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ABSTRACT Vegetable oils present important pharmacological properties, which gained ground in the pharmaceutical field. Its encapsulation in nanoemulsions is considered a promising strategy to facilitate the applicability of these natural compounds and to potentiate the actions. These formulations offer several advantages for topical and systemic delivery of cosmetic and pharmaceutical agents including controlled droplet size, protection of the vegetable oil to photo, thermal and volatilization instability and ability to dissolve and stabilize lipophilic drugs. For these reasons, the aim of this review is to report on some characteristics, preparation methods, applications and especially analyze recent research available in the literature concerning the use of vegetable oils with therapeutic characteristics as lipid core in nanoemulsions, specially from Brazilian flora, such as babassu (Orbignya oleifera), aroeira (Schinus molle L.), andiroba (Carapa guaianiensis), casca-de-anta (Drimys brasiliensis Miers), sucupira (Pterodon emarginatus Vogel) and carqueja doce (Stenachaenium megapotamicum) oils.

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ABSTRACT This study evaluates whether the integration of pharmacists into health-care teams through the delivery of pharmaceutical care-based medication therapy management (MTM) services can improve the clinical outcomes of patients with chronic health conditions in the primary health-care setting. A retrospective descriptive study of 92 outpatients assisted by MTM pharmacists in primary health-care units was carried out over 28 months (median follow-up: 05 months). Patients were followed up by MTM pharmacists, with a total of 359 encounters and a ratio of 3.9 encounters per patient. The prevalence of hypertension, diabetes mellitus and dyslipidaemia was 29.5%, 22.0% and 19.4%, respectively. There was a high prevalence of drug-related problems with a ratio of 3.4 per patient. Pharmacists performed a total of 307 interventions to prevent or resolve drug-related problems. With regard to control of the most prevalent chronic medical conditions, a high percentage of patients reached their therapy goals by the last encounter with the pharmacist: 90.0% for hypertension, 72.3% for diabetes mellitus and 90.3% for dyslipidaemia. MTM services provided by pharmacists resolved drug therapy problems and improved patients' clinical outcomes. This study provides evidence for health-care managers of the need to expand the clinical role of pharmacists within the Brazilian public health-care system.

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ABSTRACT It is well established that protein malnutrition (PM) impairs immune defenses and increases susceptibility to infection. Macrophages are cells that play a central role in innate immunity, constituting one of the first barriers against infections. Macrophages produce several soluble factors, including cytokines and growth factors, important to the immune response. Among those growth factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF). GM-CSF and M-CSF are important to monocyte and macrophage development and stimulation of the immune response process. Knowing the importance of GM-CSF and M-CSF, we sought to investigate the influence of PM on macrophage production of these growth factors. Two-month-old male BALB/c mice were subjected to PM with a low-protein diet (2%) and compared to a control diet (12%) mouse group. Nutritional status, hemogram and the number of peritoneal cells were evaluated. Additionally, peritoneal macrophages were cultured and the production of GM-CSF and M-CSF and mRNA expression were evaluated. To determine if PM altered macrophage production of GM-CSF and M-CSF, they were stimulated with TNF-α. The PM animals had anemia, leukopenia and a reduced number of peritoneal cells. The production of M-CSF was not different between groups; however, cells from PM animals, stimulated with or without TNF-α, presented reduced capability to produce GM-CSF. These data imply that PM interferes with the production of GM-CSF, and consequently would affect the production and maturation of hematopoietic cells and the immune response.

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ABSTRACT Liquid crystal systems (LCSs) have interesting cosmetic applications because of their ability to increase the therapeutic efficiency and solubility of active ingredients. The aim of the present research was to develop green tea glycolic extract-loaded LCSs, to characterize and to perform microbiological control. The ternary phase diagram was constructed using polysorbate 20, silicone glycol copolymer (SGC) - DC 193(r), and distilled water with 1.5% glycolic green tea extract. The systems were characterized by polarized light microscopy. Formulations selected were characterized as transparent viscous systems and transparent liquid system indicated mesophases lamellar structure. The results of the microbiological analysis of mesophilic aerobic microorganisms (bacteria and fungi) revealed that the above formulation showed a biologic load <10 CFU/mL in all samples. In conclusion, liquid crystalline systems that have presented formation of a lamellar mesophases were developed. Furthermore, the formulation and products tested presented the adequate microbiological quality in accordance with official recommendations.

