Medicamentos off-label e não licenciados no âmbito pediátrico: uma revisão descritiva dos últimos dez anos / Off-label and unlicensed drugs in the pediatric field: a descriptive review of the last ten years

A falta de medicamentos contendo bulas prevendo o tratamento de pacientes pediátricos representa um problema frequentemente observado em hospitais, principalmente nos setores de unidade de terapia intensiva (UTI) pediátrica e neonatais. Sabe-se que, para que um tratamento seja considerado seguro e eficaz, uma série de estudos clínicos são necessários, no entanto, relata-se um baixo número dessas pesquisas envolvendo crianças, principalmente devido a questões éticas que dificultam a condução das mesmas. Assim, poucos são os medicamentos que provam ser adequados para o tratamento desses pacientes, tornando necessário recorrer ao uso de medicamentos off-label e não licenciados. Os medicamentos são classificados como off-label quando seu uso se dá de maneira que difere de suas especificações aprovadas, por sua vez, produtos não licenciados são classificados desta forma por não possuírem aprovação para sua comercialização no país ou não possuírem comprovação de segurança e eficácia. O preparo de protocolos de estudo organizados, relato de informações aos pais e à criança de maneira clara e objetiva, aproximação entre pesquisadores e pais para o estabelecimento de uma relação de confiança e a condução das pesquisas em momentos de disponibilidade da família demonstram-se estratégias importantes para facilitar a realização dos ensaios clínicos.

The lack of medicines containing drug information leaflets considering the treatment of pediatric patients is a problem frequently observed in hospitals, especially in the pediatric and neonatal intensive care unit (ICU) sectors. It is known that, for a treatment to be considered safe and effective, a series of clinical studies are necessary; however, a low number of these studies involving children are reported, mainly due to ethical issues that make conducting them difficult. Thus, few drugs prove to be suitable for treating these patients, making it necessary to resort to using off-label and unlicensed drugs. Drugs are classified as off-label when their use differs from their approved specifications, in turn, unlicensed products are classified in this way due to not having approval for marketing in the country or do not have proof of safety and efficacy. Preparation of organized study protocols, reporting information to parents and the child in a clear and objective way, bringing researchers and parents closer to establish a relationship of trust and conducting research at moments when the family is available are important strategies to facilitate conducting clinical trials.

Evaluation of physicochemical and microbiological stability of liquid preparation from tizanidine hydrochloride tablets - a Hospital concern

Tizanidine hydrochloride is a centrally acting skeletal muscle relaxant, used in the management of spasticity. This drug is commercially available only as tablets, which highlights the need to develop oral liquid formulations. In the hospital environment, this aspect is circumvented by the preparation of suspensions, to allow administration to children and adults with impaired swallowing, but there are no data regarding their stability. The purpose of this study was to evaluate the physicochemical andmicrobiological stability of liquid dosage forms prepared in the hospital environment from tizanidine hydrochloride tablets, applying high performance liquid chromatography (HPLC) and microbiological analysis. A simple and stability-indicating HPLC method was developed and validated for specificity, linearity, limits of detection and quantification, precision, accuracy and robustness. The liquid formulations were placed in amber PET and glass bottles, which were stored under three different conditions: at room temperature, under refrigeration and at 40 ºC. The liquid formulations were analyzed and demonstrated chemical stability for 56 days, allowing their use for long periods. However, the determination of microbiological stability showed that these formulations are prone to microbial contamination, which has dramatically reduced its stability to 7 days, in both bottles and at all evaluated temperatures

Development and Stability Control of Pediatric Oral Tizanidine Hydrochloride Formulations for Hospital Use.

Tizanidine hydrochloride is a centrally acting skeletal muscle relaxant used in the treatment of spasticity. This drug is sold only as tablets or capsules, which highlights the need to develop oral liquid formulations that allow administration to children and adults with impaired swallowing. This study aim was to develop and improve tizanidine hydrochloride liquid formulations from raw material and to evaluate their stability. A stability-indicating high performance liquid chromatography method was validated for two formulations developed. Fifteen formulations were developed containing syrup and fifteen containing sodium carboxymethyl cellulose as vehicles, to select the two most suitable for stability testing. The formulations were prepared in triplicate and placed in amber polyethylene terephthalate and glass bottles, which were stored under three different conditions: at room temperature (15-30°C), under refrigeration (2-8°C), and at 40°C. The physicochemical and microbiological stability of formulations were evaluated, applying high performance liquid chromatography and microbiological count. The studied formulations at 15-30°C, 2-8°C, and 40°C can be used for a period of 70 days, and all parameters are inside of recommended specifications, enough to allow its use in the context for which it was developed, the application in hospital. The formulations developed in this work have simple components to avoid adverse reactions in vulnerable populations. Results of this study could be applied as a reference for hospital use; once it demonstrated the reliability of storage time interval and proper conditions for use.

