Anti-inflammatory drug design by molecular hybridization approach

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Development of an anti aging cream with AHA/BHA and sunscreens

The skin aging is a matter of discomfort verified in the population. Thus, every day, new products are launched on the market to offer different manners to prevent the premature aging of the skin. In this context, active substances, as alpha and beta hidroxyacids (AHA/BHA), beyond the sunscreens, are considered a way of prevention and amelioration of the effects caused in the skin due to the time. The aim of this study was to develop and evaluate a cosmetic cream containing AHA/BHA and sunscreen. It was studied in relation to its physical-chemical and microbiological characteristics. According to the results, the formulation developed present a shelf life of 758 days and the preservative system was effective. Considering the parameters evaluated, the cream probably would be commercially accepted.

Rheological characterisation and effect of abiotic factors on the antimicrobial efficacy of chitosan-based hidrogels containing alpha-hydroxy acids

The aim of this study was to investigate the rheological properties and antibacterial efficacy of chitosan/ alpha-hydroxy acids (lactic acid and glycolic acid) and cellulose polymers, both in hydrogels, in order to produce a formulation with improved activity against Propionibacterium acnes and Staphylococcus aureus, which can potentially be used in the treatment of acne. The rheological characterisation of the hydrogels was examined using continuous shear and viscoelastic creep. The antibacterial activities of formulations were performed by the well diffusion and broth microdilution. The hydrogels formulated with only chitosan showed pseudoplastic behavior while the chitosan hydrogels with cellulose polymers presented viscoelastic properties. The antibacterial activity was proportional to AHA and chitosan concentration. It was enhanced at low pH values and with high molecular weight chitosan and did not change with the incorporation of two cellulose polymers. The antibacterial mechanism of chitosan has currently been hypothesized as being related to surface interference. The results show that chitosan - based hydrogels containing AHA and cellulose polymers are viscoelastic,indicating good applicability onto the skin, and they present bacterial activity under various experimental conditions.

Comparative study over methods developed for quantification of darunavir in tablets by environmental friendly infrared and capillary electrophoretic techniques

Darunavir, a protease inhibitor used in the treatment of HIV infection, presents few methods for its determination in pharmaceuticals. Infrared (IR) spectroscopy offers the possibility of obtaining spectra relatively quickly, providing interesting information, analytically, qualitatively or quantitatively. Capillary electrophoresis (CE) performs separations of high efficiency in shorter time with reagents and samples in small quantity. These two methods are cost-benefitted when we evaluate the green level and the cost of analysis. Faster and cheaper methods without generating organic waste by IR and CE for the quantification of darunavir were developed and validated, focusing socioeconomic impact of analytical decisions. If the cost of acquisition, maintenance, production, analysis and conditioning of drugs and pharmaceuticals is high, consequently the price of this product in the market will be higher and it cannot be accessible to the patient. Treatment failure not only affects the quality of life of patients, but also contributes significantly to the economic burden of the health system. In this context there is a tool called Analysis of the Life Cycle, which comes to make us think in a multidimensional way focusing the whole, the parts and especially the interaction among the parts of a system.

Validation of a stability indicating capillary electrophoresis method for the determination of darunavir in tablets and comparison with the of infrared absorption spectroscopic method

Darunavir (DRV) is a protease inhibitor used in the treatment of HIV infection, which constitutes a keystone in the therapy of patients infected with this virus. There is no monograph described in official compendia. The literature provides few methods of analysis for the determination of DRV in pharmaceuticals which include TLC, IR, UPLC, HPLC, HPLC-MS, HPLC-MS/MS, but there are no reports of the use of capillary electrophoresis (CE) for the determination of this drug. Thus, this research proposed the development and validation of a CE method for the determination of DRV in tablets. The method was completely validated according to the International Conference on Harmonization guidelines, showing linearity, selectivity, precision, accuracy and robustness. The migration was achieved in less than 1 minute using fused-silica uncoated capillary with an id of 50 μm and total length of 21 cm and voltage of +20 kV. The sample injection was performed in the hydrodynamic mode. The method was linear over the concentration range of 50-200 μg mL-1 with correlation coefficient 0.9998 and limits of detection and quantification of 7.29 and 22.09 μg mL-1, respectively. The drug was subjected to acid, base, oxidation and photolysis degradation. Degradation products were found interfering with the assay of DRV, therefore the method can be regarded as stability indicating. The validated method is useful and appropriate for the routine quality control of DRV in tablets.

