Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Human milk microbiota associated with early colonization of the neonatal gut in Mexican newborns.

BACKGROUND: Human milk microbiota plays a role in the bacterial colonization of the neonatal gut, which has important consequences in the health and development of the newborn. However, there are few studies about the vertical transfer of bacteria from mother to infant in Latin American populations. METHODS: We performed a cross-sectional study characterizing the bacterial diversity of 67 human milk-neonatal stool pairs by high-throughput sequencing of V3-16S rDNA libraries, to assess the effect of the human milk microbiota on the bacterial composition of the neonate's gut at early days. RESULTS: Human milk showed higher microbial diversity as compared to the neonatal stool. Members of the Staphylococcaceae and Sphingomonadaceae families were more prevalent in human milk, whereas the Pseudomonadaceae family, Clostridium and Bifidobacterium genera were in the neonatal stool. The delivery mode showed association with the neonatal gut microbiota diversity, but not with the human milk microbiota diversity; for instance, neonates born by C-section showed greater richness and diversity in stool microbiota than those born vaginally. We found 25 bacterial taxa shared by both ecosystems and 67.7% of bacteria found in neonate stool were predicted to originate from human milk. This study contributes to the knowledge of human milk and neonatal stool microbiota in healthy Mexican population and supports the idea of vertical mother-neonate transmission through exclusive breastfeeding.

Characterization of the Gut Microbiota of Individuals at Different T2D Stages Reveals a Complex Relationship with the Host.

In this work, we studied 217 Mexican subjects divided into six groups with different stages of glucose intolerance: 76 Controls (CO), 54 prediabetes (PRE), 14 T2D no medication (T2D-No-M), 14 T2D with Metformin (T2D-M), 22 T2D with polypharmacy (T2D-P), and 37 T2D with polypharmacy and insulin (T2D-P+I). We aimed to determine differences in the gut microbiota diversity for each condition. At the phylum level, we found that Firmicutes and Bacteroidetes outline major changes in the gut microbiota. The gut bacterial richness and diversity of individuals in the T2D-No-M group were lesser than other groups. Interestingly, we found a significant difference in the beta diversity of the gut microbiota among all groups. Higher abundance was found for Comamonadaceae in PRE, and Sutterella spp. in T2D-No-M. In addition, we found associations of specific microbial taxa with clinical parameters. Finally, we report predicted metabolic pathways of gut microbiota linked to T2D-M and PRE conditions. Collectively, these results indicate that each group has specific predicted metabolic characteristics and gut bacteria populations for each phenotype. The results of this study could be used to define strategies to modulate gut microbiota through noninvasive treatments, such as dietary intervention, probiotics or prebiotics, and to improve glucose tolerance of individuals with prediabetes or T2D.

Influence of moderate beer consumption on human gut microbiota and its impact on fasting glucose and ß-cell function.

Beer is a beverage that has been consumed worldwide for thousands of years due to social, religious, and cultural reasons; it contains polyphenolic compounds as well as phenolic acids with a potential positive effect on human health. This study aimed to explore the impact of moderate beer consumption on human health and gut microbiota diversity. Three hundred fifty-five mL of non-alcoholic beer (NAB) or alcoholic beer (AB) were consumed daily by the participants for 30 days in each study. Anthropometric measures, blood samples for biochemistry, and fecal samples for microbiota analysis were collected on Day 1 and Day 30. Microbial diversity was characterized by high-throughput sequencing of 16S rDNA libraries, and data were analyzed using the QIIME pipeline. We found that NAB and AB have effects on the composition of the gut microbiota, favoring the proliferation of Bacteroidetes with respect to Firmicutes. No increase in weight, waist, and hip parameters was observed, and the liver and lipid profile values were not modified for NAB. In addition, the consumption of NAB induced a decrease in fasting blood serum glucose and an increase in functional ß cells, while, on the other hand, there was an increase in blood serum glucose and a decrease in functional ß cells with the consumption of AB. In general, beer consumption neither changed anthropometric values, nor affected liver function. Although the glucose values decreased with NAB or increased with AB, they remained within the normal range. Our conclusion is that moderate consumption of NAB has a positive effect on human health via supplementation of biological active polyphenol and phenolic acids, and by enrichment of the gut microbiota diversity with beneficial bacteria, while the presence of alcohol in AB interferes with this effect. More work should be done on this topic before general conclusions are drawn.

