Trypanosoma cruzi killing and immune response boosting by novel phenoxyhydrazine-thiazole against Chagas disease.

Trypanosoma cruzi (T. cruzi) causes Chagas, which is a neglected tropical disease (NTD). WHO estimates that 6 to 7 million people are infected worldwide. Current treatment is done with benznidazole (BZN), which is very toxic and effective only in the acute phase of the disease. In this work, we designed, synthesized, and characterized thirteen new phenoxyhydrazine-thiazole compounds and applied molecular docking and in vitro methods to investigate cell cytotoxicity, trypanocide activity, nitric oxide (NO) production, cell death, and immunomodulation. We observed a higher predicted affinity of the compounds for the squalene synthase and 14-alpha demethylase enzymes of T. cruzi. Moreover, the compounds displayed a higher predicted affinity for human TLR2 and TLR4, were mildly toxic in vitro for most mammalian cell types tested, and LIZ531 (IC50 2.8 µM) was highly toxic for epimastigotes, LIZ311 (IC50 8.6 µM) for trypomastigotes, and LIZ331 (IC50 1.9 µM) for amastigotes. We observed that LIZ311 (IC50 2.5 µM), LIZ431 (IC50 4.1 µM) and LIZ531 (IC50 5 µM) induced 200 µg/mL of NO and JM14 induced NO production in three different concentrations tested. The compound LIZ331 induced the production of TNF and IL-6. LIZ311 induced the secretion of TNF, IFNγ, IL-2, IL-4, IL-10, and IL-17, cell death by apoptosis, decreased acidic compartment formation, and induced changes in the mitochondrial membrane potential. Taken together, LIZ311 is a promising anti-T. cruzi compound is not toxic to mammalian cells and has increased antiparasitic activity and immunomodulatory properties.

Redução da taxa de filtração glomerular em pacientes críticos em uso de vancomicina: um estudo transversal / Decrease of the glomerular filtration rate in critically ill patients using vancomycin: a cross-sectional study

Objetivo: o presente trabalho teve como objetivo avaliar os fatores clínicos e medicamentosos relacionados com a redução da Taxa de Filtração Glomerular (TFG) em pacientes críticos em uso de vancomicina. Métodos: trata-se de um estudo transversal em que pacientes em uso de vancomicina, maiores de 18 anos, hospitalizados em terapia intensiva, foram selecionados no período de agosto a dezembro de 2019. Foram excluídos os pacientes que tiveram permanência inferior a 48h na unidade, aqueles com doença renal crônica e/ou que tiveram antimicrobiano suspenso nas primeiras 48h. Os dados clínicos e laboratoriais foram coletados do prontuário nas mesmas datas das coletas de amostras sanguíneas. As amostras de sangue foram coletadas no vale a partir do terceiro dia de tratamento. Os níveis de vancomicina foram medidos usando VANC VITROS ®. Os dados foram analisados através do software R. Resultados: 54 pacientes foram incluídos, sendo 68,5% do sexo masculino, 98,1% em ventilação mecânica, com foco respiratório (51,2%) e isolado Acinetobacter baumanni (38,0%). As concentrações de vancomicina variaram entre 5,0 e 50,0µg/mL, média 21,6 (DP: 10,6) µg/mL; 50% dos pacientes apresentaram concentração acima de 20µg/mL e 66,7% piora da TFG após o tratamento. A concentração de vancomicina foi a única variável diretamente relacionada com o desenvolvimento da alteração na função renal (p=0.0037). Não foi possível estabelecer a influência da comedicação na redução da taxa de filtração glomerular (TFG). Conclusão: as doses usuais de vancomicina ajustadas por meio da função renal não atingiram os níveis séricos terapêuticos recomendados de vancomicina, sendo relacionados à nefrotoxicidade.

