RESUMEN

BACKGROUND: YF-VAX® (Sanofi, Swiftwater, PA), a live, attenuated vaccine based on the yellow fever (YF) substrain 17D-204, is the only YF vaccine licensed in the USA. Manufacturing disruption of YF-VAX and anticipated depletion of the US supply by mid-2017 led to the importation of another YF vaccine, STAMARIL® (Sanofi, France), into the USA under an expanded access investigational new drug program (EAP) to fulfil the public health need for YF vaccination. As part of this program, Sanofi collected enhanced safety surveillance data following vaccination with STAMARIL. Here, we report the results of the enhanced safety surveillance. METHODS: STAMARIL vaccine was offered to those aged ≥9 months at high risk of YF. Vaccine recipients (or parents/guardians) were instructed to report suspected adverse reactions, any serious adverse events (SAEs) including adverse events of special interest [AESI] occurring after vaccination regardless of suspected relationship, and any inadvertent exposure in pregnancy or breastfeeding within 14 days of vaccination. The AESIs monitored were anaphylaxis, neurotropic disease (YEL-AND) and viscerotropic disease (YEL-AVD). RESULTS: Overall, 627 079 individuals received STAMARIL from May 2017 through June 2021; of these, 1308 (0.2%) reported at least one AE, of which 122 reported at least one SAE. There were seven cases of YEL-AND and three cases of YEL-AVD reported, for reporting rates of 1.1 and 0.5 per 100 000 vaccine recipients, respectively. One vaccine recipient developed an anaphylactic reaction (reporting rate: 0.16 per 100 000). No safety concerns were identified from inadvertent vaccine exposure during pregnancy (41 pregnant women) or potential neonatal exposure via breast milk (four exposed infants). CONCLUSIONS: This study supports the utility of STAMARIL in the EAP as an alternative solution for the YF vaccine shortage in the USA. SAEs were very rare and consistent with the known safety profile of STAMARIL.

Asunto(s)

Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Femenino , Humanos , Lactante , Recién Nacido , Embarazo , Drogas en Investigación , Vacunación/efectos adversos , Vacunas Atenuadas/efectos adversos , Fiebre Amarilla/prevención & control , Vacuna contra la Fiebre Amarilla/efectos adversos

RESUMEN

Current human immunodeficiency virus treatments need to be periodically administered lifelong. In this study we assess the effect of repeated doses of an anti-HIV peptide drug candidate in C57BL6 strain. Two schemes of up to 15 administrations and one of 30, daily dosing for 5 days per week, all by the subcutaneous route were evaluated. Different dose concentrations of the peptide were assayed. CIGB-210 treated animals showed no symptoms or abnormal behavior as compared with placebo. All the animals gained weight during the study. Macroscopic evaluation showed no alterations in any of the organs studied. Microscopic analysis of the tissues did not show morphological changes in thymus, stomach, small and large intestines, kidney, brain, or cerebellum. The proliferative response of splenocytes and their capacity to secrete gamma interferon were not compromised by the repeated administration of CIGB-210. There were not statistically significant differences for any of the parameters evaluated during the study among treated and non-treated groups. We can conclude that CIGB-210 is well tolerated in C57BL6 mice in the dose concentration range explored and merits subsequent toxicological studies.

Asunto(s)

Fármacos Anti-VIH/uso terapéutico , Evaluación Preclínica de Medicamentos , Drogas en Investigación/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Péptidos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL

RESUMEN

Scoring functions are essential for modern in silico drug discovery. However, the accurate prediction of binding affinity by scoring functions remains a challenging task. The performance of scoring functions is very heterogeneous across different target classes. Scoring functions based on precise physics-based descriptors better representing protein-ligand recognition process are strongly needed. We developed a set of new empirical scoring functions, named DockTScore, by explicitly accounting for physics-based terms combined with machine learning. Target-specific scoring functions were developed for two important drug targets, proteases and protein-protein interactions, representing an original class of molecules for drug discovery. Multiple linear regression (MLR), support vector machine and random forest algorithms were employed to derive general and target-specific scoring functions involving optimized MMFF94S force-field terms, solvation and lipophilic interactions terms, and an improved term accounting for ligand torsional entropy contribution to ligand binding. DockTScore scoring functions demonstrated to be competitive with the current best-evaluated scoring functions in terms of binding energy prediction and ranking on four DUD-E datasets and will be useful for in silico drug design for diverse proteins as well as for specific targets such as proteases and protein-protein interactions. Currently, the MLR DockTScore is available at www.dockthor.lncc.br .

