RESUMEN
Self-care interventions include over-the-counter contraceptives, which enable individuals to make informed, autonomous decisions about fertility management. As there is a substantial unmet need for contraception in many countries, increasing access by establishing sound, affordable and effective regulation of over-the-counter contraceptives could help reduce unintended pregnancies and improve maternal health. We performed a review of 30 globally diverse countries: (i) to assess national regulatory procedures for changing oral contraceptives, emergency contraceptives and injectable contraceptives from prescription-only to over-the-counter products; and (ii) to determine whether national lists of over-the-counter medicines included contraceptives. Of the 30 countries, 13 (43%) had formal regulatory procedures in place for changing prescription-only medicines to over-the-counter medicines, 11 (36%) had national lists of over-the-counter medicines, and four (13%) included contraceptives on those lists. Changing from prescription-only to over-the-counter medicines presents challenges for national medicines regulatory authorities and manufacturers, involving, for example, reporting side-effects, quality control and the often poorly-defined process of switching to over-the-counter products. To facilitate the over-the-counter availability of contraceptives, countries should consider adopting a formal regulatory procedure for reclassifying prescription-only contraceptives as over-the-counter contraceptives. Although the availability of over-the-counter contraceptives can increase users' independence and anonymity and improve access, there may also be disadvantages, such as higher out-of-pocket costs and the need for accurate self-assessment. Basic remedial actions to improve, harmonize and standardize regulatory procedures for the reclassification of contraceptives are proposed with the aim of enabling national medicines regulatory authorities to manage the switch to over-the-counter contraceptives and to control their quality.
Les soins autoadministrés incluent les contraceptifs en vente libre, qui permettent aux individus de prendre des décisions réfléchies et autonomes concernant le contrôle de la fécondité. Vu le besoin criant de contraception dans de nombreux pays, faciliter l'accès en proposant des méthodes de régulation sûres, efficaces et abordables par le biais de contraceptifs en vente libre pourrait contribuer à diminuer le nombre de grossesses non désirées et à améliorer la santé maternelle. Nous avons passé en revue 30 pays aux profils variés: (i) pour évaluer les procédures réglementaires nationales visant à modifier le statut des contraceptifs oraux, d'urgence et injectables afin qu'ils soient en vente libre au lieu d'être considérés comme des médicaments sur ordonnance; et (ii) pour déterminer si les contraceptifs figuraient sur les listes nationales de médicaments en vente libre. Sur les 30 pays observés, 13 (43%) avaient mis en place des procédures réglementaires officielles en vue de modifier le statut des contraceptifs, 11 (36%) possédaient des listes nationales de médicaments en vente libre et quatre (13%) y avaient inscrit les contraceptifs. Le passage du statut de médicament sur ordonnance à celui de médicament en vente libre représente un défi pour les autorités nationales de réglementation pharmaceutique et les fabricants, notamment en matière de déclaration des effets secondaires, de contrôle de la qualité et en raison d'un processus souvent mal défini. S'ils souhaitent favoriser la disponibilité des contraceptifs en vente libre, les pays devraient envisager l'adoption d'une procédure réglementaire officielle destinée à reclassifier les contraceptifs sur ordonnance en contraceptifs en vente libre. Bien que cette disponibilité puisse accroître l'autonomie et l'anonymat des usagers et améliorer l'accès à la contraception, elle présente également des désavantages car elle entraîne une hausse des frais non remboursés et requiert une autoévaluation correcte. Le présent document formule des mesures correctrices élémentaires servant à améliorer, harmoniser et normaliser les procédures réglementaires de reclassification des contraceptifs. Objectif: permettre aux autorités nationales de réglementation pharmaceutique de superviser le passage au statut de médicament en vente libre et de contrôler la qualité.
