Scielo RSS <![CDATA[Brazilian Journal of Pharmaceutical Sciences]]> vol. 54 num. 1 lang. en <![CDATA[SciELO Logo]]> <![CDATA[Importance of the agar-media in the evaluation of bacteriocin activity against the same test-microorganisms]]> Abstract Bacteriocins are peptides produced by various species of bacteria, especially lactic acid bacteria, which exhibit a large spectrum of action against spoilage bacteria and foodborne pathogens. Successful application of techniques for quantitative or qualitative bacteriocin determination relies not only on the sensitivity of the test-microorganisms, but also on the agar-medium employed. Cell free supernatants are routinely used to preliminary screen for antimicrobial activity of bacteria by means of the agar well diffusion method, but the supernatant may also include other molecules (such as medium components and/or intracellular compounds) accidentally released during cell free supernatant preparation, which may interfere with the assay. Reproducibility of bacteriocin activity against the same test-microorganisms is an important factor to be considered. Unfortunately, no specific information about bioassays standardization to determine bacteriocin activity is available in the literature. In this work, growth inhibition by means of the agar well diffusion assays were carried out on different agar-media showing a strong dependence on the agar-medium used, indicating that the inhibitory effects could also depend on the diffusion of exudates that are included in the cell-free supernatant. The results presented in this communication show that selection of the agar-medium is crucial for the bioassay response. <![CDATA[The role of selenium in insulin resistance]]> ABSTRACT In recent years, there has been growing interest in clarifying the pathogenesis of some chronic diseases, such as obesity and type 2 diabetes mellitus. Metabolic alterations in these diseases are characterized by chronic hyperglycemia and insulin resistance. Studies have demonstrated the participation of minerals in the pathogenesis of insulin resistance, more specifically their involvement in the synthesis and regulation of insulin. Selenium is an anti-inflammatory and antioxidant micronutrient that is essential for the activity of selenoproteins. Two selenoproteins (glutathione peroxidase and selenoprotein P) are known to be involved in the insulin signaling pathway. The aim of this review is to provide an update on the role of selenium in insulin resistance mechanisms. Evidence shows that adequate concentrations of selenium play a key role in the secretion and action of insulin, but an excess of selenium in the body is associated with the pathogenesis of insulin resistance and the development of diabetes mellitus. <![CDATA[Phage therapy: progress in pharmacokinetics]]> ABSTRACT The concept of phage therapy exists in the history and it has been ignored for a long time, but the consequence of drug resistance in pathogen bacteria has forced the forgotten kingdom of phage therapy to be re-explored. However, for the successful implementation and acceptance of phage therapy worldwide, the number of factors need to be addressed. In pharmacology of phage therapy, pharmacodynamics is a straightforward concept, on the other hand, owing to the unique feature of phages to replicate and their high sensitivity, pharmacokinetics is rather complex. In this review, we have discussed pharmacokinetics and some recent advances in delivery systems as to achieve the therapeutically effective concentrations of phage in their activated form. <![CDATA[Glycemic effects of simvastatin: Where do we stand?]]> ABSTRACT In clinical practice, simvastatin is usually used in the treatment of dyslipidemia patients and those at risk of or with established cardiovascular disease. However, previous studies have shown that simvastatin has the potential to affect glycemic parameters as it reportedly reduced insulin secretion and sensitivity. The exact mechanism by which simvastatin affects glycemia is still unknown, but previous studies have postulated the involvement of the glucose-insulin secretion mechanism. This review focuses on the effects of simvastatin, either alone or in combination with other lipid lowering agents, antidiabetics and antihypertensives, on glucose homeostasis. Some studies have reported that simvastatin might impair the levels of glucose metabolism markers in the blood while others have reported no effect or improvement in glycemia. <![CDATA[Medication-related inpatient falls: a critical review]]> Abstract Falls are the second leading cause of accidental and unintentional injury deaths worldwide. Inpatient falls in hospital settings are likely to prolong the length of stay of patients in nearly 6.3 days, leading to increased hospitalization costs. The causes of fall incidents in healthcare facilities are multifactorial in nature and certain medications use could be associated with these incidents. This review seeks to critically evaluate the available literature regarding the relationship between inpatient falls and medication use. A comprehensive search was performed on MEDLINE, EMBASE and Lilacs with no time restriction. The search was filtered using English, Spanish or Portuguese languages. Our study evaluated medication use and inpatients falls that effectively happen, considering all ages and populations. An assessment of bias and quality of the studies was carried out using an adapted tool from the literature. The drugs were classified according to the Anatomic Therapeutics Chemical Code. The search strategy retrieved 563 records, among which 23 met the