Asunto(s)

Descubrimiento de Drogas/métodos , Drogas en Investigación/metabolismo , Inhibidores de Proteasas/metabolismo , Proyectos de Investigación/estadística & datos numéricos , Programas Informáticos , Máquina de Vectores de Soporte , Conjuntos de Datos como Asunto , Drogas en Investigación/química , Drogas en Investigación/farmacología , Entropía , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Internet , Ligandos , Simulación del Acoplamiento Molecular , Péptido Hidrolasas/química , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Mapeo de Interacción de Proteínas

RESUMEN

INTRODUCTION: Zika virus (ZIKV) is transmitted to humans throughout bites of Aedes mosquitoes. ZIKV infection may be asymptomatic in most cases, but it may cause fever, headache, muscle pain, and rash. Guillain-Barré syndrome also may be associated with the infection. Furthermore, the Pan American Health Organization informed 3,715 cases of the congenital ZIKV syndrome (CZS) in the Americas from 2015 - 2017, which may include microcephaly and other craniofacial deformities. AREAS COVERED: This review identifies patent documents on repositioning for ZIKV infection treatment of already approved drugs or phases II/III investigated drugs for other diseases. Thirty-six patents were found reporting compounds with anti-ZIKV activity with application dates ranging from 2015 to 2019. EXPERT OPINION: The main drugs claimed in patents were ribavirin, sofosbuvir, and alpha interferons. Preventing CZS is one of the most significant challenges in ZIKV infection. Therefore, repositioning sofosbuvir and niclosamide, that pose no danger for pregnant women, is a particular issue to be considered for clinical tests involving ZIKV disease. Given the substantial costs and developing time of new a drug, repositioning of old drugs is becoming an attractive alternative for diseases with neglected treatments.

Asunto(s)

Antivirales/administración & dosificación , Drogas en Investigación/administración & dosificación , Infección por el Virus Zika/tratamiento farmacológico , Aedes/virología , Animales , Antivirales/farmacología , Reposicionamiento de Medicamentos , Drogas en Investigación/farmacología , Femenino , Humanos , Microcefalia/prevención & control , Microcefalia/virología , Patentes como Asunto , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/virología , Infección por el Virus Zika/complicaciones , Infección por el Virus Zika/virología

RESUMEN

BACKGROUND: Invasive meningococcal disease is a major cause of meningitis in children. An investigational meningococcal (serogroups A, C, Y, and W) tetanus toxoid conjugate vaccine (MenACYW-TT) could offer protection against invasive meningococcal disease in this population. This phase III study assessed the immunogenicity and safety of MenACYW-TT in children compared with a licensed quadrivalent meningococcal vaccine conjugated with diphtheria protein CRM197 (MenACWY-CRM). METHODS: Healthy children 2-9 years of age in the United States, including Puerto Rico, were randomized (1:1) to receive MenACYW-TT (n = 499) or MenACWY-CRM (n = 501) (NCT03077438). Meningococcal antibody titers to the 4 vaccine serogroups were measured using a serum bactericidal antibody assay with human complement (hSBA) before and at day 30 after vaccination. Noninferiority between the vaccine groups was assessed by comparing seroresponse rates (postvaccination titers ≥1:16 when prevaccination titers were <1:8, or ≥4-fold increase if prevaccination titers were ≥1:8) to the 4 serogroups at day 30. Safety was monitored. RESULTS: The proportion of participants achieving seroresponse at day 30 in the MenACYW-TT group was noninferior to the MenACWY-CRM group (A: 55.4% vs. 47.8%; C: 95.2% vs. 47.8%; W: 78.8% vs. 64.1%; Y: 91.5% vs. 79.3%, respectively). Geometric mean titers for serogroups C, W, and Y were higher with MenACYW-TT than for MenACWY-CRM. Both vaccines were well-tolerated and had similar safety profiles. CONCLUSIONS: MenACYW-TT was well-tolerated in children and achieved noninferior immune responses to MenACWY-CRM against each of the 4 vaccine serogroups.

