transporters that affect drug disposition. CYP3A4 and CYP3A5 variants have been demonstrated to influence the pharmacokinetics, efficacy and safety of statins. Inducers and inhibitors of CYP3A4 and CYP3A5 play an important role in reducing statin efficacy and increase the risk of adverse effects, respectively. Statins have been demonstrated to increase CYP3A expression in vitro, most likely because they are ligands to nuclear receptors (pregnane X receptor and constitutive androsterone receptor) that form heterodimers with retinoid X receptors and bind to responsive elements in the CYP3A4 and CYP3A5 promoter regions. This special report outlines the earlier studies on variability of response to statins owing to CYP3A variants and highlights findings on the induction of CYP3A4 and CYP3A5 expression by statins.

Bioequivalence Evaluation of Single Doses of Two Tramadol Formulations: A Randomized, Open-Label, Two-Period Crossover Study in Healthy Brazilian Volunteers

Background: Tramadol is a well tolerated and effective analgesic used to treat moderate to severe pain. Several generic formulations of tramadol are available in Brazil; however, published information regarding their bioequivalence in the Brazilian population is not available. A study was designed for Brazilian regulatory authorities to allow marketing of a generic formulation. Objective: The purpose of this study was to compare the bioequivalence of 2 commercial tablet preparations containing tramadol 100 mg marketed for use in Brazil. Methods: A randomized, open-label, 2 x 2 crossover study was performed in healthy Brazilian volunteers under fasting conditions with a washout period of 12 days. Two tablet formulations of tramadol 100 mg (test and reference formulations) were administered as a single oral dose, and blood samples were collected over 24 hours. Tramadol plasma concentrations were quantified using a validated HPLC method. A plasma concentration time profile was generated for each volunteer and then mean values were determined, from which C(max), T(max), AUC(0-t), AUC(0-infinity), k(e), and t(1/2) were calculated using a noncompartmental model. Bioequivalence between the products was determined by calculating 90% CIs for the ratios of C(max), AUC(0-t), and AUC(0-infinity) values for the test and reference products using log-transformed data. Tolerability was assessed by monitoring vital signs (temperature, blood pressure, heart rate), laboratory tests (hematology, blood biochemistry, hepatic function, urinalysis), and interviews with the volunteers before medication administration and every 2 hours during the study. Results: Twenty-six healthy volunteers (13 men, 13 women) were enrolled in and completed the study. Mean (SD) age was 30 (6.8) years (range, 21-44 years), mean weight was 64 (8.3) kg (range, 53-79 kg), and mean height was 166 (6.4) cm (range, 155-178 cm). The 90% CIs for the ratios of C(max) (1.01-1.17), AUC(0-t) (1.00-1.13), and AUC(0-infinity) (1.00-1.14) values for the test and reference products fell within the interval of 0.80 to 1.25 proposed by most regulatory agencies, including the Brazilian regulatory body. No clinically important adverse effects were reported; only mild somnolence was reported by 4 volunteers and mild headaches by 5 volunteers, and there was no need to use medication to treat these symptoms. Conclusion: Pharmacokinetic analysis in these healthy Brazilian volunteers suggested that the test and reference formulations of tramadol 100-mg tablets met the regulatory requirements to assume bio-equivalence based on the Brazilian regulatory definition. (Clin Ther 2010;32:758-765) (C) 2010 Excerpta Medica Inc.

Determination of Atropine Enantiomers in Ophthalmic Solutions by Liquid Chromatography Using a Chiral AGP (R) Column

Many therapeutic agents are commercialized under their racemic form. The enantiomers can show differences in the pharmacokinetic and pharmacodynamic profile. The use of a pure enantiomer in pharmaceutical formulations may result in a better therapeutic index and fewer adverse effects. Atropine, an alkaloid of Atropa belladonna, is a racemic mixture of l-hyoscyamine and d-hyoscyamine. It is widely used to dilate the pupil. To quantify these enantiomers in ophthalmic solutions, an HPLC method was developed and validated using a Chiral AGP (R) column at 20 degrees C. The mobile phase consisted of a buffered phosphate solution (containing 10 mM 1-octanesulfonic acid sodium salt and 7.5 mM triethylamine, adjusted to pH 7.0 with orthophosphoric acid) and acetonitrile (99 + 1, v/v). The flow rate was 0.6 mL/min, with UV detection at 205 nm. In the concentration range of 14.0-26.0 mu g/mL, the method was found to be linear (r > 0.9999), accurate (with recovery of 100.1-100.5%), and precise (RSD system: <= 0.6%; RSD intraday: <= 1.1%; RSD interday: <= 0.9%). The method was specific, and the standard and sample solutions were stable for up to 72 h. The factorial design assures robustness with a variation of +/-10% in the mobile phase components and 2 degrees C of column temperature. The complete validation, including stress testing and factorial design, was studied and is presented in this research.