Las intervenciones de cuidado personal incluyen los anticonceptivos de venta libre, que permiten a las personas tomar decisiones informadas y autónomas sobre la gestión de la fertilidad. Dado que en muchos países existe una importante necesidad insatisfecha de anticoncepción, aumentar el acceso mediante el establecimiento de una normativa sólida, asequible y eficaz de los anticonceptivos de venta libre podría ayudar a reducir los embarazos no deseados y mejorar la salud materna. Se realizó una revisión de 30 países de todo el mundo: (i) para evaluar los procedimientos normativos nacionales relativos al cambio de los anticonceptivos orales, los anticonceptivos de urgencia y los anticonceptivos inyectables de medicamentos de venta con receta a productos de venta libre; y (ii) para determinar si las listas nacionales de medicamentos de venta libre incluían los anticonceptivos. De los 30 países, 13 (43 %) contaban con procedimientos normativos formales para el cambio de medicamentos de venta con receta a medicamentos de venta libre, 11 (36 %) tenían listas nacionales de medicamentos de venta libre, y cuatro (13 %) incluían los anticonceptivos en esas listas. El cambio de los medicamentos de venta con receta a los de venta libre supone un desafío para las autoridades nacionales de regulación de medicamentos y para los fabricantes, ya que implica, por ejemplo, la notificación de los efectos secundarios, el control de calidad y el proceso, que suele estar mal definido, de pasar a los productos de venta libre. Para facilitar la disponibilidad de los anticonceptivos sin receta, los países deberían considerar la adopción de un procedimiento normativo formal para reclasificar los anticonceptivos de venta con receta como anticonceptivos de venta sin receta. Aunque la disponibilidad de los anticonceptivos de venta libre puede aumentar la independencia y el anonimato de los usuarios y mejorar el acceso, también puede haber desventajas, como los mayores costos de bolsillo y la necesidad de una autoevaluación precisa. Se proponen acciones correctivas básicas para mejorar, armonizar y estandarizar los procedimientos normativos para la reclasificación de los anticonceptivos, con el objetivo de que las autoridades nacionales de regulación de medicamentos puedan gestionar el cambio a los anticonceptivos sin receta y controlar su calidad.
Asunto(s)
Anticonceptivos Orales , Medicamentos sin Prescripción , Anticoncepción , Femenino , Gastos en Salud , Humanos , Embarazo , Embarazo no PlaneadoRESUMEN
The vegetation and soil microbiome within urban green spaces is increasingly managed to help conserve biodiversity and improve human health concurrently. However, the effects of green space management on urban soil ecosystems is poorly understood, despite their importance. Across 40 urban green spaces in metropolitan Adelaide, South Australia, we show that soil bacterial communities are strongly affected by urban green space type (incl. sport fields, community gardens, parklands and revegetated areas), and that plant species richness is positively associated with soil bacterial diversity. Importantly, these microbiome trends were not affected by geographic proximity of sample sites. Our results provide early evidence that urban green space management can have predictable effects on the soil microbiome, at least from a diversity perspective, which could prove important to inform policy development if urban green spaces are to be managed to optimise population health benefits.
Asunto(s)
Parques Recreativos , Suelo , Bacterias/genética , Biodiversidad , Humanos , Plantas , Microbiología del Suelo , Australia del SurRESUMEN
The World Health Organization 2019 WHO consolidated guideline on self-care interventions for health: sexual and reproductive health and rights includes recommendations on self-administration of injectable contraception, over-the-counter (OTC) oral contraception and self-management of medical abortion. A review of the regulatory status of these two self-care interventions can highlight processes required to ensure that the quality of the medicines and safety of individuals are safeguarded in the introduction and scale-up in countries. This review outlines the legal regulatory status of prescription-only medicine (POM) and OTC contraceptives, including emergency contraception, and drugs for medical abortion in Egypt, Jordan, Lebanon, Morocco and Tunisia using information obtained from internet searches, regulatory information databases and personal contacts. In addition, the review examines whether the national medicines regulatory authorities have documented procedures available to allow for a change in status from a POM to OTC to allow for increased accessibility, availability and uptake of self-care interventions recommended by WHO. Egypt, Jordan and Lebanon have a documented national OTC list available. The only contraceptive product mentioned in the OTC lists across all five countries is ellaOne (ulipristal acetate for emergency contraception), which is publicly registered in Lebanon. None of the five countries has an official documented procedure to apply for the change of POM to OTC. Informal procedures exist, such as the ability to apply to the national medicines regulatory authority for OTC status if the product has OTC status in the original country of manufacture. However, many of these procedures are not officially documented, highlighting the need for establishing sound, affordable and effective regulation of medical products as an important part of health system strengthening. From a public health perspective, it would be advantageous for licensed products to be available OTC. This is particularly the case for settings where the health system is under-resourced or over-stretched due to health emergencies. Readiness of national regulatory guidelines and OTC procedures could lead to increased access, availability and usage of essential self-care interventions for sexual and reproductive health and rights.
Asunto(s)
Anticoncepción Hormonal , Preparaciones Farmacéuticas , Femenino , Humanos , Líbano , Región Mediterránea , Marruecos , EmbarazoRESUMEN
Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. ADC development is a rapidly expanding field of research, with over 80 ADCs currently in clinical development and eleven ADCs (nine containing small-molecule payloads and two with biological toxins) approved for use by the FDA. Compared to traditional small-molecule approaches, ADCs offer enhanced targeting of cancer cells along with reduced toxic side effects, making them an attractive prospect in the field of oncology. To this end, this tutorial review aims to serve as a reference material for ADCs and give readers a comprehensive understanding of ADCs; it explores and explains each ADC component (monoclonal antibody, linker moiety and cytotoxic payload) individually, highlights several EMA- and FDA-approved ADCs by way of case studies and offers a brief future perspective on the field of ADC research.
