Ethical considerations on placebo-controlled vaccine trials in pregnant women / Consideraciones éticas sobre los ensayos de vacunas controlados con placebo en mujeres embarazadas / Considerações éticas sobre estudos de vacina controlada com placebo em gestantes

Abstract Placebo use in clinical trials, whenever a proven effective treatment exists, is one of the most debated topics in contemporary research ethics. This article addresses the ethical framework for placebo use in clinical trials assessing vaccine efficacy in pregnant women. Vaccine trial participants are healthy at the outset and some must be infected during the study to demonstrate the product's efficacy, meaning that placebo-treated participants are under risk of serious and irreversible harm. If effective vaccines exist, such risk precludes placebo use. This interdiction should be extended to any clinical trial of vaccine efficacy in pregnant women, because a demonstration of clinical efficacy in nonpregnant individuals and comparable immunogenic responses in pregnant women are predictors of efficacy in pregnancy as well. Moreover, product effectiveness in real-world use scenarios can be ascertained by observational studies conducted after its inclusion in vaccination campaigns.

Resumen El uso de placebo en ensayos clínicos es uno de los principales temas debatidos sobre la ética en investigación contemporánea cuando existe un tratamiento eficaz probado. Este artículo aborda la ética en el uso de placebo en ensayos clínicos sobre la eficacia de vacuna en mujeres embarazadas. Las participantes en los ensayos de vacunas estaban sanas al inicio del estudio, y algunas fueron vacunadas durante el estudio para demostrar la eficacia del producto. Las participantes tratadas con placebo corren el riesgo de sufrir daños graves e irreversibles. Si existen vacunas efectivas, este riesgo impide el uso de placebo. Este impedimento debe extenderse a cualquier ensayo clínico de eficacia de vacuna en embarazadas, pues la eficacia clínica demostrada en mujeres no embarazadas y las respuestas inmunogénicas comparables con las embarazadas son predictores de eficacia en el embarazo. Además, la efectividad del producto se constata en estudios observacionales realizados tras las campañas de vacunación.

Resumo O uso de placebo em ensaios clínicos, quando um tratamento comprovadamente eficaz existe, é um dos principais tópicos debatidos na ética em pesquisa contemporânea. Este artigo aborda o quadro ético para o uso de placebo em ensaios clínicos que avaliam a eficácia de vacina em gestantes. Participantes em ensaios de vacina são saudáveis no início e alguns devem ser inoculados durante o estudo para demonstrar a eficácia do produto. Ou seja, participantes tratados com placebo estão sob risco de danos graves e irreversíveis. Se existirem vacinas eficazes, esse risco impede o uso de placebo. Essa interdição deve ser estendida a qualquer ensaio clínico de eficácia de vacina em gestantes, pois a demonstração de eficácia clínica em não gestantes e as respostas imunogênicas comparáveis em gestantes também são preditoras de eficácia na gravidez. Ademais, a eficácia do produto em cenários reais de uso pode ser verificada por estudos observacionais realizados após sua inclusão em campanhas de vacinação.

Evaluation of the maternal and developmental toxicity of 6-methylmercaptopurine riboside in rats.

Thiopurine prodrugs (azathioprine, AZA, and 6-mercaptopurine, 6MP) are embryotoxic to rodents and rabbits. Little is known about the developmental toxicity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine drug metabolite that is thought to mediate its liver toxicity. A limb bud assay found that 6MMPr impairs the in vitro morphogenetic differentiation of mouse limb extremities, being more potent than 6MP in the assay. This study evaluated the embryotoxicity of 6MMPr (0, 7.5, 15, 30 mg/kg bw sc) in rats after single-dose exposure in mid organogenesis (GD10). One group of pregnant rats was similarly treated with 6MP (15 mg/kg bw sc). After C-section (GD21), fetuses were weighed, and examined for external abnormalities. One third of each litter was examined for soft-tissue abnormalities while the remaining fetuses were cleared and stained for skeleton evaluation. 6MMPr caused a dose-dependent maternal weight loss followed by recovery before term pregnancy. Except for a nonsignificant increase in embryolethality and slight reduction in fetal weight at 30 mg/kg bw, no indication of embryotoxicity was noted at this dose or at lower doses of 6MMPr. In contrast, 6MP led to nearly 98 % of post-implantation losses in the presence of slight-to-mild maternal toxicity. These results are consistent with the notion that maternal treatment with 6MMPr affects embryo development, causing a nonsignificant increase in embryolethality and a slight reduction in fetal weight at 30 mg/kg bw. However, there was no increase in abnormalities at this dose, which was severely toxic to the dams, as reflected in the maternal weight gain data.