Rubus rosaefolius Extract as a Natural Preservative Candidate in Topical Formulations

Even though the synthetic preservatives may offer a high antimicrobial efficacy, they are commonly related to adverse reactions and regarded as having potentially harmful effects caused by chronic consumption. The development of natural preservatives provides a way of reducing the amount of synthetic preservatives normally used in pharmaceutical and cosmetic preparations. In addition, these agents have less toxic effects and represent a possible natural and safer alternative of the preservatives. The purpose of this research was to evaluate the Rubus rosaefolius Smith extract efficiency as a natural preservative in base formulations. Of the extract, 0.2% (w/w) was assayed for its effectiveness of antimicrobial protection in two different base formulations (emulsion and gel). The microbial challenge test was performed following the standard procedures proposed by The United States Pharmacopoeia 33nd, European Pharmacopoeia 6th, Japanese Pharmacopoeia 15th, and the Cosmetics, Toiletries, and Fragrance Association using standardized microorganisms. The results demonstrated that R. rosaefolius extract at the studied concentration reduced the bacterial inocula, satisfying the criterion in all formulations, even though it was not able to present an effective preservative behavior against fungi. Thus, the investigation of new natural substances with preservative properties that could be applied in pharmaceutical and cosmetic products is relevant due to the possibility of substituting or decreasing the concentration of synthetic preservatives, providing a way for the development of safer formulas for the use of consumers.

Double-blind, randomized, placebo-controlled trial of a cream containing the Stryphnodendron adstringens (Martius) Coville bark extract for suppressing terminal hair growth

Background Excess of terminal hair can be defined as excessive hair that appears in male-like pattern in women. Some experts consider this condition as a result of an atypical relationship between levels of circulating androgens and sensitivity of androgen receptors in hair follicles to circulating androgens. Aims The aim of this research work was to evaluate the efficacy of a topical treatment for suppressing terminal hair growth of a cream containing 6.0% of the Stryphnodendron adstringens bark extract. Study design and subjects Study was randomized, double-blind and placebo-controlled. Subjects with excess of terminal hair were randomized to placebo and to the active treatment (cream with 6.0% of the extract). Evaluation was performed before and after 6 months, and subjects were photographed in each time. Clinical examination was carried out with the same physicians and in accordance with the Ferriman-Gallwey (FG) score. Results Benefits of the cream containing S. adstringens bark extract was observed in 60.98% (P < 0.001) of the subjects. FG score changed from 4 to 3 in the placebo group compared to 4-2 in the active. The cream suppressed the terminal hair growth and diminished the number of terminal hair. Subjects also described the reduction of skin hyperpigmentation, folliculitis and acne. Adverse events were not verified by physicians or patients. Conclusions The cream with 6.0% of the S. adstringens bark extract was effective on the reduction and on the reversion of the terminal hair excess, being considered a new promissory product for such finality.

Free Phenolic Acids from the Seaweed Halimeda monile with Antioxidant Effect Protecting against Liver Injury

Phenolic compounds are found in seaweed species together with other Substances presenting antioxidant activity. The objective of this work was to evaluate the antioxidant activity of the free phenolic acids (FPA) fraction from the seaweed Halimeda monile, and its activity to protect the expression of hepatic enzymes in rats, under experimental CCI(4) injury. The antioxidant activity was measured by the DPPH method. The FPA fraction (80 mg/kg, p.o.) was administered during 20 consecutive days to rats. The peroxidation was performed by thiobarbituric acid reactive substances (TBARS). The SOD and CAT enzymatic expressions were measured by RT/PCR. The histology technique was used to evaluate liver injuries. The expression of both, CAT and SOD genes, was more preserved by FPA. Only partial injury could be observed by histology in the liver of rats receiving FPA as compared with the control group; and CCI(4) administration induced 60% more peroxidation as compared with the rats receiving FPA. These data suggest that FPA could modulate the antioxidant enzymes and oxidative status in the liver through protection against adverse effects induced by chemical agents.

