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1.
PLoS Pathog ; 17(9): e1009633, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34547055

RESUMO

Smallpox, caused by the solely human pathogen Variola virus (VARV), was declared eradicated in 1980. While known VARV stocks are secure, smallpox remains a bioterrorist threat agent. Recent U.S. Food and Drug Administration approval of the first smallpox anti-viral (tecovirimat) therapeutic was a successful step forward in smallpox preparedness; however, orthopoxviruses can become resistant to treatment, suggesting a multi-therapeutic approach is necessary. Animal models are required for testing medical countermeasures (MCMs) and ideally MCMs are tested directly against the pathogen of interest. Since VARV only infects humans, a representative animal model for testing therapeutics directly against VARV remains a challenge. Here we show that three different humanized mice strains are highly susceptible to VARV infection, establishing the first small animal model using VARV. In comparison, the non-humanized, immunosuppressed background mouse was not susceptible to systemic VARV infection. Following an intranasal VARV challenge that mimics the natural route for human smallpox transmission, the virus spread systemically within the humanized mouse before mortality (~ 13 days post infection), similar to the time from exposure to symptom onset for ordinary human smallpox. Our identification of a permissive/representative VARV animal model can facilitate testing of MCMs in a manner consistent with their intended use.


Assuntos
Modelos Animais de Doenças , Varíola , Animais , Humanos , Camundongos , Vírus da Varíola
2.
J Infect Dis ; 220(9): 1521-1528, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31374568

RESUMO

BACKGROUND: Ebola virus (EBOV) is a highly lethal member of the Filoviridae family associated with human hemorrhagic disease. Despite being a sporadic disease, it caused a large outbreak in 2014-2016 in West Africa and another outbreak recently in the Democratic Republic of Congo. Several vaccine candidates are currently in preclinical and clinical studies but none are stable without cold chain storage. METHODS: We used preservation by vaporization (PBV), a novel processing technology to heat-stabilize FiloRab1 (inactivated rabies-based Ebola vaccine), a candidate Ebola vaccine, and stored the vials at temperatures ranging from 4°C to 50°C for 10 days to 12 months. We immunized Syrian hamsters with the best long-term stable FiloRab1 PBV vaccines and challenged them with rabies virus (RABV). RESULTS: Syrian hamsters immunized with FiloRab1 PBV-processed vaccines stored at temperatures of 4°C and 37°C for 6 months, and at 50°C for 2 weeks, seroconverted against both RABV-G and EBOV-GP. Notably, all of the FiloRab1 PBV vaccines proved to be 100% effective in a RABV challenge model. CONCLUSIONS: We successfully demonstrated that the FiloRab1 PBV vaccines are stable and efficacious for up to 6 months when stored at temperatures ranging from 4°C to 37°C and for up to 2 weeks at 50°C.


Assuntos
Estabilidade de Medicamentos , Vacinas contra Ebola/imunologia , Vacinas contra Ebola/efeitos da radiação , Doença pelo Vírus Ebola/prevenção & controle , Vacina Antirrábica/imunologia , Vacina Antirrábica/efeitos da radiação , Raiva/prevenção & controle , Animais , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/genética , Feminino , Temperatura Alta , Mesocricetus , Vacina Antirrábica/administração & dosagem , Vacina Antirrábica/genética , Temperatura , Resultado do Tratamento , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/genética , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/efeitos da radiação , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Vacinas Sintéticas/efeitos da radiação , Volatilização
3.
N Engl J Med ; 372(13): 1223-30, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25806914

RESUMO

During 2013, cutaneous lesions developed in two men in the country of Georgia after they were exposed to ill cows. The men had never received vaccination against smallpox. Tests of lesion material with the use of a quantitative real-time polymerase-chain-reaction assay for non-variola virus orthopoxviruses were positive, and DNA sequence analysis implicated a novel orthopoxvirus species. During the ensuing epidemiologic investigation, no additional human cases were identified. However, serologic evidence of exposure to an orthopoxvirus was detected in cows in the patients' herd and in captured rodents and shrews. A third case of human infection that occurred in 2010 was diagnosed retrospectively during testing of archived specimens that were originally submitted for tests to detect anthrax. Orthopoxvirus infection should be considered in persons in whom cutaneous lesions develop after contact with animals.


