Cenário da falsificação de medicamentos no Brasil entre os anos de 2015 e 2022 / Scenario of drug counterfeiting in Brazil between 2015 and 2022

A falsificação de medicamentos é uma prática criminosa frequente em situações de alta demanda, carência de produtos e preços elevados no mercado, gerando muitos riscos à saúde da população. Objetivo: Estabelecer o panorama da falsificação de medicamentos no Brasil entre os anos de 2015 e 2022. Método: Trata-se de um estudo descritivo e retrospectivo dos registros de apreensão de medicamentos com indícios de falsificação, disponibilizados pela Agência Nacional de Vigilância Sanitária. Resultados: 30 fármacos diferentes foram mencionados nos registros de falsificação do período estudado, com predomínio de medicamentos biológicos e controlados e das formas farmacêuticas de via parenteral. Os fármacos que apresentaram mais registros de falsificação foram somatropina, imunoglobulina, sofosbuvir/ledispavir, eculizumabe e defibrotida. Conclusão: Por muitos anos, a falsificação de medicamentos no Brasil foi caracterizada principalmente por estimulantes sexuais masculinos, anabolizantes e anorexígenos. Entretanto, nos últimos anos, os medicamentos de alto custo destinados ao tratamento de doenças crônicas e raras se sobressaíram. Este cenário pode estar relacionado a diversos fatores, como gravidade das doenças, avanços das terapias medicamentosas, elevada lucratividade, falta de acesso aos medicamentos e dificuldades sociais e econômicas associadas à pandemia da doença por coronavírus 2019 (COVID-19)

Drug counterfeiting is a common criminal practice in situations of high demand, lack of products and high market prices, which generates risks to the health of the population. Objective: To establish an overview of drug counterfeiting in Brazil between 2015 and 2022. Method: This is a descriptive and retrospective study of data on drugs arrest with evidence of counterfeiting made available by the Brazilian Health Surveillance Agency. Results: 30 different drugs were mentioned in counterfeiting records for the period studied with a predominance of biopharmaceuticals and controlled substances, and parenteral pharmaceutical forms. The drugs with the most falsification records were somatropin, immunoglobulin, sofosbuvir/ledispavir, eculizumab and defibrotide. Conclusion: For many years, drug counterfeiting in Brazil was mainly characterized by male sexual stimulants, anabolic steroids, and anorectic. However, high-cost drugs for treating chronic and rare diseases have recently gained prominence. This scenario may be related to several factors, such as the severity of the diseases, advances in drug therapies, high profitability, lack of access to drugs, and social and economic difficulties associated with the coronavirus disease 2019 (COVID-19) pandemic

Conformity assessment of medicines containing antibiotics - A multivariate assessment.

Pharmaceutical products must meet quality requirements to ensure the efficacy and safety of pharmacological treatment. Non-compliance of medicines can cause economic losses and compromise the patient's health. In this work, the risks of false compliance/non-compliance decisions for parenteral antibiotics (cephalothin, ciprofloxacin and metronidazole) were evaluated on the basis of analytical results, measurement uncertainties and specification limits. Physicochemical and biological quality assays were performed according to pharmacopeial procedures. Measurement uncertainties were determined using the bottom-up approach or the probability of false-positive/false-negative results. The risks of false compliance/non-compliance decisions were estimated using the frequentist approach and Monte Carlo simulations. Guard-bands were determined through a validated spreadsheet for calculating univariate and multivariate acceptance limits. All risk values (particular risks and total risk, consumer's or producer's risk) were below the maximum permissible risk value. The univariate and multivariate guard-bands defined more restrictive specification values, reducing the risks of false compliance/non-compliance decisions. One antibiotic presented unsatisfactory results regarding the drug content and was classified as out of specification product. The application of risk management tools in the pharmaceutical area contributes to improving the quality and safety of products and supports decision-making.

The application of pharmaceutical quality by design concepts to evaluate the antioxidant and antimicrobial properties of a preservative system including desferrioxamine.