eligibility criteria; ninety three different pharmacological subgroups were associated with fall incidents. Our critical review suggests that the use of central nervous system drugs (including anxiolytics; hypnotics and sedatives; antipsychotics; opioids; antiepileptics and antidepressants) has a greater likelihood of causing inpatient falls. A weak relationship was found between other pharmacological subgroups, such as diuretics, cardiovascular system-related medications, and inpatient fall. Remarkably, several problems of quality were encountered with regard to the eligible studies. Among such quality problems included retrospective design, the grouping of more than one medication in the same statistical analysis, limited external validity, problems related to medication classifications and description of potential confounders. <![CDATA[Circulating cell-free DNA as a biomarker in the diagnosis and prognosis of colorectal cancer]]> Abstract Colorectal cancer (CRC) is a disease without evident clinical symptoms in early stages, leading to late diagnosis and disease management. Current diagnostic and prognostic tools require invasive procedures and circulating molecular biomarkers fail to have optimal sensitivity and specificity. Circulating biomarkers with high clinical performance may be valuable for early diagnosis and prognosis of CRC. The purpose of this review was to investigate the application of circulating cell-free DNA (ccfDNA) in CRC diagnosis and prognosis and the analytical methods used in blood samples in articles published between 2005 and 2016. Based on specific inclusion and exclusion criteria, 26 articles were selected. Most studies used ccfDNA quantification as the molecular biomarker. The analytical method was mainly based on the quantitative polymerase chain reaction (qPCR). Biomarkers based on aberrantly methylated genes (n=6) and ccfDNA integrity/fragmentation (n=2) were also used for the CRC diagnosis. The CRC prognosis used the detection of oncogene mutations, such as KRAS and BRAF, in ccfDNA. Significant differences were found in variables among the studies revealing potential bias. ccfDNA quantification as a diagnostic biomarker for CRC has promising results but it lacks clinical specificity since other diseases present a similar increase in ccfDNA content. However, increasing research in the epigenomic field can lead the way to a clinically specific biomarker for the CRC early diagnosis. As for the analytical method, qPCR and derivatives seem to be a perfectly valid technique. The use of ccfDNA quantification in CRC prognosis seems promising. The attempt to use the ccfDNA quantification in clinical practice may reside in the prognosis using a qPCR technique. <![CDATA[Intravenous immunoglobulin therapy among pediatric patients: labeled and off-labeled indications]]> ABSTRACT This study was designed to evaluate utilization patterns and clinical outcome of intravenous immunoglobulin (IVIG) therapy among pediatric patients in a tertiary hospital. Demographic data, IVIG prescribed, and clinical outcome were retrospectively reviewed from the pharmacy dispensing data and patient medical records between 2007 and 2014. One hundred and fifteen instances of IVIG administration to 108 pediatric patients were recorded. A total of 61 cases (53%) and 54 cases (47%) of the IVIG administered were for labeled and off-labeled indications, respectively. Age, weight, specialty, total IVIG usage, length of hospital stays, and mortality rate were found to be significantly associated with the indication being labeled or off-labeled (p&lt;0.05). However, there was no significant difference in terms of adverse reactions between labeled and off-labeled indications (p&gt;0.05). Guidelines should be developed and implemented for rational and evidence-based use of IVIG to avoid unnecessary wastage. <![CDATA[Fast detection of Mycobacterium tuberculosis in culture-positive sputum samples by nitrate reductase activity]]> ABSTRACT Microscopy and bacterial culture are the main tools in the diagnosis of tuberculosis. Since the slow growth of Mycobacterium tuberculosis impairs rapid diagnosis strategies, especially in countries where the latter are the only available resources, the ongoing development of new and inexpensive tools based on mycobacterial metabolism optimizing growth detection with preliminary identification is greatly welcome. When compared to the other species from the M. tuberculosis complex, M. tuberculosis is a strong nitrate reducer. Current assay compares the nitrate reductase activity of M. tuberculosis from pulmonary specimens cultivated in nitrate-supplemented media. Fifty-five sputum samples were decontaminated and inoculated in conventional (Middlebrook 7H9, Ogawa Kudoh-OK) and in nitrate-supplemented media (Middlebrook 7H9-N, Ogawa Kudoh-N). An aliquot from the media directly reacted with Griess reagent (7H9-N and OK-N) every five days, or transferred to a nitrate substrate solution (7H9, OK). Nitrate to nitrite reduction was considered positive, revealed by the pink color, indicating bacterial growth. As reference method, the Mycobacteria Growth Indicator Tube (MGIT) was used for sensitivity calculations and statistical analysis. 