Etat des lieux de la règlementation des essais cliniques au Mali / State of play of the regulation of clinical trials in Mali

Objectif: L'objectif était de réaliser l'état des lieux de la réglementation des essais cliniques au Mali. Matériel et Méthodes: Il s'agissait d'une étude transversale descriptive réalisée du 1er septembre au 15 décembre 2019. Elle a consisté en une recherche documentaire et une enquête de terrain dans les centres de recherche, les comités d'éthique et les structures règlementaires du Mali. Résultats: En 2019, il y a eu 15 essais cliniques autorisés et réalisés par trois centres de recherche, dont 12 vaccinaux et 3 médicamenteux tous approuvés par un comité d'éthique. Le cadre juridique des essais cliniques est régi au Mali par deux textes dont l'un législatif et l'autre réglementaire. Ils prévoient l'autorisation, la suspension ou l'interdiction de la recherche biomédicale par le ministre en charge de la santé. Les insuffisances recensées sont relatives à la faible remontée et au manque d'évaluation des données de pharmacovigilance, la rareté des inspections des sites et surtout l'absence de comité technique d'évaluation règlementaire des dossiers à la Direction de la Pharmacie et du Médicament (DPM). Conclusion: Le renforcement du cadre juridique est, plus que jamais, nécessaire pour assurer la protection des droits, la sécurité et le bien-être des sujets de recherche dans un contexte de délocalisation croissante des essais cliniques vers nos pays

Objective: The objective was to take stockof the regulation of clinical trials in Mali. Material and Methods: This was a descriptive cross-sectional study carried out of the September 1 to December 15, 2019. It consisted of a literature search and a survey in research centers, ethics committees and regulatory structures in Mali. Results: In 2019, there were 15 clinical trials authorized and conducted by three research centers, including 12 vaccines and 3 drugs trials all approved by an ethics committee. The legal framework for clinical trials is governed in Mali by two texts, one legislative and the other regulatory. They provide for the authorization, suspension or prohibition of biomedical research by the minister in charge of Health. The shortcomings identified relate to the low recovery and lack of evaluation of pharmacovigilance data, the scarcity of site inspections and especially the absence of a technical committee for regulatory evaluation of files at the Pharmacy and Medicines Department (DPM). Conclusion: The strengthening of the legal framework is, more than ever, necessary to ensure the protection of the rights, safety and well-being of research subjects in a context of increasing relocation of clinical trials to our countries

PF-04620110, a Potent Antidiabetic Agent, Suppresses Fatty Acid-Induced NLRP3 Inflammasome Activation in Macrophages

BACKGROUND: Chronic inflammation has been linked to insulin resistance and type 2 diabetes mellitus (T2DM). High-fat diet (HFD)-derived fatty acid is associated with the activation of chronic inflammation in T2DM. PF-04620110, which is currently in phase 1 clinical trials as a selective acyl-CoA:diacylglycerol acyltransferase-1 (DGAT1) inhibitor, is a potent anti-diabetic agent that may be important for the regulation of chronic inflammation in T2DM. However, the mechanisms by which PF-04620110 regulates fatty acid-induced chronic inflammation remain unclear. METHODS: PF-04620110 was used in vitro and in vivo. DGAT1-targeting gRNAs were used for deletion of mouse DGAT1 via CRISPR ribonucleoprotein (RNP) system. The activation of NLRP3 inflammasome was measured by immunoblot or cytokine analysis in vitro and in vivo. RESULTS: Here we show that PF-04620110 suppressed fatty acid-induced nucleotide-binding domain, leucine-rich-repeat-containing receptor (NLR), pyrin-domain-containing 3 (NLRP3) inflammasome activation in macrophages. In contrast, PF-04620110 did not change the activation of the NLR family, CARD-domain-containing 4 (NLRC4), or the absent in melanoma 2 (AIM2) inflammasomes. Moreover, PF-04620110 inhibited K⁺ efflux and the NLRP3 inflammasome complex formation, which are required for NLRP3 inflammasome activation. PF-04620110 reduced the production of interleukin 1β (IL-1β) and IL-18 and blood glucose levels in the plasma of mice fed HFD. Furthermore, genetic inhibition of DGAT1 suppressed fatty acid-induced NLRP3 inflammasome activation. CONCLUSION: Our results suggest that PF-04620110 suppresses fatty acid-induced NLRP3 inflammasome activation.