Asunto(s)

Inmunogenicidad Vacunal , Infecciones Meningocócicas/prevención & control , Vacunas Meningococicas/inmunología , Vacunas Combinadas/inmunología , Anticuerpos Antibacterianos/sangre , Niño , Preescolar , Método Doble Ciego , Drogas en Investigación/administración & dosificación , Humanos , Infecciones Meningocócicas/inmunología , Vacunas Meningococicas/administración & dosificación , Neisseria meningitidis/inmunología , Puerto Rico , Toxoide Tetánico/administración & dosificación , Toxoide Tetánico/inmunología , Estados Unidos , Vacunación , Vacunas Combinadas/administración & dosificación , Vacunas Conjugadas/administración & dosificación , Vacunas Conjugadas/inmunología

RESUMEN

The management of genitourinary cancer, including bladder, prostate, renal and testicular cancer, has evolved dramatically in recent years due to a better understanding of tumour genetic mutations, alterations in molecular pathways, and to the development of new kinds of drugs such as targeted therapies and immunotherapies. In the field of immunotherapy, new drugs focused on stimulating, enhancing and modulating the immune system to detect and destroy cancer, have been recently discovered. Research in oncology moves quickly and new data of great relevance for clinical practice are communicated every year. For this reason, a group of experts, focused exclusively on the treatment of genitourinary tumours and who get together every year in the BestGU conference to assess the latest progress in this field have summarized the most important advances in a single review, along with a critical assessment of whether these results should alter daily clinical practice.

Asunto(s)

Neoplasias Urogenitales/genética , Neoplasias Urogenitales/terapia , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Cistectomía , Drogas en Investigación/uso terapéutico , Femenino , Humanos , Inmunoterapia/métodos , Inmunoterapia/tendencias , Neoplasias Renales/genética , Neoplasias Renales/terapia , Masculino , Terapia Molecular Dirigida/métodos , Mutación , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/terapia , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/terapia , Nefrectomía , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/terapia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia

Asunto(s)

Control de Acceso/ética , Oncología Médica/ética , Neoplasias/tratamiento farmacológico , Ensayos Clínicos como Asunto/ética , Drogas en Investigación/administración & dosificación , Accesibilidad a los Servicios de Salud/ética , Humanos

RESUMEN

Abstract Chronic inflammation is a common indication of several diseases, e.g. asthma, chronic obstructive pulmonary disease (COPD), atherosclerosis, etc. Benzimidazole derivatives are preferable compounds to design new analgesic and anti-inflammatory substances due to their unique biological features. We aimed to investigate the effect of a newly synthesized benzimidazole derivative, ORT-83, on A549 human lung adenocarcinoma cell line. ORT-83 was synthesized, and a non-cytotoxic concentration of ORT-83 on A549 cells was detected with MTT assay. To analyze the anti-inflammatory effect of ORT-83, an inflammatory cell culture model was established by stimulating A549 cell line with IL1-β (10 ng/ml). After 2 hours of treatment with IL1-β to induce inflammation, A549 cells were exposed to ORT-83 (0.78 µg/ml) for 24 hours. Thereafter gene expression analyses were performed with qRT-PCR. We found that ORT-83 significantly suppressed the gene expression levels of the proinflammatory cytokines; IL-6, NFkB, and TNF-α. However, the increased levels of IL-10 (2.8 folds) by IL-1β induction did not change after ORT-83 and/or dexamethasone (Dex: positive control) treatments. While Dex; a COX-2 inhibitor, reduced the COX-2 expression level in inflammatory cells from 10.03 folds to 0.71 folds, ORT-83 reduced its level to 4.37 folds. iNOS expression levels did not change in any experimental groups. In conclusion, we showed that ORT-83 exerted its anti-inflammatory effects by repressing the gene expression of proinflammatory cytokines in the inflammation-induced A549 cell line. Although ORT-83 had a weaker COX-2 inhibitory effect compared to Dex, it was shown to be still a strong anti-inflammatory compound.

Asunto(s)

Humanos , Bencimidazoles/farmacología , Drogas en Investigación , Analgésicos/farmacología , Antiinflamatorios/farmacología , Supervivencia Celular/efectos de los fármacos , Pruebas de Toxicidad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células A549

RESUMEN

Introduction: Binge eating disorder (BED) is the most common eating disorder and is frequently associated with psychiatric and medical comorbidities and functional impairment. Although psychological treatments have been the cornerstones of BED treatment, pharmacologic interventions also play an important part of the multimodal management of this condition.Areas covered: This review examines investigational, approved and other pharmacological agents for the treatment of BED. We searched PubMed and clinicaltrials.gov to identify pharmacological interventions for the management of this condition.Expert opinion: BED pharmacological studies have incorporated new drug targets based on our enhanced understanding of the pathophysiology of BED. Neurobiological dysregulation in the reward center and impulse control circuitry and related disturbances in dopamine neurotransmission are among the neurobiological explanations that have been suggested for BED. These mechanisms serve as a pharmacodynamic foundation for the development of new compounds such as lisdexamfetamine (LDX) and dasotraline. Despite these advances, pharmacological trials in BED have numerous challenges that must be overcome. For most compounds studied, larger and more definitive trials is a high priority.

