Abstract Inborn errors of metabolism are rare disorders with few therapeutic options for their treatments, which can make patients suffer with complications. Therefore, compounded drugs might be a promising option given that they have the ability of meeting the patient’s specific needs, (i) identification of the main drugs described in the literature; (ii) proposal of compounding systems and (iii) calculation of the budgetary addition for the inclusion of these drugs into the Brazilian Unified Health System. The research conducted a literature review and used management data as well as data obtained from official Federal District government websites. The study identified 31 drugs for the treatment of inborn errors of metabolism. Fifty eight percent (58%) (18) of the medicines had their current demand identified, which are currently unmet by the local Health System. The estimated budget for the production of compounded drugs was of R$363,16.98 per year for approximately 300 patients. This estimated cost represents a budgetary addition of only 0.17% from the total of expenditures planned for drug acquirement. There is a therapeutic gap for inborn errors of metabolism and compounding pharmacies show potential in ensuring access to medicine therapy with a low-cost investment. treatments complications Therefore patient s needs i (i ii (ii iii (iii System websites 3 58% 58 (58% 18 (18 R3631698 R 363 16 98 R$363,16.9 30 017 0 17 0.17 acquirement lowcost low investment 5 (58 1 (1 R363169 36 9 R$363,16. 01 0.1 (5 ( R36316 R$363,16 0. R3631 R$363,1 R363 R$363, R36 R$363 R3 R$36 R$3 R$

Abstract The toxic effects of venlafaxine (VLX) on aquatic organisms have already been verified and therefore are a proven matter of concern. Herein, we evaluated zebrafish embryos/adults after acute exposure to VLX. Embryos/larvae were exposed to different concentrations of VLX (100-1000 mg/L; 1.33 as a dilution factor), to evaluate mortality/developmental changos and to analyze biomarkers (0.002-100 mg/L). For adults, mortality, genotoxicity, and biomarkers were assessed in five different concentrations of VLX (1-100 mg/L). The median lethal concentration (LC50-168h) was 274.1 mg/L for embryos/larvae, and >100 mg/L for adults (LC50-96h). VLX decreased the heart rate frequency and caused premature hatching and lack of equilibrium in embryos/larvae exposed to different concentrations ranging from 100 to 562.5 mg/L. The activity of acetylcholinesterase (AChE) was inhibited in larvae exposed to 1, 25 and 100 mg/L. Glutathione-S-transferase (GST) activity was reduced in both larvae and adults after exposure to different concentrations, mainly at 25 mg/L. For both larvae and adults, lactate dehydrogenase (LDH) activity increased after 100 mg/L of VLX exposure. No DNA damage was observed in peripheral erythrocytes. Exposure to VLX may cause adverse effects on zebrafish in their early and adult life stages, interfering with embryo-larval development, and can induce physiological disturbances in adults. (VLX concern Herein embryosadults embryos Embryoslarvae Embryos 1001000 1000 (100-100 mgL mg L 133 1 33 1.3 factor, factor , factor) mortalitydevelopmental mortality developmental 0.002100 0002100 0.002 0 002 (0.002-10 . mg/L) genotoxicity 1100 (1-10 LC50168h LCh LC50 168h LC h (LC50-168h 2741 274 274. embryoslarvae >10 LC5096h. LC5096h 96h (LC50-96h) 10 5625 562 5 562. AChE (AChE 2 GlutathioneStransferase Glutathione S transferase GST (GST LDH (LDH erythrocytes stages embryolarval embryo larval development 100100 (100-10 13 3 1. 002100 0.00210 000210 0002 0.00 00 (0.002-1 110 (1-1 LC5 27 >1 (LC50-96h 56 10010 (100-1 00210 0.0021 00021 000 0.0 (0.002- 11 (1- > 1001 (100- 0021 0. (0.002 (1 (100 (0.00 ( (10 (0.0 (0. (0

Abstract In our study, we aimed to validate a method based on liquid chromatography-mass spectrometry (LC-MS) to quantify spironolactone (SPI) and its active metabolite canrenone (CAN) simultaneously in plasma samples to support in vivo experiments. Compounds were separated by using a C18 column with the isocratic elution of a mobile phase composed of 0.1% (v/v) formic acid in methanol-water (60:40 v/v) at a flow rate of 0.4 mL min−1. SPI and CAN were detected in na electrospray interface operating in a positive ionization mode and quantified using the selective ion mode monitoring of mass-charge ratios (m/z) of 439.0 for SPI and 363.1 for CAN. After calculating the matrix effect using theoretical equations, we observed the strong interference of plasma in the equipment-generated signal, which required creating analytical curves using the matrix as a solvent. The method was nevertheless linear (r 2 > 0.999) in a concentration range of 0.4-5.0 μg mL−1, as well as precise, with a coefficient of variation less than 5%. SPI’s and CAN’s recovery rates from the plasma ranged from 87.4% to 112.1%, while their limits of detection (i.e., 0.07 μg mL−1 and 0.03 μg mL−1, respectively) and quantification (i.e., 0.20 μg mL−1 and 0.08 μg mL−1, respectively) in the presence of plasma contaminants were low. Therefore, the bioanalytical method seems to be feasible for quantifying SPI and CAN in plasma. study chromatographymass chromatography mass LCMS LC MS (LC-MS (SPI (CAN experiments C C1 01 0 1 0.1 v/v vv v (v/v methanolwater methanol water 6040 60 40 (60:4 04 4 0. min1 min min−1 masscharge charge m/z mz m z (m/z 4390 439 439. 3631 363 363. equations equipmentgenerated equipment generated signal solvent r 0.999 0999 999 0.45.0 0450 5.0 5 0.4-5. mL1 precise 5% SPIs s CANs 874 87 87.4 1121 112 112.1% i.e., ie i e (i.e. 007 07 0.0 mL− 003 03 respectively 020 20 0.2 008 08 low Therefore 604 6 (60: min− 43 36 0.99 099 99 45 0.45. 045 50 5. 0.4-5 8 87. 11 112.1 i.e. (i.e 00 02 (60 3 0.9 09 9 0.45 0.4- 112. i.e (6 (