The application of quality by design in the development of the liquid chromatography method to determine empagliflozin in the presence of its organic impurities.

Analysis of impurities is an important step in the quality control of pharmaceutical ingredients and final products. From drug synthesis or excipients, even in small concentrations, impurities may affect efficacy and safety. The method was developed following Quality by Design (QbD) for the analysis of the antidiabetic empagliflozin. The concept of QbD is used as a tool for the development of methods and formulations. Through predefined objectives and risk analysis, robust methodologies and reduced solvent consumption are developed. A simple HPLC method was developed and validated for the quantitative determination of empagliflozin and its organic impurities from the synthesis process. The method was carried out in a Shim-pack phenyl column with a mobile phase consisting of an acetonitrile/water mixture (72 : 28), with isocratic elution and the detector wavelength was 230 nm. The validation process, in accordance with international guidelines, shows that the method was linear, precise and accurate for empagliflozin, impurity 1 and impurity 2. Limits of detection (0.01, 0.02 and 0.01 µg mL-1) and quantification (0.10, 0.10 and 0.05 µg mL-1) were determined for EMPA, IMP1 and IMP2, respectively. The HPLC method for impurity determination in empagliflozin was linear, precise, accurate and robust. It can be successfully applied in the quality control of empagliflozin and the synthesis of impurities, being adequate for routine analysis.

In vitro toxic evaluation of two gliptins and their main impurities of synthesis.

BACKGROUND: The presence of impurities in some drugs may compromise the safety and efficacy of the patient's treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). METHODS: MTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated. RESULTS: Cytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 µM of sitagliptin and 10 µM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations. CONCLUSIONS: This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

Development of a rapid HPLC method for quantification of the copper tetramibi tetraflourborate in a kit for preparation of Technetium 99 m Sestamibi Injection.

Radiopharmaceuticals are radioactive compounds that can be used for diagnostic and therapeutic purposes. Technetium (99mTc) Sestamibi is the most commercialized radiopharmaceutical in the world. It includes a coordination complex consisting of the radioisotope 99 m technetium bound to six copper tetramibi tetrafluorborate ligands, and is mainly used to image the myocardium via scintigraphy. As radiopharmaceuticals are regarded as drugs, they are subject to the same regulations; therefore, the objective of this study was to develop a quantification method for the active pharmaceutical ingredient before their complexation with the radioisotope by employing high-performance liquid chromatography (HPLC) methodology. A simple and efficient method (retention time = 2.5 min) was developed and validated for copper tetramibi tetrafluorborate in the final product using a buffer and organic solvent mixtures (ACN-methanol-ammonium sulfate buffer) and a C18 column. The analytical protocol was fast, taking around 30 min until evaluation of results. The validation parameters were evaluated with satisfactory results: in terms of linearity r > 0.99 (160-240 µg/mL) and no deviation was observed. The RSD of precision was <5%, and an average recovery of 99% was observed for accuracy. The proposed method was thus considered adequate for routine analysis in the pharmaceutical industries.

Stability of doripenem in reconstituted solution - thermal and oxidative decomposition kinetics and degradation products by LC-MS.

A ultra-fast liquid chromatography method applied to quantitation of doripenem in powder for injection was validated. Validation parameters were assayed and a rapid analysis was established by a reversed-phase system comprising a C18 column endcapped (50 × 4.0 mm, 2.0 µm), mobile phase consisting of phosphoric acid 0.01% (pH 3.8) and acetonitrile (98:02, v/v) and a flow rate of 0.4 mL min-1 . Drug stability was studied through submission to forced conditions, allowing the major degradation products to be detected and the kinetics parameters to be established. Thermal and oxidative degradation were determined, and indicated a kinetic decomposition following first and second order, respectively. The main degradation products were identified by LC-MS analysis, and the results were evaluated in order to suggest the chemical structures corresponding to respective masses and fragmentations. Six compounds were identified, with m/z 411, 427, 437, 634, 650 and 664. All of them resulted from cleavage of ß-lactam ring and alcoholic chain and/or dimerization. These experimental results provide valuable information about the stability of doripenem reconstituted solution and procedures for its handling and storage.

