Intranasal delivery of zidovudine by PLA and PLA-PEG blend nanoparticles

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

Biodisponibilidade relativa do ferro de fonte orgânica para leitões desmamados

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Avaliação da biodisponibilidade relativa entre betaína e metionina para frangos de corte

Três experimentos foram conduzidos com linhagens comerciais de frangos de corte em baterias metálicas para determinar a biodisponibilidade relativa de duas fontes de grupamentos metílicos (metionina e betaína). A dieta basal (controle) foi formulada com milho e farelo de soja, contendo 1.896, 1.969 e 2.010 mg/kg de colina no experimento I, II e III, respectivamente. Os níveis suplementados em betaína e metionina foram isomolar. O experimento I (fêmeas até 21 dias de idade) constou de seis níveis de metionina (0; 5,36; 10,72; 16,08; 21,45; 32,17 mMol/kg) e dois níveis de betaína (0 e 5.36 mMol/kg). No experimento II (machos até 21 dias de idade) a dieta controle foi suplementada com 0; 2,68; 5,36; 8,04; 10,72; 13,40 mMol/kg de metionina ou 0; 2,68; 5,36; 8,04; 10,72; 13,40 mMol/kg de betaína. Em relação ao experimento III (machos até 21 anos de idade) houve quatro níveis de metionina (0; 8,04; 10,72 e 13,40 mMol) e três níveis de betaína (0; 6,7 e 13,4 mMol). Para o experimento I e III foram utilizados quatro repetições de oito aves para cada tratamento. O experimento II apresentou quatro repetições para cada tratamento e oito repetições para o grupo controle, apresentando também oito aves por parcela experimental. Foi constatado para os experimentos I, II e III que os valores de inclinação da curva pra a betaína e metionina foram significativos para o peso corporal e conversão alimentar. No experimento III somente o valor de inclinação para a curva da metionina foi significativo, em relação ao consumo alimentar. No experimento III somente o valor de inclinação para a curva da metionina foi significativo, em relação ao consumo alimentar. Nem a metionina ou a betaína diminuíram a gordura abdominal em nenhum dos experimentos. Em média, os dados do experimento II e III indicaram que a biodisponibilidade relativa...

Regulamentação Sanitária de Medicamentos

A regulamentação sanitária de medicamentos é uma das oito diretrizes da Política Nacional de Medicamentos. Trata-se da fiscalização e regulamentação de registro de medicamentos e da autorização de funcionamento desde os produtores até o varejo de medicamentos, bem como das restrições àqueles sujeitos a controle especial. A regulamentação sanitária de medicamentos tem como objetivo garantir eficácia, segurança, qualidade e custo aos produtos farmacêuticos. Os estudos clínicos dos medicamentos de Referência, a bioequivalência ou biodisponibilidade relativa e testes de equivalência dos medicamentos similares e genéricos são meios de avaliar a eficácia e a segurança. A qualidade é garantida lote a lote pelas Boas Práticas de Fabricação e Controle dos produtos farmacêuticos e a certificação da empresa pela ANVISA. O custo é avaliado pela câmara técnica de medicamento (CMED), que estabelece os critérios para fixação e ajuste de preços dos produtos farmacêuticos. No pós-registro, a efetividade, segurança e qualidade dos produtos são avaliadas por meio das comprovações exigidas na renovação do registro e, principalmente, pelo programa de farmacovigilância. Palavras-chave: Registro de Produtos. Medicamentos de Referência. Medicamentos Similares. Medicamentos Genéricos. Alteração de Registro de Produtos. ABSTRACT Health Regulations for Drugs The health regulation of drugs is one of eight guidelines issued within the National Drug Policy. It refers to the supervision and regulation of drug registration and the approval of operations, from the manufacturers to the retailers of medicines, as well as the restrictions that apply to drugs under special control. The health regulation of medicines is aimed at controlling the effectiveness, safety, quality and cost of pharmaceutical products. Clinical studies of brand-name (innovator) medicines, bioequivalence or relative bioavailability and the equivalence tests of generic and ‘similar’ brand-name drugs are means used to assess efficacy and safety. Quality is assured on a batch-to-batch basis by compliance with the Good Manufacturing Practices and Control of pharmaceutical products and by the certification of companies offered by ANVISA. The cost of a medicine is assessed by the Technical Chamber of Medicine (CMED), which establishes the criteria for setting and adjusting the prices of pharmaceutical products. After registration, the effectiveness, safety and quality of products are monitored by means of the tests required on renewal of registration and especially by the pharmacovigilance program. Keywords: Product Registration. Original Brand-name Drugs. Similar Drugs. Generic Drugs. Modification of Product Registration.