BACKGROUND: The purpose of the present study was to investigate the antioxidant and antimicrobial activities of a conventional preservative system containing desferrioxamine mesylate (DFO) and optimize the composition of the system through mathematical models. METHODS: Different combinations of ethylenediaminetetraacetic acid (EDTA), sodium metabisulfite (SM), DFO and methylparaben (MP) were prepared using factorial design of experiments. The systems were added to ascorbic acid (AA) solution and the AA content over time, at room temperature and at 40 °C was determined by volumetric assay. The systems were also evaluated for antioxidant activity by a fluorescence-based assay. Antimicrobial activity was assessed by microdilution technique and photometric detection against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus brasiliensis. A multi-criteria decision approach was adopted to optimize all responses by desirability functions. RESULTS: DFO did not extend the stability of AA over time, but displayed a better ability than EDTA to block the pro-oxidant activity of iron. DFO had a positive interaction with MP in microbial growth inhibition. The mathematical models showed adequate capacity to predict the responses. Statistical optimization aiming to meet the quality specifications of the ascorbic acid solution indicated that the presence of DFO in the composition allows to decrease the concentrations of EDTA, SM and MP. CONCLUSION: DFO was much more effective than EDTA in preventing iron-catalyzed oxidation. In addition, DFO improved the inhibitory response of most microorganisms tested. The Quality by Design concepts aided in predicting an optimized preservative system with reduced levels of conventional antioxidants and preservatives, suggesting DFO as a candidate for multifunctional excipient.

Unmet Quality Needs in Oral Drug Delivery: Contrasts of Drug Content and Uniformity on Distinct Approaches for Achieving Individual Dosing.

Individualized dosing is often required in pharmacotherapy, particularly for pediatric and geriatric patients and adjustment of drugs that demand dose adaptation. This study aimed to evaluate critical quality attributes (CQAs) of doses obtained by distinct approaches for achieving individual dosing. Approaches were evaluated as follows: subdivision of tablets by splitter and hand (haloperidol) and delivery by plastic dropper bottle (haloperidol), glass dropper bottle (clonazepam), dosing cup (sodium valproate), and dosing syringe (carbamazepine), including brand name, generic, and similar marketed products. Measuring devices were packaged with their respective product. Drug content uniformity was assessed to each substance according to pharmacopeial methods. Tablets subdivided by splitter had the poorest performance among all approaches, in which doses ranged around 60% of the labeled amount (Acceptance Value = 58.1 and RSD = 23.2%). The greatest performances were observed for the dosing syringe which fulfilled all the requirements for dose precision and for the glass dropper bottle. There were significant differences in dose delivery between manufacturers of the same medicine when measuring the same volume or number of drops. High drug content variability is extremely harmful to pharmacotherapy and may result in therapeutic failure or toxicity. It is crucial that measuring devices and scoring of tablets be checked for functionality and standardized for different manufacturers of the same medicine. Part of the approaches for achieving individual dosing did not meet the quality needs for drug content and uniformity. Yet, our findings show that more accurate and precise dosing can be accessed when using the dosing syringe and glass dropper bottle.

Mesilato de desferroxamina como candidato a adjuvante farmacêutico e cosmético / Desferroxamine mesylate as a candidate for pharmaceutical and cosmetic adjuvant

Este trabalho propôs o uso do fármaco quelante mesilato de desferroxamina (DFO) como agente adjuvante para estabilização química e microbiológica de formulações. Soluções de ácido ascórbico (AA) 5,0% (p/v) foram preparadas com sistemas antioxidantes constituídos por diferentes combinações de DFO, ácido etilenodiamino tetra-acético (EDTA) e metabissulfito de sódio, cada adjuvante na concentração máxima de 0,1% (p/v). Os sistemas foram testados previamente quanto à atividade antioxidante, mediante adição de um complexo de ferro (III) redox-ativo e ensaio baseado em fluorescência. Os sistemas também foram associados ao metilparabeno e avaliados quanto à atividade antimicrobiana pelo método turbidimétrico, utilizando-se a técnica de microdiluição em meios líquidos e cepas padrão de bactérias e fungos, incluindo S. aureus (ATCC 6538), E. coli (ATCC 8739), P. aeruginosa (ATCC 9027), C. albicans (ATCC 10231) e A. brasiliensis (ATCC 16404). As soluções de AA foram expostas a condições de teste de estabilidade acelerada e avaliadas quanto à estabilidade química, empregando-se método volumétrico validado para quantificar AA. Verificou-se que o EDTA foi o agente quelante que melhor contribuiu na estabilidade química da solução de AA, entretanto, o DFO apresentou desempenho muito superior ao EDTA para bloquear a atividade pró-oxidante do ferro. Além disso, o DFO foi fator relevante na inibição do crescimento microbiano e demonstrou sinergia com o metilparabeno. A otimização estatística dos resultados indicou que o uso do DFO nos sistemas antioxidante e conservante pode reduzir consideravelmente a concentração dos adjuvantes convencionais, EDTA, metabissulfito e metilparabeno, os quais são muitas vezes associados a reações de hipersensibilidade ou a danos ao meio ambiente