Evaluation of the developmental toxicity of solvents, metals, drugs, and industrial chemicals using a freshwater snail (Biomphalaria glabrata) assay.

A freshwater snail assay was employed to assess the embryotoxicity of solvents including acetone, methanol, ethanol, isopropanol, dimethyl-sulfoxide, glycerin, metals/metalloids including mercuric chloride (HgCl2), cadmium chloride (CdCl2,), antimony salts Sb+3 and Sb+5, drugs including colchicine, hydroxyurea, cyclophosphamide, an industrial chemical sodium azide (SA), an anionic surfactant dodecyl sodium sulfate-(DSS), H2O2 and sodium chloride (NaCl). The assay consists of exposing Biomphalaria glabrata egg masses (EM) to the substances for 96-hr and following up embryo/snail development for lethality, abnormal morphology (teratogenicity), and day of hatching up to day 10 or 14 after spawning. Based upon concentration-response relationships, LC50%s (embryolethality), EC50%s (teratogenicity) and IC50%s (hatching retardation) and 95%CIs were determined for tested chemicals. The LOECs indicated that HgCl2 (37 nM) and CdCl2 (140 nM) are potent embryotoxic agents in snails. Teratogenic indices (TI = LC50/EC50) for almost all tested chemicals were lower than or close to unity suggesting that these compounds were not teratogenic in this assay. The snail assay may be adequately performed in a cost-effective standardized protocol which enables testing a number of environmental chemicals over a broad concentration range. The snail assay needs to undergo further validation to be recognized for an internationally harmonized hazard identification in ecotoxicity risk assessment.

On the safety and effectiveness of COVID-19 vaccines, certainties and uncertainties / Sobre a segurança e efetividade das vacinas para COVID-19, certezas e incertezas

Introduction: The COVID-19 vaccines in use (inactivaded virus, encapsulated m-RNA, non-replicating adenovirus-vectored DNA) were clinically tested in randomized placebo- controlled phase-3 studies. Objective: To address certainties and uncertainties about safety and effectiveness of COVID-19 vaccines that were approved for use in various countries.Method: The evidence provided by clinical studies on the efficacy and safety of COVID-19 vaccines was critically appraised. Results: COVID-19 vaccines proved to be efficacious and safe in clinical trials. Adverse events were mostly those of minor severity commonly noted with other vaccines such as injection site pain, mild flu-like symptoms, headache and asthenia. Although being very rare, anaphylaxis-like reactions were noted with mRNA vaccines. Uncertainties regarding vaccine effectiveness refer mainly to the (long-term) duration of immunity provided by vaccination, the degree of protection conferred to elderly people, and how effective vaccines are against emerging SARS-CoV-2 variants. There are few uncertainties about vaccine safety including the absence of clinical trial data in pregnant women (and the impact on the unborn child), children and adolescents. Conclusions: Notwithstanding the knowledge gaps about effectiveness and safety of COVID-19 vaccines (to be further addressed by observational studies), there is overwhelming evidence that public health benefits of vaccination by far outweigh any foreseeable risk.