Objective: we aimed to evaluate clinical and drug factors related to the Glomerular Filtration Rate (GFR) reduction in critically ill patients using vancomycin. Methods: This is a cross-sectional study where critically ill patients using vancomycin, aged over 18 years, were selected from August to December 2019. Patients were excluded when hospitalized for less than 48 hours in the unit, those with chronic kidney disease, and/or who had their antimicrobial suspended in the first 48 hours. Clinical and laboratory data were collected from the medical record on the same days as the blood sample collection. All blood samples were collected at the trough during the third day of vancomycin treatment. Vancomycin levels were measured using VANC VITROS ®. Data analysis was analyzed by R software. Results: 54 patients were included, 68.5% male, 98.1% mechanical ventilation, respiratory focus (51.2%), and isolation of Acinetobacter baumanni (38.0%). Vancomycin concentrations ranged between 5.0 and 50.0µg/mL, mean of 21.6 (SD: 10.6) µg/mL; 50% of patients with concentrations above 20µg/mL and 66.7% worsened GFR after vancomycin treatment. Vancomycin concentration was the only variable directly related to the development of renal malfunction (p=0.0037). It was not possible to establish the influence of co-medication in the reduction of the glomerular filtration rate (GFR). Conclusion: the usual doses of vancomycin adjusted by renal function did not reach the recommended therapeutic serum levels of vancomycin, being related to nephrotoxicity.

Dimethoate absorption: A complementary in vitro and in vivo assessment.

This work attempts to evaluate dermal exposure (DE) of farm workers to dimethoate after 4 h of routine application to a lemon plantation. Dimethoate was measured on the workers' clothes as well as in stratum corneum (SC) and in saliva. In vitro permeation tests (IVPT) were performed through rat, pig and human skin and pig buccal, esophageal and sublingual mucosas. The mean of dimethoate DE was 342.19 ± 487.14 mg/d, the percentage of toxic dose per hour was higher than the other pesticides, and the SC penetration factors ranged between 0.5 and 14.81 and 0.05-53.96 % for back of neck and arms respectively. In the supporting IVPT study, dimethoate absorption through human skin was 14.75 % and the default value in the absence of experimental data for this product is 70%. These results show that in family farming the deficiency of correct clothing during the application of pesticides leaves workers more vulnerable.

Development of the stability-indicating method, structural elucidation of new photodegradation products from terconazole by LC-MS TOF, and in vitro toxicity.

Terconazole (TCZ) was the first triazole antifungal drug launched in the market and has been used in the treatment of vulvovaginal candidiasis. It is also indicated to treat dermatophytosis and fungal ocular infections. However, some of the degradation products from triazole drugs have been reported to be toxic, justifying the need of further investigations about the stability of TCZ. identification of its degradation products and evaluation of their toxicity considering the new possibilities of therapeutic indications. Therefore, in this work a systematic investigation regarding photostability of TCZ was conducted. The active pharmaceutical ingredient (API) and its methanolic solution (100 µg mL-1) were kept into a photostability chamber under a UV light (200 Wh/m2; 1.2 × 106 lux/h) during 5 days and 90 min, respectively. A high-efficiency liquid chromatography method was developed for separation and identification of TCZ and its degradation products. The solid-state API remained stable throughout the test, whereas an extensive degradation was observed when in solution. In this case, four degradation products not yet reported in the literature were identified and characterized by electrospray ionization high-resolution quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS). Two degradation products presented m/z of 498 and the other two of 496 and 464, respectively. The results suggest that the degradation follows a first-order kinetic and involves the loss of chlorine atoms from the 2,4-dichlrophenyl moiety. Finally, TCZ submitted to the same stress condition as the API solution, increased significantly the opacity during the bovine corneal opacity and permeability test method (BCOP) indicating a potential to cause ocular toxicity. Further studies using the pure photolysis degradation products of TCZ characterized in this work are still necessary to confirm this find.

Selective LC-MS/MS determination of citalopram enantiomers and application to a pharmacokinetic evaluation of generic and reference formulations.