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ABSTRACT The purpose of the work was to assess the incidence of potential drug interactions (pDDI), major pDDI, and the use of potentially inappropriate medication (PIM) at hospital admission, during hospitalization, and at discharge to evaluate whether hospital admission provides an opportunity for improving pharmacotherapy in elderly patients at a University hospital that has a clinical pharmacist. A prospective cohort study was carried out using data from the medical records of patients admitted to an internal medicine ward. All admissions and prescriptions were monitored between March and August 2006. Micromedex(r) DrugReax(r) and Beers Criteria 2015 were used to identify pDDI, major pDDI, and PIMs, respectively. A comparison of admission and discharge prescriptions showed the following: an increase in the proportion of patients using antithrombotic agents (76 versus 144; p<0.001), lipid modifying agents (58 versus 81; p=0.024), drugs for acid-related disorders (99 versus 152; p<0.001), and particularly omeprazole (61 versus 87; p=0.015); a decrease in the number of patients prescribed psycholeptics (73 versus 32; p<0.001) and diazepam (54 versus 13; p<0.001); and a decrease in the proportion of patients exposed to polypharmacy (16.1% versus 10.1%; p=0.025), at least one pDDI (44.5% versus 32.8%; p=0.002), major pDDI (19.9% versus 12.2%; p=0.010) or PIM (85.8% versus 51.9%; p<0.001). The conclusion is that admission to a hospital ward that has a clinical pharmacist was associated with a reduction in the number of patients exposed to polypharmacy, pDDI, major pDDI, and the use of PIMs among elderly inpatients.

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ABSTRACT This study was conducted to determine the antimicrobial susceptibility patterns among common pathogens in the intensive care units (ICUs) of a university hospital in northwestern Iran. A retrospective study was done on laboratory records of patients with nosocomial infection who were admitted to five ICUs of Imam Reza Hospital during a 21-month period from March 2010 to January, 2012. A total number of 556 isolates from 328 patients were evaluated. The most common sites of infections included respiratory (51.7%), urinary (24.8%), and blood (10.4%). The most frequently isolated microorganisms were Enterobacter aerogenes (50.6%) followed by Escherichia coli (16.7%) and Pseudomonas aeruginosa (7.5%). Staphylococcus aureus was the most frequent pathogen among gram-positives (39.7%). The rate of methicillin-resistant Staphylococcus aureus (MRSA) was 87.5%. Multidrug-resistant (MDR) gram-negative bacteria were documented in 25.8% of Acinetobacter, 20% of Klebsiella, and 16.6% of Pseudomonas. The most active antimicrobials were vancomycin (93.5%) followed by amikacin (71.5%) and gentamicin (46%). The overall antibiotic susceptibility was as follows: 36% ciprofloxacin, 19% imipenem, 20% trimethoprim-sulfamethoxazole, 20.5% ceftazidime, and 12% ceftriaxone. Due to the high rate of antimicrobial resistance in the ICU setting, more surveillance and control of the use of antimicrobials is needed to combat infections.

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ABSTRACT Murva is an important drug in Ayurveda. Wattakaka volubilis is used as one of the botanical sources of Murva. The aim of this study is to evaluate the effect of the alcohol extract of W. volubilis root in streptoztocin (STZ) induced diabetes and diabetic neuropathy. Diabetes mellitus (DM) was induced by the administration of STZ (45 mg/kg, i.p). DM was induced within 72 h. Diabetic animals were treated with glimepiride (0.5 mg/kg) and ethyl alcohol extract 100 and 200 mg/kg for 21 d. After determining the changes in fasting serum glucose and lipid profile, animals were further treated for a period of 15 d to determine the protective effect of extract against diabetic neuropathy. All the alcohol extract treated animals, showed a significant decrease in serum glucose level (P<0.001), and overall decrease in the severity of diabetic neuropathy. Alcohol extract of W. volubilis root showed antihyperglycemic activity and beneficial protection against diabetic neuropathy and hence can be a promising agent for treatment and prevention of diabetic neuropathy.