In this work it was proposed the use of the chelating drug desferroxamine mesylate (DFO) as adjuvant for chemical and microbiological stabilization of formulations. Ascorbic acid (AA) solutions 5.0% (w/v) were prepared with antioxidant systems containing different combinations of DFO, ethylenediaminetetraacetic acid (EDTA) and sodium metabisulphite, using a maximum concentration of 0.1% (w/v) for each adjuvant. Previously, the systems were spiked with a redox-active iron (III) complex and tested for antioxidant activity by fluorescence-based assay. The systems also were associated with methylparaben and evaluated for antimicrobial activity by turbidimetric method, using the microdilution technique and standard strains of bacteria and fungi, including S. aureus (ATCC 6538), E. coli (ATCC 8739), P. aeruginosa (ATCC 9027), C. albicans (ATCC 10231) and A. brasiliensis (ATCC 16404). The AA solutions were exposed to accelerated stability test conditions and evaluated for chemical stability, using a volumetric method that was validated to quantify AA. It was found that EDTA was the chelating agent that most contributed to the chemical stability of AA solution, however, DFO demonstrated a much higher performance to EDTA to block the pro-oxidant activity of iron. In addition, DFO was a relevant factor in the inhibition of microbial growth and showed synergy with methylparaben. The statistical optimization of the results indicated that the use of DFO in the antioxidant and preservative systems might considerably reduce the concentration of the conventional adjuvants, EDTA, metabisulphite and methylparaben, which are often associated with hypersensitivity reactions or environmental damage

Actual Versus Expected Doses of Half Tablets Containing Prescribed Psychoactive Substances: A Systematic Review.

OBJECTIVE: To assess through a systematic review of the literature if the practice of splitting tablets containing psychoactive/psychotropic medications for medical or economic reasons would result in the expected doses. DATA SOURCES: A MEDLINE and PsycInfo comprehensive search of English-language publications from January 1999 to December 2015 was conducted using the terms describing tablet splitting (tablet splitting, split tablets, tablet subdivision, divided tablets, and half tablets) and psychoactive substances (psychoactive medicines, psychotropic medicines, antidepressants, anxiolytics, anticonvulsants, antipsychotics, and antiparkinsonian agents). An additional supplementary search included the references from the articles found. STUDY SELECTION/DATA EXTRACTION: Studies were included if splitting content was directly related to psychoactive medications and examined the effect of tablet splitting on drug uniformity, weight uniformity, and adherence of psychoactive drugs. Articles were systematically reviewed and examined regarding the study design, methodology, and results of the study. A total of 125 articles were screened, and 13 were selected. RESULTS: Tablet splitting implications are extensive, yet substantial deviations from the ideal weight, potency, and dose uniformity are more prone to be important to patient safety. The uneven division of tablets might result in the administration of different doses than what was prescribed, causing under- or overdosing, which might be relevant depending on the drug. In 55% of the cases, splitting psychoactive drugs was satisfactory. CONCLUSIONS: It cannot be generalized that splitting psychoactive drugs compromises dose accuracy, thus tablet splitting might still be employed in cases in which the advantages outweigh the disadvantages. It is recommended that alternatives be adopted to prevent the disadvantages related to tablet splitting.

Alteração do aspecto de medicamentos: indicativo de desvios de qualidade / Altered appearance of medicines: a quality deviation indicative

O medicamento é um produto farmacêutico com finalidade profilática, curativa ou para fins de diagnóstico. A forma farmacêutica está relacionada à via de administração. O objetivo deste trabalho foi avaliar a alteração do aspecto de medicamentos, provenientes de queixas técnicas e de programas de monitoramento da qualidade. No período de 2010 a 2014, 119 amostras coletadas pelos Serviços de Vigilância Sanitária foram analisadas quanto ao aspecto e as alterações foram confrontadas com as especificações técnicas dos medicamentos, sendo que 73,1% das amostras foram insatisfatórias. Apresentaram resultados insatisfatórios 82,0% das suspensões e 63,0% dos comprimidos, principalmente devido a alterações na suspensibilidade e na cor, respectivamente. Os desvios de qualidade constatados estavam relacionados à forma farmacêutica, independente da propriedade farmacológica. A principal consequência do uso de medicamentos com aspecto alterado é a não adesão ao tratamento e a interrupção de esquemas terapêuticos de doenças com metas de erradicação, como tuberculose e sífilis. Os resultados insatisfatórios contribuem no direcionamento de ações estratégicas de políticas públicas de medicamentos, na criação de modelos de intervenção preventiva, na regulação sanitária e na promoção do uso racional de medicamentos, desta maneira evitando riscos sanitários...