Farmacocinética do Benznidazol administrado em coelhos na forma de comprimidos de liberação imediata e comprimidos de liberação prolongada

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

Lamivudine salts with improved solubilities

To optimize solubility of drugs, current strategies mainly focus on engineering and screening of smart crystal phases. Two salts of the anti-human immunodeficiency virus (HIV) drug lamivudinenamely, lamivudine hydrochloride and lamivudine hydrochloride monohydrate, were prepared in the course of screening the crystallization conditions of lamivudine duplex, an uncommon DNA-mimic, double-stranded helical structure made up of partially protonated drug pairs. Here, water solubilities of lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex are reported. The aqueous solubility of this anti-HIV drug was significantly increased in both salts and also in lamivudine duplex in relation to the water solubility of lamivudine form II. In comparison with the lamivudine form II incorporated into therapeutic formulations, the drug solubility was increased at a temperature of 299 +/- 2 K by factors of 1.2, 3.3, and 4.5 in lamivudine hydrochloride, lamivudine hydrochloride monohydrate, and lamivudine duplex, respectively, demonstrating that this solid-state property of lamivudine can be improved by crystal engineering strategies. Solubility profiles were understood on the basis of structural and solventsolute interaction approaches. At last, correlations between solubility and crystal structures allowed for a rational approach to understand how this physicochemical feature could be enhanced by engineering new salts of the drug. (C) 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:21432154, 2012

Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

A D-optimal designed population pharmacokinetic study of itraconazole capsules and solution in adults with cystic fibrosis