The gut microbiome of Mexican children affected by obesity.

Obesity is a metabolic disorder and global health issue. In Mexico 34.4% of children between 5 and 11 years-old are overweight or obese. Here we address this issue studying the gut microbiome in a sample of Mexican children affected by obesity. We performed metagenomic shotgun-sequencing of DNA isolated from fecal samples from a cohort of normal weight and obese Mexican children using Illumina platform with HiSeq 2500. We also examined their metabolic factors and fecal short-chain fatty acids concentration. The results show that a remarkable dysbiosis of bacteria, archaea and viruses was not observed in the obese children group compared to the normal weight group; however, the archaeal community exhibited an increase of unclassified Methanobrevibacter spp. in obese children. The bacterial communities of all participants were clustered into three different enterotypes. Most normal weight children have a gut bacterial community dominated by Ruminococcus spp. (Enterotype 3), while most obese children had a community dominated by Prevotella spp. (Enterotype 2). On the other hand, changes in the gut microbiome were correlated with clinical metadata and could be used to stratify individuals based on their phenotype. The species Megamonas spp. were over-represented in obese children, whereas members of the family Oscillospiraceae were depleted in the same individuals and negatively correlated with levels of serum cholesterol. A microbiome comparative metabolic pathway analysis showed that two KEGG pathway modules of glycolysis, Glycolysis I (from Glucose 6-Phosphate), and Glycolysis II (from Fructose 6-Phosphate) were significantly overrepresented in normal weight children. Our results establish specific alterations in the gut microbiome of Mexican children affected of obesity, along with clinical alterations, providing information on the microbiome composition that may be useful for prognosis, diagnosis, and treatment.

Gut Microbiota and Endothelial Dysfunction Markers in Obese Mexican Children and Adolescents.

Obesity is a metabolic disease characterized by low-grade inflammation and accompanied by dyslipidemia and up-regulation of other bioactive molecules, creating a predisposition to endothelial dysfunction and metabolic syndrome. We studied the association between gut microbiota diversity and endothelial dysfunction (EDF) markers in obese Mexican children and adolescents. We examined clinical data including metabolic factors and EDF markers in blood samples. Gut bacterial diversity was characterized by high-throughput sequencing of V3-16S rDNA libraries. Triglycerides, insulin, homeostasis model assessment-insulin resistant (HOMA-IR), leptin, C-reactive protein (CRP), and EDF marker intercellular adhesion molecule 1 (ICAM-1) were significantly higher in obese children and adolescents. Multivariate analysis showed statistically significant positive associations between vascular cell adhesion molecule 1 (VCAM-1) and Veillonellaceae, and between ICAM-1 and Ruminococcus in obese children. In obese adolescents, there was a statistically significant positive association between total cholesterol and Ruminococcus, and between ICAM-1 and Bacteroides. LEfSe analysis showed that the genus Lactobacillus and family Coriobacteriaceae were enriched in children, and genera Collinsella and Prevotella were enriched in obese adolescents. Obese children and adolescents had higher levels of insulin resistance and metabolic syndrome. These results suggest that obese Mexican children and adolescents had increased levels of CRP and a reduction of adiponectin, which causes higher expression of EDF markers, affecting endothelial function and associating with changes in the gut microbiota.

Profiling of bacterial and fungal communities of Mexican cheeses by high throughput DNA sequencing.