HPLC method for simultaneous analysis of ticagrelor and its organic impurities and identification of two major photodegradation products.

A simple, fast and sensitive analytical method by high-performance liquid chromatography (HPLC) was developed and validated for the simultaneous determination of ticagrelor and two synthesis impurities. The HPLC method was established using an Agilent 1200 Series equipment coupled to photodiode array detector (PDA) at 270nm with a Zorbax Plus C8 column (150×4.6mm, 5.0µm), injection volume of 20µL, and a constant temperature of 25°C. The mobile phase consisted of acetonitrile: ammonium acetate 50mM (57:43, v/v) and pH adjusted to 8.2 with ammonium hydroxide 6M, at a flow rate of 0.7mL/min. No interference peaks from excipients and diluent system indicated the specificity of the method. The calibration curves showed determination coefficients (r2)>0.99, calculated by linear regression. The limit of quantitation (LOQ) for impurities 1 and 2 were 2.0 and 0.2µg/mL, respectively. Intra and interday relative standard deviations (RSDs) were <2% for ticagrelor and <6% for the impurities, proving the precision of the method. Besides, two mayor degradation products formed when sample solutions of ticagrelor were exposed to UVC radiation were elucidated and the mechanisms involved in the photolytic degradation of ticagrelor were proposed.

Structural elucidation of gemifloxacin mesylate degradation product.

Gemifloxacin mesylate (GFM), chemically (R,S)-7-[(4Z)-3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid methanesulfonate, is a synthetic broad-spectrum antibacterial agent. Although many papers have been published in the literature describing the stability of fluorquinolones, little is known about the degradation products of GFM. Forced degradation studies of GFM were performed using radiation (UV-A), acid (1 mol L(-1) HCl) and alkaline conditions (0.2 mol L(-1) NaOH). The main degradation product, formed under alkaline conditions, was isolated using semi-preparative LC and structurally elucidated by nuclear magnetic resonance (proton - (1) H; carbon - (13) C; correlate spectroscopy - COSY; heteronuclear single quantum coherence - HSQC; heteronuclear multiple-bond correlation - HMBC; spectroscopy - infrared, atomic emission and mass spectrometry techniques). The degradation product isolated was characterized as sodium 7-amino-1-pyrrolidinyl-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, which was formed by loss of the 3-(aminomethyl)-4-(methoxyimino)-1-pyrrolidinyl ring and formation of the sodium carboxylate. The structural characterization of the degradation product was very important to understand the degradation mechanism of the GFM under alkaline conditions. In addition, the results highlight the importance of appropriate protection against hydrolysis and UV radiation during the drug-development process, storage, handling and quality control.

Development and evaluation of tablets from spray dried extract of yerba mate (Ilex paraguariensis St. Hil A) / Desarrollo y evaluación de las tabletas de extracto seco por aspersión de yerba mate (Ilex paraguariensis St. Hil A)

Introduction: yerba mate (Ilex paraguariensis St. Hil A) is a South American plant species of Aquifoliaceae family. The presence of methylxanhtines and clorogenic acids was reported in this species. These compounds have antioxidant activity and could be included in tablets, a pharmaceutical form presently unavailable in the market. Objective: to develop tablets containing yerba mate spray dried extract. Methods: the tablets were produced by direct compression with yerba mate dried extract. The dried extract was evaluated for yield, repose angle, compressibility index, residual moisture and caffeine content. The tablets were evaluated in the following parameters: external appearance, weight, hardness, friability, disintegration and caffeine content. Results: the tablets complied with the general pharmacopoeial specifications. Conclusions: this method is effective to produce tablets containing spray dried extract from yerba mate.

Introducción: la yerba mate (Ilex paraguariensis St. Hil A) es una planta de América del Sur, de la familia Aquifoliaceae. Para esta especie se informó la presencia de ácidos clorogénico y metilxantinas. Estos compuestos tienen actividad antioxidante y podría incluirse en tabletas, una forma farmacéutica que no está disponible. Objetivo: desarrollar comprimidos que contienen extracto seco por aspersión de yerba mate. Métodos: se produjeron comprimidos por compresión directa. Se determinaron al extracto seco los parámetros de rendimiento, ángulo de reposo, índice de compresibilidad, humedad y contenido de cafeína, y a los comprimidos, apariencia externa, peso, dureza, friabilidad, desintegración y contenido de cafeína. Resultados: los comprimidos cumplieron con las especificaciones generales planteadas en farmacopeas. Conclusión: el método empleado es eficaz en la producción de comprimidos que contienen extracto seco de yerba mate.