Background: Oral itraconazole (ITRA) is used for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis (CF) because of its antifungal activity against Aspergillus species. ITRA has an active hydroxy-metabolite (OH-ITRA) which has similar antifungal activity. ITRA is a highly lipophilic drug which is available in two different oral formulations, a capsule and an oral solution. It is reported that the oral solution has a 60% higher relative bioavailability. The influence of altered gastric physiology associated with CF on the pharmacokinetics (PK) of ITRA and its metabolite has not been previously evaluated. Objectives: 1) To estimate the population (pop) PK parameters for ITRA and its active metabolite OH-ITRA including relative bioavailability of the parent after administration of the parent by both capsule and solution and 2) to assess the performance of the optimal design. Methods: The study was a cross-over design in which 30 patients received the capsule on the first occasion and 3 days later the solution formulation. The design was constrained to have a maximum of 4 blood samples per occasion for estimation of the popPK of both ITRA and OH-ITRA. The sampling times for the population model were optimized previously using POPT v.2.0.[1] POPT is a series of applications that run under MATLAB and provide an evaluation of the information matrix for a nonlinear mixed effects model given a particular design. In addition it can be used to optimize the design based on evaluation of the determinant of the information matrix. The model details for the design were based on prior information obtained from the literature, which suggested that ITRA may have either linear or non-linear elimination. The optimal sampling times were evaluated to provide information for both competing models for the parent and metabolite and for both capsule and solution simultaneously. Blood samples were assayed by validated HPLC.[2] PopPK modelling was performed using FOCE with interaction under NONMEM, version 5 (level 1.1; GloboMax LLC, Hanover, MD, USA). The PK of ITRA and OH‑ITRA was modelled simultaneously using ADVAN 5. Subsequently three methods were assessed for modelling concentrations less than the LOD (limit of detection). These methods (corresponding to methods 5, 6 & 4 from Beal[3], respectively) were (a) where all values less than LOD were assigned to half of LOD, (b) where the closest missing value that is less than LOD was assigned to half the LOD and all previous (if during absorption) or subsequent (if during elimination) missing samples were deleted, and (c) where the contribution of the expectation of each missing concentration to the likelihood is estimated. The LOD was 0.04 mg/L. The final model evaluation was performed via bootstrap with re-sampling and a visual predictive check. The optimal design and the sampling windows of the study were evaluated for execution errors and for agreement between the observed and predicted standard errors. Dosing regimens were simulated for the capsules and the oral solution to assess their ability to achieve ITRA target trough concentration (Cmin,ss of 0.5-2 mg/L) or a combined Cmin,ss for ITRA and OH-ITRA above 1.5mg/L. Results and Discussion: A total of 241 blood samples were collected and analysed, 94% of them were taken within the defined optimal sampling windows, of which 31% where taken within 5 min of the exact optimal times. Forty six per cent of the ITRA values and 28% of the OH-ITRA values were below LOD. The entire profile after administration of the capsule for five patients was below LOD and therefore the data from this occasion was omitted from estimation. A 2-compartment model with 1st order absorption and elimination best described ITRA PK, with 1st order metabolism of the parent to OH-ITRA. For ITRA the clearance (ClItra/F) was 31.5 L/h; apparent volumes of central and peripheral compartments were 56.7 L and 2090 L, respectively. Absorption rate constants for capsule (kacap) and solution (kasol) were 0.0315 h-1 and 0.125 h-1, respectively. Comparative bioavailability of the capsule was 0.82. There was no evidence of nonlinearity in the popPK of ITRA. No screened covariate significantly improved the fit to the data. The results of the parameter estimates from the final model were comparable between the different methods for accounting for missing data, (M4,5,6)[3] and provided similar parameter estimates. The prospective application of an optimal design was found to be successful. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but still at times that were near optimal for estimating the popPK parameters. The final model was one of the potential competing models considered in the original design. The asymptotic standard errors provided by NONMEM for the final model and empirical values from bootstrap were similar in magnitude to those predicted from the Fisher Information matrix associated with the D-optimal design. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily (bd) would provide a target Cmin,ss (0.5-2 mg/L) for only 35% of patients when administered as the solution and 31% when administered as capsules. The optimal dosing schedule was 500mg bd for both formulations. The target success for this dosing regimen was 87% for the solution with an NNT=4 compared to capsules. This means, for every 4 patients treated with the solution one additional patient will achieve a target success compared to capsule but at an additional cost of AUD $220 per day. The therapeutic target however is still doubtful and potential risks of these dosing schedules need to be assessed on an individual basis. Conclusion: A model was developed which described the popPK of ITRA and its main active metabolite OH-ITRA in adult CF after administration of both capsule and solution. The relative bioavailability of ITRA from the capsule was 82% that of the solution, but considerably more variable. To incorporate missing data, using the simple Beal method 5 (using half LOD for all samples below LOD) provided comparable results to the more complex but theoretically better Beal method 4 (integration method). The optimal sparse design performed well for estimation of model parameters and provided a good fit to the data.

Paediatric population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in cystic fibrosis and bone marrow transplant patients

Objectives: The aim of the study was to characterise the population pharmacokinetics (popPK) properties of itraconazole (ITRA) and its active metabolite hydroxy-ITRA in a representative paediatric population of cystic fibrosis (CF) and bone marrow transplant (BMT) patients. The goals were to determine the relative bioavailability between the two oral formulations, and to explore improved dosage regimens in these patients. Methods: All paediatric patients with CF taking oral ITRA for the treatment of allergic bronchopulmonary aspergillosis and patients undergoing BMT who were taking ITRA for prophylaxis of any fungal infection were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. ITRA and hydroxy-ITRA plasma concentrations were measured by HPLC[1]. A nonlinear mixed-effect modelling approach (NONMEM 5.1.1) was used to describe the PK of ITRA and hydroxy-ITRA simultaneously. Simulations were used to assess dosing strategies in these patients. Results: Forty-nine patients (29CF, 20 BMT) were recruited to the study who provided 227 blood samples for the population analysis. A 1-compartment model with 1st order absorption and elimination best described ITRA kinetics, with 1st order conversion to hydroxy-ITRA. For ITRA, the apparent clearance (ClItra/F) and volume of distribution (Vitra/F) was 35.5L/h and 672L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h-1 and for the oral solution formulation it was 0.959 h-1. The capsule comparative bioavailability (vs. solution) was 0.55. For hydroxy-ITRA, the apparent volume of distribution and clearance were 10.6 L and 5.28 L/h, respectively. Of several screened covariates only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. Conclusion: The developed popPK model adequately described the pharmacokinetics of ITRA and hydroxy-ITRA in paediatric patients with CF and patients undergoing BMT. High inter-patient variability confirmed previous data in CF[2], leukaemia and BMT[3] patients. From the population model, simulations showed the standard dose (5 mg/kg/day) needs to be doubled for the solution formulation and even 4 times more given of the capsules to achieve an adequate target therapeutic trough plasma concentration of 0.5 mg/L[4] in these patients.

Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery

The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump(EOP)tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two factor, three level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the elementary osmotic pump (EOP) tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo

Nutritional strategies to modulate metabolism and heat stress resilience in dairy cattle

Physiological and environmental stressors can disrupt barrier integrity at epithelial interfaces (e.g., uterine, mammary, intestinal, and lung), which are constantly exposed to pathogens that can lead to the activation of the immune system. Unresolved inflammation can result in the emergence of metabolic and infectious diseases. Maintaining cow health and performance during periods of immune activation such as in the peripartum or under heat stress represents a significant obstacle to the dairy industry. Feeding microencapsulated organic acids and pure botanicals (OAPB) has shown to improve intestinal health in monogastric species and prevent systemic inflammation via the gut-liver axis. Feeding unsaturated fatty acids (FA) such as oleic acid (OA) and very-long-chain omega-3 (VLC n-3) FA are of interest in dairy cow nutrition because of their potential to improve health, fertility, and milk production. In the first study, we evaluated the effects of heat stress (HS) conditions and dietary OAPB supplementation on gut permeability and milk production. In parallel with an improved milk performance and N metabolism, cows supplemented with OAPB also had an enhanced hepatic methyl donor status and greater inflammatory and oxidative stress status compared to the HS control group. In a second study, we evaluated the relative bioavailability of VLC n-3 in cows fed a bolus of rumen-protected (RP) fish oil (FO). In a third study, we proved the interaction between RPFO and RP choline to promote the synthesis of phosphatydilcholines. Lipid forms that support hepatic triglyceride export and can prevent steatosis in dairy cows. The last study, demonstrated that algae oil outperforms against a toxin challenge compared to FO and that feeding RPOA modulates energy partitioning relative to n-3 FA-containing oils. Overall, this thesis confirms the need and the effectiveness of different strategies that aimed to improve dairy cows’ health and performance under heat stress, inflammation or metabolic disease.

Relative proportions of polycyclic aromatic hydrocarbons differ between accumulation bioassays and chemical methods to predict bioavailability

Chemical methods to predict the bioavailable fraction of organic contaminants are usually validated in the literature by comparison with established bioassays. A soil spiked with polycyclic aromatic hydrocarbons (PAHs) was aged over six months and subjected to butanol, cyclodextrin and tenax extractions as well as an exhaustive extraction to determine total PAH concentrations at several time points. Earthworm (Eisenia fetida) and rye grass root (Lolium multiflorum) accumulation bioassays were conducted in parallel. Butanol extractions gave the best relationship with earthworm accumulation (r2 ≤ 0.54, p ≤ 0.01); cyclodextrin, butanol and acetone–hexane extractions all gave good predictions of accumulation in rye grass roots (r2 ≤ 0.86, p ≤ 0.01). However, the profile of the PAHs extracted by the different chemical methods was significantly different (p < 0.01) to that accumulated in the organisms. Biota accumulated a higher proportion of the heavier 4-ringed PAHs. It is concluded that bioaccumulation is a complex process that cannot be predicted by measuring the bioavailable fraction alone. The ability of chemical methods to predict PAH accumulation in Eisenia fetida and Lolium multiflorum was hindered by the varied metabolic fate of the different PAHs within the organisms.

