Resumo em Inglês:

ABSTRACT For the release of pharmaceutical products into the drug market; most of the pharmaceutical companies depend on acceptance criteria - that are set internally, regulatory and/or pharmacopeially. However, statistical process control monitoring is underestimated in most quality control in cases; although it is important not only for process stability and efficiency assessment but also for compliance with all appropriate pharmaceutical practices such as good manufacturing practice and good laboratory practice, known collectively as GXP. The current work aims to investigate two tablet inspection characteristics monitored during in-process control viz. tablet average weight and hardness. Both properties were assessed during the compression phase of the tablet and before the coating stage. Data gathering was performed by the Quality Assurance Team and processed by Commercial Statistical Software packages. Screening of collected results of 31 batches of an antibacterial tablet - based on Fluoroquinolone -showed that all the tested lots met the release specifications, although the process mean has been unstable which could be strongly evident in the variable control chart. Accordingly, the two inspected processes were not in the state of control and require strong actions to correct for the non-compliance to GXP. What is not controlled cannot be predicted in the future and thus the capability analysis would be of no value except to show the process capability retrospectively only. Setting the rules for the application of Statistical Process Control (SPC) should be mandated by Regulatory Agencies.

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ABSTRACT Giardiasis, an intestinal infection caused by Giardia lamblia, was recently included in the ‘Neglected Diseases Initiative’ by the World Health Organization. Symptomatic patients can develop mild diarrhea up to a severe malabsorption syndrome, and children may show significantly impaired cognitive and physical development. Currently, nitroimidazoles are the main class of antibiotic used to treat giardiasis. Despite the efficacy of these drugs, adverse effects and reported resistance have increased, encouraging studies to identify and develop therapeutic alternatives. In this context, probiotics may represent an attractive option. Probiotics are defined as live microorganisms that, when administered in suitable amounts, confer a health benefit to the host. The use of probiotics in the treatment of parasitosis has been suggested because of its beneficial effects, such as a reduced time of gastrointestinal symptoms and parasite load in animal models and humans. Probiotics have been studied as an alternative treatment for giardiasis. In this review, we evaluated probiotic effectiveness in the treatment and prevention of this disease. Based on the studies examined herein, we conclude that probiotics have a beneficial effect on the modulation of giardiasis.

Resumo em Inglês:

ABSTRACT A drug delivery system (DDS) with analgesic and antibacterial properties would be desirable for the local control of post-operatory pain and the prevention for surgical site infection (SSI). The objective of the present study was to evaluate the antinociceptive effect of the combination between dexketoprofen trometamol (DXT) and chlorhexidine gluconate (CHX) in the formalin pain model. Different doses of CHX were combined with DXT and were locally administered in rats paw simultaneously with 5% formalin dilution. Flinches were documented and the antinociceptive effect was calculated. The area under the curve of each experimental group were calculated and the % of antinociception were compared. The groups of CHX and DXT showed similar antinociceptive effect. The combination groups (DXT-CHX) showed higher antinociceptive effect that the one obtained with individual molecules. Besides the confirmation of DXT local antinociceptive properties, CHX also showed a positive effect; and an additive effect when combined with DXT.

Resumo em Inglês:

ABSTRACT We investigated whether oral lactate could prevent seizures and deaths in mice with severe hypoglycemia induced by a high dose of insulin. For this purpose, mice were fasted for 15 h and then given an intraperitoneal injection of regular insulin (5.0 U/kg or 10.0 U/kg). Immediately after insulin injection, the mice received an oral dose of saline (control), glucose (5.5 mmol/kg), or lactate (18.0 mmol/kg). Glucose and lactate levels were measured in the blood and brain before and after the seizures began. Glucose and lactate delayed (p < 0.05) the onset of seizures associated with severe insulin-induced hypoglycemia. Elevated (p < 0.05) brain levels of lactate were associated with an absence of seizures in mice that received glucose or lactate, suggesting that lactate could prevent convulsions associated with severe insulin-induced hypoglycemia. However, the same oral dose of lactate that delayed the onset of convulsions also increased the mortality rate. In contrast, diazepam (3.0 mg/kg) prevented seizures and markedly decreased the frequency of death during severe insulin-induced hypoglycemia. The results demonstrated that in contrast to oral glucose, oral lactate intensifies insulin toxicity.