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ABSTRACT Arctium lappa is known to have antioxidant and antidiabetic effects in traditional medicine. Objectives: The aim of this paper was to study the effects of A. lappa root extract (AE) on lipid profile and hepatic enzyme levels in sucrose-induced metabolic syndrome (MS) in female rats. The study used 40 adult female Wistar rats weighing 150 g-250 g randomly divided into five groups: control, metabolic syndrome (MS), metabolic syndrome+AE at 50,100, 200 mg/kg. MS was induced by administering 50% sucrose in drinking water for 6 weeks. AE was intra-peritoneally administered daily at doses of 50,100, and 200 mg/kg for two sequential weeks at the end of the fourth week in metabolic syndrome rats. Twenty-four hours after the last administration of AE, blood was collected and centrifuged, and then the serum was used for the measurement of lipid profile and hepatic enzyme. Serum glucose, insulin, fasting insulin resistance index, body weight, water intake, lipid profile, and hepatic enzymes were significantly increased although food intake was decreased in MS rats compared to the control rats. The lipids and liver enzymes were reduced by AE extracts in the MS group. This study showed that the A. lappa root aqueous extract exhibits a hypolipidemic activity of hyperlipidemic rats. This activity is practically that of a triple-impact antioxidant, hypolipidemic, and hepatoprotective.

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ABSTRACT Punarnava (Boerhaavia diffusa L.- Nyctaginaceae) is a promising drug to rejuvenate new cells in the body. It is well known in Ayurvedic medicine and locally called Tambadivasu. Superficially it is similar to other species of Boerhaavia and species of Trianthema and Sesuvium. Due to the minute morphological differences, the above plants are erroneously used in medicine as Punarnava, and at times on purpose as an adulterant. Therefore, it is necessary to highlight the anatomical features of Punarnava for proper identification of the medicinal plant species for local people and for scientific research. Due to the ambiguity in local names and similar apparent appearance, market samples of Punarnava are often adulterated with various species of Trianthema and Sesuvium. These adulterated samples contain neither the Punarnavine alkaloid, nor does it possess anisocytic stomata but possess paracytic stomata. Comparative study of stem anatomy showed two main characteristic differences. First, plenty of starch grains can be seen in both the ground parenchymatous tissues present in between successive cambia and xylem parenchyma of Punarnava which is not observed in species of Trianthema, and second, the phloem around the xylem of Punarnava root has semi-circular or eccentric patches, while that of Trianthema only has narrow strips. This study is focused on comparative SEM study of leaf morphologies and anatomy of leaf, stem, and root of Boerhaavia diffusa L., Trianthema portulacastrum L. and Sesuvium portulacastrum L.

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ABSTRACT The interaction between 6-shogaol, a pharmacologically active ginger constituent, and human serum albumin (HSA), the main in vivo drug transporter, was investigated using isothermal titration calorimetry (ITC). The value of the binding constant, Ka (5.02 ± 1.37 × 104 M−1) obtained for the 6-shogaol-HSA system suggested intermediate affinity. Analysis of the ITC data revealed feasibility of the binding reaction due to favorable enthalpy and entropy changes. The values of the thermodynamic parameters suggested involvement of van der Waals forces, hydrogen bonds and hydrophobic interactions in the 6-shogaol-HSA complex formation.

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ABSTRACT Fusidic acid is an antibiotic steroid indicated for the treatment of infections caused by the genus Staphylococcus, including methicillin resistant Staphylococcus aureus strains, and other Gram-positive bacteria. In the present study, a stability-indicating reversed-phase liquid chromatography (RP-LC) method was developed and validated for the determination of fusidic acid in dermatological cream as an alternative to existing methods. Analyses were performed using a C18 column and guard column at room temperature, eluting with an isocratic mobile phase of acetonitrile and water (72:28, v/v), adjusted to pH 3.5 with acetic acid, pumped at a flow rate of 1.0 mL min-1, detection at 210 nm and 20 µL of injection volume. The forced degradation study was conducted under acidic, alkaline, neutral, photolytic, and oxidative stress conditions. The method was validated according to ICH and FDA guidelines; it was linear, precise, accurate, selective, and robust over concentrations of 5-95 µg mL-1, with detection and quantification limits of 0.43 and 1.31 μg mL-1, respectively. Therefore, we conclude that this method is suitable for quantifying fusidic acid in pharmaceutical dermatological creams and determining its stability, representing a more economical and practical alternative for routine analysis in quality control.