7H9-N and OK-N assays proved to perform better in detecting M. tuberculosis than conventional assays (7H9 and OK). Indeed, broth nitrate-supplemented medium (7H9-N) was comparable to MGIT to detect M. tuberculosis, except in growth detection time. Results show that 7H9-N may be used as an alternative tool particularly in low-income countries since it is a simple and cheap technique, and does not restrict diagnosis to single-source products. <![CDATA[In vitro cytotoxicity of chemical preservatives on human fibroblast cells]]> ABSTRACT Preservatives are widely used substances that are commonly added to various cosmetic and pharmaceutical products to prevent or inhibit microbial growth. In this study, we compared the in vitro cytotoxicity of different types of currently used preservatives, including methylparaben, imidazolidinyl urea (IMU), and sodium benzoate, using the human newborn fibroblast cell line CCD1072Sk. Of the tested preservatives, only IMU induced a reduction in cell viability, as shown using the MTT assay and propidium iodide staining (IMU&gt;methylparaben&gt;sodium benzoate). IMU was shown to promote homeostatic alterations potentially related to the initiation of programed cell death, such as decreased mitochondrial membrane potential and caspase-3 activation, in the treated cells. Methylparaben and sodium benzoate were shown to have a very low cytotoxic activity. Taken together, our results suggest that IMU induces programed cell death in human fibroblasts by a canonical intrinsic pathway via mitochondrial perturbation and subsequent release of proapoptotic factors. <![CDATA[Evaluation of the influence of fluoroquinolone chemical structure on stability: forced degradation and in silico studies]]> ABSTRACT Fluoroquinolones are a known antibacterial class commonly used around the world. These compounds present relative stability and they may show some adverse effects according their distinct chemical structures. The chemical hydrolysis of five fluoroquinolones was studied using alkaline and photolytic degradation aiming to observe the differences in molecular reactivity. DFT/B3LYP-6.31G* was used to assist with understanding the chemical structure degradation. Gemifloxacin underwent degradation in alkaline medium. Gemifloxacin and danofloxacin showed more degradation perceptual indices in comparison with ciprofloxacin, enrofloxacin and norfloxacin in photolytic conditions. Some structural features were observed which may influence degradation, such as the presence of five member rings attached to the quinolone ring and the electrostatic positive charges, showed in maps of potential electrostatic charges. These measurements may be used in the design of effective and more stable fluoroquinolones as well as the investigation of degradation products from stress stability assays. <![CDATA[Pharmacists in dispensing drugs (PharmDisp): protocol for a clinical trial to test the effectiveness of distance education in training pharmacists for dispensing drugs]]> ABSTRACT Dispensing drug is a moment in which the pharmacist is able to analyze pharmacotherapy and contribute to its rational use. However, research has shown that some pharmacists lack adequate knowledge to perform this service. This study aims to describe a research protocol for a clinical trial to test the effectiveness of a distance learning program to train pharmacists in dispensing drugs. This is a protocol for an open diagnostic, non-randomized, single group clinical trial. A 12-week duration distance learning course was structured on the Moodle platform for training community pharmacists who are registered in the Regional Board of Pharmacy and work as employees or owners in Brazilian community pharmacies. The course curricula involves concepts and practice of dispensing drugs applied to the treatment of hypertension, diabetes mellitus, dyslipidemia and asthma. Pharmacists are divided randomly into groups, to which previously selected tutors give directions to the discussion and clarify questions. A validated questionnaire is being used before and after the course to measure participants’ knowledge. Participant satisfaction with the course is also being measured. Pharmacists who work in the study headquarters municipality receive two visits from a mystery shopper, before and after the course, to evaluate their performance in dispensing drugs. The virtual platform and the content of the course material were evaluated by judges. The study has been approved by the Research Ethics Committee of the School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo. The sample size was estimated to provide desired power for testing the significance of the difference between baseline-to-endpoint change scores. Information about the course is being released through channels such as social networks. The results will be submitted for publication in scientific journals, but information enabling the identification of the study subjects will be kept confidential. The trial has been registered in The Brazilian Clinical Trials Registry with number RBR7mbrp3 on January 15th, 2015. <![CDATA[Alpha amylase and Alpha glucosidase inhibitory effects of aqueous stem extract of Salacia oblonga and its GC-MS analysis]]> ABSTRACT Our present investigation deals with the phytochemical screening, estimation of total flavonoids, terpenoids and tannin contents to evaluate the anti-diabetic activities of Salacia oblonga stem followed by GC-MS analysis. It explores the natural compounds and the potential α-amylase and α-glucosidase inhibitory actions of stem extracts. The aqueous stem extract was selected from other extracts (ethanol, acetone, petroleum ether and chloroform) for the in vitro study of anti-diabetic activity by alpha amylase and alpha glucosidase inhibitory assays. The stem extract was also analyzed by gas chromatography mass spectrometry to identify the natural chemical components. Phytochemical analysis of aqueous stem extract showed major classes of secondary metabolites such as phenols, flavonoids, alkaloids, terpenoids, tannins, saponins. The