Cheese is a live food whose preparation involves procedures and microbial communities playing an important role for the final product. We characterized the bacterial and fungal diversity of seventeen different Mexican cheeses by high-throughput DNA sequencing of 16S/18S rDNA libraries. We propose the existence of bacterial and fungal core communities, where at genera level, bacteria include Streptococcus spp., Lactococcus spp., Lactobacillus spp., Aerococcus spp., and Weisella spp. while at species level, the fungal community includes Galactomyces reessii, Scheffersomyces stipitis, Saccharomyces cerevisiae (baker's yeast), and S. cerevisiae_rm11-1a. In addition to the bacterial and fungal core communities, we found members of the cheese microbiota that could be associated to other factors of the cheese manufacturing process. Co-occurrence analysis made in this work, indicates that bacterial and fungal communities maintain positive and negative interactions which are important to shape the resident microbial communities in cheeses. This work is a contribution to the description of the microbial diversity found in some Mexican cheeses.

Gut microbiome production of short-chain fatty acids and obesity in children.

Obesity has been a worldwide multifactorial epidemic malady for the last 2 decades. Changes in gut microbiota composition and its metabolites - short-chain fatty acids (SCFAs) - have been associated with obesity. Recent evidence suggests that SCFAs made by the gut microbiota may regulate directly or indirectly physiological and pathological processes in relation to obesity. We review the influence of gut microbiota in energy, glucose, and lipid homeostasis control via their metabolites. Gut microbial disturbances in obese children may have a role in their metabolism. At first glance, excessive short-chain fatty acids produced by a particular gut microbiota represent an additional energy source, and should cause an imbalance in energy regulation, contributing to obesity. However, simultaneously, SCFA participates in glucose-stimulated insulin secretion from the pancreatic ß-cells through interaction with the FFA2 and FFA3 receptors, and release of peptide hormones which control appetite. This apparent contradictory situation may indicate the involvement of additional particular bacteria or bacterial components or metabolites that may trigger regulatory cascades by interaction with some G-protein-coupled membrane receptors.

Anti-inflammatory Potential of Petiveria alliacea on Activated RAW264.7 Murine Macrophages.

BACKGROUND: Defense and protection to multiple harmful stimuli are the inflammation, when is self-amplified and uncontrolled is the basis of the pathogenesis of a wide variety of inflammatory illness. The aim of this study was to evaluate if Petiveria alliacea could attenuate inflammation in a murine model of RAW264 macrophages the involved model and its involved mechanism. MATERIALS AND METHODS: The ethanol extract from P. alliacea was precipitated with water and supernatant was used for this study (PW). The anti-inflammatory effects of PW were investigated through evaluating of the production of several cytokines, chemokines, and expression of nuclear factor-kappa B (NF-κB) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Also was determined the ability to decrease the oxidative stress in RAW264.7 cells with carboxy-2',7'-dichloro-dihydro-fluorescein diacetate. RESULTS: PW significantly suppress the secretion of prostaglandin E2, leukotriene C4, interleukin (IL)-1 ß, IL-6, IL-10, interferon gamma nitric oxide (NO), inducible NO synthase, IL-1 ß, IL-4, in RAW264.7 cells in a dose-dependent manner. In addition, PW also markedly inhibited the transcriptional activity of NF-κB. PW produced significant anti-inflammatory activity through inhibiting the production of inflammatory mediators through the NF-κB inactivation in the LPS-stimulated RAW24.7 cells. CONCLUSIONS: PW exerts significant antioxidant and anti-inflammatory activities, and this effect can be attributed in part, to the presence of dibenzyl disulfide, dibenzyl trisulfide pinitol, coumarin, myricetin, glutamyl-S-benzyl cysteine, and petiveriins A and B. SUMMARY: Treatment with ethanol extract from Petiveria alliacea which was previously precipitated with water and supernatant (PE) was tested in LPS-stimulated RAW264.7 cells. PE suppressed the level of oxidative stress and the induction of proinflammatory mediators, as PGE2, LTC4, IL-1 ß, IL-6, IL-10, IFN- NO, iNOS, IL-1 ß, IL-4, in RAW264.7 macrophages through NF-B inactivation. These findings suggest that P. alliacea affords promising therapeutic in inflammatory diseases. Abbreviation used: COX-2: Ciclooxigenasa 2; DCFHDA: Carboxy-2',7'-dichloro-dihydro-fluorescein diacetate; DMEM: Dulbecco's modified eagle's medium; FBS: Fetal bovine serum; HSP70: Heat shock protein; IFN-γ: Interferon gamma; IL-1 ß: Interleukin 1 ß, IL-6: Interleukin 6; IL-10: Interleukin 10; IL-4: Interleukin 4; iNOS: Nitric oxide synthase; KCl: Potassium chloride; LPS: Lipopolysaccharides; LTC4: leukotriene C 4; MgCl2: Magnesium chloride; MTT: 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B-cells or transcriptional activity of nuclear factor-kB; NO: Nitric oxide; PBS: Phosphate-buffered saline; PGE2: Prostaglandin E2, PMSF: Phenylmethylsulfonyl fluoride; PTC: Chloroform extract from Petiveria alliacea; PE: Ethanol extract from Petiveria alliacea; PTH: Hexane extract from Petiveria alliacea; PW: Supernatant of PTE precipitated with water; RAW264.7: Cell line murine macrophages; ROS: Reactive oxygen species; TNF-α: Tumor necrosis factor.