Asunto(s)

Trastorno por Atracón/tratamiento farmacológico , Desarrollo de Medicamentos , Drogas en Investigación/administración & dosificación , Animales , Trastorno por Atracón/fisiopatología , Trastorno por Atracón/psicología , Dopamina/metabolismo , Drogas en Investigación/farmacología , Humanos , Recompensa

RESUMEN

Background:There is still a need for new alternatives in pharmacological therapy for neglected diseases, as the drugs available show high toxicity and parenteral administration. That is the case for the treatment of leishmaniasis, particularly to the cutaneous clinical form of the disease. In this study, we present the synthesis and biological screening of eight 4-phenyl-1,3-thiazol-2-amines assayed against Leishmania amazonensis. Herein we propose that these compounds are good starting points for the search of new antileishmanial drugs by demonstrating some of the structural aspects which could interfere with the observed activity, as well as suggesting potential macromolecular targets.Methods:The compounds were easily synthesized by the methodology of Hantzsch and Weber, had their purities determined by Gas Chromatography-Mass spectrometry and assayed against the promastigote forms of Leishmania amazonensis as well as against two white cell lines (L929 and THP-1) and the monkey's kidney Vero cells. PrestoBlue® and MTT viability assays were the methodologies applied to measure the antileishmanial and cytotoxic activities, respectively. A molecular modeling target fishing study was performed aiming to propose potential macromolecular targets which could explain the observed biological behavior.Results:Four out of the eight compounds tested exhibited important anti-promastigote activity associated with good selectivity indexes when considering Vero cells. For the most promising compound, compound 6, IC50 against promastigotes was 20.78 while SI was 5.69. Compounds 3 (IC50: 46.63 μM; SI: 26.11) and 4 (IC50: 53.12 μM; SI: 4.80) also presented important biological behavior. A target fishing study suggested that S-methyl-5-thioadenosine phosphorylase is a potential target to these compounds, which could be explored to enhance activity and decrease the potential toxic side effects....(AU)

Asunto(s)

Leishmaniasis/tratamiento farmacológico , Leishmania , Aminas/uso terapéutico , Drogas en Investigación

RESUMEN

La psoriasis es una enfermedad cutánea incurable que afecta a 2.9 % de la población mexicana, por lo que es trascendente analizar el impacto de la medicina traslacional en el desarrollo de medicamentos antipsoriásicos. En esta revisión se discuten conceptos etiopatogénicos de la enfermedad y se analizan artículos publicados entre 2005 y 2017 en torno a medicamentos en desarrollo, además, se presenta un análisis crítico sobre las perspectivas futuras en el desarrollo de nuevos tratamientos. El uso de estrategias bidireccionales de la medicina traslacional ha permitido incrementar significativamente el número de tratamientos antipsoriásicos disponibles. Se encontraron 18 nuevos fármacos en exploración. La caracterización de antígenos responsables de la activación inmunológica, la identificación de biomarcadores predictivos de eficacia farmacológica, el desarrollo de modelos más representativos de la enfermedad, así como la integración de aspectos farmacogenómicos a estrategias de medicina traslacional fueron identificados como elementos relevantes que deben ser incorporados en el desarrollo de nuevas opciones terapéuticas.Psoriasis is an incurable cutaneous disease that affects 2.9% of the Mexican population, and it is therefore important for the impact of translational medicine on the development of anti-psoriatic drugs to be analyzed. In this review, current etiopathogenic concepts of the disease are discussed, and articles on drugs under development published between 2005 and 2017 are reviewed; in addition, a critical analysis on future perspectives for the development new treatments is presented. The use of translational medicine bi-directional strategies of has allowed to significantly increase the number of available anti-psoriatic therapies. Eighteen new investigational drugs were found. Characterization of antigens responsible for immune activation, identification of predictive biomarkers with pharmacologic efficacy, and the development of more representative disease models, as well as the integration of pharmacogenomic aspects to translational medicine strategies were identified as relevant aspects that should be incorporated in the development of new therapeutic options.

Asunto(s)

Fármacos Dermatológicos/uso terapéutico , Desarrollo de Medicamentos/métodos , Psoriasis/tratamiento farmacológico , Biomarcadores/metabolismo , Drogas en Investigación/uso terapéutico , Humanos , México/epidemiología , Farmacogenética/métodos , Psoriasis/epidemiología , Psoriasis/genética , Investigación Biomédica Traslacional/métodos

RESUMEN

New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients' quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.