Assuntos
Doenças dos Bovinos/transmissão , Orthopoxvirus/isolamento & purificação , Infecções por Poxviridae/transmissão , Zoonoses/transmissão , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Anticorpos Antivirais/sangue , Bovinos , DNA Viral/análise , Feminino , Georgia , Humanos , Masculino , Glândulas Mamárias Animais/virologia , Pessoa de Meia-Idade , Orthopoxvirus/genética , Filogenia , Infecções por Poxviridae/virologia , Roedores/virologia , Musaranhos/virologia , Vacina Antivariólica , Adulto Jovem , Zoonoses/virologia
4.
J Infect Dis ; 216(12): 1505-1512, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29029254

RESUMO

Serologic cross-reactivity, a hallmark of orthopoxvirus (OPXV) infection, makes species-specific diagnosis of infection difficult. In this study, we used a variola virus proteome microarray to characterize and differentiate antibody responses to nonvaccinia OPXV infections from smallpox vaccination. The profile of 2 case patients infected with newly discovered OPXV, Akhmeta virus, exhibited antibody responses of greater intensity and broader recognition of viral proteins and includes the B21/22 family glycoproteins not encoded by vaccinia virus strains used as vaccines. An additional case of Akhmeta virus, or nonvaccinia OPXV infection, was identified through community surveillance of individuals with no or uncertain history of vaccination and no recent infection. The results demonstrate the utility of microarrays for high-resolution mapping of antibody response to determine the nature of OPXV exposure.


Assuntos
Anticorpos Antivirais/sangue , Proteínas Sanguíneas/análise , Imunidade Humoral , Orthopoxvirus/imunologia , Infecções por Poxviridae/imunologia , Proteoma/análise , Soro/química , Adolescente , Adulto , Humanos , Análise Serial de Proteínas , Estudos Retrospectivos , Adulto Jovem
6.
Virus Genes ; 53(6): 856-867, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28685222

RESUMO

The genome of Eptesipoxvirus (EPTV) is the first poxvirus genome isolated from a microbat. The 176,688 nt sequence, which is believed to encompass the complete coding region of the virus, is 67% A+T and is predicted to encode 191 genes. 11 of these genes have no counterpart in GenBank and are therefore unique to EPTV. The presence of a distantly related ortholog of Vaccinia virus F5L in EPTV uncovered a link with fragmented F5L orthologs in Molluscum contagiosum virus/squirrelpox and clade II viruses. Consistent with the unique position of EPTV approximately mid-point between the orthopoxviruses and the clade II viruses, EPTV has 11 genes that are specific to the orthopoxviruses and 13 genes that are typical, if not exclusive, to the clade II poxviruses. This mosaic nature of EPTV blurs the distinction between the old description of the orthopoxvirus and clade II groups. Genome annotation and characterization failed to find any common virulence genes shared with the other poxvirus isolated from bat (pteropoxvirus); however, EPTV encodes 3 genes that may have been transferred to or from deerpox and squirrelpox viruses; 2 of these, a putative endothelin-like protein and a MHC class I-like protein are likely to have immunomodulatory roles.


Assuntos
Quirópteros/virologia , Poxviridae/genética , Animais , DNA Viral/genética , Genoma Viral/genética , Anotação de Sequência Molecular/métodos , Orthopoxvirus/genética , Vaccinia virus/genética , Proteínas Virais/genética , Virulência/genética
7.
Clin Infect Dis ; 60(2): 195-202, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25301210