Identification, characterization and cytotoxicity in vitro assay of nitazoxanide major degradation product.

Stress studies of the broad-spectrum antiparasitic nitazoxanide were conducted in order to isolate and elucidate the major degradation product involved in thermal, acid, alkaline, oxidative and photolytic decomposition of the drug in solution and solid state. The major degradation product was identified and characterized using techniques namely LC-DAD, (1)H NMR, (13)C NMR, IR, and MS/MS. The stability of nitazoxanide raw material and nitazoxanide in tablets and in suspension powder was studied under different conditions and the results suggest the formation of the same deacetylated degradation product occur in all cases. This product was also studied in order to determine the preliminary cytotoxicity in vitro with mononuclear cells. Compared with nitazoxanide, the degradation product showed a higher cytotoxicity at a concentration of 40 µg mL(-1) after 48 h of incubation, under tested conditions. Therefore, stress studies showed that special care must be taken during the preparation, manufacture, and storage of this pharmaceutical drug.

Homeopatia para o tratamento de transtornos gastrintestinais em crianças / Homeopathy for the treatment of gastrointestinal disorders in children

Background: Colic and diarrhea are among the most common gastrointestinal disorders in childhood, which manifest spontaneously and acute. The allopathic treatment consists, in most cases, in the administration of the association homatropine-dimethicone to relieve colic, and oral rehydration and loperamide in cases of diarrhea [1,2]. The ineffectiveness of the conventional treatment and the possible adverse effects they may cause have led to increase the demand from children? parents for complementary and alternative therapies, and homeopathy can be one of the first choices in this disorders [3]. Aims: make a literature review evaluating the effectiveness of homeopathic treatment for colic and diarrhea in children, observing the relation between the main medicines prescribed in these disorders and their pathogenesis described in materia medica. Methodology: a literature research was performed applying electronic database, including Medline, HomeoIndex, BIREME, LILACS, PubMed, SciELO, and ScienceDirect in the period from September to December 2010. Results: Data found indicate that few studies are available in the literature to prove the effectiveness of homeopathic medicines for colic and diarrhea in children, but the applicability of this therapeutic modality seems to be useful, safe and low cost, which are important factors for less favored communities. Besides, studies concerning diarrhea are more frequent, not only because of its gravity, but also for the duration, which makes more adequate the monitoring, on the contrary to acute colic. The most cited medicines were Chamomilla, Nux vomica, Arsenicum album and Mercurius solubilis. Conclusions: Homeopathy can be an important source of colic and diarrhea relief. However, more investigations should be performed in order to show parents how valuable this kind of therapy can be to children and the whole family.(AU)

Introdução: a cólica e a diarreia estão entre os transtornos gastrintestinais mais comuns da infância, os quais se manifestam de forma espontânea e aguda. O tratamento alopático consiste, na maioria dos casos, na administração da associação homatropina-dimeticona para o alívio da cólica, e, reidratação oral e loperamida nos casos de diarreia [1,2]. A falta de eficácia do tratamento convencional e os possíveis efeitos adversos que o mesmo pode causar têm levado ao aumento da demanda por parte dos pais por terapias alternativas e complementares e a homeopatia pode ser uma das primeiras escolhas nestas situações [3]. Objetivos: fazer uma revisão da literatura avaliando a efetividade do tratamento homeopático para cólica e diarreia em crianças, observando a relação entre os principais medicamentos prescritos nestes casos e suas patogenesias descritas na matéria médica. Metodologia: foi realizada uma pesquisa na literatura usando as bases de dados eletrônicas, incluindo Medline, Homeoindex, BIREME, Lilacs, Pubmed, Scielo e Sciencedirect, no período de setembro a dezembro de 2010. Resultados: os dados encontrados indicam que poucos estudos estão disponíveis na literatura para provar a efetividade dos medicamentos homeopáticos em cólica e diarreia em crianças, mas a aplicabilidade desta modalidade terapêutica parece ser útil, segura e de baixo custo, que são fatores importantes para comunidades de baixa renda. Além disso, os estudos em relação a diarreia são mais frequentes, não apenas por sua gravidade, mas também pela duração, que torna mais adequado o monitoramento, ao contrário da cólica que é aguda. Os medicamentos mais citados foram Chamomilla, Nux vomica, Arsenicum album e Mercurius solubilis. Conclusões: a homeopatia pode ser um importante recurso para o alívio da cólica e da diarreia. Entretanto, mais pesquisas devem ser realizadas a fim de mostrar aos pais quão valiosa este tipo de terapia pode ser para as crianças e toda a família.(AU)