Asunto(s)

Erupciones por Medicamentos/etiología , Drogas en Investigación/efectos adversos , Inmunoterapia/efectos adversos , Melanoma/terapia , Terapia Molecular Dirigida/efectos adversos , Neoplasias Cutáneas/terapia , Terapias en Investigación/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Erupciones por Medicamentos/patología , Humanos , Melanoma/patología , Terapia Molecular Dirigida/métodos , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/inmunología , Neoplasias Cutáneas/patología

RESUMEN

PURPOSE: Participants' rights and safety must be guaranteed not only while a clinical trial is being conducted but also when a clinical trial finishes. The criteria for post-trial access to experimental drugs, however, are unclear in various countries. The objectives of this study were (i) to ascertain if there were regulations or guidelines related to patients' access to drugs after the end of clinical trials in the countries selected in the study and (ii) to analyze trends in post-trial access in countries classified by their level of economic development. METHODS: This study is a retrospective review. The data are from the records of clinical trials from 2014 registered in the World Health Organization's International Clinical Trials Registry Platform (ICTRP) database. RESULTS: Among the countries selected, provision of drugs post-trial is mandatory only in Argentina, Brazil, Chile, Finland, and Peru. The plans for post-trial access tend to be more present in low- and middle-income and upper middle-income countries, in comparison with high-income countries. Studies involving vulnerable populations are 2.53 times more likely to have plans for post-trial access than studies which do not. CONCLUSIONS: The guaranteeing of post-trial access remains mandatory in few countries. Considering that individuals seen as vulnerable have been included in clinical trials without plans for post-trial access, stakeholders must discuss the need to develop regulations mandating the guaranteeing of post-trial access in specified situations.

Asunto(s)

Ensayos Clínicos como Asunto/legislación & jurisprudencia , Drogas en Investigación , Seguridad del Paciente/legislación & jurisprudencia , Ensayos Clínicos como Asunto/normas , Accesibilidad a los Servicios de Salud/legislación & jurisprudencia , Accesibilidad a los Servicios de Salud/normas , Humanos , Legislación de Medicamentos , Sistema de Registros , Estudios Retrospectivos , Organización Mundial de la Salud

RESUMEN

The typical hemolytic uremic syndrome (HUS) is an orphan disease caused by Shiga toxin(Stx) producing Escherichia coli strains and characterized by acute kidney damage, microangiopathic hemolytic anemia and low platelet count. It is endemic in Argentina, the country with the highest incidence of HUS in the world. Stx is essential for its development and therefore, HUS is considered a toxemic non-bacteremic disorder, which could be treated with antibodies. Herein we describe the development of a new treatment capable of neutralizing the toxic effect of Stx and its variants. The treatment consists of F(ab')2 fragments from an equine antiserum whose efficacy and potency against Stx1 and Stx2 were proved in different preclinical models. The product was shown to be safe in animals. Furthermore, the anti-Stx F(ab')2 pharmacokinetic was shown to be similar to that of analogous compounds and a therapeutic window for its administration was determined. Altogether, these preclinical results warrant testing in humans. The phase I clinical trial will be performed at the Hospital Italiano in Buenos Aires to evaluate the safety and pharmacokinetics of the product in healthy adult volunteers. Based on the results of this study, a phase II clinical trial will be planned in pediatric patients diagnosed with infection by Stx-producing E. coli strains.

Asunto(s)

Drogas en Investigación , Infecciones por Escherichia coli/tratamiento farmacológico , Síndrome Hemolítico-Urémico/prevención & control , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Toxina Shiga I/antagonistas & inhibidores , Toxina Shiga II/antagonistas & inhibidores , Anticuerpos/inmunología , Argentina , Ensayos Clínicos Fase II como Asunto , Escherichia coli/inmunología , Escherichia coli/aislamiento & purificación , Infecciones por Escherichia coli/complicaciones , Síndrome Hemolítico-Urémico/inmunología , Humanos , Toxina Shiga I/inmunología , Toxina Shiga II/inmunología

RESUMEN

El síndrome urémico hemolítico (SUH) típico es una enfermedad huérfana causada por cepas de Escherichia coli productoras de toxina Shiga (Stx) y caracterizada por daño renal agudo, anemia hemolítica microangiopática y plaquetopenia. Es endémico en Argentina, el país con mayor incidencia de SUH en el mundo. Debido al rol fundamental de la Stx en su patogenia, se puede considerar que, como otras toxemias conocidas, el SUH podría ser tratado con anticuerpos. Este trabajo describe el desarrollo de un nuevo tratamiento capaz de neutralizar el efecto tóxico de distintas variantes de la Stx. El tratamiento consiste en fragmentos F(ab')2 provenientes de un antisuero equino cuya eficacia y potencia contra Stx1 y Stx2 se comprobó en diferentes modelos preclínicos. El producto mostró ser seguro en animales, presentó la farmacocinética descripta para compuestos similares y se pudo establecer una posible ventana terapéutica para su adecuada administración. En conjunto, los resultados preclínicos obtenidos validan la realización de un estudio clínico de primer uso en humanos. En dicho estudio, que se realizará en el Hospital Italiano de Buenos Aires, se analizará la seguridad y la farmacocinética del producto en voluntarios adultos sanos. Estos resultados sentarán las bases para la realización del estudio clínico fase II en pacientes pediátricos con infección por cepas de E. coli productoras de Stx.