Carcinogenic risk of emerging persistent organic pollutant perfluorooctane sulfonate (PFOS): A proposal of classification.

Perfluoroalkyls are stable synthetic chemicals, able to repel oils, fats and water. These compounds have been used in the manufacturing of products such as Teflon®, lubricants, paints, fire-fighting foams, coatings for pans, carpets, clothes, and paperboard for packaging, among others. It is believed that populations are exposed constantly to them. Its regulation in the world is under development and several controversies are in the course of litigation. One occupational study shows bladder cancer risk. This paper intends to review scientific information on the most critical perfluoroalkyl compound and proposes a procedure to get a cancer-risk categorization which PFOS can cause to populations. METHODS: As a guiding axis, we used the IARC process for developing monographs of carcinogenic risks. We used the SIGN guides for evaluating the quality of studies in human populations; and finally, we used the Squire method for evaluating studies in laboratory animals. Inadequate evidence of carcinogenicity was found in human studies mainly due to chance, threshold effect and confounders. In experimental animal studies, inadequate evidence of carcinogenicity was found in view of the number of affected species, different types of neoplasms, dose-response relationship and genotoxicity found in in-vivo and in-vitro studies. In this proposal, we concluded that cancer risk for PFOS, according to the IARC method, is not classifiable as carcinogenic to humans (group 3).

Expression of candidate genes associated with obesity in peripheral white blood cells of Mexican children.

INTRODUCTION: Obesity is a chronic, complex, and multifactorial disease, characterized by excess body fat. Diverse studies of the human genome have led to the identification of susceptibility genes that contribute to obesity. However, relatively few studies have addressed specifically the association between the level of expression of these genes and obesity. MATERIAL AND METHODS: We studied 160 healthy and obese unrelated Mexican children aged 6 to 14 years. We measured the transcriptional expression of 20 genes associated with obesity, in addition to the biochemical parameters, in peripheral white blood cells. The detection of mRNA levels was performed using the OpenArray Real-Time PCR System (Applied Biosystems). RESULTS: Obese children exhibited higher values of fasting glucose (p = 0.034), fasting insulin (p = 0.004), low-density lipoprotein (p = 0.006), triglycerides (p < 0.001), systolic blood pressure and diastolic blood pressure (p < 0.001), and lower values of high-density lipoprotein (p < 0.001) compared to lean children. Analysis of transcriptional expression data showed a difference for ADRB1 (p = 0.0297), ADIPOR1 (p = 0.0317), GHRL (p = 0.0060) and FTO (p = 0.0348) genes. CONCLUSIONS: Our results suggest that changes in the expression level of the studied genes are involved in biological processes implicated in the development of childhood obesity. Our study contributes new perspectives for a better understanding of biological processes involved in obesity. The protocol was approved by the National Committee and Ethical Committee Board from the Mexican Social Security Institute (IMSS) (IMSS FIS/IMSS/PRIO/10/011).