Two methods using LC-MS/MS were validated to quantify citalopram (CTP) racemate [(R/S)-CTP] and the enantiomers (R)-CTP and (S)-CTP in human plasma, respectively. Paroxetine hydrochloride was used as the internal standard, and samples were extracted by protein precipitation with acetonitrile. The non-enantioselective method was conducted using a C18 column, and the mobile phase consisted of water for solvent A and acetonitrile for solvent B, both with 0.1% formic acid. For the chiral method, an analytical column Lux Cellulose-1 was used. Mobile phase A was composed of water with 0.025% of formic acid and 0.05% of diethylamine, and mobile phase B consisted of acetonitrile:2-propanol (95:5, v/v). No significant matrix effects were observed at the retention times of analytes and internal standard. The mean recovery was 89%, and the assays were linear in the concentration range of 1-50 and 5-30 ng/mL for the non-enantioselective and enantioselective methods, respectively. The intra- and inter-day precisions of both methods were less than 12.30%, and the accuracies were less than 12.13%. The validated methods were successfully applied to a pharmacokinetic study in which 20-mg CTP tablets were administered to healthy volunteers, and their plasma levels were monitored over time in a bioequivalence study. HIGHLIGHTS: Simple and rapid LC-MS/MS method for the quantification of citalopram and its enantiomers in human plasma. Both methods were demonstrated to be selective, reliable, and sensitive. Both methods have sufficient sensitivity to quantify the steady state through concentrations already reported for citalopram and escitalopram. Validated method presented in this study can be suitably applied to pharmacokinetic studies involving citalopram and escitalopram. Bland-Altman analysis suggested that non-enantioselective and enantioselective methods can be applied in pharmacokinetic studies.

Mupirocin ointments: In vitro x In vivo bioequivalence evaluation

Abstract Bioequivalence (BE) assessment of topical drug products is a long-standing challenge. Agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published several drafts in recent years suggesting different approaches as alternative to evaluate the BE. A proposed Topical Classification System (TCS) has even been discussed. Given the above, the objective of this research was to use in vitro and in vivo BE approaches to evaluate Brazilian marketed mupirocin (MPC) ointments, previously classified as TCS class The in vitro permeation test (IVPT) was performed by applying formulations to pig skin by Franz cells. The in vivo methodology was dermatopharmacokinetic (DPK). These approaches (in vivo tape stripping and IVPT) demonstrated capability of distinguishing among different formulations, thus making them useful methodologies for BE evaluation.

Characterization, in vitro dissolution, and pharmacokinetics of different batches of efavirenz raw materials.

OBJECTIVE: To perform the solid-state characterization and the in vitro-in vivo correlation (IVIVC) of three batches of efavirenz (EFV) active pharmaceutical ingredients. SIGNIFICANCE: EFV is an effective anti-HIV drug. Due to the poor aqueous solubility, the rate and extent of EFV absorption deeply depend on its dissolution characteristics. METHODS: Thermal analyses, x-ray diffraction, and particle size distribution were performed. The saturation solubility and dissolution profiles were assessed in 0.5% (w/v) sodium lauryl sulfate (SLS), fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) using a flow-through cell. Each batch was orally administered to Wistar rats and the pharmacokinetic parameters were correlated with those obtained from in vitro dissolution. RESULTS: All batches of EFV consisted polymorph I. EFV-A presented the lowest particle size distribution [d(v,0.5) = 197.8 µm; d(v,0.9) = 444.6 µm] followed by EFV-B [d(v,0.5) = 223.9 µm; d(v,0.9) = 481.1 µm], and EFV-C [d(v,0.5) = 240.8 µm; d(v,0.9) = 497.3 µm]. The saturated solubility in FaSSIF was 36% and 40% of that in FeSSIF and SLS, respectively. EFV-A presented the fastest rate and largest extension of dissolution than EFV-B and C (79.15%, 69.93% and 54.22%, respectively, as well as the highest maximum plasma concentration. Levels B, C, and multiple-C of IVIVC models were achieved. CONCLUSION: The FaSSIF medium discriminated the dissolution profiles of EFV APIs. Small differences in particle size distribution had a significant impact on the biopharmaceutical parameters of EFV, suggesting that strict control of such parameter is an important aspect during API development and drug formulation.

Levobupivacaine-Loaded Liposome Associated with Thermogel for Prolonged Analgesia.