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The typical hemolytic uremic syndrome (HUS) is an orphan disease caused by Shiga toxin(Stx) -producing Escherichia coli strains and characterized by acute kidney damage, microangiopathic hemolytic anemia and low platelet count. It is endemic in Argentina, the country with the highest incidence of HUS in the world. Stx is essential for its development and therefore, HUS is considered a toxemic non-bacteremic disorder, which could be treated with antibodies. Herein we describe the development of a new treatment capable of neutralizing the toxic effect of Stx and its variants. The treatment consists of F(ab')2 fragments from an equine antiserum whose efficacy and potency against Stx1 and Stx2 were proved in different preclinical models. The product was shown to be safe in animals. Furthermore, the anti-Stx F(ab')2 pharmacokinetic was shown to be similar to that of analogous compounds and a therapeutic window for its administration was determined. Altogether, these preclinical results warrant testing in humans. The phase I clinical trial will be performed at the Hospital Italiano in Buenos Aires to evaluate the safety and pharmacokinetics of the product in healthy adult volunteers. Based on the results of this study, a phase II clinical trial will be planned in pediatric patients diagnosed with infection by Stx-producing E. coli strains.

Asunto(s)

Humanos , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Drogas en Investigación , Toxina Shiga I/antagonistas & inhibidores , Toxina Shiga II/antagonistas & inhibidores , Infecciones por Escherichia coli/tratamiento farmacológico , Síndrome Hemolítico-Urémico/prevención & control , Argentina , Ensayos Clínicos Fase II como Asunto , Toxina Shiga I/inmunología , Toxina Shiga II/inmunología , Escherichia coli/aislamiento & purificación , Escherichia coli/inmunología , Infecciones por Escherichia coli/complicaciones , Síndrome Hemolítico-Urémico/inmunología , Anticuerpos/inmunología

RESUMEN

INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) represents 3% of all strokes in the US. When the patient survives it can lead to permanent incapacity especially if the patient develops vasospasm. The vasospasm is a multifactorial disorder and can lead to delayed cerebral ischemia (DCI). Most of the drugs tested to treat vasospasm failed to improve outcome and the only exception is nimodipine. AREAS COVERED: In this review, the authors describe the multifactorial process of vasospasm leading DCI after aSAH, discussing the treatments available based on the past and latest researches. EXPERT OPINION: Nimodipine is the only FDA-approved medication with neuroprotective effect and able to improve outcomes after aSAH. Understanding nimodipine trials is mandatory to understand and criticize all the drug trials published until now. The mechanism to vasospasm is multifactorial and not completely understood and all the other attempts to find a better medication could not prove superior results. Newton and PEGylated Carboxyhemoglobin Bovine can be potentially effective to prevent vasospasm but we still need more data and large studies. Future research should investigate newer drugs, as well as the combination of multiple drugs therapy and the association with blood evacuation techniques.

Asunto(s)

Drogas en Investigación/uso terapéutico , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/tratamiento farmacológico , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/prevención & control , Diseño de Fármacos , Humanos , Fármacos Neuroprotectores/uso terapéutico , Nimodipina/uso terapéutico , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Hemorragia Subaracnoidea/tratamiento farmacológico , Vasoespasmo Intracraneal/etiología

RESUMEN

BACKGROUND: The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations. OBJECTIVES: Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions. METHODS: The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies. FINDINGS: The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death. MAIN CONCLUSIONS: These results suggest the studied combinations could be used in the treatment of Chagas disease.

Asunto(s)

Enfermedad de Chagas/tratamiento farmacológico , Nitroimidazoles/farmacología , Triosa-Fosfato Isomerasa/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Anticuerpos Antiprotozoarios/sangre , Combinación de Medicamentos , Sinergismo Farmacológico , Drogas en Investigación , Inmunoglobulina G/sangre , Masculino , Ratones , Ratones Endogámicos BALB C , Triosa-Fosfato Isomerasa/antagonistas & inhibidores , Triosa-Fosfato Isomerasa/química , Trypanosoma cruzi/inmunología

RESUMEN

The search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identified in vitro to be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPC mRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23-231) as the substrate and PrPSc seeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90-231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPC globular domain. J8 also reduced the fibrillation of mouse rPrP23-231 seeded with in vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPC on the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPC content on the cell surface.