Use of Molecular Imaging in Clinical Drug Development: a Systematic Review / 대한핵의학회잡지

BACKGROUND: Molecular imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) can provide the crucial pharmacokinetic-pharmacodynamic information of a drug non-invasively at an early stage of clinical drug development. Nevertheless, not much has been known how molecular imaging has been actually used in drug development studies.METHODS: We searched PubMed using such keywords as molecular imaging, PET, SPECT, drug development, and new drug, or any combination of those to select papers in English, published from January 1, 1990, to December 31, 2015. The information about the publication year, therapeutic area of a drug candidate, drug development phase, and imaging modality and utility of imaging were extracted.RESULTS: Of 10,264 papers initially screened, 208 papers met the eligibility criteria. The more recent the publication year, the bigger the number of papers, particularly since 2010. The two major therapeutic areas using molecular imaging to develop drugs were oncology (47.6%) and the central nervous system (CNS, 36.5%), in which efficacy (63.5%) and proof-of-concept through either receptor occupancy (RO) or other than RO (29.7%), respectively, were the primary utility of molecular imaging. PET was used 4.7 times more frequently than SPECT. Molecular imaging was most frequently used in phase I clinical trials (40.8%), whereas it was employed rarely in phase 0 or exploratory IND studies (1.4%).CONCLUSIONS: The present study confirmed the trend that molecular imaging has been more actively employed in recent clinical drug development studies although its adoption was rather slow and rare in phase 0 studies.

Trends of clinical trials from 2014 to 2016 in South Korea

Mandatory registration of clinical trials in public registry can ensure the transparency of clinical trials. Public clinical trial registry of can provide current chronological and geographical distribution of clinical trial throughout the country. We used public clinical trial registry provided by Ministry of Food and Drug Safety to analyze current status of clinical trial from 2014 to 2016 in South Korea. The number of clinical trials in antineoplastic and immunomodulating agents area was the greatest, followed by cardiovascular system and antiinfectives for systemic use as a whole. From 2014 to 2016, overall number of clinical trials decreased while the number of phase I clinical trials increased. Seoul accounted for more than half number of clinical trials in Korea. Supports for clinical trials in non-metropolitan area needs to be considered.

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser. MATERIALS AND METHODS: This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA. RESULTS: PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss. CONCLUSION: The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Targeted Cancer Therapy Using Engineered Salmonella typhimurium / 전남의대학술지

Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models. An attenuated strain of S. typhimurium, VNP20009, successfully targeted human metastatic melanoma and squamous cell carcinoma in Phase I clinical trials; however, the efficacy requires further refinement. Along with the characteristics of self-targeting, proliferation, and deep tissue penetration, the ease of genetic manipulation allows for the production of more attenuated strains with greater safety profiles and vector systems that deliver designable cargo molecules for cancer diagnosis and/or therapy. Here, we discuss recent progress in the field of Salmonellae-mediated cancer therapy.