The efficacy of the appetite suppressant, diethylpropion, is dependent on both when it is given (day vs. night) and under conditions of high fat dietary restriction.

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.

Allele frequency distribution of CYP2C9 2 and CYP2C9 3 polymorphisms in six Mexican populations.

Allele frequency differences of functional CYP2C9 polymorphisms are responsible for some of the variation in drug response observed in human populations. The most relevant CYP2C9 functional variants are CYP2C9*2 (rs1799853) and CYP2C9 3 (rs1057910). These polymorphisms show variation in allele frequencies among different population groups. The present study aimed to analyze these polymorphisms in 947 Mexican-Mestizo from Mexico City and 483 individuals from five indigenous Mexican populations: Nahua, Teenek, Tarahumara, Purepecha and Huichol. The CYP2C9*2 allele frequencies in the Mestizo, Nahua and Teenek populations were 0.051, 0.007 and 0.005, respectively. As for CYP2C9 3, the allelic frequencies in the Mestizo, Nahua and Teenek populations were 0.04, 0.005 and 0.005, respectively. The CYP2C9 2 and CYP2C9 3 alleles were not observed in the Tarahumara, Purepecha and Huichol populations. These findings are in agreement with previous studies reporting very low allele frequencies for these polymorphisms in American Indigenous populations.

Alkaloids from piper: a review of its phytochemistry and pharmacology.

OBJECTIVE: Piper has been used for long timelike condiment and food, but also in traditional medicine around of the world. This work resumes the available and up to date work done on members of the Piperaceae family and their uses for therapeutic purposes. METHODS: Information on Piper genus was gathered via internet using scientific databases such as Scirus, Google Scholar, CAB-abstracts, MedlinePlus, Pubmed, SciFinder, Scopus and Web of Science. RESULTS: The largeleafed perennial plant Piper is used for its spicy aromatic scent and flavor. It has an important presence in the cuisine of different cultures. Another quality of these plants is their known medicinal properties. It has been used as emollient, antirheumatic, diuretic, stimulant, abortifacient, anti-inflammatory, antibacterial, antifungal and antidermatophytic. A survey of the literature shows that the genus Piper is mainly known for its alkaloids with cytotoxic, chemopreventive, antimetastatic and antitumor properties in several types of cancer. Studies of its alkaloids highlight the existence of various potential leads to develop new anti-cancer agents. Modern pharmacology studies have demonstrated that its crude extracts and active compounds possess wide pharmacological activities, especially asantioxidant, anti-depressive, hepatoprotective, antimicrobial, anti-obesity, neuropharmacological, to treat cognitive disorders, anti-hyperlipidemic, anti-feedant, cardioactive, immuno-enhancing, and anti-inflamatory. All this evidence supporting its traditional uses. AIM OF THE REVIEW: This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of Piper together with its toxicology, and discusses the possible trend and scope for further research on Piper in the future.

Effect of flavonoids from Prosthechea michuacana on carbon tetrachloride induced acute hepatotoxicity in mice.