Resumo em Inglês:

ABSTRACT Altered metabolites level in the biosystems, is the potential cause of cancer, the primary reason of alteration of metabolism is change in nutrient consumption and waste excretion, as a result genetic mutation leads to cancer initiation and progression. Aberration of specific metabolites such as fumarate, succinate, 2-hydroxyglutarate may alter cell signaling. We collected liver and kidney samples and prepared for 1H NMR analysis, then executed NMR spectroscopy. We used a set of domestic R scripts to perform an unsupervised principal component analysis (PCA) and a supervised orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA). It signifies class discrimination for getting a clear separation, whereas PCA scores plot signifies the model group kept further away from the control group than drug group on the horizontal axis. In another PCA scores plots, most parts of the control group was overlapping with the drug group but was distant from the model group. Marsdenia tenacissima extract (MTE) (Chines name: Xiao-Ai-Ping, XAP) modulates level of crucial metabolites such as fumarate, lactate, succinate, determined by 1H NMR spectroscopy and their altered level contributes major role in cancer.

Resumo em Inglês:

ABSTRACT The present study investigates the effect of cinnamon (Cinnamomum zeylanicumon) powder supplementation on glucose levels, lipid profiles, and oxidative stress parameters in alloxan-induced diabetic rats. Diabetes was induced in adult male Wistar rats via a single subcutaneous alloxan injection (15 mg/kg). Cinnamon powder was mixed with the standard feed of the rats in an amount of 5% for 28 consecutive days. Serum concentrations of total cholesterol (TC) and triglycerides (TG) were assayed at the end of the experimental period in all investigated groups. Anti-oxidative enzymes such as glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) were sought in the serum and pancreas. Alloxan caused the fasting blood sugar level to increase. The administration of cinnamon blocked the increase of blood glucose. There was also a significant difference in the TG and TC levels between control and treated diabetic rats. In diabetic rats, cinnamon treatment restored the activities of SOD, CAT and GPx. These findings suggested that cinnamon has an anti-hyperglycemic effect, improves lipid profiles, and protect against damage induced by oxidative stress in the diabetic state.

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ABSTRACT The use of a commercial kit for the monocyte-activation test (MAT) was evaluated for assessing pyrogenic contamination of hyperimmune sera . Three batches of sera, two pyrogen free and one pyrogenic, were tested. Endotoxin spike recover indicated that sample dilutions from 1/2 to 1/10 are suitable. Kit transport and storage conditions were also evaluated, proving that an adequate cold chain must be assured to achieve good results. Furthermore, the commercial MAT kit seemed suitable to replace the rabbit pyrogen test (RPT) for pyrogen testing of hyperimmune sera, although further tests are needed to a full validation.

Resumo em Inglês:

ABSTRACT Temozolomide is a poorly soluble anti-cancer drug used in the treatment of some brain cancers. Following literature reports about the enhancement of solubility and stability for these kinds of drugs upon complexation with cyclodextrins, we aimed to form an inclusion complex between temozolomide and the different types of cyclodextrins (CDs) to enhance its solubility. In this study, three different cyclodextrins (β -CD, hydroxyl-β-CD and γ-CD) were used, and changes in solubility was measured by UV-Vis Spectroscopy and HPLC. Morphological changes upon complexation were shown by the Scanning Electron Microscope (SEM), and weight loss profiles with respect to temperatures which were unique to the compounds were shown by Thermogravimetric Analysis. Changes in heat release profiles were shown by Differential Scanning Calorimeter (DSC). Drug solubility was measured to be increased to around 25% for 1:1 molar ratio for all used CD complexations. Changes of morphology, heat release and weight loss profiles are consistent with the formation of an inclusion complex between CDs and temozolomide. In this study, success was shown in the enhancement of temozolomide solubility upon complexation with different types of CDs. It has been demonstrated that cyclodextrins can be used as complexing agents for poorly soluble anti-cancer drugs, increasing their solubility and hence drug availability.

