RESUMEN
BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (nâ =â 36) or placebo (nâ =â 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.
Asunto(s)
Infecciones por Coronavirus , Coronavirus del Síndrome Respiratorio de Oriente Medio , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/prevención & control , Dipeptidil Peptidasa 4/metabolismo , Humanos , Inmunoglobulina G , Ratones , Glicoproteína de la Espiga del CoronavirusRESUMEN
Zoliflodacin is a novel spiropyrimidinetrione antibiotic being developed as single oral dose treatment to address the growing global threat of Neisseria gonorrhoeae. To evaluate the cardiac safety of zoliflodacin, a thorough QT/QTc (TQT) study was performed in healthy subjects. In this randomized, double-blind, placebo-controlled, 4-period crossover study, 72 subjects in a fasted state received a single dose of zoliflodacin at 2 g (therapeutic), zoliflodacin at 4 g (supratherapeutic), placebo, and moxifloxacin at 400 mg as a positive comparator. Cardiac repolarization was measured by duration of the corrected QT interval by Fridericia's formula (QTcF). At each time point up to 24 h after zoliflodacin administration, the upper limit of the one-sided 95% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms, indicating an absence of a clinically meaningful increase in QT prolongation. The lower limit of the one-sided multiplicity-adjusted 95% CI of ΔΔQTcF for moxifloxacin was longer than 5 ms at four time points from 1 to 4 h after dosing, demonstrating adequate sensitivity of the QTc measurement. There were no clinically significant effects on heart rate, PR and QRS intervals, electrocardiogram (ECG) morphology, or laboratory values. Treatment-emergent adverse events (AEs) were mild or moderate in severity and transient. This was a negative TQT study according to regulatory guidelines (E14) and confirms that a single oral dose of zoliflodacin is safe and well tolerated. These findings suggest that zoliflodacin is not proarrhythmic and contribute to the favorable assessment of cardiac safety for a single oral dose of zoliflodacin. (This study has been registered at ClinicalTrials.gov under registration no. NCT03613649.).
Asunto(s)
Gonorrea , Síndrome de QT Prolongado , Adulto , Barbitúricos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrocardiografía , Fluoroquinolonas , Voluntarios Sanos , Frecuencia Cardíaca , Humanos , Isoxazoles , Morfolinas , Oxazolidinonas , Compuestos de EspiroRESUMEN
Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid. This phase 1 double-blind, randomized, placebo-controlled crossover study specifically examined the effect of single-dose administration of pretomanid 400 or 1000 mg and pretomanid 400 mg plus moxifloxacin 400 mg on the QTc interval in 74 healthy subjects. Subjects were fasting at the time of drug administration. Pretomanid concentrations following single 400- or 1000-mg doses were not associated with any QT interval prolongation of clinical concern. Moxifloxacin did not alter the pharmacokinetics of pretomanid, and the effect of pretomanid 400 mg plus moxifloxacin 400 mg on the individually corrected QT interval was consistent with the effect of moxifloxacin alone. Both drugs were generally well tolerated. Although supratherapeutic exposure of pretomanid relative to the now-recommended dosing with food was not achieved, these findings contribute to the favorable assessment of cardiac safety for pretomanid.
Asunto(s)
Antituberculosos/administración & dosificación , Síndrome de QT Prolongado/inducido químicamente , Moxifloxacino/administración & dosificación , Nitroimidazoles/administración & dosificación , Adolescente , Adulto , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino/efectos adversos , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Adulto JovenRESUMEN
CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 µg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).
Asunto(s)
Antibacterianos/administración & dosificación , Benzopiranos/administración & dosificación , Clostridioides difficile/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Tiofenos/administración & dosificación , Administración Oral , Adolescente , Adulto , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Benzopiranos/efectos adversos , Benzopiranos/farmacocinética , Clostridioides difficile/enzimología , Clostridioides difficile/genética , Infecciones por Clostridium/tratamiento farmacológico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Electrocardiografía , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Masculino , Metionina-ARNt Ligasa/antagonistas & inhibidores , Metionina-ARNt Ligasa/genética , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. METHODS: Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. RESULTS: Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C(max)) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C(max) values of AS and DHA were increased proportionally to the AS climbing multiple doses. DISCUSSION: The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.
Asunto(s)
Antimaláricos/efectos adversos , Antimaláricos/farmacocinética , Artemisininas/efectos adversos , Artemisininas/farmacocinética , Adulto , África , Antimaláricos/administración & dosificación , Artemisininas/administración & dosificación , Artesunato , Resinas Compuestas , Femenino , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Placebos/administración & dosificación , Estados Unidos , Adulto JovenRESUMEN
The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Sustancias para la Guerra Química/toxicidad , Compuestos Organotiofosforados/toxicidad , Animales , Encéfalo/metabolismo , Hibridación in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Compuestos Organotiofosforados/administración & dosificaciónRESUMEN
The development of vaccines for microorganisms and bacterial toxins with the potential to be used as biowarfare and bioterrorism agents is an important component of the US biodefense program. DVC is developing two vaccines, one against inhalational exposure to botulinum neurotoxins A1 and B1 and a second for Yersinia pestis, with the ultimate goal of licensure by the FDA under the Animal Rule. Progress has been made in all technical areas, including manufacturing, nonclinical, and clinical development and testing of the vaccines, and in assay development. The current status of development of these vaccines, and remaining challenges are described in this chapter.