Asunto(s)
Antineoplásicos/uso terapéutico , Inmunoconjugados/uso terapéutico , Neoplasias/tratamiento farmacológico , Antineoplásicos/química , Ensayos Clínicos como Asunto , Aprobación de Drogas , Humanos , Inmunoconjugados/químicaRESUMEN
Tuberculosis (TB), an infectious disease caused by the bacterium Mycobacterium tuberculosis, was the leading cause of mortality worldwide in 2019 due to a single infectious agent. The growing threat of strains of M. tuberculosis untreatable by modern antibiotic regimens only exacerbates this problem. In response to this continued public health emergency, research into methods of potentiating currently approved antimicrobial agents against resistant strains of M. tuberculosis is an urgent priority, and a key strategy in this regard is the design of mycobacterial efflux pump inhibitors (EPIs). This review summarises the current state of knowledge surrounding drug-related efflux pumps in M. tuberculosis and presents recent updates within the field of mycobacterial EPIs with a view to aiding the design of an effective adjunct therapy to overcome efflux-mediated resistance in TB.
Asunto(s)
Antiinfecciosos , Mycobacterium tuberculosis , Tuberculosis , Antiinfecciosos/farmacología , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Proteínas Bacterianas/farmacología , Farmacorresistencia Bacteriana , Humanos , Tuberculosis/terapiaRESUMEN
In antibody-drug conjugates (ADCs), monoclonal antibodies (mAbs) act as carriers for a cytotoxic payload providing the therapy with targeted action against cells expressing a target cell surface antigen. An appropriate choice of mAb is crucial to developing a successful ADC for clinical development. However, problems such as immunogenicity, poor pharmacokinetic (PK) and pharmacodynamic (PD) profiles and variable drug-antibody ratios (DARs) plague ADCs. In this review, we detail recent mAb-based innovations and factors that should be considered to overcome these problems to achieve a new generation of more effective ADC therapeutics.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Desarrollo de Medicamentos , Inmunoconjugados/farmacología , Neoplasias/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/normas , Desarrollo de Medicamentos/tendencias , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Mejoramiento de la CalidadRESUMEN
Diabetic complications are associated with overexpression of aldose reductase, an enzyme that catalyzes the first step of the polyol pathway. Osmotic stress in the hyperglycemic state is linked with the intracellular accumulation of sorbitol along with the depletion of NADPH and eventually leads to oxidative stress via formation of reactive oxygen species and advanced glycation end products (AGEs). These kinds of mechanisms cause the development of various diabetic complications including neuropathy, nephropathy, retinopathy, and atherosclerotic plaque formation. Various aldose reductase inhibitors have been developed to date for the treatment of diabetic complications, but all have failed in different stages of clinical trials due to toxicity and poor pharmacokinetic profiles. This toxicity is rooted in a nonselective inhibition of both ALR2 and ALR1, homologous enzymes involved in the metabolism of toxic aldehydes such as methylglyoxal and 3-oxyglucosazone. In the present study, we developed a series of thiosemicarbazone derivatives as selective inhibitors of ALR2 with both antioxidant and antiglycation potential. Among the synthesized compounds, 3c exhibited strong and selective inhibition of ALR2 (IC50 1.42 µM) along with good antioxidant and antiglycative properties. The binding mode of 3c was assessed through molecular docking and cluster analysis via MD simulations, while in silico ADME evaluation studies predicted the compounds' druglike properties. Therefore, we report 3c as a drug candidate with promising antioxidant and antiglycative properties that may be useful for the treatment of diabetic complications through selective inhibition of ALR2.
RESUMEN
The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.
Asunto(s)
Complicaciones de la Diabetes , Tiosemicarbazonas , Aldehído Reductasa , Inhibidores Enzimáticos/química , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Tiosemicarbazonas/química , Tiosemicarbazonas/farmacologíaRESUMEN
The novel coronavirus (SARS-CoV-2) pandemic has created a global public health emergency. The pandemic is causing substantial morbidity, mortality and significant economic loss. Currently, no approved treatments for COVID-19 are available, and it is likely to takes at least 12-18 months to develop a new vaccine. Therefore, there is an urgent need to find new therapeutics that can be progressed to clinical development as soon as possible. Repurposing regulatory agency-approved drugs and experimental drugs with known safety profiles can provide important repositories of compounds that can be fast-tracked to clinical development. Globally, over 500 clinical trials involving repurposed drugs have been registered, and over 150 have been initiated, including some backed by the World Health Organisation (WHO). This review is intended as a guide to research into small-molecule therapies to treat COVID-19; it discusses the SARS-CoV-2 infection cycle and identifies promising viral therapeutic targets, reports on a number of promising pre-approved small-molecule drugs with reference to over 150 clinical trials worldwide, and offers a perspective on the future of the field.