Pain is a phenomenon present in the majority of the population, affecting, among others, the elderly, overweight people, and especially recently operated patients, analgesia being necessary. In the specific case of relief of postoperative pain, different kinds of anesthetics are being used, among them bupivacaine, a widely used drug which promotes long-lasting analgesic effects. However, cardiotoxicity and neurotoxicity are related to its repetitive use. To overcome these shortcomings, Novabupi® (a racemic mixture) was developed and is marketed as an injectable solution. This formulation contains an enantiomeric excess of the levogyre isomer, which has reduced toxicity effects. Seeking to rationalize its use by extending the duration of effect and reducing the number of applications, the objectives of this work were to develop and evaluate liposomes containing Novabupi (LBPV), followed by incorporation into thermogel. Liposomes were prepared using the lipid hydration method, followed by size reduction using sonication, and the developed formulations were characterized by hydrodynamic diameter, polydispersity index (PDI), surface zeta potential, and encapsulation efficiency. The selected optimal liposomal formulation was successfully incorporated into a thermogel without loss of thermoresponsive properties, being suitable for administration as a subcutaneous injection. In the ex vivo permeation studies with fresh rodent skin, the thermogel with liposomes loaded with 0.5% LBPV (T-gel formulation 3) showed higher permeation rates compared to the starting formulation, thermogel with 0.5% LBPV (T-Gel 1), which will probably translate into better therapeutic benefits for treatment of postoperative analgesia, especially with regard to the number of doses applied.

Critical analysis on the use of cholecalciferol as a COVID-19 intervention: a narrative review.

BACKGROUND: The World Health Organization has declared that a pandemic situation exists in relation to the disease caused by the new coronavirus, COVID-19. So far, the absence of a vaccine against the new coronavirus has led people worldwide to seek various therapeutic alternatives, including use of cholecalciferol. DESIGN AND SETTING: Narrative review developed by a research group at a public university in Recife (PE), Brazil. METHODS: We searched the literature on the use of cholecalciferol for prevention or treatment of COVID-19, using the MEDLINE and LILACS databases, with the keywords "vitamin D", "cholecalciferol", "SARS-CoV-2", "COVID-19" and "coronavirus", from January 1, 2020, to June 10, 2020. Narrative reviews, cohort studies and ecological studies were selected. RESULTS: We retrieved 32 references, of which 8 were considered eligible for intensive review and critical analysis. These comprised five narrative reviews, two observational studies and one protocol proposal. Most of the studies selected reported positive effects from use of vitamin D for prevention or treatment of COVID-19. However, there was little quantitative data to assess the real impact of using this vitamin as an intervention against this disease. CONCLUSIONS: Current studies on vitamin D used for purposes other than bone health promotion cannot be taken as support to justify its use in a disease as recent as COVID-19. Studies of greater robustness, with higher levels of clinical evidence, need to be conducted. Rational use of this vitamin needs to be ensured, thereby minimizing the impacts on the patient and the public healthcare system.

Critical analysis on the use of cholecalciferol as a COVID-19 intervention: a narrative review

ABSTRACT BACKGROUND: The World Health Organization has declared that a pandemic situation exists in relation to the disease caused by the new coronavirus, COVID-19. So far, the absence of a vaccine against the new coronavirus has led people worldwide to seek various therapeutic alternatives, including use of cholecalciferol. DESIGN AND SETTING: Narrative review developed by a research group at a public university in Recife (PE), Brazil. METHODS: We searched the literature on the use of cholecalciferol for prevention or treatment of COVID-19, using the MEDLINE and LILACS databases, with the keywords "vitamin D", "cholecalciferol", "SARS-CoV-2", "COVID-19" and "coronavirus", from January 1, 2020, to June 10, 2020. Narrative reviews, cohort studies and ecological studies were selected. RESULTS: We retrieved 32 references, of which 8 were considered eligible for intensive review and critical analysis. These comprised five narrative reviews, two observational studies and one protocol proposal. Most of the studies selected reported positive effects from use of vitamin D for prevention or treatment of COVID-19. However, there was little quantitative data to assess the real impact of using this vitamin as an intervention against this disease. CONCLUSIONS: Current studies on vitamin D used for purposes other than bone health promotion cannot be taken as support to justify its use in a disease as recent as COVID-19. Studies of greater robustness, with higher levels of clinical evidence, need to be conducted. Rational use of this vitamin needs to be ensured, thereby minimizing the impacts on the patient and the public healthcare system.

A proposed eye ex vivo permeation approach to evaluate pesticides: Case dimethoate.