total flavonoid, terpenoid, and tannin contents were quantified as 19.82±0.06 mg QE/g, 96.2±0.20 mg/g and 11.25±0.03 mg TAE/g respectively. The percentage inhibition of assays showed maximum inhibitory effects (59.46±0.04% and 68.51±0.01%) at a concentration of 100 mg/mL. The IC50 values of stem extract was found to be 73.56 mg/mL and 80.90 mg/mL for alpha amylase and alpha glucosidase inhibition. Fifteen chemical constituents were found by GC-MS analysis. This study suggest the aqueous stem extract of Salacia oblonga might be considered as potential source of bio active constituents with excellent antidiabetic activity. <![CDATA[Effects of high fat diet on kidney lipid content and the Na,K-ATPase activity]]> ABSTRACT It is widely known that high fat diet (HFD) can contribute to the advent of health problems. Recent studies have indicated that obesity imposes a hemodynamic overload to the kidneys. In order to further investigate such injuries, two groups of six Swiss mice each were fed with a controlled AIN93G diet or a high fat (AIN93G modified) diet for eight weeks. Blood samples were collected to determine the hormonal, lipid profile, glucose, urea, and creatinine levels. Histopathological and immunohistochemical analysis were carried out to analysis the kidney damage. Fractions of renal membranes were prepared to assess the Na,K-ATPase activity, lipid peroxidation, total cholesterol, and phospholipid content. The results indicated that the blood lipid profile, urea and creatinine was not altered by the HFD. On the other hand, it was observed in HFD diet mice elevated glucose blood levels along with an augment on insulin and a decrease on corticosterone release. HFD provoked a reduction in the diameter of the convoluted tubules and cell volume in Bowman’s capsule and an increased number of positive cells with Na,K-ATPase, but reduced the Na,K-ATPase activity and the cholesterol content in the kidney cell membrane but favored the lipid peroxidation. <![CDATA[Preparation and characterization of non-viral gene delivery systems with pEGFP-C1 Plasmid DNA]]> ABSTRACT In recent years, non-viral delivery systems for plasmid DNA have become particularly important. They can overcome the disadvantages of viral systems such as insertional mutagenesis and unpredicted immunogenicity. Some additional advantages of non-viral gene delivery systems are; good stability, low cost, targetability, delivery of a high amount of genetic materials. The aim of the study was to develop novel non-viral nanosystems suitable for gene delivery. Two formulations were developed for this purpose: water-in-oil microemulsion (ME) and solid lipid nanoparticles (SLN). The microemulsion was composed of Peceol, Tween 80, Plurol oleique, ethanol and water. The SLN was consisting of Precirol, Esterquat-1 (EQ1), Tween 80, Lecithin, ethanol and water. Characterization studies were carried out by measuring particle size, zeta potential, viscosity and pH. TEM imaging was performed on SLN formulations. Protection against DNase I degradation was examined. Cytotoxicity and transfection efficacy of selected formulations were tested on L929 mouse fibroblast cells. Particle sizes of complexes were below 100 nm and with high positive zeta potential. TEM images revealed that SLNs are spherical. The SLN:DNA complexes have low toxicity and good transfection ability. All results showed that the developed SLN formulations can be considered as suitable non-viral gene delivery systems. <![CDATA[Pre-clinical interaction of ayahuasca, a brew used in spiritual movements, with morphine and propofol]]> ABSTRACT Ayahuasca is a beverage with psychoactive properties used in religious and ceremonial rituals by some religious groups. The main active components of ayahuasca are dimethyltryptamine and the harmala alkaloids with β-carboline structure acting as monoamine oxidase A inhibitors. This combination produces a pronounced activation of serotonergic pathways and presents potential interaction with other psychotropics. The objective of this study was to investigate the possible interactions between ayahuasca and agents employed in general anesthesia. The pharmacological interactions between ayahuasca and morphine or propofol were evaluated in mice using doses of 12, 120 and 1200 mg/kg (0.1 to 10 times the average dose consumed by humans in religious rituals). Ayahuasca alone showed an antinociceptive effect in the writhing and formalin tests, and intensified the analgesic effect of morphine in the hot plate test. Concerning the pharmacological interactions between ayahuasca and propofol, the results were opposite; ayahuasca intensified the depressant effect of propofol in the rotarod test, but decreased the sleeping time induced by propofol. These set of results showed the occurrence of some interactions between ayahuasca and the drugs morphine and propofol, possibly by both pharmacokinetics and pharmacodynamics mechanisms. <![CDATA[Sleep quality and <em>OPRM1</em> polymorphisms: a cross-sectional study among opioid-naive individuals]]> ABSTRACT Opioidergic system involves in regulation of sleep and wakefulness. It is possible, therefore, that genetic polymorphisms in OPRM1 influence sleep quality. This study investigated the association of OPRM1 polymorphisms with subjective sleep quality among opioid-naive individuals. This cross-sectional observational study involved 161 opioid-naive males (mean age = 27.74 years; range: 18−63 years). Subjective sleep quality was assessed with the translated and validated Malay version of the Pittsburgh Sleep Quality Index (PSQI). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR)-genotyping for two OPRM1 polymorphisms (118A&gt;G and IVS2+691G&gt;C). Subjects with combined 118A and IVS2+691G alleles (AC haplotype) had significantly lower PSQI scores [mean (SD) = 4.29 (1.76)] compared to those without the haplotype [4.99 (2.50)] (p = 0.004). On the other hand, subjects with combined heterozygous genotype (GC/AG diplotype) had significantly higher PSQI scores compared to those without the diplotype [6.04 (2.48) vs 4.54 (2.22), p = 0.004]. In opioid-naive individuals, AC haplotype and GC/AG diplotype for the 118A&gt;G and IVS2+691G&gt;C polymorphisms of OPRM1 are associated with better and poorer sleep quality, respectively. <![CDATA[Influence of different cosmetic vehicles in mechanical and physical properties of hair treated with oxidative hair dyes]]> ABSTRACT Hair care products play a significant role in the cosmetic market and aim at improving hair brightness, breakage resistance, and color change. In this study, we analyzed the possibility of the formulation of oxidative dyes in different vehicles impacting the hair’s both mechanical and physical properties. Light brown and light blond dyes were prepared using eight different vehicles. Among these, four vehicles were emulsifying agents and four gelling agents. Each formulation was applied to two types of virgin Caucasian hair (light blond and dark brown). Physical, chemical, and organoleptic properties of each formulation were assessed, as well as changes in hair parameters after oxidative dyeing, such as staining intensity, brightness, and breaking strength. The parameters of color and brightness differed in some formulations, but the hair type also responded differently. Brightness parameter was increased in dark brown hair colored with both dyes, whereas light blond hair showed the opposite result. Regarding the breaking strength, there were no significant differences between the two kinds of tresses. Cosmetic formulations should adjust the consumer desired effects (e.g. color change) in order to present minimal drawbacks (e.g. decrease of hair brightness and strength). Thus, the study of different vehicles is important when establishing the best oxidative dye formulation. <![CDATA[Antibacterial and antibiofilm activity of carvacrol against Salmonella enterica serotype Typhimurium]]> ABSTRACT The present study evaluated the antibacterial and antibiofilm activity of carvacrol against Salmonella Typhimurium. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined and the time-kill curve and scanning electron microscopy (SEM) were performed to evaluate antibacterial activity. Antibiofilm activity was evaluated by quantifying total biomass using crystal violet assay, and metabolic activity was determined using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. The action of carvacrol against preformed biofilm on polypropylene and stainless steel was also evaluated by colony counting and SEM. The MIC and MBC was 312 µg mL-1. Carvacrol at MIC and 2 x MIC eliminated cells after 6 and 1 h of treatment, respectively, as exhibited in the time-kill curve. The greatest reduction in biofilm biomass and metabolic activity was 1,719 OD550 and 0,089 OD550 respectively, both at 4 x MIC of carvacrol. In carvacrol treated biofilms of S. Typhimurium on polypropylene, a reduction of 5.12 log was observed with 4 x MIC, while on stainless steel, carvacrol at 4 x MIC reduced bacterial counts by 5 log. The results showed that carvacrol exhibits antibacterial activity and can be used as an alternative for the control of S. Typhimurium biofilms. <![CDATA[Anchusa italica extract: phytochemical and neuroprotective evaluation on global cerebral ischemia and reperfusion]]> Abstract Stroke is the third leading cause of mortality and disability in industrial countries. Treatment with herbs with antioxidant properties has been reported to be an alternative to the conventional treatments. This study was conducted to investigate the effect of Anchusa italica extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in the rat. To do so, 50 rats were randomly assigned to five groups; control, sham, ischemia, and 50 or 100 mg/kg of Anchusa italica treated animals. Ischemia was induced by occlusion of carotid artery for 30 minutes. Afterward, behavioral tests and biochemical analyses were conducted. Induction of ischemia/reperfusion caused a decline in learning and passive avoidance memory in rats. Moreover, Anchusa italica caused an increase in learning and improved the passive avoidance memory. Induction of ischemia/reperfusion caused a decrease in the antioxidant capacity of the brain and serum as well as an increase in the malondialdehyde of the brain and serum. Anchusa italica led to an increase in the antioxidant capacity of the brain and serum and decrease in the malondialdehyde of the brain and serum. Overall, because of its protective effects on spatial memory, passive avoidance learning, antioxidant capacity, and lipid peroxidation during ischemia/reperfusion, Anchusa italica might be beneficial in ischemic patients. <![CDATA[Antioxidant activity of ethyl acetate and methanolic extracts of two marine algae, Nannochloropsis oculata and Gracilaria gracilis - an in vitro assay]]> ABSTRACT The aim of this study was to evaluate the antioxidant activity of ethyl acetate and methanolic extracts of two marine algae, Nannochloropsis oculata and Gracilaria gracilis. The extracts were assayed for total phenol and flavonoid content, DPPH free radical scavenging capacity, nitric oxide activity, iron chelation activity, and reducing power activity. Total phenol and flavonoid content were