Asunto(s)

Chalconas/farmacología , Drogas en Investigación/farmacología , Neuronas/efectos de los fármacos , Oxadiazoles/farmacología , Proteínas Priónicas/antagonistas & inhibidores , Animales , Sitios de Unión , Línea Celular Tumoral , Chalconas/síntesis química , Clonación Molecular , Drogas en Investigación/síntesis química , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/ultraestructura , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Cinética , Ratones , Simulación del Acoplamiento Molecular , Neuronas/metabolismo , Neuronas/patología , Oxadiazoles/síntesis química , Proteínas Priónicas/química , Proteínas Priónicas/genética , Proteínas Priónicas/metabolismo , Unión Proteica , Conformación Proteica en Hélice alfa , Dominios y Motivos de Interacción de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Termodinámica

RESUMEN

BACKGROUND: Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors activated by endogenous fatty acids and prostaglandins that are classified into three types: α, γ and δ, which have different functions and tissue distribution. PPAR modulators have been exploited to the treatment of important metabolic diseases, such as type 2 diabetes mellitus and metabolic syndrome, which are considered relevant epidemic diseases currently. Along the last decades, several studies have reported structural differences between the three PPAR subtypes associated with the discovery of selective ligands, dual and pan-agonists. Nowadays, there are several approved drugs that activate PPARα (fibrates) and PPARγ (glitazones), but up to now there is none clinically used drug targeting PPARδ. Additionally, several side-effects associated with the use of PPARα and γ agonists are reported by regulatory agencies, which do not indicate anymore their use as first-line drugs. OBJECTIVE: A significant new market has grown in the last years, focusing on the development of new PPARδ agonists as drug candidates to treat metabolic diseases and, in this sense, this study proposes to review the structural requirements to achieve selective PPARδ activation, as well to discuss the most relevant agonists in clinical trials, providing information on the current phase in the drug discovery and design targeting PPARδ. CONCLUSION: Several PPARδ ligands with high potency were reported in the literature and were designed or discovered by a combination of experimental and computational approaches. Furthermore, the reported importance of pockets and individual residues at PPARδ binding site as well as the importance of substituent and some physicochemical properties that could help to design of new classes of agonists.

Asunto(s)

Diseño de Fármacos , Drogas en Investigación , PPAR delta/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Drogas en Investigación/química , Drogas en Investigación/farmacología , Humanos , Ligandos , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad Cuantitativa

RESUMEN

De acordo com a Organização Mundial de Saúde, existem atualmente 17 doenças tropicais negligenciadas prevalentes em 149 países, afetando aproximadamente um bilhão de pessoas, a nível global. A leishmaniose, problema de saúde prevalente nos países em desenvolvimento, é endêmica em aproximadamente 98 países e territórios, com 350 milhões de pessoas em risco e 12 milhões de casos de infecção no mundo. A transmissão da doença ocorre pela picada de flebotomíneos fêmeas infectadas. Essa doença apresenta três formas principais: leishmaniose cutânea (LC), leishmaniose mucocutânea (LMC) e leishmaniose visceral (LV). Enquanto a leishmaniose cutânea é a forma mais comum da doença, a leishmaniose visceral é a mais grave e pode ser fatal se não for tratada. Em 2016, o Brasil reportou 3.626 e 12.690 casos de LC e LV, respectivamente. O candidato a fármaco hidroximetilnitrofural (NFOH) mostrou atividade contra o parasita da doença de chagas e da leishmaniose. Embora o NFOH seja promissor para o tratamento da leishmaniose, esse possui baixa solubilidade em água. A nanotecnologia tem sido empregada como plataforma para o desenvolvimento de formas farmacêuticas inovadoras com maior eficácia e segurança. A redução do tamanho de partículas em escala nanométrica permite aumentar a biodisponibilidade oral de fármacos pouco solúveis em água. Os nanocristais apresentam vantagens, tais como, o aumento da solubilidade de saturação e da velocidade de dissolução, decorrentes do aumento da área superficial da partícula. Além disso, esses apresentam maior adesividade às membranas biológicas, membrana celular e superfície do trato gastrointestinal. No presente trabalho utilizou-se a moagem por via úmida em escala reduzida para a obtenção dos nanocristais de NFOH. Diferentes tensoativos foram avaliados empregando o método selecionado, os tensoativos poloxamer 188 e poloxamer 407 foram os que favoreceram a redução do tamanho das partículas. Tal característica foi observada na caracterização físico-química das nanosuspensões de NFOH. A utilização desse método permitiu a obtenção de nanocristais de NFOH, com diâmetro hidrodinâmico médio (DHM) de 184,8 ± 0,5 a 325,9 ± 2,2 nm, índice de polidispersão (IP) de 0,21 ± 0,01 a 0,57 ± 0,01 e DHM de 191,3 ± 2,1 a 326,8 ± 4,6 nm e IP de 0,21 ± 0,01 a 0,50 ± 0,01, respectivamente para o poloxamer 188 e 407. O uso de ambos os tensoativos resultaram em distribuição monomodal de tamanho das partículas. As formulações foram obtidas por meio de planejamento fatorial completo e experimentos por superfície de resposta tendo como variáreis independentes as concentrações de NFOH, dos tensoativos e o tempo de moagem. A resposta, DHM, foi determinada utilizando espalhamento de luz dinâmica (DLS). Adicionalmente, as avaliações empregando calorimetria exploratória diferencial (DSC) e difração de raio X (DRX) revelaram que não houve interação entre o fármaco e os excipientes, assim como, não foi observada alteração na estrutura cristalina do NFOH. A microscopia eletrônica de varredura demonstrou a morfologia característica do estado cristalino. Além disso, a preparação liofilizada apresentou instabilidade após armazenamento por três meses a temperatura de 25 e 4 °C