Targeted Cancer Therapy Using Engineered Salmonella typhimurium / 전남의대학술지

Obligate or facultative anaerobic bacteria such as Bifidobacterium, Clostridium, Salmonella, or Escherichia coli specifically colonize and proliferate inside tumor tissues and inhibit tumor growth. Among them, attenuated Salmonella typhimurium (S. typhimurium) has been widely studied in animal cancer models and Phase I clinical trials in human patients. S. typhimurium genes are easily manipulated; thus diverse attenuated strains of S. typhimurium have been designed and engineered as tumor-targeting therapeutics or drug delivery vehicles that show both an excellent safety profile and therapeutic efficacy in mouse models. An attenuated strain of S. typhimurium, VNP20009, successfully targeted human metastatic melanoma and squamous cell carcinoma in Phase I clinical trials; however, the efficacy requires further refinement. Along with the characteristics of self-targeting, proliferation, and deep tissue penetration, the ease of genetic manipulation allows for the production of more attenuated strains with greater safety profiles and vector systems that deliver designable cargo molecules for cancer diagnosis and/or therapy. Here, we discuss recent progress in the field of Salmonellae-mediated cancer therapy.

The "mild-torture economy": exploring the world of professional research subjects and its ethical implications / "A tortura da economia moderada": explorando o mundo dos sujeitos de pesquisa profissionais e suas implicações éticas

AbstractThis paper documents the emergence of the subject of professional research in Phase I clinical trials that test the safety of drugs in development. Based on ethnographic research among subjects self-identified as "professional guinea pigs" in Philadelphia, USA, it examines their experiences and opinions on the conduct of trials and risks they take. The author argues that the risks posed by the continued participation, such as exposure to potentially dangerous drug interactions are minimized or ignored by research subjects because of the prospect of financial gain. Risks to the professional guinea pigs are also ignored by the pharmaceutical industry, which has become dependent on the usual participation of experienced research subjects. Arguing that financial incentives undermine the ethical imperative of informed consent to be given freely by volunteers, this research confirms the need to reform the policies governing the participation of paid subjects in Phase I clinical trials.

ResumoEste artigo documenta o surgimento do sujeito da pesquisa profissional na Fase I de ensaios clínicos que testam a segurança de medicamentos em desenvolvimento. Baseado em pesquisas etnográficas entre sujeitos autoidentificados "cobaias profissionais" na Filadélfia, EUA, o estudo examina suas experiências e opiniões sobre a condução dos ensaios e os riscos que assumem na participação. O autor argumenta que os riscos apresentados pela participação contínua, como a exposição às interações medicamentosas potencialmente perigosas, são minimizados ou ignorados pelos sujeitos de pesquisa devido à perspectiva de ganhos financeiros. Os riscos para as cobaias profissionais também são ignorados pela indústria farmacêutica, que se tornou dependente da participação habitual de sujeitos de pesquisa experientes. Argumentando que os incentivos financeiros comprometem o imperativo ético de consentimento informado a ser dado livremente pelos voluntários, esta pesquisa confirma a necessidade de reformar as políticas que regulam a participação de sujeitos pagos na Fase I de ensaios clínicos.

Advances in measles virus for cancer therapy / 浙江大学学报·医学版

Oncolytic virotherapy is a novel cancer therapy. Vaccine-attenuated strains of measles virus(MV)is an ideal candidate for oncolytic virotherapy which has an excellent safety record. Vaccine-attenuated MV uses CD46 and Nectin-4 molecule as major entry receptors into cells. Vaccine-attenuated MV can selectively infect and kill a wide variety of cancer cells in vitro and in vivo. With the development of molecular cloning, scientists have successfully rescued cDNA of vaccine-attenuated MV and increased its oncolytic efficiency with molecular engineering techniques. Phase I clinical trials of virotherapy for ovarian cancer and multiple myeloma with vaccine-attenuated MV are underway. The preliminary results indicate the promising antitumor potential of vaccine-attenuated MV.