Introdução: As vacinas contra COVID-19 (vírus inativado, m-RNA encapsulado, vetor adenovírus não replicante) foram testadas em ensaios clínicos randomizados (fase-3) controlados com placebo. Objetivo: Abordar as certezas e incertezas sobre segurança e efetividade das vacinas para COVID-19 já aprovadas para uso em vários países. Método: A evidência clínica de eficácia e segurança das vacinas contra COVID-19 foram examinadas criticamente. Resultados: As vacinas (COVID-19) mostraram ser eficazes e seguras nos ensaios clínicos. Os eventos adversos foram predominantemente os de menor gravidade comumente observados com outras vacinas, tais como dor no local da injeção, sintomas gripais leves, cefaleia e fraqueza. Embora sejam raras, reações do tipo anafilático foram registradas com vacinas mRNA. As incertezas sobre efetividade referem-se à duração da imunidade conferida pela vacina, o grau de proteção de idosos, e a efetividade das vacinas contra as novas variantes do SARS-CoV-2. As incertezas sobre segurança são poucas e incluem a ausência de estudos clínicos em grávidas (e sobre o bebê no útero), em crianças e adolescentes. Conclusões: Não obstante as poucas lacunas acerca da efetividade e segurança das vacinas contra COVID-19 (a serem abordadas por estudos observacionais), os previsíveis benefícios da vacinação para a saúde pública excedem de longe quaisquer riscos antecipáveis.

Preliminary studies on drug delivery of polymeric primaquine microparticles using the liver high uptake effect based on size of particles to improve malaria treatment.

Malaria is the most common parasitic disease around the world, especially in tropical and sub-tropical regions. This parasitic disease can have a rapid and severe evolution. It is transmitted by female anopheline mosquitoes. There is no reliable vaccine or diagnostic test against malaria; instead, Artesunate is used for the treatment of severe malaria and Artemisinin is used for uncomplicated falciparum malaria. However, these treatments are not efficient against severe malaria and improvements are needed. Primaquine (PQ) is one of the most widely used antimalarial drugs. It is the only available drug to date for combating the relapsing form of malaria. Nevertheless, it has severe side effects. Particle drug-delivery systems present the ability to enhance the therapeutic properties of drugs and decrease their side effects. Here, we report the development of Polymeric Primaquine Microparticles (PPM) labeled with 99mTc for therapeutic strategy against malaria infection. The amount of primaquine encapsulated into the PPM was 79.54%. PPM presented a mean size of 929.47 ± 37.72 nm, with a PDI of 0.228 ± 0.05 showing a homogeneous size for the microparticles and a monodispersive behavior. Furthermore, the biodistribution test showed that primaquine microparticles have a high liver accumulation. In vivo experiments using mice show that the PPM treatments resulted in partial efficacy and protection against the development of the parasite compared to free Primaquine. These results suggest that microparticles drug delivery systems of primaquine could be a possible approach for malaria prevention and treatment.

Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues.

When Covid-19 emerged in December last year, there was no vaccine nor was there specific effective treatment for this fast-spreading and life-threatening viral respiratory infection. Clinical trials were planned and are in progress to investigate whether drugs used for influenza, HIV and other viruses, and also anthelmintics (ivermectin, nitazoxanide, niclosamide), and antimalarials (chloroquine, hydroxychloroquine) showing antiviral activity in in vitro assays, are effective and safe for Covid-19. So far there is no convincing evidence that these antiviral and antiparasitic drugs are of any benefit for Covid-19. Notwithsanding the absence of evidence of clinical efficacy, these drugs are widely used outside of clinical trials (off label) for prophylaxis and treatment of this viral infection. The rationale behind the prescription of macrolide antibiotics (azithromycin) for Covid-19 is obscure as well. The widespread prescription and use of drugs of unproven efficacy and safety for Covid-19 is at odds with the rational use of medicines, a cornerstone principle of pharmacotherapy advanced by WHO in 1985. This irrational use of drugs is cause for concern because some of them are associated with serious heart disorders and deaths.