A importância da atenção farmacêutica após a verificação da qualidade microbiológica de medicamentos contendo paracetamol encontrados em algumas residências de Américo Brasiliense - SP

It is known that a high microbial count can compromise the stability of medicines, thus reducing their therapeutic efficacy. This work tried to demonstrate that the microbial contamination can be directly related to the inadequate handling of the medicines stored in homes, making it possible to draw strategies to reduce the possible risks of medical therapy offering correct information and advising. The objective of this work was to evaluate the quality of the medicines containing paracetamol found in the residences of Américo Brasiliense-SP, using the microbial analysis of non-sterile method described in the Brazilian Pharmacopoeia (1988). The medicine samples (30 samples) were obtained directly from the interviewed local residents, who had received new medicine bottles of the same product. An analysis of viable microorganisms (bacteria and fungus) was carried out to identify pathogens found in the collected samples. Although 90% of the analyzed samples have shown some microbial contamination, the results indicated the absence of pathogenic microorganisms, and the total count of viable microorganisms was below the maximum value for non-sterile (104 UFC/g or mL). It was also verified that the local residents stored the medicines in appropriate places, according to the orientations received when they bought the medicines in pharmacies and drugstores, showing the importance of information for the correct use and conservation of pharmaceuticals.

Validation of an alternative analitycal method for the quantification of antioxidant activity in plant extracts

SUMMARY. A new method was developed to evaluate the total antioxidant activity in plant extracts, which was based on radical scavenging using 2,2’-azinobis-(3-ethylbenzothiazoline)-6-sulfonic acid. The proposed method was linear in the range of 0.86 to 26.0 μg/mL, displaying a correlation coefficient of 0.999. Moreover, the accuracy and precision analysis showed agreement with ANVISA guidelines (96.66 to 98.46 % and < 5.0%, respectively). The method demonstrated sensitivity, robustness and efficiency in detecting low concentrations of plant extracts (detection and quantification limit of 0.86 and 2.87 μg/mL, respectively) that may be present in pharmaceuticals and cosmetics preparations, again in agreement with ANVISA. In addition, the assay is inexpensive and easy to perform.

Regulatory issues on pharmacovigilance in Latin American countries

Pharmacovigilance is responsible for monitoring the safety of medicines in normal clinical use andduring clinical trials. Legal requirements for pharmacovigilance in some Latin American countries (Argentina, Brazil, Chile, Paraguay and Uruguay) were reviewed. Disparities in the legal framework among the countries are observed being those for marketing authorization holders one of the most evident. Theactive rol of the universities and drug information centers for/of pharmacovilance seems to be a positivecommon point. Legal requirements regarding pharmacovigilance of biosimilar medicines, is still a pointto be developed.

Método para controle da qualidade de medicamentos sólidos por difração de raios X

Pós-graduação em Química - IQ

Optimization of in situ derivatization SPME by experimental design for GC-MS multi-residue analysis of pharmaceutical drugs in wastewater

This paper presents the development of a procedure, which enables the analysis of nine pharmaceutical drugs in wastewater using gas chromatography-mass spectrometry (GC-MS) associated with solid-phase microextraction (SPME) for the sample preparation. Experimental design was applied to optimize the in situ derivatization and the SPME extraction conditions. Ethyl chloroformate (ECF) was employed as derivatizing agent and polydimethylsiloxane-divinylbenzene (PDMS-DVB) as the SPME fiber coating. A fractional factorial design was used to evaluate the main factors for the in situ derivatization and SPME extraction. Thereafter, a Doehlert matrix design was applied to find out the best experimental conditions. The method presented a linear range from 0.5 to 10 mu g/L, and the intraday and interday precision were lower than 16%. Applicability of the method was verified from real influent and effluent samples of a wastewater treatment plant, as well as from samples of an industry wastewater and a river.

Role of common mental and physical disorders in partial disability around the world

Background Mental and physical disorders are associated with total disability, but their effects on days with partial disability (i.e. the ability to perform some, but not full-role, functioning in daily life) are not well understood. Aims To estimate individual (i.e. the consequences for an individual with a disorder) and societal effects (i.e. the avoidable partial disability in the society due to disorders) of mental and physical disorders on days with partial disability around the world. Method Respondents from 26 nationally representative samples (n=61 259, age 18+) were interviewed regarding mental and physical disorders, and day-to-day functioning. The Composite International Diagnostic Interview, version 3.0 (CIDI 3.0) was used to assess mental disorders; partial disability (expressed in full day equivalents) was assessed with the World Health Organization Disability Assessment Schedule in the CIDI 3.0. Results Respondents with disorders reported about 1.58 additional disability days per month compared with respondents without disorders. At the individual level, mental disorders (especially post-traumatic stress disorder, depression and bipolar disorder) yielded a higher number of days with disability than physical disorders. At the societal level, the population attributable risk proportion due to physical and mental disorders was 49% and 15% respectively. Conclusions Mental and physical disorders have a considerable impact on partial disability, at both the individual and at the societal level. Physical disorders yielded higher effects on partial disability than mental disorders.