Resumo em Inglês:

ABSTRACT Multifunctional drug anisomycin was subjected to forced degradation in accordance with International Conference on Harmonisation (ICH) guidelines for the first time. The drug was exposed to the recommended stress conditions of hydrolysis (acidic, alkaline and neutral), oxidation, thermal stress and photolysis, in order to investigate its stability. Optimized LC-MS/MS method was validated as recommended by ICH Q2(R1) guideline with respect to the specificity, accuracy, precision, limits of detection and quantitation, linearity and robustness. Anisomycin exhibited high instability under alkaline and thermal (neutral hydrolysis) conditions. It showed moderate stability under acidic, neutral, oxidative, thermal (acidic hydrolysis) and photolytic conditions, with the lowest degradation level observed in the case of light and oxidation stress. Formation of the same degradation product, identified as deacetylanisomycin, was observed under all applied stress conditions.

Resumo em Inglês:

Abstract The risk of having microvascular complication is high among Type 2 Diabetes Mellitus (T2DM) patients. However, factors associated with the glycemic control and progression of diabetic retinopathy (DR) in T2DM patients is limited. This study aims to determine association between anti-diabetic agents, glycemic control and progression of diabetic retinopathy in a Malaysian population. A retrospective study conducted in a tertiary teaching hospital in Malaysia, from January 2009 until March 2014. This study enrolled 104 patients aged 40-84 years, with a mean age 63.12 ± 9.18 years. patients had non-proliferative diabetic retinopathy (NPDR, 77%) and 35% had proliferative diabetic retinopathy (PDR). Diabetic macula edema (DME) was present in 20% of NPDR patients, compared with 7% in PDR. Alpha-glucosidase inhibitor (p=0.012), age (p=0.014) and number of antidiabetic agents used (p=0.015) were significantly associated with stages of diabetic retinopathy. Family history of T2DM (p=0.039) was associated with DME. Identifying factors influencing the progression of diabetic retinopathy may aid in optimizing the therapeutic effects of anti-diabetic agents in T2DM patients.

Resumo em Inglês:

ABSTRACT The leaves of Acacia modesta Wall. have been shown to possess diverse pharmacological properties. Therefore, we aimed at evaluating anti-diabetic, cytotoxic and proliferative effects of extracts of Acacia modesta Wall. leaves. After evaluating the primary and secondary metabolites, anti-diabetic activity of various extracts was assessed by α-amylase inhibition, glucose uptake by yeast cells and non-enzymatic glycosylation of hemoglobin assay. Cytotoxicity and proliferative potential was assessed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and short term proliferation assays, respectively, using human liver carcinoma cell line, HepG2. Among other extracts, chloroform extract exhibited 34.16% inhibition of α-amylase, 90.65% inhibition of hemoglobin glycosylation and 94.75% glucose uptake employing α-amylase inhibition, non-enzymatic glycosylation of hemoglobin and glucose uptake by yeast cells assays, respectively. Moreover, extracts exhibited no significant effects on HepG2 cell viability and proliferation. So, this data suggested that chloroform extract of leaves of Acacia modesta Wall., exhibited higher anti-hyperglycemic activity in comparison to extracts in other solvents, while no extract demonstrated cytotoxic and proliferation effects when tested using HepG2 cell line.