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ABSTRACT The aim of this work was the obtainment of Opuntia fícus-indica (L.) Mill extract for the development of cosmetic formulations and in vivo evaluation of its moisturizing effects. The formulations were tested for preliminary and accelerated stability. Organoleptic characteristics, pH values and rheological behavior were assessed. The evaluation of moisturizing efficacy of the emulsions formulated with 3.0% of Polyacrylamide (and) C13-14 Isoparaffin (and) Laureth-7 containing 1.0 and 3.0% of O. ficus-indica hydroglycolic extract (EHG001) was performed using the capacitance method (Corneometer(r)) and the transepidermal water loss - TEWL evaluation (Tewameter(r)). The emulsions formulated were stable, exhibiting pseudoplastic and thixotropic behavior. The results of evaluation of moisturizing efficacy showed increased skin hydration after five hours by mainly increasing the skin barrier effect. The formulations containing 1.0 and 3.0% of EHG001 enhanced the skin barrier effect by reducing TEWL up to four hours after application. The results observed suggest that O. ficus-indica hydroglycolic extract may act through a humectant and occlusion mechanism.

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ABSTRACT A series of molecules bearing multiple functional groups were synthesized to study their antibiotic effect against Gram-positive and Gram-negative bacteria and lipoxygenase activity as well. 2,4-Dimethylcarbolic acid (1) was refluxed with ethyl 2-bromoacetate to synthesize ethyl 2-(2,4-dimethylphenoxy)acetate (2). Compound 2 was converted to the corresponding hydrazide 3, again on refluxing with hydrazine. The compound 5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-thiol (4) was synthesized by the reaction of 3 and CS2 in the presence of KOH. Compound 4 was further converted to the corresponding ester 5 and then 2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide (6). The final molecules N'-substituted-2-(5-((2,4-dimethylphenoxy)methyl)-1,3,4-oxadiazol-2-ylthio)acetohydrazide, 8a-m, bearing ether, 1,3,4-oxadiazole, thioether, hydrazone and azomethine functional groups were synthesized by stirring the aryl carboxaldehydes 7a-m with 6 in methanol at room temperature. The depicted structures of all synthesized molecules were corroborated by IR, 1H-NMR and EIMS spectral data analysis. 8m and 8i showed substantial antibacterial activity and lipoxygenase inhibitory activity, respectively.

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ABSTRACT The evaluation of drug permeation/penetration of semisolid formulations into animal skin can be useful to supplement the pharmaceutical equivalence. This paper describes the in vitro assessment of acyclovir (ACV) into porcine skin from commercial formulations with etermination of drug concentration in different layers of cutaneous tissue to correlate with effective antiviral concentration in order to improve the equivalence decision. Studies were conducted using Franz cells and porcine skin. Selected pharmaceutical creams containing ACV had identical (reference and generic) and different (similar) excipients. A software program was employed for the simulation of antiviral effectiveness in the skin. Regarding ACV skin penetration, the first batch of the generic product showed a significant difference from reference and similar products, while in the second batch all products demonstrated equivalent drug penetration in the skin. Simulation studies suggest that formulations analysed exhibit a pharmacological effect even when in contact with Herpes simplex strains of high IC50 (inhibitory concentration required to reduce viral replication by 50%). According to results, it can be assumed that the in vitro cutaneous permeation/penetration study does not supply sensitivity information regarding small alterations of ACV semisolid formulations due to the variability inherent to the method, although it can be relevant to pharmaceutical equivalence studies in the development of semisolid products.

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ABSTRACT The objective of the study is to formulate and evaluate a topical herbal gel containing Cardiospermum halicacabum and Vitex negundo leaf extracts for their anti-arthritic activity in rats. Twelve herbal gel formulations were prepared using 1.5% of gelling agents carbopol 934 (F1-F6) and carbopol 940 (F6-F12) and they were evaluated for physical appearance, net content, viscosity, extrudability, pH, spreadability, in vitro diffusion profile and primary skin irritation tests. The stability study for the topical herbal gel formulation was done as per ICH guidelines and anti-arthritic activity was evaluated by Freund's Complete Adjuvant (FCA) induced arthritis method. Assessment of body weight, paw volume, hematological and biochemical parameters, histopathological examination and In vitro determination of serum biomarkers were also carried out. Formulated gels were homogenous, stable and complied with the guidelines. Among the formulations, F4 showed better release (98.4 %) characteristics than other formulations. No erythema or edema was observed in the skin irritation test confirming the gel was non-toxic and safe. Topical application of the herbal gel F4 containing carbopol 934 displayed significant (p < 0.001) anti-arthritic activity compared to diseased rats. Reduction in paw volume, no agglutination in C - reactive protein and rheumatic factor, reduction in TNF level, regaining of normal hematological, and biochemical parameters, reduction in spleen and thymus weight and histopathological examination supported the anti-arthritic activity of the gel formulation.