CONTEXT: Prosthechea michuacana W.E. Higgins (LaLlave & Lex) (Orchidaceae) is an orchid that has been used in traditional medicine for the treatment of inflammation, diabetes, wound, and liver disorders. Therefore, we thought it would be worthwhile to study the effect of this orchid on liver damage using mice as model. OBJECTIVE: The present study investigates the effect of flavonoids isolated from methanol extract of P. michuacana on carbon tetrachloride (CCl(4))-induced liver damage in mice. MATERIALS AND METHODS: The methanol extract was purified by repeated column chromatography, resulting in the identification of five metabolites whose hepatoprotective effects were evaluated by measuring aspartate transaminase, alanine transaminase, alkaline phosphatase, glutamate, total bilirubin level, lactate dehydrogenase, total serum protein, and lipid peroxidation (thiobarbituric acid reactive substances assay) in CCl(4)-induced hepatic injury in mice. RESULTS: From the bulbs of P. michuacana, four known flavonoids were isolated (scutellarein 6-methyl ether, dihydroquercetin, apigenin 7-O-glucoside, and apigenin-7-neohesperidoside), together with the new flavonol glycoside apigenin-6-O-ß-D-glucopyranosil-3-O-α-L-rhamnopyranoside. Their structures were characterized by 1D and 2D nuclear magnetic resonance experiments. Treatment with flavonoids significantly prevented the biochemical measurable changes induced by CCl(4) in the liver. Compounds 1, 4, and 5 were found to exhibit good hepatoprotective effect. These effects were comparable to that of the standard drug silymarin, a well-known hepatoprotective agent. DISCUSSION: These results demonstrate that flavonoids contained in the bulbs of P. michuacana contribute to the hepatoprotective activity attributed to the plant.

Anti-diabetic activity of an hexane extract of Prosthechea michuacana in streptozotocin-induced diabetic rats / Actividad antidiabética de un extracto de hexane de Prosthechea michuacana en ratas diabéticas inducidas por estreptozotocina

In this study we investigated the antihyperglycaemic, antihyperlipidaemic and antiglycation effects of some extracts of Prosthechea michuacana bulbs in normoglycemic and diabetic rats induced by streptozocin (STZ). Hexane, chloroform and methanol extracts of P. michuacana were screened for hypoglycemic activity, and biochemical parameters as serum triglycerides, total cholesterol, lipid peroxidation, liver glycogen, skeletal muscle glycogen levels, superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase activity in diabetic rats. Additionally we determined Glucose 6 Phosphatase and glucokinase activities in liver, inhibition of insulin and protein glycation. Glucose levels in blood plasma were determined by using GOD-POD method. Administration of chloroform and methanol extracts showed no effect on STZ induced diabetic rats (SD). On the other hand, treatment with hexane extract at 200 and 400 mg/kg doses, resulted in a reversal of diabetes and its complications. Both doses significantly brought down blood glucose concentration (35.75 and 47.78 percent in diabetic rats, 50.64 and 57.10 percent in nondiabetic rats), increased glycogenesis and decreased glyconeogenesis bringing the glucose metabolism toward normalcy. These doses also reversed the hyperlipidemia by reducing cholesterol (41.56 percent, 46.08 percent) and triglycerides (37.5 percent, 46.27 percent) and improved hepatic antioxidant enzyme activities. Its effect was compared with that of glibenclamide and tolbutamide, as reference antidiabetic drugs. The hexane extract decreased the hyperinsulinemia by 24 percent in SD and showed a significant change on AGEs formation in vitro with IC50 values of 48.3 ug/ml comparable to inhibitory effect of aminoguanidine with IC50 values of 27.2 ug/ml. It reduced HbA1C levels by 6.4 percent in chronic STZ-diabetic rats. It is concluded that hexane extract of Prosthechea michuacana bulbs possesses anti-hyperglycemic and antihyperlipemic...