Resumo em Inglês:

ABSTRACT Linseed hydrogel (LSH) was evaluated by acute toxicity for its potential application in oral drug delivery design. White albino mice and rabbits were divided in four groups (I-IV) and different doses of LSH (1, 2 and 5 g/kg body weight) were given except to the control group (I) that was left untreated. Rabbits were monitored for eye irritation, acute dermal toxicity and primary dermal irritation, whereas, body weight, food and water consumption, hematology and clinical biochemistry, gross necropsy and histopathology of vital organs were scrutinized in mice. LSH was considered safe after eye irritation test as no adverse signs or symptoms were seen in the eye. In dermal toxicity and irritation study, skin of treated rabbits was found normal in color without any edema or erythema. After oral administration, there was no sign of any abnormalities in treated group animals (II-IV). The hematology and clinical biochemistry of treated group animals was comparable with the control group. Histopathology of vital organs has not shown any lesion or abnormalities. In the light of these outcomes, it can be concluded that LSH is not a hazardous biomaterial and could be incorporated as an excipient in oral and dermal preparations.

Resumo em Inglês:

ABSTRACT Bone substitutes based on hydroxyapatite (HA) and Bonefill® (BO - inorganic bovine bone) associated with poly(lactic-co-glycolic acid) (PLGA) (HA/PLGA and BO/PLGA) were evaluated concerning cytotoxicity, genotoxicity and mutagenicity as potential candidates for bone repair. The materials were developed and provided by Bionnovation Biomedical Products Ltda. Eluates from these bone substitutes were prepared for toxicity evaluations using eukaryotic cell cultures. HA/PLGA was used as a comparison for Bonefill®. Cell viability was evaluated by XTT assay and surviving fraction was calculated for clonogenic survival. Additionally, tail moment was used to assess genotoxicity (comet assay). The frequencies of binucleated cells with micronucleus (FBMN), micronucleus (FMN), nucleoplasmic bridges (NPBs), and nuclear buds (NBUDs) were analysed by cytokinesis-block micronucleus assay (CBMN assay). Results showed no statistical difference in cell viability compared with negative control (NC) The eluates did not promote delayed cytotoxicity whereas the surviving fraction rate for cultured cells was similar to NC. Furthermore, no genotoxicity or mutagenicity effects were observed for cultured cells with the Bonefill/PLGA and HA/PLGA eluates. In conclusion, the negative cytotoxicity, genotoxicity and mutagenicity results indicate that these bone substitutes presented interesting preliminary results as potential biomaterials for bone repair.

Resumo em Inglês:

ABSTRACT Gleevec (imatinib) is an antineoplastic chemotherapeutic agent used in the treatment of many types of cancer. The current study was conducted to examine the possible modifying effects of grape seeds proanthocyandins extract (GSPE) against apoptosis, liver injury and Ki67 alterations induced by Gleevec in male rats. 40 male albino rats were equally divided into four groups (First and second groups were control and GSPE groups; third group was Gleevec group and fourth group was treated with Gleevec and GSPE). Gleevec induced elevations in P53 and depletion of Bcl2 levels in liver tissues were compared with the control group. Liver sections in rats treated with Gleevec exhibited marked cellular infiltrations, vacuolar degeneration hepatocytes, numerous apoptotic cells, and congestion in central and portal veins, as well as a significant increase in the proliferating of Ki67 after Gleevec injection as compared with control group. In contrast, treatment with Gleevec and GSPE showed a moderate to good degree of improvement in hepatocytes with a significant increase in Ki67, a decrease in P53 and an increase in Bcl2 levels in liver tissues compared to treatment with Gleevec. Therefore, Gleevec induces apoptosis, injury and Ki67 changes in rat liver, whereas GSPE modulates these alternations.

Resumo em Inglês:

ABSTRACT In the search for new anti-schistosomal agents, a series of fifteen ortho-nitrobenzyl derivatives was assayed in vitro against both the schistosomulum (somule) and adult forms of Schistosoma mansoni. Compounds 8 and 12 showed significant activity against somules at low micromolar concentrations, but none was active against adults. The SAR demonstrated that the compounds most active against the parasite were mutagenic to the human cell line RKO-AS45-1 only at concentrations 10- to 40-fold higher than the worm-killing dose. Given their electrophilicity, compounds were also screened as inhibitors of the S. mansoni cysteine protease (cathepsin B1) in vitro. Amides 5 and 15 exhibited a modest inhibition activity with values of 55.7 and 50.6 % at 100 µM, respectively. The nitrobenzyl compounds evaluated in this work can be regarded as hits in the search for more active and safe anti-schistosomal agents.