In general, topical ophthalmic drug products, especially those used for treating infections, present low effectiveness because of various reasons, from unfavorable drug physicochemical properties to physiological protective mechanisms of the eye. The fact is such group of products holds room for improvement, which could mean the development of better drugs or dosage forms. To achieve this, the knowledge of market composition is essential. The present work studied and compared the antimicrobial ophthalmic markets of Brazil and of the United States (US). Official databank of Brazilian Health Regulatory Agency and of US Food and Drug Administration were assessed for registered antimicrobial topical ophthalmic drug products. Brazilian market has registered greater number of drug products (119) than the US (94), but the latter involves more variety of substances and dosage forms. In both countries, non-innovative products registered as solutions of antibacterials, especially fluoroquinolones and aminoglycosides lead the market. Despite the clinical demand, the US has only one group of antimycotics (polyenes) registered, while in Brazil, there is not any ophthalmic antimycotic product marketed. This study evidences there is not only space for development of newer drugs and formulations but also a demand for already existing technologies and products in both countries.

A avaliação comparativa exigida para registro das formulações tópicas genéricas no Brasil é feita por meio do estudo de equivalência farmacêutica que avalia apenas os parâmetros físico-químicos e microbiológicos dos medicamentos. Internacionalmente, estudos clínicos ou farmacodinâmicos vêm sendo exigidos para comprovar a eficácia e a segurança das formulações genéricas tópicas semissólidas. Este trabalho apresenta uma comparação entre os diferentes requerimentos para registro de uma formulação tópica, considerando diferentes autoridades regulatórias, e faz um levantamento dos produtos tópicos dermatológicos registrados no Brasil até 2013. Tal levantamento demonstrou haver uma grande quantidade de cópias desse tipo de formulação no Brasil em comparação com os EUA. Este fato, associado à grande quantidade de estudos encontrados na literatura demonstrando bioinequivalência de medicamentos tópicos, evidencia a grande importância de uma readequação da legislação brasileira no que se refere aos requisitos técnicos para o registro de medicamentos genéricos e similares de aplicação tópica dermatológica no Brasil.

The comparative evaluation required for the registration of generic topical medicines in Brazil is conducted by means of a pharmaceutical equivalence study, which merely assesses the physical/chemical and microbiological parameters of the formulations. At the international level, clinical or pharmacodynamic studies are now being required to prove the efficacy and safety of semisolid topical generic formulations. This work presents a comparison of the different requirements for the registration of topical formulations, taking into consideration the various regulatory authorities, and presents a survey of topical medicines registered in Brazil prior to 2013. The survey revealed that in comparison with the USA there were many more copies of these formulations registered in Brazil. This fact, together with the large number of studies in the literature showing the lack of bioequivalence of topical medication, is clear proof of the major importance of the need to realign Brazilian legislation with respect to the technical requirements for the registration of generic and similar medication for dermatological topical application in Brazil.

A avaliação comparativa exigida para registro das formulações tópicas genéricas no Brasil é feita por meio do estudo de equivalência farmacêutica que avalia apenas os parâmetros físico-químicos e microbiológicos dos medicamentos. Internacionalmente, estudos clínicos ou farmacodinâmicos vêm sendo exigidos para comprovar a eficácia e a segurança das formulações genéricas tópicas semissólidas. Este trabalho apresenta uma comparação entre os diferentes requerimentos para registro de uma formulação tópica, considerando diferentes autoridades regulatórias, e faz um levantamento dos produtos tópicos dermatológicos registrados no Brasil até 2013. Tal levantamento demonstrou haver uma grande quantidade de cópias desse tipo de formulação no Brasil em comparação com os EUA. Este fato, associado à grande quantidade de estudos encontrados na literatura demonstrando bioinequivalência de medicamentos tópicos, evidencia a grande importância de uma readequação da legislação brasileira no que se refere aos requisitos técnicos para o registro de medicamentos genéricos e similares de aplicação tópica dermatológica no Brasil.

The comparative evaluation required for the registration of generic topical medicines in Brazil is conducted by means of a pharmaceutical equivalence study, which merely assesses the physical/chemical and microbiological parameters of the formulations. At the international level, clinical or pharmacodynamic studies are now being required to prove the efficacy and safety of semisolid topical generic formulations. This work presents a comparison of the different requirements for the registration of topical formulations, taking into consideration the various regulatory authorities, and presents a survey of topical medicines registered in Brazil prior to 2013. The survey revealed that in comparison with the USA there were many more copies of these formulations registered in Brazil. This fact, together with the large number of studies in the literature showing the lack of bioequivalence of topical medication, is clear proof of the major importance of the need to realign Brazilian legislation with respect to the technical requirements for the registration of generic and similar medication for dermatological topical application in Brazil.

Physicochemical constraints severely limit the number of molecules that can be considered as candidates for transdermal delivery. Iontophoresis is a non-invasive technique in which a weak electric current is used to enhance the penetration of molecules into or through the skin. In this review the underlying mechanisms that drive iontophoresis and the impact of key experimental parameters - namely, formulation, drug concentration and pH - on iontophoretic delivery efficiency are discussed. In the final section some devices that are currently commercialized are also described.