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ABSTRACT Abamectin is a drug with antiparasitic properties used in several pharmaceutical formulations. The objective of this research was to develop and validate a high performance liquid chromatographic (HPLC) method for quantification of the two abamectin homologs (H2B1a and H2B1b) in gel formulation. This HPLC method was validated using a LichroCart(r) 100 RP-18 (125 x 4 mm, 5 µm) column. The mobile phase contained of acetonitrile and water (95:5 v/v) with 1% acetic acid. The flow rate was 1.0 mL min-1 and UV detection was performed at 245 nm. Mobile phase solutions were prepared containing a nominal concentration 185.2 µg mL-1 H2B1a and 9.6 µg mL-1 H2B1b. The method displayed good linearity in the concentration range of 148.1 - 222.3 µg mL-1 and 7.7 - 11.5 µg mL-1, for H2B1a and H2B1b, respectively, with a correlation coefficient of (r)> 0.99 for both compounds, calculated by the least mean squares method. Detection limits (DLs) were 2.8 µg mL-1 and 1.2 µg mL-1 and quantitation limits (QLs) were 8.6 µg mL-1 and 3.8 µg mL-1, for H2B1a and H2B1b, respectively. The method is simple, economical and efficient for the quantitative determination of abamectin H2B1a and H2B1b homologs in pharmaceutical preparations.

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ABSTRACT The objective of this study was to identify drugs that received dose adjustments (DA) and pharmaceutical alternatives (PA) that avoid DA, and calculate the economic percentage of this replacement. A descriptive, observational and cross-sectional study was performed in a second level hospital. The pharmacy and nursing services was accompanied to identify the drugs that received DA and the compounding techniques. After identifying all the drugs that received DA, was identified in the Brazilian market the corresponding pharmaceutical alternative, with the Drugs Price List of Brazilian Health Regulatory Agency. For those drugs that was not available any PA, was performed a research of studies that describe compounding techniques in international scientific databases. Was identify 88 drugs that received DA, and these, 50 do not have any PA. Were identified compounding techniques to 40 drugs. Although any drug has your own particularity of compounding, the compounding techniques can be grouped in five categories. The standardization of 29 drugs can reduce in 28% the DA procedure and cost saving of 34,85%/month. We can conclude that every three drugs prescribed, one received DA and every three DA, one can be avoided by the selection of 29 PA, saving cost as well. The use and standardization of five techniques would attend the pharmaceutics recommendations for better dissolution, bioavailability and patient safety.

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ABSTRACT The skin barrier function has been attributed to the stratum corneum and represents a major challenge in clinical practice pertaining to cutaneous administration of drugs. Despite this, a large number of bioactive compounds have been successfully administered via cutaneous administration because of advances in the design of topical and transdermal formulations. In vitro and in vivo evaluations of these novel drug delivery systems are necessary to characterize their quality and efficacy. This review covers the most well-known methods for assessing the cutaneous absorption of drugs as an auxiliary tool for pharmaceutical formulation scientists in the design of drug delivery systems. In vitro methods as skin permeation assays using Franz-type diffusion cells, cutaneous retention and tape-stripping methods to study the cutaneous penetration of drugs, and in vivo evaluations as pre-clinical pharmacokinetic studies in animal models are discussed. Alternative approaches to cutaneous microdialysis are also covered. Recent advances in research on skin absorption of drugs and the effect of skin absorption enhancers, as investigated using confocal laser scanning microscopy, Raman confocal microscopy, and attenuated total reflectance Fourier-transform infrared spectroscopy, are reviewed.