This study aims to propose different ex vivo methodologies for pesticide evaluation when in contact with ocular mucosa. The first ex vivo study was performed using vertical Franz cells with fresh and refrigerated excised bovine corneas. The second evaluated the permeation through the cornea by using fresh, refrigerated and damaged whole bovine eyes. Both experiments were evaluated by applying 50 µl (of 5 mg/ml solution) of an emulsifiable pesticide formulation (Dimetoato 500 EC®). In the first study, dimethoate profiles and permeation fluxes showed no statistical differences (p < .05) between fresh and refrigerated excised corneas, probably due to the excision procedure generating damage to the cornea by altering stromal structure, irrespective of the refrigeration procedure. In relation to the results obtained for developed ex vivo permeation method in whole eyes, there was a statistical difference (p < .05) between experiments performed with fresh eyes and those performed with refrigerated/damaged eyes. Damage generated by both the refrigeration process and exposure to irritant products led to a five-fold reduction in the amount of corneal-permeated pesticide as well as a two-fold increase in retention. Thus, the ex vivo permeation approach with whole eyes seems to be a simple and reproducible method to evaluate pesticides. It is evident that further evaluations need to be performed using other pesticides with distinct physicochemical characteristics.

Quality by design applied to olanzapine and quetiapine LC-MS/MS bioanalysis.

One major challenge in quantifying drugs in biological matrices is to manage interfering compounds. A technique such liquid chromatography coupled to mass spectrometry in tandem (LC-MS/MS) is especially suitable for this application due to its high sensitivity and selectivity in detecting low concentrations of analytes in a complex system. Due to the complexity of LC-MS/MS systems, a number of experimental parameters must be optimized to provide an adequate separation and detection of the analyte. In the present work, a design of experiments approach was developed to optimize an LC-MS/MS-based bioanalytical method to extract olanzapine (OLZ) and quetiapine (QTP) from human plasma. Three steps for the optimization process were conducted: central composite face-centered design to optimize chromatographic parameters (Step 1), ionization in mass spectrometry (Step 2) and a full 32 factorial design to optimize analyte extraction conditions (Step 3). After the optimization process, resolutions and QTP and OLZ retention time (2.3 and 4, respectively) were optimum with pH of 4.7 and 85.5% of acetonitrile for the chromatographic step. Mass spectrometry optimization step provided an increase of (±50%) in the average peak area with high signal-to-noise relationship for the analytes studied. The proposed extraction method was 70% more efficient than the initial method for all drugs analyzed.

Ethephon and fosetyl residues in fruits from São Francisco Valley, Brazil.

This survey describes the occurrence of Ethephon (ETH) and Fosetyl in fruits intended for export produced in the São Francisco Valley, Brazil. The determination of these compounds was carried out by the QuPPe-method (Quick Polar Pesticides Method), which was optimised and successfully validated according to the SANTE/11813/2017. From January 2016 to December 2018 a total of 1048 samples were analysed for ETH residues. In 547 (53%) of the samples, residues below the EU MRL of 1 mg kg-1 were present. In 17 samples (2%) ETH residues were above 1 mg kg-1. Overall, the mean ETH level decreased after 2016. Analyses of fosetyl showed that (18%) of 109 mango samples were positive for this compound. Phosphonic acid was found in concentrations ranging from 0.12 to 3.2 mg kg-1 and 5% of the measurements were above the EU MRL of 2 mg kg-1. The results emphasise the quality control of fruits produced in this region.

Third-Generation Transdermal Delivery Systems Containing Zidovudine: Effect of the Combination of Different Chemical Enhancers and a Microemulsion System.

This study aimed to examine the influence of the combination of chemical enhancers and a microemulsion on the transdermal permeation of zidovudine (AZT). Ethanol, 1,8-cineole, and geraniol were incorporated in a microemulsion. The droplet size, zeta potential, rheology, and SAXS analysis were performed. The permeation enhancer effect was evaluated using pig ear skin. Snake skin (Boa constrictor) treated with the formulations was also used as a stratum corneum model and studied by attenuated total reflectance-infrared spectroscopy. As a result, it was observed that the incorporation of the chemical enhancers promoted a decrease of the droplet size and some rheological modifications. The 1,8-cineole associated with the microemulsion significantly increased the permeated amount of AZT. Conversely, ethanol significantly increased the quantity of the drug retained in the skin. The probable mechanism for the cineole and ethanol effects was respectively: fluidization and increasing of the diffusion coefficient, and increasing of the partition coefficient. Surprising, geraniol + microemulsion drastically decreased both the permeated and the retained amount of AZT into the skin. Thus, the adequate association of microemulsion and chemical enhancers showed to be a crucial step to enable the topical or transdermal use of drugs.