Antenatal exposure to antidepressant drugs and the risk of neurodevelopmental and psychiatric disorders: a systematic review.

This study investigated whether antenatal exposure to antidepressants (ADs) increases the risks of autism spectrum disorders (ASD), attention deficit/hyperactivity disorders (ADHD), schizophrenia and other mental illnesses, and cognitive and developmental deficits in infants or preschool children. PubMed, EMBASE, BIREME/BVS databases were searched to identify studies examining associations of ADs in pregnancy with neurodevelopmental and psychiatric disorders. Twenty studies addressed ASD and/or ADHD risks while 30 focused on developmental and cognitive deficits in infants or preschool children. Most studies detected no association of antenatal AD with ASD after adjustment of risk ratios for maternal depression or psychiatric disorders. Some studies showed that maternal depression, regardless of whether it is treated or untreated, increased ASD risks. Seven out of 8 studies found no increase in ADHD risk associated with antenatal exposure to selective serotonin reuptake inhibitors, the most commonly used AD. No consistent evidence was found linking AD in pregnancy to neurocognitive developmental deficits in infants or preschool children. A residual confounding by indication (depression severity) remained in almost all studies. This systematic review found no consistent evidence suggesting that ADs in pregnancy increase risks of ASD, ADHD, and neurocognitive development deficits. Some studies, however, found evidence that maternal depression increases ASD risks.

Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues / Uso off label, compassivo e irracional de medicamentos na pandemia de Covid-19, consequências para a saúde e questões éticas

Abstract When Covid-19 emerged in December last year, there was no vaccine nor was there specific effective treatment for this fast-spreading and life-threatening viral respiratory infection. Clinical trials were planned and are in progress to investigate whether drugs used for influenza, HIV and other viruses, and also anthelmintics (ivermectin, nitazoxanide, niclosamide), and antimalarials (chloroquine, hydroxychloroquine) showing antiviral activity in in vitro assays, are effective and safe for Covid-19. So far there is no convincing evidence that these antiviral and antiparasitic drugs are of any benefit for Covid-19. Notwithsanding the absence of evidence of clinical efficacy, these drugs are widely used outside of clinical trials (off label) for prophylaxis and treatment of this viral infection. The rationale behind the prescription of macrolide antibiotics (azithromycin) for Covid-19 is obscure as well. The widespread prescription and use of drugs of unproven efficacy and safety for Covid-19 is at odds with the rational use of medicines, a cornerstone principle of pharmacotherapy advanced by WHO in 1985. This irrational use of drugs is cause for concern because some of them are associated with serious heart disorders and deaths.

Resumo Quando a Covid-19 surgiu em dezembro do ano passado, não havia vacina nem tratamento eficaz específico para esta infecção respiratória viral de rápida disseminação e risco de vida. Ensaios clínicos foram planejados e estão em andamento para investigar se os medicamentos usados para influenza, HIV e outros vírus e também anti-helmínticos (ivermectina, nitazoxanida, niclosamida) e antimaláricos (cloroquina, hidroxicloroquina) mostrando atividade antiviral em ensaios in vitro são eficazes e seguros para Covid-19. Até o momento, não há evidências convincentes de que esses medicamentos antivirais e antiparasitários sejam benéficos para a Covid-19. Não obstante a ausência de evidência de eficácia clínica, esses medicamentos são amplamente utilizados fora dos ensaios clínicos (off label) para profilaxia e tratamento dessa infecção viral. A lógica por trás da prescrição de antibióticos macrolídeos (azitromicina) para a Covid-19 também é obscura. A ampla prescrição e uso de medicamentos de eficácia e segurança não comprovadas para a Covid-19 está em desacordo com o uso racional de medicamentos, um princípio fundamental da farmacoterapia promovido pela OMS em 1985. Esse uso irracional de medicamentos é motivo de preocupação, porque alguns deles estão associados a graves doenças cardíacas e mortes.