En este estudio se determinaron los efectos antidiabéticos, antihiperlipidemico y glicación (AGEs) de algunos extractos de Prosthechea michuacana (PM) en ratas normoglucémicas y con diabetes inducida por estreptozotocina (STZ). Se probó el efecto de los extractos de hexano, cloroformo, metanol de PM sobre la actividad hipoglucemiante, la carga de glucosa, los parámetros bioquímicos tales como triglicéridos, niveles de colesterol total, peroxidación lipídica, glucógeno del hígado, los niveles de glucógeno muscular, niveles de superoxide dismutase, catalasa, glutation reductasa and glutation peroxidasa en ratas normales y diabéticas. También se determinó la glucosa 6 Phosphatasa y las actividades de GK en el hígado, la inhibición de la insulina y la glicosilación de las proteínas. Los niveles de glucosa sanguínea se determinaron por el método de GOD-POD. La administración de los extractos de cloroformo y metanol no presentaron ningún efecto sobre la SD, en cambio el tratamiento con el extracto de hexano (PM) a dosis de 200 y 400 mg/kg, inhibió la diabetes y sus complicaciones. Ambas dosis redujeron significativamente los niveles de glucosa sanguínea (35.75 y 47.78 por ciento en las ratas diabéticas, 50.64 y 57.10 por ciento en las ratas diabéticas), el aumento de la glucogénesis y la disminución de la gluconeogénesis conduce el metabolismo de la glucosa hacia la normalidad. Estas dosis disminuyeron la hiperlipidemia reduciendo el colesterol (41.56 por ciento, 46.08 por ciento) y los triglicéridos (37.5 por ciento, 46.27 por ciento) así como también mejoran las actividades antioxidantes de las enzimas hepáticas. Su efecto se comparó con la glibenclamida y tolbutamida, fármacos usados como antidiabeticos. El extracto de hexano disminuyo la hiperinsulinemia en un 24 por ciento en SD. PM mostró un cambio significativo in vitro sobre la formación de los AGEs con valores de IC50 de 48.3 mg/ml comparable al efecto inhibidor de la aminoguanidina con valores de IC50 de...

Isobolographic analysis of the dual-site synergism in the antinociceptive response of tramadol in the formalin test in rats.

Tramadol is an atypical opioid with a complex mechanism of action including a synergistic interaction between the parent drug and an active metabolite. The local action of the parent drug is poorly documented. This study was designed to evaluate the site-site interaction of the antinociception produced by tramadol given by two different routes. The effects of individual and fixed-ratio combinations of intraplantar (i.pl.) and intraperitoneal (i.p.) tramadol were evaluated using the formalin test in rats. Isobolographic analysis was employed to identify the synergy produced by combinations. In both first and second phases of the formalin test, tramadol was active not only by the systemic (ED50 10.2+/-2.1 and 7.1+/-0.5 mg/kg i.p.) but also by the local route (ED50 171.0+/-44.8 and 134.6 microg/paw i.pl.). The isobolographic analysis revealed a "self-synergism" in the antinociceptive effect between the two routes of administration, as the experimental ED50 (211.1+/-13.6 and 45.9+/-3.9 "dose units" phase 1 and 2, respectively) of the combination was significantly lower than the theoretical ED50 (422.2+/-50.5 and 138.5+/-9.2 "dose units"). The mechanism underlying this self-synergism appears to be partially opioid since systemic but not local naloxone reversed the potentiation. The observed dual-site interaction in the antinociceptive action of tramadol provides insights for alternatives in the management of pain.

Impact of long-term partial aeration on the removal of 2,4,6-trichlorophenol in an initially methanogenic fluidized bed bioreactor.