found to be high in both algae. Ethyl acetate extracts of both algae were found to exhibit significant antioxidant activity. Ethyl acetate extract of N. oculata exhibited a good capacity for iron chelation, nitrate oxide, and scavenging DPPH free radicals (72.95±2.30, 73.73±1.76, and 39.03±0.97% inhibition at 400 µg mL-1 respectively). <![CDATA[Changes in hepatic metabolic enzyme activities and biliary excretion of 4-nitrophenol in streptozotocin induced diabetic rats]]> Abstract Activity of hepatic metabolic enzymes of glucuronidation and sulfation of 4-nitrophenol (PNP) and biliary excretion of its glucuronide (PNP-G) and sulfate (PNP-S) conjugates have been investigated in control and streptozotocin (STZ)-induced diabetic rats. 500 μM PNP solution was luminally perfused in a cannulated jejunal loop for 90 minutes. It was found that biliary excretion of PNP-G was significantly decreased in the diabetic rats. This effect of STZ could be completely reversed by administration of rapid-acting insulin. Activity of hepatic UDP-glucuronyltransferase and β-glucuronidase was also depressed by the STZ pretreatment. Administration of insulin antagonized the inhibitory action of STZ on UDP-glucuronyltransferase, but the reduced activity of β-glucuronidase was not reversed. Biliary excretion of PNP-S was also depressed in the diabetic rats. Whereas, different effects of insulin administration were observed. Namely, the lower biliary excretion rate of PNP-S was not changed after administration of insulin. Activity of the sulfotransferase and the arylsulfatase enzymes was not altered either by STZ pretreatment or by insulin administration. Biliary excretion of PNP was also significantly depressed by STZ and this depression was not changed after insulin administration. The results call attention to hepatobiliary circulation of low molecular weight xenobiotics and their glucuronide and sulfate conjugates. <![CDATA[Dual effect of Algerian propolis on lung cancer: antitumor and chemopreventive effects involving antioxidant activity]]> Abstract The purpose of our study was to divulge the antiproliferative effect of an ethanolic extract of Algerian propolis (EEP) in the human lung adenocarcinoma cell line (A549) and reveal the chemopreventive role against benzo(a)pyrene-induced lung carcinogenesis in albino Wistar rats. Cytotoxicity of EEP was evaluated using the MTT assay and cell adhesion in A549 cells. Moreover, rats were given 25 mg/kg of propolis for 5 days before induction of experimental lung cancer by a single intraperitoneal dose of 200 mg/kg benzo(a)pyrene. Body weight, lung weight, lipid peroxidation, marker enzymes, and enzymatic and non-enzymatic antioxidants were estimated. The EEP demonstrated an inhibitory effect on proliferation of A549 at 24 and 72 hours in a dose-dependent manner and blocked adhesion of the cells by fibrinogen. Moreover, EEP reduced the oxidative stress generated by benzo(a)pyrene. The pre-treatment showed that enzymatic and non-enzymatic antioxidants increased and lipid peroxidation decreased. A histological analysis further supported these findings and showed a decrease in the number of side effects. These results are particularly important for both clinical applications of propolis and the possibility for its use as a potential chemotherapeutic agent. <![CDATA[The curative effects of methylsulfonylmethane against glycerol-induced acute renal failure in rats]]> Abstract The present study was performed to explore the curative effect of Methylsulfonylmethane (MSM) in an experimental model of myoglobinuric acute renal failure (ARF). In this experimental model, Rats were injected with 50% glycerol (10 mL/kg, im) followed by an hour later and daily in the next six days by MSM (400 mg/kg) or saline. Kidney’s function (urea and creatinine), and reduced glutathione were analyzed. A renal failure produced by glycerol injection, with a significant increase of blood urea and serum creatinine was observed. Rats that received MSM in addition to glycerol had significantly lower blood urea and serum creatinine levels compared to those receiving glycerol alone. However, glutathione has markedly increased after MSM treatment. The effect is probably due to the antioxidant activity of MSM. This may provide therapeutic opportunities for treating humans, myoglobinuric ARF. <![CDATA[Protective effects of silymarin on methotrexate-induced damages in rat testes]]> Abstract The present study aimed to investigate the protective effects of silymarin (SMN), an antioxidant, on methotrexate (MTX)-induced damage in rat testes. Thirty-two Wistar albino rats were divided into four groups (n = 8): control, MTX (20 mg/kg, i.p. on days 1 and 5), SMN (200 mg/kg, orally), and MTX + SMN (20 mg/kg, i.p. on days 1 and 5 and SMN 200 mg/kg orally) groups. At the end of the 6-week trial period, histopathological, immunohistochemical, biochemical, and spermatological analyses were performed on testes tissues. Histopathologically, MTX-induced damage, including depletion of germ cell and loos of spermatozoa, was significantly improved with SMN treatment. Immunohistochemically, the immunoreactivity of glutathione peroxidase 1 (GPx1) and manganese superoxide dismutase 2 (SOD2) were detected more intensely in the MTX + SMN group than in the MTX group. Biochemical examinations revealed that SMN supplementation decreased the lipid peroxidation and increased enzymatic antioxidants in the SMN-treated rats. Spermatologically, significant differences were found in the density, motility, dead-to-live sperm ratio, and abnormal sperm rate in the MTX + SMN group compared to the MTX group. In