RESUMEN
OBJECTIVE: INP105 is a drug-device combination of olanzapine and technology that delivers a powder formulation of olanzapine to the vascular-rich upper nasal space. This study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of single ascending doses of INP105, olanzapine intramuscular (OLZ IM), and olanzapine oral disintegrating tablet (OLZ ODT). METHODS: This was a phase 1, active and double-blind placebo comparator-controlled, ascending-dose, 2-period, incomplete-block, 1-way crossover study in 40 healthy subjects, randomized to single doses of OLZ IM (5 or 10 mg) or OLZ ODT (10 mg) in Period 1 and then 1 of 3 doses (5 mg, 10 mg, or 15 mg) of INP105 or placebo in Period 2 between July and October 2018. Sedation and attention were evaluated by visual analog scale (VAS), the Agitation/Calmness Evaluation Scale (ACES), and the Digit Symbol Substitution Test (DSST). RESULTS: At equivalent doses, INP105 provided similar area under the drug concentration-time curve (AUC) from time 0 to the last measurable concentration, AUC from time 0 to infinity, and maximum observed concentration (Cmax) as OLZ IM and greater Cmax than but similar AUCs to OLZ ODT. Median time to maximum concentration was less for INP105 (15, 10, and 9.5 min for 5 mg, 10 mg, and 15 mg, respectively) than for OLZ IM (20 and 15 min for 5 mg and 10 mg, respectively) or OLZ ODT (120 min). Effects as measured with the VAS, ACES, and DSST with INP105 5 mg were comparable to those with OLZ IM 5 mg, with earlier onset for INP105 10 mg and 15 mg and greater effects than placebo and OLZ ODT. The incidence of treatment-emergent adverse events with INP105 5 mg, 10 mg, and 15 mg was 80%, 66.7%, and 75%, respectively, compared to 90% and 100% for OLZ IM 5 mg and 10 mg, respectively, and 83.3% for OLZ ODT; most common were dizziness, hypotension, and orthostatic symptoms. CONCLUSIONS: INP105 has rapid absorption and pharmacodynamic effects and may represent an effective, convenient, noninvasive, and well-tolerated alternative for treating acutely agitated patients by self- or caregiver administration in the home, community, or hospital environments. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03624322.
Asunto(s)
Olanzapina/efectos adversos , Olanzapina/farmacocinética , Administración Intranasal , Administración Oral , Adolescente , Adulto , Antipsicóticos/administración & dosificación , Antipsicóticos/efectos adversos , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Atención/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Hipnóticos y Sedantes/farmacología , Inyecciones Intramusculares , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Olanzapina/administración & dosificación , Olanzapina/farmacología , Adulto JovenRESUMEN
Simian foamy viruses (SVF) are ubiquitous in nonhuman primates (NHP). SFV can be zoonotically transmitted to humans who either work with or live commensally with NHP. We analyzed the blood of 45 Bangladeshi performing monkey owners (an ethnic group called the Bedey) for SFV infection. Surprisingly, a PCR assay failed to detect SFV infection in any of these participants. This is in contrast to our previously reported infection rate of about 5% among Bangladeshi villagers.
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Infecciones por Retroviridae/epidemiología , Virus Espumoso de los Simios/aislamiento & purificación , Migrantes , Zoonosis/epidemiología , Animales , Bangladesh/epidemiología , Femenino , Humanos , Macaca , Masculino , Reacción en Cadena de la Polimerasa , ARN Viral/sangre , Virus Espumoso de los Simios/genéticaRESUMEN
Simian Foamy Virus (SFV) can be transmitted from non-human primates (NHP) to humans. However, there are no documented cases of human to human transmission, and significant differences exist between infection in NHP and human hosts. The mechanism for these between-host differences is not completely understood. In this paper we develop a new Bayesian approach to the detection of APOBEC3-mediated hypermutation, and use it to compare SFV sequences from human and NHP hosts living in close proximity in Bangladesh. We find that human APOBEC3G can induce genetic changes that may prevent SFV replication in infected humans in vivo.
Asunto(s)
Citosina Desaminasa/genética , Mutación , Infecciones por Retroviridae/genética , Infecciones por Retroviridae/transmisión , Virus Espumoso de los Simios/genética , Zoonosis/genética , Zoonosis/transmisión , Desaminasas APOBEC , Desaminasa APOBEC-3G , Animales , Bangladesh , Teorema de Bayes , Codón de Terminación , Biología Computacional , Citidina Desaminasa/genética , Interacciones Huésped-Patógeno/genética , Humanos , Macaca/genética , Macaca/virología , Modelos Genéticos , ARN Viral/genética , Virus Espumoso de los Simios/patogenicidad , Virus Espumoso de los Simios/fisiología , Especificidad de la Especie , Replicación ViralRESUMEN
Foamy viruses (FV) are complex retroviruses that naturally infect all nonhuman primates (NHP) studied to date. Zoonotic transmission of Old World NHP simian foamy viruses (SFV) has been documented, leading to nonpathogenic persistent infections. To date, there have been no reports concerning zoonotic transmission of New World monkey (NWM) SFV to humans and resulting infection. In this study, we developed a Western blot assay to detect antibodies to NWM SFV, a nested PCR assay to detect NWM SFV DNA, and a ß-galactosidase-containing indicator cell line to assay replication of NWM SFV. Using these tools, we analyzed the plasma and blood of 116 primatologists, of whom 69 had reported exposures to NWM. While 8 of the primatologists tested were seropositive for SFV from a NWM, the spider monkey, none had detectable levels of viral DNA in their blood. We found that SFV isolated from three different species of NWM replicated in some, but not all, human cell lines. From our data, we conclude that while humans exposed to NWM SFV produce antibodies, there is no evidence for long-term viral persistence.