RESUMEN
The pharmacokinetics of good manufacturing process injection of artesunate (AS) were evaluated after single doses at 0.5, 1, 2, 4, and 8 mg/kg with a 2-minute infusion in 40 healthy subjects. Drug concentrations were analyzed by validated liquid chromatography and mass spectrometry system (LC-MS/MS) procedures. The drug was immediately converted to dihydroartemisinin (DHA), with elimination half-lives ranging 0.12-0.24 and 1.15-2.37 hours for AS and DHA, respectively. Pharmacokinetic model-dependent analysis is suitable for AS, whereas DHA fits both model-dependent and -independent methods. Although DHA concentration was superior to that of AS with a 1.12-1.87 ratio of area under the curve (AUC)(DHA/AS), peak concentration of AS was much higher than that of DHA, with a 2.80- to 4.51-fold ratio of peak concentration (C(max AS/DHA)). Therefore, AS effectiveness has been attributed not only to its rapid hydrolysis to DHA, but also to itself high initial C(max).
Asunto(s)
Antimaláricos/administración & dosificación , Antimaláricos/farmacocinética , Artemisininas/administración & dosificación , Artemisininas/farmacocinética , Adolescente , Adulto , Antimaláricos/efectos adversos , Antimaláricos/sangre , Área Bajo la Curva , Artemisininas/efectos adversos , Artemisininas/sangre , Artesunato , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
In virtually every mammalian species examined, some males exhibit reflexive testosterone release upon encountering a novel female (or female-related stimulus). At the same time, not every individual male (or every published study) provides evidence for reflexive testosterone release. Four experiments using house mice (Mus musculus) examined the hypothesis that both the male's genotype and his degree of sexual arousal (as indexed by ultrasonic mating calls) are related to such variability. In Experiment 1, CF-1 males exhibited reflexive testosterone elevations 30 min after encountering female urine. CK males, on the other hand, did not exhibit testosterone elevations 20, 30, 50, 60, or 80 min after encountering female urine (Experiments 1 and 2) suggesting this strain incapable of reflexive release. In Experiment 3, we measured both mating calls and reflexive testosterone release in response to female urine in CF-1 and CK males. Most males of both strains called vigorously to female urine but not to water. But, only CF-1 males exhibited significant testosterone elevations to female urine. In Experiment 4, DBA/2J males called vigorously to females followed by testosterone elevations 30 min later. The first 3 experiments support the hypothesis that male genotype is an important variable underlying mammalian reflexive testosterone release. Statistically significant correlations between mating calls in the first minute after stimulus exposure and testosterone elevations 30 min later (Experiments 3 and 4) support the hypothesis that, in capable males, reflexive testosterone release is related to the male's initial sexual arousal.
Asunto(s)
Nivel de Alerta/fisiología , Conducta Sexual Animal/fisiología , Medio Social , Testosterona/sangre , Vocalización Animal/fisiología , Análisis de Varianza , Animales , Femenino , Genotipo , Masculino , Ratones , Ratones Endogámicos , Feromonas/orina , Estimulación Física/métodos , Olfato/fisiología , Especificidad de la Especie , Testosterona/metabolismoRESUMEN
STUDY OBJECTIVES: Pharmacologic enhancement of daytime sleep may help sustain optimal cognitive performance. At effective doses, zolpidem induces sleep but also impairs performance. Combining melatonin with low-dose zolpidem may promote daytime sleep without exacerbating performance impairments seen with high-dose zolpidem alone. DESIGN AND METHODS: Following an 8-hour undisturbed nighttime sleep period, 80 subjects (50 men, 30 women) were administered oral zolpidem 0, 5, 10, or 20 mg at 10:00 am (n = 20 per group) and then oral melatonin 0 or 5 mg at 10:30 am (thus, n = 10 per drug combination) in a double-blind randomized fashion. Subjects napped from 10:00 am to 11:30 am, at which time they were awakened and cognitive tests administered (Restricted Reminding, Paired-Associates, and Psychomotor Vigilance). A second nap ensued from 12:45 pm to 4:00 pm, followed immediately by further testing. RESULTS: Melatonin 5 mg plus zolpidem 0 mg enhanced daytime sleep (P < .05) with no memory or performance impairment (P > .05). Zolpidem 20 mg plus melatonin 0 mg also enhanced daytime sleep (albeit nonsignificantly), but memory and vigilance were impaired (P < .05). Melatonin's sleep-promoting effects were not evident until the second nap. CONCLUSIONS: No advantages to administering melatonin plus zolpidem "cocktails" were evident. Unlike zolpidem, melatonin 5 mg alone improved daytime sleep without impairing memory and vigilance. Functional coupling of sleep-inducing and memory-impairing effects may be specific to benzodiazepine-receptor agonists such as zolpidem, suggesting potential advantages to using melatonin in the operational environment. That melatonin's sleep-promoting effects were delayed for several hours presents a practical consideration that may limit melatonin's usefulness when daytime sleep periods cannot be reliably anticipated or planned in advance.