A fluidized bed bioreactor (FBBR) was operated for more than 1000 days under two regimes, Methanogenic (M) and Methanogenic-Aerobic (M-A), to remove 2,4,6-trichlorophenol (TCP) and phenol (Phe) from a synthetic wastewater, containing different amounts of TCP and Phe, using different aeration flow-rates (0, 2.13, and 1.06 NL O(2)/L.day). M conditions (80:20 mg/L of TCP:Phe, 0 NL O(2)/L.day) showed similar TCP and Phe removal (>95%). Nevertheless accumulation of 4-chlorophenol (4CP) up to 16 mg/L and Phe up to 4 mg/L was observed, while in M-A conditions (80:20 mg/L of TCP:Phe, 2.13 NL O(2)/L.day) TCP and Phe removal achieved 99.9(+)% and after 70 days no accumulation of intermediates were detected. The increase of TCP and Phe in the influent under M-A conditions from 80:20 to 120:30 mg/L of TCP:Phe did not negatively affect the removal of TCP, intermediates and Phe; in fact, they were similar to those in previous M-A conditions. The decrease in the oxygen flow rate from 2.13 to 1.06 NL O(2)/L.day had no negative effect on pollutant removals, which were as high as in previous two M-A conditions. The specific methanogenic activity of bioparticles of the fluidized bed decreased with long-term partial aeration, starting from 1.097 mmol CH(4)/h.g(TKN) in the M regime (day 60) to <0.02 mmolCH(4)/h.g(TKN) at day 1050, suggesting aerobic regime in the bioreactor rather than an M-A regime. In conclusion, complete removal of TCP and less chlorinated intermediates could be achieved in an initially methanogenic FBBR under conditions of partial aeration, although long-term operation seemed to negatively affect the methanogenic activity of biomass. It is also likely that after extended aeration the microbial community was finally enriched with strains with the ability to attack 2,4,6-TCP under aerobic conditions. This report represents the first evidence of a long exposure to oxygen of an anaerobic microbial consortium that efficiently remove TCP.

Pharmacokinetic properties of pravastatin in Mexicans: An open-label study in healthy adult volunteers.

BACKGROUND: The pharmacokinetic properties of pravastatin, particularlyAUC and Cmax, are variable by population. A description of the pharmacokinetic properties of pravastatin in Mexican mestizos was not found in a search of MEDLINE/PubMed (key terms: pravastatin, Mexican, and pharmacokinetics; years: 1966-2005). Because Mexicans and Japanese have common ancestors (Mongoloid group), they also have a common gene pool. This gene pool was modified by genetic "bottlenecks" that occurred when these populations migrated to the Americas and when the Mexican population mixed with the Spanish population during the 16th and 17th centuries. Previous studies in Japanese subjects showed 5 main mutations on the hepatic drug transporter OATP-C, resulting in higher Cmax and AUC values compared with whites. In the Japanese population, the rates of expression of the (*) 1b and (*) 15 alleles were 46% and 15%, respectively. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic propertiesof pravastatin in healthy Mexican mestizo volunteers and to compare them with those in white and Japanese populations described in the literature. METHODS: This open-label, uncontrolled pilot study of the pharmacokineticproperties of pravastatin was conducted at the Division of Pharmacology, Center for Research and Advanced Studies, Mexico City, Mexico. Healthy, adult, Mexican volunteers received a single dose of pravastatin 10 mg PO (tablet). High-performance liquid chromatography was used to determine plasma pravastatin concentrations between 15 minutes and 12 hours after dosing. RESULTS: Twenty-four subjects (15 women, 9 men; mean age, 30.6 years)participated in the study. The mean (SD) Cmax was 9.5 (2.4) ng/mL; Tmax, 0.8 (0.3) hours; AUC0-∞ 35.7 (19.7) ng/mL - h; t1/2, 2.7 (1.1) hours; and mean residence time, 3.1 (1.1) hours. One volunteer (4%) had an AUC value that differed substantially from the rest of the study population, producing a bimodal distribution of the pharmacokinetic parameters. No adverse events were observed or reported during the trial. CONCLUSIONS: In this small pilot study of the pharmacokinetic properties of pravastatin in Mexican mestizos, AUC was not statistically significantly different from previous studies, either in a white or Japanese population. However, we did not find the high values reported for Cmax in some Japanese subjects carrying recently reported mutations on the pravastatin transporter.