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Enfermedades de los Monos/virología , Infecciones por Retroviridae/veterinaria , Infecciones por Retroviridae/virología , Virus Espumoso de los Simios/fisiología , Animales , Secuencia de Bases , Línea Celular , Humanos , Macaca mulatta , Datos de Secuencia Molecular , Platirrinos , Virus Espumoso de los Simios/genética , Virus Espumoso de los Simios/aislamiento & purificación , Zoonosis/transmisión , Zoonosis/virologíaRESUMEN
Simian foamy viruses (SFV) are complex retroviruses that are ubiquitous in nonhuman primates (NHP) and are zoonotically transmitted to humans, presumably through NHP saliva, by licking, biting, and other behaviors. We have studied SFV in free-ranging rhesus macaques in Bangladesh. It has been previously shown that SFV in immunocompetent animals replicates to detectable levels only in superficial epithelial cells of the oral mucosa, although latent proviruses are found in most, if not all, tissues. In this study, we compare DNA sequences from latent SFV proviruses found in blood cells of 30 Bangladesh rhesus macaques to RNA sequences of transcriptionally active SFV from buccal swabs obtained from the same animals. Viral strains, defined by differences in SFV gag sequences, from buccal mucosal specimens overlapped with those from blood samples in 90% of animals. Thus, latent proviruses in peripheral blood mononuclear cells (PBMC) are, to a great extent, representative of viruses likely to be transmitted to other hosts. The level of SFV RNA in buccal swabs varied greatly between macaques, with increasing amounts of viral RNA in older animals. Evidence of APOBEC3-induced mutations was found in gag sequences derived from the blood and oral mucosa.
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Macaca mulatta/virología , Enfermedades de los Primates/virología , Provirus/genética , Infecciones por Retroviridae/veterinaria , Virus Espumoso de los Simios/genética , Transcripción Genética , Latencia del Virus , Animales , Bangladesh , Mejilla/virología , Femenino , Productos del Gen gag/genética , Leucocitos Mononucleares/virología , Masculino , Provirus/aislamiento & purificación , Provirus/fisiología , ARN Viral/genética , Infecciones por Retroviridae/virología , Virus Espumoso de los Simios/aislamiento & purificación , Virus Espumoso de los Simios/fisiología , Replicación ViralRESUMEN
Foamy viruses are complex retroviruses that have been shown to be transmitted from nonhuman primates to humans. In Bangladesh, infection with simian foamy virus (SFV) is ubiquitous among rhesus macaques, which come into contact with humans in diverse locations and contexts throughout the country. We analyzed microsatellite DNA from 126 macaques at six sites in Bangladesh in order to characterize geographic patterns of macaque population structure. We also included in this study 38 macaques owned by nomadic people who train them to perform for audiences. PCR was used to analyze a portion of the proviral gag gene from all SFV-positive macaques, and multiple clones were sequenced. Phylogenetic analysis was used to infer long-term patterns of viral transmission. Analyses of SFV gag gene sequences indicated that macaque populations from different areas harbor genetically distinct strains of SFV, suggesting that geographic features such as forest cover play a role in determining the dispersal of macaques and SFV. We also found evidence suggesting that humans traveling the region with performing macaques likely play a role in the translocation of macaques and SFV. Our studies found that individual animals can harbor more than one strain of SFV and that presence of more than one SFV strain is more common among older animals. Some macaques are infected with SFV that appears to be recombinant. These findings paint a more detailed picture of how geographic and sociocultural factors influence the spectrum of simian-borne retroviruses.
RESUMEN
Simian foamy viruses (SFVs) are ubiquitous in non-human primates (NHPs). As in all retroviruses, reverse transcription of SFV leads to recombination and mutation. Because more humans have been shown to be infected with SFV than with any other simian borne virus, SFV is a potentially powerful model for studying the virology and epidemiology of viruses at the human/NHP interface. In Asia, SFV is likely transmitted to humans through macaque bites and scratches that occur in the context of everyday life. We analyzed multiple proviral sequences from the SFV gag gene from both humans and macaques in order to characterize retroviral transmission at the human/NHP interface in Bangladesh. Here we report evidence that humans can be concurrently infected with multiple SFV strains, with some individuals infected by both an autochthonous SFV strain as well as a strain similar to SFV found in macaques from another geographic area. These data, combined with previous results, suggest that both human-facilitated movement of macaques leading to the introduction of non-resident strains of SFV and retroviral recombination in macaques contribute to SFV diversity among humans in Bangladesh.