Involvement of oxidative stress in the hepatotoxicity induced by aromatic antiepileptic drugs

The use of the classic aromatic antiepileptic drugs (AAEDs) has recently been expanded to a broad spectrum of psychiatric and neurological disorders. However, the clinical use of these drugs is limited by several adverse effects, mainly idiosyncratic hepatotoxicity. AAED-induced hepatotoxicity has been attributed to a defective detoxification by the epoxide hydrolase and accumulation of arene oxides. The underlying mechanism has been proposed as immune-mediated, but direct toxicity has also been suggested. In general, idiosyncratic drug-induced hepatotoxicity may be mediated, at least in part, by oxidative stress. On the other hand, the oxidative stress induced by the AAED metabolites has not been demonstrated yet. Therefore, in the present study we have evaluated the induction of oxidative stress by three classical AAEDs: carbamazepine. phenytoin and phenobarbital as well as by their metabolites. The toxic effects of the metabolites were evaluated by incubating the drug with rat liver microsomes. The AAED-induced oxidative stress was demonstrated by the increased malondialdehyde levels, oxidation of cardiolipin; oxidation of sulfhydryl proteins and alteration of the cellular redox status. Results suggest that the hepatotoxicity associated with AAED might be mediated by the oxidative stress induced by the drugs metabolites. (C) 2008 Elsevier Ltd. All rights reserved

Trypanosoma cruzi: evaluation of (-)-cubebin derivatives activity in the messenger RNAs processing

No fully effective treatment has been developed since the discovery of Chagas` disease. Since drug-resistant Trypanosoma cruzi strains are occurring and the current therapy is effective in the acute phase but with various adverse side effects, more studies are needed to characterize the susceptibility of T. cruzi to new drugs. Pre-mRNA maturation in trypanosomatids occurs through a process called trans-splicing, which is unusual RNA processing reaction, and it implies the processing of polycistronic transcription units into individual mRNAs; a short transcript spliced leader (SL RNA) is trans-spliced to the acceptor pre-mRNA, giving origin to the mature mRNA. Cubebin derivatives seem to provide treatments with less collateral effects than benznidazole and showed similar or better trypanocidal activities than benznidazole. Therefore, the cubebin derivatives ((-)-6,6`-dinitrohinokinin (DNH) and (-)-hinokinin (HQ)) interference in the mRNA processing was evaluated using T. cruzi permeable cells (Y and BOL (Bolivia) strains) following by RNase protection reaction. These substances seem to intervene in any step of the RNA transcription, promoting alterations in the RNA synthesis, even though the RNA processing mechanism still occurs. Furthermore, HQ presented better activity against the parasites than DNH, meaning that BOL strain seems to be more resistant than Y.

Protective properties of quercetin against DNA damage and oxidative stress induced by methylmercury in rats

Aim of the study was to find out whether consumption of quercetin (QC), an abundant flavonoid in the human diet, protects against DNA damage caused by exposure to organic mercury. Therefore, rats were treated orally with methylmercury (MeHg) and the flavonoid with doses that reflect the human exposure. The animals received MeHg (30 mu g/kg/bw/day), QC (0.5-50 mg/kg/bw/day), or combinations of both over 45 days. Subsequently, the glutathione levels (GSH) and the activities of glutathione peroxidase (GPx) and catalase (CAT) were determined, and DNA damage was measured in hepatocytes and peripheral leukocytes in single cell gel electrophoresis assays. MeHg decreased the concentration of GSH and the activity of GPx by 17 and 12%, respectively and caused DNA damage to liver and blood cells, while with QC no such effects were seen. When the flavonoid was given in combination with MeHg, the intermediate and the highest concentrations (5.0 and 50.0 mg/kg/bw/day) were found to cause DNA protection; DNA migration was reduced by 54 and 65% in the hepatocytes and by 27 and 36% in the leukocytes; furthermore, the reduction in GSH and GPx levels caused by MeHg treatment was restored. In summary, our results indicate that consumption of QC-rich foods may protect Hg-exposed humans against the adverse health effects of the metal.

Prevention of hypertension in patients with pre-hypertension: protocol for the PREVER-prevention trial

Background: Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage. Methods: This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution. Discussion: The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.

The azo dye Disperse Orange 1 induces DNA damage and cytotoxic effects but does not cause ecotoxic effects in Daphnia similis and Vibrio fischeri

Azo dyes constitute the largest group of colorants used in industry and can pass through municipal waste water plants nearly unchanged due to their resistance to aerobic treatment, which potentially exposes humans and local biota to adverse effects. Unfortunately, little is known about their environmental fate. Under anaerobic conditions, some azo dyes are cleaved by microorganisms forming potentially carcinogenic aromatic amines. In the present study, the azo dye Disperse Orange 1, widely used in textile dyeing, was tested using the comet, Salmonella/microsome mutagenicity, cell viability, Daphnia similis and Microtox (R) assays. The human hepatoma cell line (HepG2) was used in the comet assay and for cell viability. In the mutagenicity assay. Salmonella typhimurium strains with different levels of nitroreductase and o-acetyltransferase were used. The dye showed genotoxic effects with respect to HepG2 cells at concentrations of 0.2, 0.4, 1.0, 2.0 and 4.0 mu g/mL. In the mutagenicity assay, greater responses were obtained with the strains TA98 and YG1041, suggesting that this compound mainly induces frameshift mutations. Moreover, the mutagenicity was greatly enhanced with the strains overproducing nitroreductase and o-acetyltransferase, showing the importance of these enzymes in the mutagenicity of this dye. In addition, the compound induced apoptosis after 72 h in contact with the HepG2 cells. No toxic effects were observed for either D. similis or Vibrio fischeri. (C) 2011 Elsevier B.V. All rights reserved.