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According to the World Health Organization, there are currently 17 neglected tropical diseases prevalent in 149 countries, affecting approximately one billion people globally. Leishmaniasis, a health problem prevalent in developing countries, is endemic in approximately 98 countries and territories, with 350 million people at risk and 12 million cases of infection worldwide. The transmission of the disease occurs by the bite of infected female sandflies. This disease has three main forms: cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL) and visceral leishmaniasis (VL). While cutaneous leishmaniasis is the most usual form of the disease, visceral leishmaniasis is the most serious and can be fatal if left untreated. In 2016, Brazil reported 3.626 and 12.690 cases of LC and LV, respectively. The drug candidate for hydroxymethylnitrofurazone (NFOH) showed activity against the parasite of chagas disease and leishmaniasis. Although NFOH is promising for the treatment of leishmaniasis, it has low solubility in water. Nanotechnology has been used as a platform for the development of innovative pharmaceutical forms with greater effectiveness and safety. Particle size reduction on the nanoscale enables the oral bioavailability of poorly water-soluble drugs to be increased. Nanotechnology has been used as a platform for the development of innovative pharmaceutical forms, improving effectiveness and safety. Particle size reduction on the nanoscale enables the oral bioavailability of poorly water-soluble drugs to be increased. Nanocrystals have advantages such as increased saturation solubility and dissolution rate due to the increase in the surface area of the particle. In addition, this present greater adhesiveness to the biological membranes, cell membrane and surface of the gastrointestinal tract. In the present work, wet scale milling was used to obtain NFOH nanocrystals. Different surfactants were evaluated using the selected method, poloxamer 188 and poloxamer 407 surfactants favored the reduction of particle size. This characteristic was observed in the physical-chemical characterization of NFOH nanosuspensions. The use of NFOH nanocrystals with a mean hydrodynamic diameter (DHM) of 184.8 ± 0.5 to 325.9 ± 2.2 nm, polydispersity index (IP) of 0.21 ± 0, 01 to 0.57 ± 0.01 for poloxamer 188 and DHM of 191.3 ± 2.1 at 326.8 ± 4.6 nm and IP of 0.21 ± 0.01 at 0.50 ± 0.01 for poloxamer 407, both with monomodal size distribution. The formulations were obtained by means of complete factorial planning and surface response experiments having as independent variables the concentrations of NFOH, surfactants and milling time. The response, DHM, was determined using dynamic light scattering (DLS). In addition, evaluations using differential scanning calorimetry (DSC) and X-ray diffraction (DRX) revealed that there was no change in the crystal structure of NFOH and interaction between the drug and the excipients. Scanning electron microscopy demonstrated the characteristic morphology of the crystalline state. In addition, the lyophilized preparation was instable after storage for three months at 25 and 4 ° C

Asunto(s)

Técnicas In Vitro/instrumentación , Leishmaniasis/tratamiento farmacológico , Nanopartículas/análisis , Drogas en Investigación/análisis , Enfermedades Desatendidas