Assessment of statistical power for covariate effects in data from phase I clinical trials

One of the important purposes in population pharmacokinetic studies is to investigate the relationships between parameters and covariates to describe parameter variability. The purpose of this study is to evaluate the model's ability to correctly detect the parameter-covariate relationship that can be observed in phase I clinical trials. Data were simulated from a two-compartment model with zero-order absorption and first-order elimination, which was built from valsartan's concentration data collected from a previously conducted study. With creatinine clearance (CLCR) being used as a covariate to be tested, 3 different significance levels of 0.001

Conocimiento de los especialistas y residentes de Medicina Natural y Tradicional sobre los ensayos clínicos / Knowledge of the specialist and residents of Natural and Traditional Medicine on the clinical researches

La Medicina Natural y Tradicional ha entrado en una nueva etapa de desarrollo con el incremento en la demanda de sus alternativas terapéuticas. Se realizó una investigación descriptiva transversal, mediante la cual se identificaron las necesidades de aprendizaje de 20 médicos, entre especialistas y residentes de Medicina Natural y Tradicional, acerca de los aspectos básicos de ensayos clínicos. Existe desconocimiento acerca de las fases y pilares fundamentales de un ensayo clínico y los aspectos éticos importantes al ser una investigación en seres humanos, por lo que demuestra la falta de capacitación que existe sobre el tema. Es imprescindible fomentar una cultura de ensayos clínicos en los médicos que se desempeñan en el área de la Medicina Natural y Tradicional. Esto permitiría elevar la calidad y rapidez con que se desarrollan estos estudios en Cuba.

The Natural and Traditional Medicine has entered a new developmental stage with the increase in the requests of its therapeutic alternatives. We carried out a crossed descriptive research, through which we identified the learning necessities of 20 doctors, between specialist and residents of Traditional and Natural Medicine, about the main aspects of clinical researches. There is a lack of knowledge on the main phases and bases of a clinical research and on the important ethical aspects for being a research in human beings, showing the lack of knowledge on the theme. It is unavoidable to promote a culture of clinical researches among the doctors working in the area of Traditional and Natural Medicine. This will allow increasing the quality and speed of these researches development in Cuba.

Eficacia del diazepam retrolabial en el tratamiento de la convulsión febril / Effectiveness of buccal diazepam in the treatment of febrile convulsion

El diazepam por vía intravenosa o rectal constituye el tratamiento de elección en niños con convulsión febril. Algunos autores consideran que pudiera ser la vía bucal una alternativa más práctica y efectiva. Objetivo: evaluar la eficacia y seguridad del diazepam administrado por vía retrolabial en el tratamiento de niños con convulsión febril en el Hospital Pediátrico de Gambia, desde julio de 2007 hasta julio de 2008. Método: Se realizó un ensayo clínico, aleatorizado, paralelo, unicéntrico, a ciego por tercero, de eficacia del diazepam retrolabial controlado con diazepam intravenoso en el tratamiento de la convulsión febril. Fueron incluidos 66 niños, con convulsión y fiebre, mayores de seis meses y menores de cinco años de edad, de ambos sexos y con consentimiento informado del familiar. Se determinó el tiempo que transcurrió para alcanzar la vía de administración, el tiempo de alivio de la convulsión una vez administrado el medicamento y la aparición de reacciones adversas. Al grupo de tratamiento se le administró diazepam retrolabial 0,50 mg/kg/dosis y al grupo control diazepam intravenoso 0,25 mg/kg/dosis. Resultados: el tiempo necesario para alcanzar la vía de administración fue significativamente menor para el grupo que recibió diazepam retrolabial y más prolongado para la administración intravenosa. El tiempo al que se logró la acción anticonvulsivante una vez administrado el medicamento no varió entre los dos grupos. El diazepam administrado por vía retrolabial fue bien tolerado y presentó menor riesgo de padecer reacciones adversas medicamentosas que el intravenoso. Conclusiones: el diazepam por vía retrolabial es eficaz y seguro para tratar la crisis de convulsión febril en niños.