Conformational polymorphism of the antidiabetic drug chlorpropamide

In this paper, the main features of Raman spectroscopy, one of the first choice methods in the study of polymorphism in pharmaceuticals, are presented taking chlorpropamide as a case of study. The antidiabetic drug chlorpropamide (1-[4-chlorobenzenesulphonyl]-3-propyl urea), which belongs to the sulfonylurea class, is known to exhibit, at least, six polymorphic phases. These forms are characterized not only by variations in their molecular packing but also in their molecular conformation. In this study, the polymorphism of chlorpropamide is discussed on the basis of Raman scattering measurements and quantum mechanical calculations. The main spectroscopic features that fingerprint the crystalline forms are correlated with the corresponding crystalline structures. Using a theoretical approach on the energy dependence of the conformers, simulated molecular torsion angles are plotted versus the formation energy, which provides a satisfactory agreement between the torsion angles at the energy minima and the experimental values observed in the different solid forms of chlorpropamide. Copyright (C) 2011 John Wiley & Sons, Ltd.

Sorafenib in Combination With Capecitabine: An Oral Regimen for Patients With HER2-Negative Locally Advanced or Metastatic Breast Cancer

Purpose Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. Patients and Methods Patients were randomly assigned to first-or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). Results In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand-foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). Conclusion Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Structural synaptic elements are differentially regulated in superior temporal cortex of schizophrenia patients

Inaccurate wiring and synaptic pathology appear to be major hallmarks of schizophrenia. A variety of gene products involved in synaptic neurotransmission and receptor signaling are differentially expressed in brains of schizophrenia patients. However, synaptic pathology may also develop by improper expression of intra- and extra-cellular structural elements weakening synaptic stability. Therefore, we have investigated transcription of these elements in the left superior temporal gyrus of 10 schizophrenia patients and 10 healthy controls by genome-wide microarrays (Illumina). Fourteen up-regulated and 22 downregulated genes encoding structural elements were chosen from the lists of differentially regulated genes for further qRT-PCR analysis. Almost all genes confirmed by this method were downregulated. Their gene products belonged to vesicle-associated proteins, that is, synaptotagmin 6 and syntaxin 12, to cytoskeletal proteins, like myosin 6, pleckstrin, or to proteins of the extracellular matrix, such as collagens, or laminin C3. Our results underline the pivotal roles of structural genes that control formation and stabilization of pre- and post-synaptic elements or influence axon guidance in schizophrenia. The glial origin of collagen or laminin highlights the close interrelationship between neurons and glial cells in establishment and maintenance of synaptic strength and plasticity. It is hypothesized that abnormal expression of these and related genes has a major impact on the pathophysiology of schizophrenia.

Gray Matter Volumes in Obsessive-Compulsive Disorder Before and After Fluoxetine or Cognitive-Behavior Therapy: A Randomized Clinical Trial

Serotonin reuptake inhibitors and cognitive-behavior therapy (CBT) are considered first-line treatments for obsessive-compulsive disorder (OCD). However, little is known about their modulatory effects on regional brain morphology in OCD patients. We sought to document structural brain abnormalities in treatment-naive OCD patients and to determine the effects of pharmacological and cognitive-behavioral treatments on regional brain volumes. Treatment-naive patients with OCD (n = 38) underwent structural magnetic resonance imaging scan before and after a 12-week randomized clinical trial with either fluoxetine or group CBT. Matched-healthy controls (n = 36) were also scanned at baseline. Voxel-based morphometry was used to compare regional gray matter (GM) volumes of regions of interest (ROIs) placed in the orbitofrontal, anterior cingulate and temporolimbic cortices, striatum, and thalamus. Treatment-naive OCD patients presented smaller GM volume in the left putamen, bilateral medial orbitofrontal, and left anterior cingulate cortices than did controls (p<0.05, corrected for multiple comparisons). After treatment with either fluoxetine or CBT (n = 26), GM volume abnormalities in the left putamen were no longer detectable relative to controls. ROI-based within-group comparisons revealed that GM volume in the left putamen significantly increased (p<0.012) in fluoxetine-treated patients (n = 13), whereas no significant GM volume changes were observed in CBT-treated patients (n = 13). This study supports the involvement of orbitofronto/cingulo-striatal loops in the pathophysiology of OCD and suggests that fluoxetine and CBT may have distinct neurobiological mechanisms of action. Neuropsychopharmacology (2012) 37, 734-745; doi: 10.1038/npp.2011.250; published online 26 October 2011