Homeopatia como uma alternativa para o tratamento da asma / Homeopathy as an alternative for asthma treatment

Introdução: a asma é uma doença inflamatória crônica caracterizada por uma obstrução reversível e uma hiper-reatividade das vias aérea inferiores [1]. É responsável por modificações no estilo de vida, e, considerando sua alta frequência, se tornou um problema importante no orçamento dos serviços de saúde pelo mundo. Aspectos como a falta de resultados definitivos e a presença de efeitos adversos, observados para o tratamento convencional, bem como a busca por melhor qualidade de vida têm aumentado o interesse dos pacientes por terapias alternativas e complementares, sendo a homeopatia uma das mais citadas [2]. Em 2001, a asma estava entre os 10 diagnósticos mais tratados pelos homeopatas nos Estados Unidos [3]. Objetivos: neste trabalho, uma pesquisa qualitativa foi realizada, objetivando avaliar a real contribuição que homeopatia pode representar para os pacientes com asma e o papel do farmacêutico neste tratamento. Metodologia: as bases de dados Medline, Sciencedirect e BIREME foram usadas para encontrar artigos científicos, aplicando as expressões ?asma?, ?homeopatia? e ?terapias alternativas e complementares. Resultados: pelo menos seis trabalhos demonstram aplicações de sucesso da homeopatia no tratamento de adultos ou crianças com asma. Os principais benefícios citados são a diminuição da frequência e da gravidade das crises, além de alguns casos de cura. Conclusões: Os dados ainda são escassos em relação ao tratamento homeopático da asma. Os poucos trabalhos encontrados mostraram que esse tipo de terapia é muito adequada, principalmente pelo componente emocional, mas também por ser livre de efeitos adversos, muito comuns no tratamento convencional (por exemplo, corticoides). Para assegurar que um tratamento correto está sendo feito, o farmacêutico deve estar presente e ativo na identificação e documentação dos pacientes, dando-lhes orientações corretas sobre o uso e o armazenamento dos medicamentos homeopáticos, além de estimular um relacionamento próximo e de confiança com o homeopata. Da mesma forma, a preparação dos medicamentos deve estar de acordo com as guias oficiais a fim de garantir a sua qualidade.(AU)

Background: Asthma is a chronic inflammatory disease characterized by a reversible obstruction and hyperactivity of inferior aerial treat [1]. It is responsible for lifestyle modification and, considering its high frequency, it became an important issue in the budget of health services around the world. Aspects like the lack of definitive results and presence of adverse effects, observed for traditional therapy, as well as the search for better quality of life have increased patients? interest for complementary and alternative medicines (CAM), being homeopathy one of the most cited [2]. In 2001, asthma was between the 10 diagnostics most treated by homeopaths in USA [3]. Aims: In this work, a qualitative research was made focusing the evaluation of the real contribution that homeopathy can represent for asthma patients and the role of pharmacist in this therapy. Methodology: databases such as Medline, Sciencedirect and Bireme were used to find scientific articles, applying the expressions ?asthma?, ?homeopathy? and ?complementary and alternative medicine?. Results: At least six works demonstrate successful applications of homeopathic treatment in children or adults with asthma. The main benefits cited are the decrease of frequency and gravity of the crises, besides of some cure cases. Conclusions: Data available are still scanty about asthma homeopathic treatment. The few works found showed this kind of therapy is very adequate, mainly because of the emotional component of the disease, but also because it represents to be away from the adverse effects commonly related to the traditional therapy (e. g. corticoids). To ensure a correct therapy is being made, the pharmacist must be present and active in the patients? identification and documentation, giving them right orientations about the use and storage of homeopathic medicines, besides of stimulating a close and confidence relationship with the homeopath. Also, the manufacturing of remedies must be according to the official guidelines in order to guarantee their quality.(AU)