Asunto(s)
Antioxidantes/farmacología , Ritmo Circadiano , Hipnóticos y Sedantes/farmacología , Melatonina/farmacología , Desempeño Psicomotor/efectos de los fármacos , Piridinas/farmacología , Sueño/efectos de los fármacos , Adolescente , Adulto , Antioxidantes/administración & dosificación , Antioxidantes/análisis , Cognición/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Femenino , Humanos , Hipnóticos y Sedantes/administración & dosificación , Masculino , Melatonina/administración & dosificación , Melatonina/análisis , Recuerdo Mental/efectos de los fármacos , Piridinas/administración & dosificación , Saliva/química , Vigilia/efectos de los fármacos , ZolpidemRESUMEN
Acute social defeat in mice activates the hypothalamic-pituitary-adrenal axis (HPA) and induces long-term behavioral changes, including exaggerated fear responses and inhibition of territorial behavior. Stress-induced hormonal and neurotransmitter release may contribute to disruption of expression of genes important for cell survival, neuronal plasticity, and neuronal remodeling. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor associated with structural cellular changes that occur during nervous system development and contributes to neural plasticity in the adult brain. In rats, acute (1-2 h) restraint stress transiently reduces BDNF mRNA expression in the hippocampus, a region important in the memory and in HPA regulation; restraint stress also decreases BDNF expression in the basolateral amygdala (BLA), a region important for fear consolidation and emotional memory. We hypothesized that a brief (10 min) exposure to intense social stress, a more naturalistic stressor than restraint stress, would also reduce BDNF mRNA in the hippocampus and BLA of mice. In the present study, we examined the time course of expression of BDNF mRNA expression in the hippocampus and amygdala, as well as other subcortical and cortical brain regions, following acute social stress. In situ hybridization analysis for BDNF mRNA expression showed that there was a significant decrease in BDNF mRNA expression in all regions studied in mice 24 h after social defeat when compared to control (naive) mice (P<0.05). These findings support our hypothesis that BDNF mRNA levels are reduced by social stress, and may have implications for brain plasticity and behavioral changes following social stress.
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Corteza Cerebral/metabolismo , Factores de Crecimiento Nervioso/biosíntesis , Conducta Social , Estrés Psicológico/metabolismo , Animales , Regulación de la Expresión Génica/fisiología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Police trainees who were ready to graduate from the Federal Law Enforcement Training Center (FLETC) volunteered to participate in an exercise designed to evaluate their survivability. In a highly stressful interactive scenario, which included a hostage situation, performance was evaluated for a range of responses, including: shooting judgment and accuracy, communications, and coping with a weapon malfunction. Nineteen percent of subjects shot the hostage, a failure rate that falls in the reported range of friendly fire casualties in military combat. The Spielberger Trait Anger Scale showed an association with shot placement and performance during the gunfight as well as with overall performance scores.
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Policia/educación , Desempeño Psicomotor/fisiología , Adulto , Ira/fisiología , Comunicación , Toma de Decisiones/fisiología , Falla de Equipo , Armas de Fuego , Humanos , Pruebas Psicológicas , Psicometría , Estrés Psicológico/psicologíaRESUMEN
Cushing's syndrome is the clinical expression of the overproduction of glucocorticoids and is well recognized in both human and veterinary medicine. Spontaneous diabetes mellitus is well known in Macaca spp., however the occurrence of hyperadrenocorticism and diabetes mellitus concurrently in macaques has not been reported previously. This unusual case presents a rare opportunity to examine the relationships between two important endocrine diseases in a nonhuman primate. A male, 14-year-old rhesus macaque (Macaca mulatta) was diagnosed with hyperadrenocorticism and concurrent diabetes mellitus. Initially, the monkey had mildly elevated blood glucose values upon routine semi-annual physical examination. Further diagnostic work-up demonstrated hypercortisolism. Adrenocorticotropic hormone-dependent Cushing's syndrome was subsequently diagnosed in light of results from dexamethasone testing, magnetic resonance imaging, and computed tomography scans. A therapeutic course of L-deprenyl (Anipryl(r)) was begun, and 8 weeks later, insulin therapy was initiated. The patient responded well to insulin therapy, however the dosage was rapidly increased. After 6 months, Anipryl(r) therapy was determined to be of little or no value, and ketoconazole was selected as the drug of choice to control the hypercortisolism. The monkey has shown remarkable improvement with the dual therapies of insulin and ketoconazole. Approximately 2 months after the initiation of ketoconazole therapy, the animal was returned to an experimental protocol under the conditions of twice-daily treatment and strict dietary control. The ongoing plan for clinical management includes periodic blood glucose and liver function surveillance.