Bed shear stress measurements in dam break and swash flows

A novel shear plate was used to make direct bed shear stress measurements in laboratory dam break and swash flows on smooth, fixed, impermeable beds. The pressure gradient due to the slope of the fluid free-surface across the plate was measured using pressure transducers. Surface elevation was measured at five locations using acoustic displacement sensors. Flow velocity was measured using an Acoustic-Doppler Velocimeter and calculated using the ANUGA inundation model. The measured bed shear stress at the dam break fluid tip for an initially dry, horizontal bed was close to twice that estimated using steady flow theory. The temporal variation of swash bed shear stress showed a large peak in landward directed stress at the uprush tip, followed by a rapid decay throughout the uprush flow interior. The peak seaward directed stress during the backwash phase was less than half that measured in the uprush. Close to the still water line, in the region of bore collapse and at the time of initial uprush, favourable pressure gradients were measured. In the lower swash region predominately weak adverse pressure gradients were measured.

Can globalisation result in less efficient and more vulnerable industries?

Growing economic globalisation (a means of market extension) may increase the economic vulnerability of firms in modern industries, especially those in which firms experience substantial economies of scale. The possibility is explored that globalisation activates competitive pressures that forces firms into a situation where their leverage (fixed costs relative to variable costs, or overhead cost relative to operating costs or capital intensity) rises substantially. Consequently, they become increasingly vulnerable to a sudden adverse change in economic conditions, such as a collapse in the demand for their industry’s product. This is explored for monopolistically competitive markets and also for oligopolistic markets of the type considered and modelled by Sweezy using kinked demand curves. In addition, globalisation is hypothesised to induce firms to become more uniformly efficient. While this has static efficiency advantages, this lack of heterogeneity in productive efficiency of firms can make for economic inefficiency in the adjustment of the industry to altered economic conditions. It is shown that lack of variation in the economic efficiency of firms can impede the speed of market adjustment to new equilibria and may destabilise market equilibria.

Outcome with calcium channel antagonists after myocardial infarction: A community-based study

Objectives. We sought to estimate the risk of death and recurrent myocardial infarction associated with the use of calcium antagonists after myocardial infarction in a population-based cohort study. Background. Calcium antagonists are commonly prescribed after myocardial infarction, but their long-term effects are not well established. Methods. Patients 25 to 69 years old with a suspected myocardial infarction were identified and followed up through a community-based register of myocardial infarction and cardiac death (part of the World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease [MONICA] Project in Newcastle, Australia). Data were collected by review of medical records, in-hospital interview and review of death certificates. Results. From 1989 to 1993, 3,982 patients with a nonfatal suspected myocardial infarction were enrolled in the study. At hospital discharge, 1,001 patients were treated with beta-adrenergic blocking agents, 923 with calcium antagonists, 711 with both beta-blockers and calcium antagonists and 1,346 with neither drug. Compared with patients given beta-blockers, patients given calcium antagonists were more likely to suffer myocardial infarction or cardiac death (adjusted relative risk [RR] 1.4, 95% confidence interval [CI] 1.0 to 1.9), cardiac death (RR 1.6, 95% CI 1.0 to 2.7) and death from all causes (RR 1.7, 95% CI 1.1 to 2.6). Compared with patients given neither beta-blockers nor calcium antagonists, patients given calcium antagonists were not at increased risk of myocardial infarction or cardiac death (RR 1.0, 95% CI 0.8 to 1.3), cardiac death (RR 0.9, 95% CI 0.6 to 1.2) or death from all causes (RR 1.0, 95% CI 0.7 to 1.3). No excess in risk of myocardial infarction or cardiac death was observed among patients taking verapamil (RR 0.9, 95% CI 0.6 to 1.6), diltiazem (RR 1.1, 95% CI 0.8 to 1.4) or nifedipine (RR 1.3, 95% CI 0.7 to 2.2) compared,vith patients taking neither calcium antagonists nor beta-blockers. Conclusions. These results are consistent with randomized trial data showing benefit from beta blockers after myocardial infarction and no effect on the risk of recurrent myocardial infarction and death with the use of calcium antagonists. Comparisons between beta-blockers and calcium antagonists favor beta blockers because of the beneficial effects of beta-blockers and not because of adverse effects of calcium antagonists. (C) 1998 by the American College of Cardiology.