Antenatal exposure to antidepressant drugs and the risk of neurodevelopmental and psychiatric disorders: a systematic review / Exposição intrauterina a antidepressivos e risco de transtornos de neurodesenvolvimento e psiquiátricos: uma revisão sistemática / Exposición prenatal a medicamentos antidepresivos y riesgo de trastornos psiquiátricos y en el desarrollo neurológico: una revisión sistemática

Abstract: This study investigated whether antenatal exposure to antidepressants (ADs) increases the risks of autism spectrum disorders (ASD), attention deficit/hyperactivity disorders (ADHD), schizophrenia and other mental illnesses, and cognitive and developmental deficits in infants or preschool children. PubMed, EMBASE, BIREME/BVS databases were searched to identify studies examining associations of ADs in pregnancy with neurodevelopmental and psychiatric disorders. Twenty studies addressed ASD and/or ADHD risks while 30 focused on developmental and cognitive deficits in infants or preschool children. Most studies detected no association of antenatal AD with ASD after adjustment of risk ratios for maternal depression or psychiatric disorders. Some studies showed that maternal depression, regardless of whether it is treated or untreated, increased ASD risks. Seven out of 8 studies found no increase in ADHD risk associated with antenatal exposure to selective serotonin reuptake inhibitors, the most commonly used AD. No consistent evidence was found linking AD in pregnancy to neurocognitive developmental deficits in infants or preschool children. A residual confounding by indication (depression severity) remained in almost all studies. This systematic review found no consistent evidence suggesting that ADs in pregnancy increase risks of ASD, ADHD, and neurocognitive development deficits. Some studies, however, found evidence that maternal depression increases ASD risks.

Resumo: O estudo teve como objetivo investigar se a exposição intrauterina a antidepressivos (ADs) aumenta o risco de transtornos do espectro autista (TEA), transtorno de déficit de atenção e hiperatividade (TDAH), esquizofrenia e outros transtornos mentais e déficits cognitivos e de desenvolvimento em lactentes e pré-escolares. Foram realizadas buscas nas bases PubMed, EMBASE e BIREME/BVS para identificar estudos sobre associações entre o uso de ADs durante a gestação e transtornos de neurodesenvolvimento e psiquiátricos. Vinte estudos trataram de riscos de TEA e/ou TDAH, enquanto 30 focaram em déficits cognitivos e de desenvolvimento em lactentes ou pré-escolares. A maioria dos estudos não detectou associação entre AD na gestação e TEA, depois de ajustar as razões de risco para depressão ou outros transtornos psiquiátricos maternos. Alguns estudos mostraram que a depressão materna, quer tratada ou não, aumenta o risco de TEA. Sete entre oito estudos não detectaram aumento de risco de TDAH associado à exposição intrauterina a inibidores seletivos da recaptação da serotonina, o AD mais comumente utilizado. Não foram encontradas evidências consistentes entre o uso de AD na gestação e déficits de desenvolvimento neurocognitivo em lactentes ou pré-escolares. Em quase todos os estudos, permaneceu um confundimento residual por indicação (gravidade da depressão). A revisão sistemática não encontrou evidências consistentes de que os ADs na gestação aumentassem o risco de TEA, TDAH ou déficits de desenvolvimento neurocognitivo. Entretanto, alguns estudos evidenciaram que a depressão materna aumenta o risco de TEA.