Asunto(s)
COVID-19 , Antivirales/uso terapéutico , Reposicionamiento de Medicamentos , Humanos , Pandemias , SARS-CoV-2RESUMEN
The fluoroquinolone class of antibiotics has a well-established structure-activity relationship (SAR) and a long history in the clinic, but the effect of electron-rich benzofused substituents at the N1 position remains poorly explored. Because groups at this position are part of the topoisomerase-DNA binding complex and form a hydrophobic interaction with the major groove of DNA, it was hypothesized that an electron-rich benzofused N1 substituent could enhance this interaction. Molecular modeling techniques were employed to evaluate the binding of certain N1-modified fluoroquinolones to DNA gyrase targets from both Staphylococcus aureus and Klebsiella pneumoniae species compared with ciprofloxacin and norfloxacin. Seven N1-modified fluoroquinolones were subsequently synthesized and tested against a panel of Gram-negative pathogens to determine minimum inhibitory concentration (MIC) values. Gram-negative outer membrane penetration was investigated using the membrane permeabilizer polymyxin B nonapeptide and compound efflux via resistance-nodulation-division-family efflux transporters was evaluated using the known efflux pump inhibitor phenylalanine-arginine ß-naphthylamide. Additionally, the target inhibitory activity of representative compound 6e was determined in a cell-free environment. A correlation between N1 substituent hydrophobicity and activity was observed across the MIC panel, with compound activity decreasing with increased hydrophobicity. Those compounds with highest hydrophobicity were inactive because of poor solubility profiles whereas compounds with intermediate hydrophobicity were inactive because of impaired outer membrane penetration, and reduced inhibition of topoisomerase targets, the latter in contrast to modeling predictions. This study adds new information to the fluoroquinolone SAR and suggests limited utility of large hydrophobic substituents at the N1 position of fluoroquinolones.
RESUMEN
Infections of antibiotic-resistant pathogens pose an ever-increasing threat to mankind. The investigation of novel approaches for tackling the antimicrobial resistance crisis must be part of any global response to this problem if an untimely reversion to the pre-penicillin era of medicine is to be avoided. One such promising avenue of research involves so-called antibiotic resistance breakers (ARBs), capable of re-sensitising resistant bacteria to antibiotics. Although some ARBs have previously been employed in the clinical setting, such as the ß-lactam inhibitors, we posit that the broader field of ARB research can yet yield a greater diversity of more effective therapeutic agents than have been previously achieved. This review introduces the area of ARB research, summarises the current state of ARB development with emphasis on the various major classes of ARBs currently being investigated and their modes of action, and offers a perspective on the future direction of the field.
Asunto(s)
Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Investigación Biomédica/tendencias , Farmacorresistencia Microbiana/efectos de los fármacos , Animales , Infecciones Bacterianas/tratamiento farmacológico , Ensayos Clínicos como Asunto , Descubrimiento de Drogas/tendencias , Humanos , Ratones , Inhibidores de beta-Lactamasas/farmacología , Inhibidores de beta-Lactamasas/uso terapéuticoRESUMEN
The development of new antitubercular agents for the treatment of infections caused by multidrug-resistant (MDR) Mycobacterium tuberculosis is an urgent priority. Pyrrolobenzodiazepines (PBDs) are a promising class of antibacterial agents that were initially discovered and isolated from a range of Streptomyces species. Recently, C8-linked PBD monomers have been shown to work by inhibiting DNA gyrase and have demonstrated activity against M. tuberculosis. However, both PBD monomers and dimers are toxic to eukaryotic cells, limiting their development as antibacterial agents. To eliminate the toxicity associated with PBDs and explore the effect of C8-modification with a known antibacterial agent with the same mechanism of action (i.e., ciprofloxacin, a gyrase inhibitor), we synthesized a C8-linked PBD-ciprofloxacin (PBD-CIP, 3) hybrid. The hybrid compound displayed minimum inhibitory concentration values of 0.4 or 2.1 µg/mL against drug-sensitive and drug-resistant M. tuberculosis strains, respectively. A molecular modeling study showed good interaction of compound 3 with wild-type M. tuberculosis DNA gyrase, suggesting gyrase inhibition as a possible mechanism of action. Compound 3 is a nontoxic combination hybrid that can be utilized as a new scaffold and further optimized to develop new antitubercular agents.