conclusion, SMN seems to have protective effects as an antioxidant against MTX-induced damage in rat testes. <![CDATA[Investigation on the <em>in vitro</em> antioxidant capacity of methanol extract, fractions and flavones from <em>Oroxylum indicum</em> Linn bark]]> ABSTRACT Antioxidants from natural sources hold high values regarding their indispensible roles in the development of nutraceuticals, pharmaceuticals and cosmetic products. Oroxylum indicum L. is a common medicinal plant with a wide range of therapeutic properties, including a notable antioxidant potency that was reported, yet has not been subjected to more detailed studies. The present study evaluated the potency of Oroxylum indicum methanol stem bark extract, along with its hexane, ethyl acetate, methanol fractions, three flavones including baicalein, oroxylin A and chrysin using DPPH assay. In terms of IC50 values, the crude extract (65,48 μg/mL) exhibited moderate inhibitory activity which was as half potent as that of its ethyl acetate fraction (32,94 μg/mL). This fraction was also superior to the methanol and hexane fractions, as their IC50 were 57,19 and 137,95 μg/mL respectively. Remarkably, a yellow powdery sub-fraction consisted of isolated compounds showed powerful activity (32,89 μg/mL) compared to those of its components, revealing the intriguing effect of synergism while giving evidence for the theory of structure-activity relationship between some flavones and their antioxidant capability. Perpetual search for new radical scavenging agents in Oroxylum indicum is emboldened considering its partially exploited potential in this study. <![CDATA[Development of self-nanoemulsifying tablet (SNET) for bioavailability enhancement of sertraline]]> Abstract The purpose of the study was to combine the advantages of self-nanoemulsifying drug delivery systems and tablets as a conventional dosage form. Self-nanoemulsifying drug delivery system (SNEDDS) was prepared to enhance the solubility and thus oral bioavailability of sertraline. Aqueous titration method was used to prepare the liquid SNEDDS; ternary phase diagrams were constructed and based on smaller droplet size (24.8 nm), minimum viscosity (153.63 cP) and polydispersity index (0.182), higher percentage transmittance (95%) and in vitro drug release (97%), an optimum system was designated. Liquid SNEDDS was transformed into free-flowing powder by solid adsorption technique followed by compression into tablets. In vitro release of sertraline from liquid and solid SNEDDS was found to be highly significant compared to plain sertraline (p&lt;0.01). Pharmacokinetic studies after oral administration of liquid and solid SNEDDS in rats showed about 6-and 5-fold increased absorption of sertraline compared to the aqueous suspension of sertraline. These studies demonstrate that the solid SNEDDS are promising strategies for successful delivery of poorly water-soluble drug like sertraline. <![CDATA[Star anise extracts modulation of reproductive parameters, fertility potential and DNA fragmentation induced by growth promoter Equigan in rat testes]]> ABSTRACT Equigan is an anabolic steroid that has been developed for veterinary use and derived from endogenous sex hormone testosterone that plays a key role in the development of male reproductive tissue as well as in puberty and spermatogenesis. The current study is aimed to investigate the possible prophylactic effect of star anise extracts (SAE) on the toxicity of rat testes, sexual hormones alternations, sperm count, sperm abnormalities and testicular DNA damage by Equigan. Forty adult male rats were equally divided into four groups (1st Control group, 2nd SAE group, 3rd Equigan and 4th Equigan+SAE group). Food and fluid intakes, relative body weight, potassium, chloride, phosphorous, non-progressive and immotile sperms were significantly increased in Equigan group as compared to control group. In contrast; relative testes weight, sodium, magnesium, total calcium, testosterone, FSH, LH, PRL, sperm count, progressive motility, and viability showed a significant decrease in Equigan group as compared to control groups. The relative weight of epididymis, seminal vesicles, prostates and serum calcium ions didn’t change significantly in different studied groups. Co-administration of SAE with Equigan improved the sexual toxicity, electrolyte alternations, sperm count, abnormalities and DNA damage induced by Equigan. <![CDATA[Augmented cytotoxic, mutagenic and genotoxic response triggered by carvedilol and celecoxib combinations]]> Abstract It is understood that drugs regardless of their order of administration can exhibit drug interactions. Established on the fact that treatment of hypertension may last for decades and prolong usage of multiple drug regimen may induce substantial pathophysiological changes. Hence, This study was designed to evaluate the possible synergistic toxic effects of anti-hypertensive (carvedilol), and anti-inflammatory drug (celecoxib) alone and in combinations. Well-established MTT assay, Single Cell Gel Electrophoresis (SCGE) and Ames assay were employed to evaluate the toxicity at cellular level. Results from MTT assay on Vero cell line revealed that drug combinations have more pronounced anti-proliferative activity with combine IC50 value of 13.7:47.8 µg/mL. Likewise, exposure of peripheral blood mononuclear cells with drug combinations revealed significant (P&lt;0.05) DNA damage (Class 3) in a dose dependent manner at concentrations ≥ 0.78: 2.34 µg/mL. However, carvedilol and celecoxib were non mutagenic against either mutant strain (TA 100 and TA 98) and combinations have also