Resumo em Inglês:

Abstract The treatment of infections caused by resistant microorganisms represents a big challenge in healthcare due to limited treatment options. For this reason, the discovery of new active substances which are able to perform innovative and selective actions is of great impact nowadays. Statins and triazenes (TZC) have consolidated as a promising class of compounds, characterized by the expressive biological activity, especially antimicrobial activities. The aim of this study was to assess the in vitro synergistic antibacterial effect of the association of statins and a new TZC complex {[1-(4-bromophenyl)-3-phenyltriazene N 3-oxide-κ 2 N 1,O 4](dimethylbenzylamine-κ 2 C 1,N 4)palladium(II)} (Pd(DMBA)LBr) against American Type Culture Collection (ATCC) strains and clinical isolates. The complex and the statins showed bacterial activity of all tested strains and clinical isolates, evidencing that TZC complexion with metals can be promising. Simvastatin showed synergy when associated to the complex (FICI≤0.5), being the minimum inhibitory concentration (MIC) of 16 µg mL-1 found in 6 samples. Thus, it is possible to infer that the association between Pd(DMBA)LBr and simvastatin consists of an alternative to increase the pontential of these compounds, since statins have low toxicity.

Resumo em Inglês:

ABSTRACT The aim of this study was to evaluate anti-hypoxia activity of polyphenolic extracts of Crataegus microphylla and Crataegus pentaegyn on mice. Three experimental models of hypoxia were considered, including asphyctic hypoxia, haemic hypoxia, and circulatory hypoxia. Polyphenolic extract of both plants exhibited significant anti-hypoxic activity and prolonged animal survival time. Anti-hypoia activity of C. pentaegyn was found to be superior to that of C. microphylla in circulatory and asphyctic hypoxia. Antihypoxic activity of these extracts may be attributed to their phenolic compounds.

Resumo em Inglês:

Abstract With the aim of controlling various symptoms, possible to use mixtures of different drugs within infusion devices. This should take into account the compatibility of the mixture. Factors influence the compatibility and stability of the mixtures are: drug type, concentration, solvent, temperature and light. When evaluating the compatibility of the mixtures for infusion for subcutaneous via is important to consider infusion devices used and the conditions of light and temperature should simulate as far as possible the conditions in practice assistance. There are diverse studies that analyze the compatibility of drug mixtures, but there are still many possible combinations of drugs for which evidence is not available. The objective of this work is to study the compatibility and stability of several mixtures of haloperidol and morphine that can be used in solution for subcutaneous infusion.

Resumo em Inglês:

ABSTRACT The aim of the present study was to characterize biotin-decorated docetaxel-loaded bovine serum albumin nanoparticles (DTX-BIO-BSA-NPs) and evaluate their antiproliferative activity in vitro. The particle size of prepared DTX-BIO-BSA-NPs was found to be always lower than 200 nm, with sizes of 166.9, 160.3, 159.0, 176.1 and 184.8 nm and the zeta potential was -29.51, -28.54, -36.54, -36.08 and -27.56 mV after redissolution with water for 0, 1, 2, 4 and 8 hours, respectively. The polydispersity index (PDI) was stable in the range of 0.170 - 0.178. In the in vitro drug-release study, the DTX-BIO-BSA-NPs targeted a human breast cancer cell line MCF-7 effectively. The x-ray diffraction spectrum and DSC curve of DTX-BIO-BSA-NPs suggested that docetaxel was in an amorphous or disordered crystalline phase in DTX-BIO-BSA-NPs. In vitro cytotoxicity results showed that DTX-BIO-BSA-NPs inhibits proliferation of MCF-7, SGC7901, LS-174T and A549 cells in a concentration-dependent manner after exposure to DTX-BIO-BSA-NPs for 48 hours. Taken together, these results indicate that DTX-BIO-BSA-NPs may have potential as an alternative delivery system for parenteral administration of docetaxel.