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ABSTRACT Fibrates are drugs used for the treatment of hypertriglyceridemia and for the prevention of atherosclerosis. Three drugs in the fibrate class, ciprofibrate, fenofibrate and bezafibrate, were chosen for this study because their raw materials are readily available and because scientific publications on these compounds is limited. To evaluate their intrinsic stability, the drugs were exposed to a test condition (temperature, oxidation, UV light exposure, hydrolysis at different pH values and metal ions in solution) and then were subjected to analysis by HPLC. The samples were run on a C18 column, with a flow rate of 1.0 mL min-1 in a mobile phase consisting of methanol: 0.01 % phosphoric acid v/v (80:20), with variable detection wavelengths in the UV spectra. The analysis methodology showed satisfactory performance parameters. The three drugs were very unstable, degrading in each of the conditions evaluated. The test conditions of acid and basic hydrolysis showed the most significant degradation. The results demonstrated that the drugs in this class are unstable. Based on these experimentally determined degradation kinetics, it is easy to understand and emphasize the importance of the lack of liquid dosage forms on the market for fibrates because of their instability.

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ABSTRACT The present research work was envisaged to develop bilayer tablets to improve therapeutic efficacy of antibiotic combination for the treatment of sexually transmitted diseases. The combination of two antibiotics i.e. cefixime trihydrate and ofloxacin were used for the preparation of bilayer tablets which act against genito-urinary infections. The formulations comprise of cefixime trihydrate as immediate release layer formulated using different superdisintegrants and ofloxacin as extended release layer containing HPMC K100M. Evaluation of bilayer tablets were performed for the immediate release cefixime layer and sustain release ofloxacin layer with optimization of excipients. The immediate release layer of cefixime showed complete release within 30 min and ofloxacin release was extended up to 24 hours. The similarity factor value of ofloxacin sustained release layer was found to be 87.01 for initial and 80.35 after 3 months stability when compared with marketed reference product. The present study revealed that cefixime trihydrate and ofloxacin bilayer tablets were successfully developed for the use against sexually transmitted infections.

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ABSTRACT The effect of glutamine dipeptide (GDP) supplementation in patients with diabetic foot syndrome was evaluated. A total of 22 patients took part in the study. GDP was supplied in 10 g sachets, and was dissolved in water immediately before use, with ingestion once a day, after lunch or after dinner (20 g/day) over a period of 30 days. Quantification of foot insensitive areas, oxidative stress, blood cytokines, and biochemical, hematological and toxicological parameters was performed before and after GDP supplementation. We observed an increase in blood levels of interferon-α (P=0.023), interferon-γ (P=0.038), interleukin-4 (P=0.003), interleukin-6 (P=0.0025), interleukin-7 (P=0.028), interleukin-12 p40 (P=0.017), interleukin-13 (P=0.001), leukocytes (P=0.037), eosinophils (P=0.049), and typical lymphocytes (P<0.001) due to GDP administration. In addition, we observed a reduced number (P=0.048) of insensitive areas on the foot, and reduction (P=0.047) of fasting hyperglycemia. Patients also showed increased blood high density lipoprotein (P<0.01) and protein thiol groups (P=0.004). These favorable results were associated with the absence of renal and hepatic toxicity. These results are of clinical relevance, since supplementation with GDP over 30 days improved clinical responses in patients with diabetic foot syndrome.

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ABSTRACT The use of drugs in fixed-dose combination (FDC) is now recommended by the World Health Organization (WHO) due to the emergence of multidrug-resistant strains of Mycobacterium tuberculosis. FDC uses different drugs against tuberculosis (TB) in a single tablet for phase-intensive therapeutic intervention. This therapy aims to optimize treatment, to prevent inappropriate use of drugs, and to prevent the emergence of new resistant strains. This study aims to evaluate the susceptibility of clinical isolates of M. tuberculosis against rifampicin, isoniazid, ethambutol, and pyrazinamide. The antimicrobials were tested separately and in associations according to FDC. This was used for broth microdilution method, which was compared to the proportions method previously considered as the gold standard. In antimicrobials testing alone, several strains were resistant to one, two, or three drugs. However, when applied to association of drugs in FDC, there was no antimicrobial resistance. The results strengthen the FDC's concept, which aims to unite the four anti-TB drugs to combat bacterial resistance.