Iron bioavailability from ferric pyrophosphate in rats fed with fructan-containing yacon (Smallanthus sonchifolius) flour

The effects of inulin-type fructans (ITF)-containing yacon flour (YF) on Fe bioavailability from ferric pyrophosphate (FP) were evaluated in Fe-deficient rats using the Hb repletion efficiency (HRE) assay. Weanling male Wistar rats were fed a low-Fe diet (12 mg/kg) for 15 days followed by 2 weeks of Fe repletion with diets providing 35 mg Fe/kg as either ferrous sulphate (FS) or FP, supplemented with 7.5% ITF as either YF or Raftilose (RAF), a purified ITF. ITF increased caecal fermentation, whereas YF was more butyrogenic than RAF. ITF improved FIRE in FP-fed rats, and those fed YF had a higher relative biological value compared with those fed FP and RAF. Liver Fe was increased by ITF, but only YF led to values similar to those in the FS group. It is observed that ITF increased caecal fermentation and Fe bioavailability. These effects were more pronounced when YF was the ITF source. (C) 2010 Elsevier Ltd. All rights reserved.

Speciation and absolute bioavailability: risk assessment of arsenic-contaminated sites in a residential suburb in Canberra

Watson is a fully developed suburb of some 30 years in Canberra (the capital city of Australia), A plunge dip using arsenical pesticides for tick control was operated there between 1946 and 1960, Chemical investigations revealed that many soil samples obtained from the study area contained levels of arsenic exceeding the current health-based investigation levels of 100 mg kg(-1) set by the National Health and Medical Research Council in Australia, For the speciation study, nine composite samples of surface and sub-surface soils and a composite sample of rocks were selected. ICP-MS analysis showed that arsenic levels in these samples ranged from 32 to 1597 mg kg(-1), Chemical speciation of arsenic showed that the arsenite (trivalent) components were 0.32-56% in the soil and 44.8% in the rock composite samples. Using a rat model, the absolute bioavailability of these contaminated soils relative to As3+ or As5+ ranged from 1.02 to 9.87% and 0.26 to 2.98%, respectively, An attempt was made to develop a suitable leachate test as an index of bioavailability. However, the results indicated that there was no significant correlation between the bioavailability and leachates using neutral pH water or 1 M HCl. Our results indicate that speciation is highly significant for the interpretation of bioavailability and risk assessment data; the bioavailable fractions of arsenic in soils from Watson are small and therefore the health impact upon the environment and humans due to this element is limited.

Extracellular superoxide dismutase is a major determinant of nitric oxide bioavailability: in vivo and ex vivo evidence from ecSOD-deficient mice.

The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O2.-). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O2.- is unknown. We determined the involvement of ecSOD in the control of blood pressure and endothelium-dependent responses in angiotensin II-induced hypertension and renovascular hypertension induced by the two-kidney, one-clip model in wild-type mice and mice lacking the ecSOD gene. Blood pressure was identical in sham-operated ecSOD+/+ and ecSOD-/- mice. After 6 days of angiotensin II-treatment and 2 and 4 weeks after renal artery clipping, blood pressure was significantly higher in ecSOD-/- than ecSOD+/+ mice. Recombinant ecSOD selectively decreased blood pressure in hypertensive ecSOD-/- mice, whereas ecSOD had no effect in normotensive and hypertensive ecSOD+/+ mice. Compared with sham-operated ecSOD+/+ mice, sham-operated ecSOD-/- mice exhibited attenuated acetylcholine-induced relaxations. These responses were further depressed in vessels from clipped animals. Vascular O2.-, as measured by lucigenin chemiluminescence, was higher in ecSOD-/- compared with ecSOD+/+ mice and was increased by clipping. The antioxidant tiron normalized relaxations in vessels from sham-operated and clipped ecSOD-/-, as well as from clipped ecSOD+/+ mice. In contrast, in vivo application of ecSOD selectively enhanced endothelium-dependent relaxation in vessels from ecSOD-/- mice. These data reveal that endogenous ecSOD is a major antagonistic principle to vascular O2.-, controlling blood pressure and vascular function in angiotensin II-dependent models of hypertension. ecSOD is expressed in such an abundance that even in situations of high oxidative stress no relative lack of enzyme activity occurs.