Resumo em Inglês:

Abstract Considering the high prevalence of human cervical cancer and the adverse effects of the available treatments, it is important to develop studies involving plants. Eugenia uniflora L. is a Brazilian native plant widely used in folk medicine and some biological effects have already been described. In this study, we investigated the biologicals effects of the aqueous crude extract of E. uniflora leaves in relation to the viability of human cervical cancer cells (SiHa), non-tumorigenic cells HaCaT and human lymphocytes. Our results demonstrated that different concentrations of E. uniflora’s extract significantly inhibited the viability of the Siha cell line at 24, 48 and 72 hours of treatment, but did not induce significant changes in the HaCat cell line and human lymphocytes. Tumor cells had adhesion capacity, migration processes, ability of colony forming and the potential to recover its viability after treatment. withdrawal, significantly reduced. The nuclear morphology revealed chromatin condensation, and the flow cytometry showed predominantly cell death by apoptosis in the treated tumor cells. Therefore, the E. uniflora’s extract may contribute for future studies aiming at new therapeutic perspectives for human cervical cancer.

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ABSTRACT Lippia origanoides is a honey shrub which has showed hypotensive potential assessed by in vivo studies. The aim of this work is the development of a pharmaceutical formulation composed by an optimized extract obtained from aerial parts of L. origanoides. The quantification of the naringenin marker in the dry extract and tablets developed was performed, as well as the assessment of the oral acute toxicity in rats. The hydroalcoholic extract of L. origanoides was spray-dried with the addition of colloidal silicon dioxide (Lo-HAE/CSD), and then applied in the preparation of eight different lots of tablets. The influence of the diluent (cellulose or babassu mesocarp), the presence of binder, and the percentage of lubricant, as well as organoleptic and physicochemical characteristics were screened. For the quantification of the marker content both in Lo-HAE/CSD and in the tablets, an analytical curve of the naringenin standard was fitted, and the samples were then analyzed in UFLC. The toxicological assessment was performed in female Wistar rats according to the Acute Toxic Class Method from OECD. The developed tablets produced meet acceptable macroscopic characteristics, and the presence of babassu as diluent provided improved physicochemical properties. The best content of Lo-HAE/CSD in the tablet (100.27%) was identified for the lot containing babassu, composed by 1.0% magnesium stearate, without PVP binder in its formulation. Moreover, Lo-HAE/CSD showed no signs of toxicity. Therefore, the babassu mesocarp powder is a promising pharmaceutical excipient for the development of herbal tablets containing the Lippia origanoides extract.

Resumo em Inglês:

ABSTRACT Interpolyelectrolyte complexes, which constitute a type of polymeric material obtained through the self-assembly of oppositely charged polymers, exhibit interesting properties for use in the design of smart matrices for drug delivery. In the present study, a stoichiometric interpolyelectrolyte complex (SIPEC) composed of Eudragit E® and Eudragit® L100 was obtained at pH 6.0 and characterized and evaluated as a hydrophilic matrix for dexibuprofen. The formation of a SIPEC was monitored by ζ-potential measurements and characterized using infrared spectroscopy, thermal analysis, and scanning electron microscopy. The results indicated that a SIPEC obtained under these conditions can be used as a matrix for controlling the release of dexibuprofen and exhibit a pH-triggered release.