Diazepam administered rectal or intravenously constitutes the election treatment in children with febrile convulsion. Some authors consider that buccal route could be more practice and effective alternative. Objective: to evaluate the effectiveness of diazepam administered by buccal route in the treatment of children with febrile convulsion at the Pediatric Hospital of Gambia, from July 2007 to July 2008. Method: a randomized, parallel, unicentric, third blind clinical trial was conducted on the effectiveness of the controlled buccal diazepam with intravenous diazepam in the treatment of febrile convulsion. Sixty-six children were included with convulsion and fever, older than six months and under five years old, from both sexes and with their relative informed consent. The time to reach the administration route; the relief time of convulsion once the drug was administered and the appearance of adverse reactions were determined. To the treatment group was administered buccal diazepam 0,50 mg/kg/dose and to the control group intravenous diazepam 0,25 mg/kg/dose. Results: the necessary time to reach the administration route was significantly smaller for the group that received buccal diazepam and more prolonged than the one of intravenous administration. The time to which the anticonvulsant action was achieved once the drug was administered didn't vary among the two groups. Diazepam administered by buccal route was well tolerated and it presented lower risk of suffering adverse reactions than intravenous one. Conclusions: diazepam administered by buccal route is effective and safe to treat febrile seizures in children.

Implementación de la iniciativa de registro de ensayos clínicos / Implementing the clinical trials registry initiative

La Organización Mundial de la Salud (OMS)/Organización Panamericana de la Salud (OPS) considera que el registro prospectivo de todos los ensayos clínicos en bases de datos públicamente accesibles es una responsabilidad científica y ética. El registro de ensayos es “la publicación de un conjunto de datos consensuados internacionalmente sobre el diseño, la conducción y la administración de los ensayos clínicos. Esta información se publica en un sitio web de acceso público administrado por un registro que cumple con los estándares de la OMS”. Se considera que el registro de los ensayos clínicos debe ser un requisito para la autorización, puesta en marcha y la ulterior publicación en las revistas biomédicas (1)...

The evolution of phase I trials in cancer medicine: a critical review of the last decade / 癌症

The advent of targeted therapies, combined with an unsustainable rate of failure in oncology drug development, has resulted in a number of new approaches to clinical trials. Early clinical trials are no exception, with efforts to improve the eventual success rate of late stage trials through evolving phase I trial methodologies, the addition of extensive pharmacodynamic studies, and early adoption of patient selection strategies. Unfortunately, some of these new approaches have met with mixed results. Furthermore, no clear metrics are available to determine whether these designs are more successful than previous strategies. This review examines the evolution of phase I trials and draws upon several examples of strategies that have been successful as well as those that have not, and outlines a pragmatic approach to phase I trials as our understanding of the molecular biology of individual malignancies emerges.

Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.

Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.

Sugammadex - A short review and clinical recommendations for the cardiac anesthesiologist.

This review outlines the basic pharmacodynamic and pharmacokinetic properties of sugammadex for the cardiac anesthesiologist. It describes the different clinical scenarios when sugammadex can be used during cardiac surgery and gives clinical recommendations. Sugammadex is a unique reversal drug that binds a chemical complex with rocuronium and vecuronium, by which the neuromuscular blockade is quickly reversed. It is free of any clinical side-effects and doses of 2 mg/kg or more reliably reverse neuromuscular blockade within 5-15 min, depending on the depth of the neuromuscular blockade. Doses below 2 mg/kg should be avoided at any time because of the inherent risk of recurarization. Sugammadex should not replace good clinical practice - titration of neuromuscular blocking drugs to clinical needs and objective monitoring of neuromuscular blockade in the operating room or intensive care unit. Neuromuscular transmission should be determined in all patients before sugammadex is considered and 5 min after its administration to ensure that extubation is performed with normal neuromuscular transmission.