Evaluation of in vitro biological properties of Senna occidentalis (L) Link / Avaliação in vitro de propriedades biológicas de Senna occidentalis (L) Link

Senna species have been widely used by American, African and Indian ethic groups mainly in the treatment of feebleness, constipation, liver disorders and skin infections. Senna occidentalis (L.) Link is a perennial shrub native to South America and indigenous to tropical regions throughout the world. Current study evaluated the antimicrobial activity of aqueous and hydroalcoholic extracts from S. occidentalis prepared from different parts of the plant. Antimicrobial activity was assessed against standard pharmaceutical microorganisms by spectrophotometry and microdilution technique. Escherichia coli was sensitive only to compounds extracted from seeds which may be proteinaceous. A broader antimicrobial spectrum was demonstrated by the hydroalcoholic extract of seeds, mostly against Pseudomonas aeruginosa. The in vitro toxicity using mouse fibroblasts indicated that the extract might be a biocompatible ingredient for topical formulations, while the hydroalcoholic extract of aerial parts demonstrated to be potentially cytotoxic.

Espécies de Senna são amplamente utilizadas por tribos americanas, africanas e indianas, principalmente para tratar a fraqueza, a constipação, as desordens do fígado e também em preparações tópicas para infecções de pele. A Senna occidentalis (L.) Link é um arbusto perene nativo da América do Sul encontrado em regiões tropicais. Este trabalho avaliou a atividade antimicrobiana de extratos aquosos e hidroalcoólicos de diferentes partes da planta. A atividade antimicrobiana foi estabelecida frente aos microrganismos padrões farmacêuticos por espectrofotometria e técnica de microdiluição. A Escherichia coli apresentou sensibilidade apenas a componentes extraídos das sementes, os quais podem ser de natureza proteica. O espectro mais amplo de atividade antimicrobiana foi obtido com o extrato hidroalcoólico das sementes, principalmente contra Pseudomonas aeruginosa. A toxicidade in vitro utilizando fibroblastos de camundongo indicou que este extrato pode ser um ingrediente biocompatível para formulações de uso tópico. Já o extrato hidroalcoólico de partes aéreas demonstrou ser potencialmente citotóxico.

Isolation and structural characterization of microcystin-LR and three minor oligopeptides simultaneously produced by Radiocystis feernandoi (Chroococcales, Cyanobacteriae): a Brazilian toxic cyanobacterium.

Several blooms of cyanobacteria naturally occurring in freshwater reservoirs have been associated to numerous fatalities and cases of livestock and human poisoning. Microcystins (Mcs) are the most frequently found cyclic heptapeptide toxins in the cyanobacterial extracts. In previous work, Radiocystis fernandoi (strain SPC 714) lyophilized extracts were found to be hepatotoxic to mice with LD100 of about 60 mg kg(-1) and Mc LR was suggested as responsible for that toxicity. Here, we describe the isolation of four oligopeptides from R. fernandoi methanol extract by reversed-phase high performance liquid chromatography (RP-HPLC). The major component, which eluted with 65% acetonitrile from acetonitrile/water gradient, was identified as Mc-LR and its structure was confirmed by the presence of molecular related ion species [M+H]+ at m/z 996.3, ([M+H-Adda])+ at m/z 861.5, [Arg-Adda-Glu+H]+ at m/z 599.8, and [PhCH2CH(OMe)]+ at m/z 135.1 in the ESI spectra. Two components corresponding to small signals eluted from C18 column, respectively, with 44 and 45% acetonitrile had their structures proposed as isomers of aeruginosin derivatives showing molecular ions at m/z 651.7 and a [CHOI]+ immonium at m/z 140.1. Finally, the structure of the third minor and most hydrophobic component (68% acetonitrile elution) isolated from R. fernandoi extract seemed to correspond to a cyclic cyanopeptolin like micropeptin K139, a trypsin inhibitor firstly isolated from Microcystis aeruginosa, showing similar ions fragmentation pattern and [M+H]+ at m/z 987.6 in its ESI spectra.