Resumo em Inglês:

ABSTRACT Diabetes is a metabolic disease caused by abnormal insulin secretion or action. In the present study, the effects of betulinic acid (BA, a triterpene) are evaluated on glucose, α-amylase and plasma insulin levels, insulin resistance and the histopathology of pancreatic islets in streptozotocin-nicotinamide (STZ-NA) diabetic mice. Seventy adult male NMRI mice were randomly divided into seven groups: control, sham, diabetic, diabetic treated with BA (10, 20 and 40 mg/kg) and diabetic treated with metformin (200 mg/kg). Diabetes was induced in mice by intraperitoneal injection of streptozotocin 50 mg/kg after a dose of nicotinamide 120 mg/kg. Two weeks after treatment with BA, blood samples were collected for measuring glucose, α-amylase and insulin levels, and the pancreas was isolated for histopathology evaluation. Diabetes reduced the number and diameter of pancreatic islets, and increased α-amylase and insulin resistance. BA treatment reduced blood glucose, α-amylase and improved insulin sensitivity as well as pancreas histopathology. In addition, BA showed stronger effects on the pancreatic histology and insulin resistance compared to the metformin group.

Resumo em Inglês:

ABSTRACT A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the quantification of cabozantinib (CZ) in human plasma using cabozantinib-d4 (CZD4) as an internal standard (IS). Chromatographic separation was performed on Xbridge C18, 50 x 4.6 mm, 5 mm column with an isocratic mobile phase composed of 10mM Ammonium formate and Methanol in the ratio of (20:80 v/v), at a flow-rate of 0.7 mL/min. CZ and CZD4 were detected with proton adducts at m/z 502.2 ® 391.1 and 506.3 ® 391.2 in multiple reaction monitoring (MRM) positive mode respectively. Liquid-Liquid extraction method was used to extract the drug and IS. The method was validated over a linear concentration range of 5.0-5000.0 pg/mL with correlation coefficient (r2) ≥ 0.9994. This method demonstrated intra and inter-day precision within 1.95 to 2.37 and 2.93 to 9.3 % and Accuracy within 101.4 to 102.4 and 99.5 to 104.8 %. Cabozantinib was found to be stable throughout freeze-thawing cycles, bench top and postoperative stability studies.

Resumo em Inglês:

ABSTRACT Griseofulvin (GF) and terbinafine (TF) are commonly used drugs to treat dermatophytosis, a fungal infection of the skin. Today there is an increase in drug resistance to these antifungals which highlight the need for alternative synergistic therapies. Minimum Inhibitory Concentration (MIC) of GF and TF were determined against fungi clinical isolates from local hospitals with values ranging 0.03-2.0 µg mL-1 and 0.24-4.0 µg mL-1, respectively. A checkboard test was used to determine the combination of GF:TF which could induce an additive effect against the fungi isolates Multidrug-resistant isolates showed susceptibility after treatment with 16:2 µg mL-1 GF:TF. An MTT assay further verified that GF and TF combinations have greater additive effect against pathological and multidrug-resistant isolates than antifungals alone. Herein we disclose GF:TF combinations that could constitute as a possible new anti-dermatophyte therapy.

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ABSTRACT The purpose of this work was to evaluate the influence of the clinical profile on lamotrigine (LTG) plasma concentrations from patients with refractory epileptic seizures. In this cross-sectional study, therapeutic monitoring of LTG, and questionnaires with 75 patients with refractory epileptic seizures of a Hospital in Ribeirão Preto-SP-Brazil were performed. The multiple linear regression model was used to verify association between the LTG plasma concentrations and the independent variables. Covariance analysis was used to compare the mean LTG plasma concentration among the co-medication groups. The LTG plasma concentration was associated both with the LTG dosage (mg/kg/day) (p=0.0096) and with the use of first generation antiepileptic drugs (AED) (p<0.01), being carbamazepine (CBZ) and phenytoin (PHT), the AEDs showing the most prominent influence in reducing LTG plasma concentrations. Adverse events, adherence to the pharmacological treatment, and epileptic seizures frequency, did not show significant correlation with LTG plasma concentration values. The conclusion is that LTG plasma concentration is significantly influenced by the LTG dosage and by the concomitant use of a first generation AED.