Hahnemann and the methodology of pathogenetic trials in healthy volunteers: a reappraisal / Hahnemann e a metodologia de ensaios patogenéticos em voluntários saudáveis: uma reavaliação / Hahnemann y la metodología de ensayos patogenéticos en voluntarios sanos: una reevaluación

This article assesses the guidelines and protocols that Hahnemann developed for homeopathic pathogenetic trials (HPTs) - often referred to as proving - and reappraise them in the light of more recent knowledge and protocols for clinical trials involving human subjects. Innovative features and methods introduced by Hahnemann and aimed at reducing bias are noted. A number of features which are now known to lead to bias in trials and which may be included in the reporting of symptoms are discussed in relation to HPTs. These features include: absence of control groups, absence of random allocation, absence of blinding, the inclusion of trivial and pre-existing symptoms, the inclusion of well-known acquaintances as trial participants, and the lack of definition of the healthy state. Advice from experts and papers published in recent decades related to the design of HPTs are discussed. The importance of developing methods to screen participants in HPTs for susceptibility to the tested medicine is discussed. The absence of trials meeting high quality standards in their design is highlighted. The article concludes with a plea for researchers to show the same desire for rigour and innovation that Hahnemann did in the development of HPTs, whilst fully recognising the requirements and protocols necessary for any trial of medicines on human beings, so that, as Hahnemann wanted, only reliable symptoms from HPTs will be admitted in the materia medica and clinical practice.

Este artigo discute as orientações e protocolos desenvolvidos por Hahnemann, para a realização de ensaios homeopáticos patogenésicos e reavalia-os com base no conhecimento e protocolos atuais, usados em pesquisas clínicas envolvendo humanos. Técnicas e métodos inovadores foram introduzidos por Hahnemann objetivando a redução de viéses estatísticos. Alguns aspectos metodológicos que podem induzir viéses em ensaios patogenésicos e que podem levar a inclusão incorreta de sintomas são discutidos. Dentre vários, podemos citar: ausência de grupo controle, ausência de randomização, ausência de protocolo cego, inclusão de sintomas triviais e pré-existentes, inclusão de conhecidos como participantes no estudo e a falta de definição do estado saudável. Recomendações de especialistas e de trabalhos publicados recentemente, relacionados aos ensaios patogenésicos são discutidos. A importância do desenvolvimento de métodos capazes de identificar a susceptibilidade dos participantes, aos medicamentos testados, é discutida. A ausência de ensaios desenhados com alto padrão metodológico é destacada. Este artigo termina com um apelo para que pesquisadores mantenham o mesmo desejo pela inovação e rigor metodológico, como Hahnemann, no desenvolvimento dos ensaios patogenésicos, não obstante atendendo plenamente os protocolos e requerimentos necessários para qualquer ensaio de medicamentos, com humanos, de forma que, como Hahnemann queria, somente sintomas confiáveis possam ser admitidos na matéria medica e na prática clínica.

Este artículo reevalúa las orientaciones y protocolos que Hahnemann formuló para los ensayos patogenéticos homeopáticos (HPTs) a la luz de conocimientos y protocolos recientes para la investigación en seres humanos. Son mencionados algunos aspectos y métodos innovadores formulados por Hahnemann, en particular aquellos destinados a reducir sesgos. Un número de aspectos actualmente conocidos que llevan a sesgos en ensayos y que pueden aparecer en el reporte de síntomas son discutidos en el contexto de los HPTs. Entre estos aspectos se menciona: ausencia de grupos-controle, ausencia de distribución aleatoria, falta de cegamiento, inclusión de síntomas triviales y pre-existentes, inclusión de personas conocidas como participantes del estudio y la falta de definición del concepto de estado de salud. Se discute la opinión de expertos así como la literatura especializada publicada en las últimas décadas sobre el diseño de HPTs. También es abordad la importancia de formular métodos para seleccionar participantes en HPTs en función de su susceptibilidad a la droga estudiada. Es resaltada la falta de estudios de alta calidad metodológica. O artículo concluye con una convocatoria para que los investigadores utilicen el mismo rigor e espíritu innovador que Hahnemann en el desarrollo de HPTs, y que al mismo tiempo reconozcan plenamente los requisitos y protocolos necesarios en cualquier ensayo de drogas en seres humanos de modo a cumplir el desiderátum de Hahnemann: admitir solamente síntomas confiables en la materia médica y la práctica clínica.