Resumen: Este estudio investigó si la exposición prenatal a antidepresivos (ADs) incrementa los riesgos de trastornos del espectro autista (TEA), trastornos de déficit de atención/hiperactividad (TDAH), esquizofrenia, así como otras enfermedades mentales, cognitivas, y déficits en el desarrollo de niños de primaria o preescolares. Se consultaron las bases de datos PubMed, EMBASE, BIREME/BVS para identificar estudios de asociaciones de ADs durante el embarazo con trastornos de desarrollo neurológico y psiquiátricos. Veinte estudios estaban centrados en riesgos de TEA y/o TDAH, mientras que 30 se centraron en déficits de desarrollo y cognitivos en niños de primaria o preescolares. La mayor parte de los estudios no detectaron asociación de AD, durante la etapa prenatal, con TDA tras el ajuste de las ratios de riesgo para depresión materna o trastornos psiquiátricos. Algunos estudios mostraron que la depresión materna, independientemente de si es tratada o no, incrementó los riesgos de TEA. Siete de los 8 estudios no encontraron un incremento en el riesgo de TDAH, asociado con la exposición prenatal a inhibidores selectivos de la recaptación de serotonina, el antidepresivo más usado habitualmente durante el período prenatal. No se encontraron evidencias consistentes relacionando AD durante el embarazo y déficits en el desarrollo neurocognitivo de niños de primaria o preescolares. En casi todos los estudios hubo una desviación residual señalada como gravedad de la depresión. Esta revisión sistemática no halló evidencias consistentes, sugiriendo que el consumo de ADs durante el embarazo incremente el riesgo de TEA, TDAH, y déficits en el desarrollo neurocognitivo. Algunos estudios, no obstante, encontraron evidencias de que la depresión materna incrementa riesgos de TEA.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues.

In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

The tale of lenalidomide clinical superiority over thalidomide and regulatory and cost-effectiveness issues / A narrativa de que a lenalidomida é clinicamente superior à talidomida, e questões regulatórias e de custo-efetividade

Abstract In April 2017, the National Sanitary Surveillance Agency (ANVISA-Brazil) approved lenalidomide (LEN) for multiple myeloma (MM) and myelodysplastic syndrome. ANVISA had rejected the first application in 2010, and denied a request for reconsideration in 2012. The reason for rejection was the lack of comparative effectiveness studies proving that LEN was more effective than thalidomide (THAL), a strictly controlled drug regulated by Federal law 10.651/2003 and dispensed to patients (at no costs) through public health system units and hospitals. ANVISA unexplained retreat on the LEN approval for marketing was an unquestionable triumph of the lobbying that ensued the denial, at the forefront of which were politicians, Congress members, patient organizations and medical societies. Two randomized (phase III) trials and three observational (case-control and population-based cohort) compared the effectiveness of THAL- versus LEN-based therapies in MM. Overall, these studies showed no difference in efficacy between LEN- and THAL-based therapies. LEN caused less neuropathy, and more severe hematologic adverse effects. It is much costlier than THAL, and substitution of THAL by LEN shall raise considerably public healthcare costs in Brazil.

Resumo A Agência Nacional de Vigilância Sanitária (ANVISA) aprovou em abril de 2017 a lenalidomida (LEN) para o mieloma múltiplo (MM) e síndrome mielodisplásica. A ANVISA havia negado o registro em 2010, e indeferido um recurso apresentado em 2012. O motivo do indeferimento foi a falta de estudos comparativos de efetividade demonstrando que LEN era mais eficaz do que a talidomida (TAL), um medicamento rigorosamente controlado pela lei federal 10.651/2003 e dispensado gratuitamente a pacientes através de unidades de saúde e hospitais públicos. O recuo não explicado da ANVISA em relação ao registro da LEN foi um inquestionável triunfo do lobby que sucedeu a recusa inicial do registro, a frente do qual estavam políticos, membros do Congresso, associações de pacientes e sociedades médicas. Dois ensaios randomizados (fase III) e três estudos observacionais (caso-controle e coorte de base populacional) compararam a efetividade de terapias para o MM com TAL- e com LEN. Em conjunto, esses estudos mostraram que não havia diferenças quanto a eficácia de tratamentos com LEN- e aqueles com TAL. A LEN causou menos neuropatias, e efeitos adversos hematológicos mais graves. Ela é muito mais cara do que a TAL, e a substituição da TAL pela LEN aumentará muito os custos da assistência pública à saúde no Brasil.