shown mild to moderate mutagenic potential. Nevertheless, upon addition of metabolic activation enzyme, concentration &lt;12.5:37.5 µg/plate exhibited significant (P&lt;0.05) mutagenicity against both tester strains. In conclusion, this study provides additional genotoxicity and mutagenicity data that could be used in considering options for formulating regimens with reduced mutagenic potential. <![CDATA[Insulin-loaded polymeric mucoadhesive nanoparticles: development, characterization and cytotoxicity evaluation]]> Abstract Mucoadhesive nanoparticles are particularly interesting for delivery through nasal or pulmonary routes, as an approach to overcome the mucociliary clearance. Moreover, these nanoparticles are attractive for peptide and protein delivery, particularly for insulin to treat diabetes, as an alternative to conventional parenteral administration. Thus, chitosan, a cationic mucoadhesive polysaccharide found in shells of crustaceans, and the negatively-charged dextran sulfate are able to form nanoparticles through ionic condensation, representing a potential insulin carrier. Herein, chitosan/dextran sulfate nanoparticles at various ratios were prepared for insulin loading. Formulations were characterized for particle size, zeta potential, encapsulation efficiency, scanning electron microscopy, differential scanning calorimetry, and in vitro drug release. Moreover, the interaction with mucin and the cytotoxicity against a lung cell line were studied, which altogether have not been addressed before. Results evidenced that a proper selection of polyelectrolytes is necessary for smaller particle size formation and also the composition and zeta potential impact encapsulation efficiency, which is benefited by the positive charge of chitosan. Insulin remained stable after encapsulation as evidenced by calorimetric assays, and was released in a sustained manner in the first 10 h. Positively-charged nanoparticles based on chitosan/dextran-sulfate at the ratio of 6:4 successfully interacted with mucin, which is a prerequisite for delivery to mucus-containing tissues. Finally, insulin-loaded nanoparticles displayed no cytotoxicity effect against lung cells at tested concentrations, suggesting the potential for further in vivo studies. <![CDATA[Guideline values and human risk assessment for the presence of anti-inflammatory drugs remaining in drinking water after lab scale treatment]]> Abstract This study aimed to determine whether the anti-inflammatory drugs that are most commonly consumed in Brazil, including diclofenac, ketoprofen, naproxen, indomethacin, ibuprofen and acetaminophen, are present in drinking water and to derive guideline values to characterize the human risk. These pharmaceuticals were quantified in surface waters by LC-MS/MS with solid phase extraction, both before and after conventional treatment on a laboratory scale, using a jar test assay. The methods used to quantify these drugs showed good results: the chromatographic analysis obtained correlation coefficients between 0.9952 and 0.9991, with limits of quantification of 0.5 ng.mL-1 - 50 ng.mL-1 and precision standard deviations (0.08 - 2.08). Only ketoprofen and ibuprofen were not completely removed through the jar test. Environmental samples were collected and handled by the same method; the values ‌for ketoprofen and ibuprofen after treatment were 18.67 - 19.65 ng.L-1 (±17%) and 166.70 - 244.73 ng.L-1 (±14%), respectively. Human risk was assessed by comparing the guideline values for each compound to the concentrations obtained in the environmental samples, considering the toxicological backgrounds, following WHO (2011) method. The results suggest that the concentrations of ketoprofen and ibuprofen found in drinking water do not pose a risk to human health, even with chronic consumption. <![CDATA[Simultaneous determination of candesartan and hydrochlorothiazide in human plasma by LC-MS/MS]]> Abstract A simple, sensitive, rapid and highly efficient LC-MS/MS method was developed for the determination of Candesartan and Hydrochlorothiazide simultaneously in human plasma. The method employed Zorbax eclipse C18 (150 X 4.6 mm, 5µ) column using acetate buffer: acetonitrile (25:75%, v/v) as the mobile phase. The mobile phase flow rate is 1 mL/min which was delivered into the mass spectrometer electron spray ionization chamber. The Liquid/liquid extraction procedure was used in the method for the extraction of analytes. The chromatograph was attached to a negative ion mode tandem mass spectrometer and the method was validated for all the parameters as per the guidelines of US-FDA. The ions were detected in multiple reaction monitoring mode and the transitions are m/z 439.00®309.10 and 295.80®268.80 for candesartan and hydrochlorothiazide respectively. Isotopic standards were used as internal standards for effective recovery of the analytes. The drugs were analyzed over a calibration range of 1.027-302.047 ng/mL for candesartan and 1.044-306.945 ng/mL for hydrochlorothiazide respectively with regression coefficient greater than 0.99. The mean extraction recoveries are 96.95±5.61 and 100.55±4.82 for candesartan and hydrochlorothiazide respectively. The precision and accuracy values for all the studies were within the range of ≤15% and 85-115%. The performed stability studies indicate that the developed method is stable in plasma for 15 h at room temperature (bench top); 52 h (in injector); for 112 days at -70 ºC for long term stability; five successive freeze and thaw cycles. The developed method could be successfully employed for the determination of selected drugs in biological samples.