Levobupivacaine Thermogel for Long-acting Analgesia.

The adequate management of analgesia, by pharmacological methods or not, is a great challenge. Local anesthetics are used for pain relief, mainly by parenteral, intramuscular, catheter, and other routes of administration. The use of in situ forming systems becomes an alternative for the control of pain. The present research investigates development of thermogels containing poloxamer and levobupivacaine. All formulations were prepared by the cold method; the compatibilities of the excipients were evaluated by DSC, rheology and viscosities, transition temperature, syringeability, release kinetics, and permeation. The compatibility of the tested excipients with the drug was initially observed; all formulations had a viscosity increase at 37°C. Different delivery rates were observed in both the release and permeation studies. The developed systems maintained the in vitro release of the drug for a long period, likely decreasing side effects in vivo and avoiding the need for supplementary analgesia by other routes.

Microemulsion Formulations for the Transdermal Delivery of Lapachol.

This project was carried out to investigate the feasibility of using microemulsions for transdermal delivery of lapachol. From the screening of surfactants and oils, a range of microemulsions were developed using oleic acid, a mixture of Cremophor EL and Tween 20 and water. The solubility of lapachol was determined in these ingredients and in the formulated microemulsions. The microemulsions were characterised using cross-polarising light microscopy, their electrical conductivity, pH, zeta potential and rheology were analysed, and they were also investigated using small-angle X-ray scattering and differential scanning calorimetry. Ex vivo studies were performed using porcine ear skin and Franz diffusion cells to investigate the permeation and retention of lapachol. Systems containing different concentrations of Cremophor EL (8.4-41.6%), Tween 20 (5.4-41.6%) and oleic acid (12-31.9%) are able to form microemulsions. Lapachol was delivered more effectively through the skin from all of the microemulsions tested than by the control (oleic acid). These studies indicated that microemulsions incorporating lapachol were formed successfully and that these enhanced drug delivery and retention in the skin. Microemulsion systems may, therefore, provide promising vehicles for percutaneous delivery of lapachol.

Topical bio(in)equivalence of metronidazole formulations in vivo.

The topical bioavailabilities of metronidazole from a commercially available 'reference' product (Rozex®) and two extemporaneous test formulations were compared. With the reference drug product, a full skin pharmacokinetic profile, in vivo in human volunteers (following a 6-h uptake and clearance over the subsequent 22 h), was obtained using an improved stratum corneum (SC) sampling procedure. Then, a two-time point SC sampling method enabled the bio(in)equivalence of the test formulations to Rozex® to be evaluated. One test formulation was shown to be bioequivalent to Rozex®, both for uptake and clearance, whereas the other (more viscous and less spreadable) formulation was not. The delivery of metronidazole into the underlying viable epidermal tissue from Rozex® and from the equivalent test formulation was 2.5 to 3.5-fold higher than that from the inequivalent extemporaneous vehicle. The results highlight that the quantitative composition of a formulation, as well as its physical properties that influence events that take place at the vehicle-skin interface, can have a dramatic impact on the delivery of drug into the SC and subsequently to the viable skin layers below. The reproducible, sensitive and facile in vivo methodology employed may prove of particular value where regulatory approval of generic formulations lacks objective rigour.

Metronidazole thermogel improves retention and decreases permeation through the skin

ABSTRACT Metronidazole (MTZ) is widely used as the standard antibiotic for the treatment of rosacea and, more recently, is being used off label in Brazilian hospitals for the treatment of wounds. Following oral administration, minimal amounts of active agent reaches the skin and side effects are strongly induced. Consequently, MTZ is currently being applied topically in order to improve the therapeutic efficacy with reduced side effects, with Rozex(r) (RZ) (an MTZ gelled formulation) being the only marketed product. This study examined whether the use of MTZ 0.75% from thermogel formulations could improve drug retention and reduce dermal exposure compared to that by Rozex(r). Following a 21 h permeation study, the highest total amount of MTZ permeated through the rat healthy and disturbed skin was seen with Rozex(r), but similar to all formulations regardless of the skin condition. On the other hand, the amount retained in the epidermis/dermis was larger for thermogel formulations; at least 4 fold that of Rozex(r), when the stratum corneum was present as a barrier. In conclusion, thermogel formulations can be favorable alternatives to Rozex(r) for the topical application of MTZ with improved efficacy and reduced side effects.