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ABSTRACT Repirinast is a new, synthetic, disodium cromoglycate-like antiallergic agent for oral administration in humans. This study evaluated the safety, tolerability and pharmacokinetics of repirinast tablets in healthy Chinese volunteers. This was a phase I, open-label, randomized, single- and multiple-dose study. Subjects were assigned to receive a single dose of repirinast tablet at either 150, 300, or 450 mg, or multiple doses of 150 mg twice daily for 5 days. Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of active metabolite MY-1250 (deesterified repirinast) were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 0.75 hour, and the mean t1/2 was approximately 16.21 hours. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 150 to 450 mg. In the multiple-dose study, the steady-state was reached within 3 days with no accumulation. Repirinast tablet was well tolerated in healthy Chinese subjects.

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ABSTRACT Cancer has high morbidity and mortality rates related to medication use and produce a costly impact in health care. Thus, patients require constant monitoring and proper coordination of care between different professionals. This study aimed to evaluate the impact generated by a Medication Therapy Management service (MTM) offered to patients with breast cancer in use of polypharmacy. Observational, exploratory, descriptive and retrospective study of a MTM service that included 93 patients. Sociodemographic and clinical data related to pharmacotherapy and the processes associated with the systematization of the service were collected and analyzed. Patients were followed-up by the MTM service on average for 18 months (±4.31) and 185 drug-related problems (DRP) were identified, an average of two DRP per patient. Of these DRP, 48.11% were resolved and 49.73% were in the resolution process. The most common DRP were in the categories of Indication (37.84%), followed by Safety (23.78%). The safety category showed the highest resolution rate (59.09%). The study revealed an increased risk of DRP for patients with three or more comorbidities and using 5 or more medications. The process of systematization of a MTM service in oncology was associated with positive outcomes.

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ABSTRACT The treatment of infections caused by resistant microorganisms is limited, and vancomycin (VAN) treatment failures for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are not uncommon, even when MRSA clinical isolates are susceptible to VAN. Thus, this study proposed the association of VAN with usnic acid and β-lapachone encapsulated into liposomes as a novel therapeutic option for infections caused by MRSA. Liposomes containing β-lap (β-lap-lipo) or usnic acid (UA-lipo) were prepared by the thin lipid film hydration method followed by sonication. Antimicrobial activity against MRSA clinical isolates was investigated by the microdilution method according to the Clinical and Laboratory Standards Institute (CLSI). The interaction studies were carried out using the checkerboard method and epsilometer test (Etest). The interaction between VAN and β-lap or β-lap-lipo was synergistic (FICI = 0.453 and FICI = 0.358, respectively). An additive interaction between VAN and UA (FICI = 0.515) was found. UA-lipo resulted in synergism with VAN (FICI = 0.276). The Etest reproduced the results obtained by the checkerboard method for approximately 82% of the analysis. Thus, the present study demonstrated that VAN in combination with UA-lipo, β-lap or β-lap-lipo synergistically enhanced antibacterial activity against MRSA.

Resumo em Inglês:

ABSTRACT The aim of the present study was to investigate the effect of donor pH on the transdermal permeability of the model drugs across rat skin and also to determine the major route of transport of the drugs. Weakly acidic drugs (partition coefficient) ibuprofen (3.6), aceclofenac (3.9), glipizide (1.9) and weakly basic drugs olanzapine (3.6), telmisartan (6.0), and sildenafil citrate (1.9) were selected for the study. The ex vivo permeation studies of these drugs at different donor pH (pH - 1.2, 4, 5, 6.8, 7.4, and 8) using Franz diffusion cell (area, 7.54 cm2) has shown a pH-dependent permeability. Among these drugs the weakly acidic drugs has shown higher permeation rates compared to the weakly basic drugs. The permeability coefficient and the distribution coefficient of the weakly basic drugs increased on increasing the pH whereas the weakly acidic drugs showed an inverse relation. The weakly basic drugs also showed an increase in permeation with increase in the fraction of unionized species indicating dominance of transcellular route of permeation. With an exception of sildenafil citrate, a weakly basic salt form of the drug which showed a high permeation value at pH 7.4 where 57% of the drug was unionized, indicating the involvement of both paracellular and transcellular route in its permeation.