Evaluation of Microemulsion and Lamellar Liquid Crystalline Systems for Transdermal Zidovudine Delivery.

This study proposed to investigate and to compare colloidal carrier systems containing Zidovudine (3'-azido-3'-deoxythymidine) (AZT) for transdermal administration and optimization of antiretroviral therapy. Microemulsion (ME) and lamellar phase (LP) liquid crystal were obtained and selected from pseudoternary diagrams previously developed. Small-angle X-ray scattering and rheology analysis confirmed the presence of typical ME and liquid crystalline structures with lamellar arrangement, respectively. Both colloidal carrier systems, ME, and LP remained stable, homogeneous, and isotropic after AZT addition. In vitro permeation study (using pig ear skin) showed that the amount of permeated drug was higher for ME compared to the control and LP, obtaining a permeation enhancing effect on the order of approximately 2-fold (p < 0.05). Microscopic examination after in vivo skin irritation studies using mice suggested few histological changes in the skin of animals treated with the ME compared to the control group (hydrogel). Thus, ME proved to be adequate and have promising effects, being able to promote the drug permeation without causing apparent skin irritation. On the order hand, LP functioned as a drug reservoir reducing AZT partitioning into the skin.

Desenvolvimento e validação de metodologias analíticas para quantificação de um derivado tiofênico em sistemas microemulsionados / Development and validation of analytical methodologies for measurement of a tiophene derivative in microemulsion systems

O presente trabalho teve por objetivo validar métodos por espectrofotometria UV-Vis e por CLAE para a análise quantitativa de um derivado do tiofeno, o 2-[(3,4-dicloro-benzilideno)-amino]-5,6-diidro-4H-ciclopen-ta[b]tiofeno-3-carbonitrila (5CN05) e aplicá-los no doseamento da molécula contida em microemulsões, Os métodos propostos foram validados conforme a Resolução 899/2003 da Agência Nacional de Vigilância Sanitária (ANVISA), O comprimento de onda de máxima absorção do fármaco 5CN05 foi detectado em λ max= 387nm, O método espectrofotométrico validado mostrou-se seletivo, apresentando linearidade na faixa de 3 a 16 µg.mL-1, coeficiente de correlação (r) igual a 0,9998 e limites de detecção e quantificação de 0,12 µg.mL-1 e 0,41 µg.mL-1, respectivamente, Para o método CLAE, observou-se linearidade na faixa de 0,1 a 3,0 µg.mL-1, r = 0,99915, limites de detecção e quantificação de 0,07 µg.mL-1 e 0,10 µg.mL-1 respectivamente, Para ambos os métodos, os parâmetros precisão, exatidão e robustez mostraram-se adequados para o uso pretendido, As metodologias propostas podem ser seguramente aplicadas para quantificação do 5CN05 em produtos farmacêuticos como microemulsões...

This study aims to validate methods of Uv-Vis) and HPLC for quantitative determination of a thiophene derivative, 2 - [(3,4-dichloro -benzylidene)-amino] -5,6-dihydro-4H-cyclopentyl-ta [b] thiophene-3- carbonitrile referred in this study as 5CN05, and apply them to quantify the 5CN05 in microemulsions. The proposed methods were validated according to the Resolution RE 899/2003 of the National Health Surveillance Agency (ANVISA). The 5CN05 was detected by UV-Vis at λ max= 387nm. The validated UVVis UVVis method proved to be selective, showing linearity in the range of 3-16 µg.mL-1, correlation coefficient (r) of 0.9998 and limits of detection and quantification of 0.12 µg.mL-1 and 0.41 µg.mL-1 respectively. For the CLAE method the linearity was observed in the range 0.1 to 3.0 µg.mL-1, r = 0.99915, limits of detection and quantification of 0.07 µg.mL-1 and 0.10 µg.mL-1 respectively. For both UV-Vis and CLAE methods, the precision parameters, accuracy and robustness were adequate for the intended use. The proposed methodologies can be safely applied to quantify the 5CN05 in pharmaceutical microemulsions products...