RESUMO

BACKGROUND: Some human poxvirus infections can be acquired through zoonotic transmission. We report a previously unknown poxvirus infection in 2 patients, 1 of whom was immunocompromised; both patients had known equine contact. METHODS: The patients were interviewed and clinical information was abstracted from the patients' medical files. Biopsies of the skin lesions were collected from both patients for histopathology, immunohistochemistry, and transmission electron microscopy analysis. Oral and skin swabs were collected from animals with frequent contact with the patients, and environmental sampling including rodent trapping was performed on the farm where the immunosuppressed patient was employed. "Pan-pox and high Guanine-cytosine" polymerase chain reaction assays were performed on patient, animal, and environmental isolates. Amplicon sequences of the viral DNA were used for agent identification and phylogenetic analysis. RESULTS: Specimens from both human cases revealed a novel poxvirus. The agent shares 88% similarity to viruses in the Parapoxvirus genus and 78% to those in the Molluscipoxvirus genus but is sufficiently divergent to resist classification as either. All animal and environmental specimens were negative for poxvirus and both patients had complete resolution of lesions. CONCLUSIONS: This report serves as a reminder that poxviruses should be considered in cutaneous human infections, especially in individuals with known barnyard exposures. The clinical course of the patients was similar to that of parapoxvirus infections, and the source of this virus is currently unknown but is presumed to be zoonotic. This report also demonstrates the importance of a comprehensive approach to diagnosis of human infections caused by previously unknown pathogens.


Assuntos
Infecções por Poxviridae/diagnóstico , Infecções por Poxviridae/virologia , Poxviridae/classificação , Poxviridae/isolamento & purificação , Biópsia , DNA Viral/genética , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Poxviridae/genética , Infecções por Poxviridae/patologia , Análise de Sequência de DNA , Pele/patologia , Pele/virologia , Estados Unidos
8.
Emerg Infect Dis ; 19(6): 1002-4, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23735421

RESUMO

A wildlife hospital and rehabilitation center in northwestern United States received several big brown bats with necrosuppurative osteomyelitis in multiple joints. Wing and joint tissues were positive by PCR for poxvirus. Thin-section electron microscopy showed poxvirus particles within A-type inclusions. Phylogenetic comparison supports establishment of a new genus of Poxviridae.


Assuntos
Quirópteros/virologia , Poxviridae/classificação , Animais , Genoma Viral , Masculino , Dados de Sequência Molecular , Filogenia , Poxviridae/genética , Poxviridae/isolamento & purificação , Poxviridae/ultraestrutura
9.
Sci Rep ; 12(1): 9403, 2022 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-35672343

RESUMO

Human rabies remains a globally significant public health problem. Replacement of polyclonal anti-rabies immunoglobulin (RIG), a passive component of rabies post-exposure prophylaxis (PEP), with a monoclonal antibody (MAb), would eliminate the cost and availability constraints associated with RIG. Our team has developed and licensed a human monoclonal antibody RAB1 (Rabishield©), as the replacement for RIG where canine rabies is enzootic. However, for the highly diverse rabies viruses of North America, a cocktail containing two or more MAbs targeting different antigenic sites of the rabies glycoprotein should be included to ensure neutralization of all variants of the virus. In this study, two MAb cocktails, R172 (RAB1-RAB2) and R173 (RAB1-CR57), were identified and evaluated against a broad range of rabies variants from North America. R173 was found to be the most potent cocktail, as it neutralized all the tested North American RABV isolates and demonstrated broad coverage of isolates from both terrestrial and bat species. R173 could be a promising candidate as an alternative or replacement for RIG PEP in North America.


Assuntos
Antineoplásicos Imunológicos , Vacina Antirrábica , Vírus da Raiva , Raiva , Animais , Anticorpos Monoclonais , Anticorpos Antivirais , Cães , Humanos , Profilaxia Pós-Exposição
10.
Zoonoses Public Health ; 69(5): 587-592, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35426241

RESUMO

SARS-CoV-2 infection has been described in a wide range of species, including domestic animals such as dogs and cats. Illness in dogs is usually self-limiting, and further diagnostics may not be pursued if clinical signs resolve or they respond to empirical treatment. As new variants emerge, the clinical presentation and role in transmission may vary in animals. This report highlights different clinical presentations and immunological responses in two SARS-CoV-2 Delta-variant-positive dogs with similar exposure to the same fully vaccinated human with a SARS-CoV-2 infection and emphasizes the need for active surveillance and additional One Health research on SARS-CoV-2 variant infections in companion animals and other species.


Assuntos
COVID-19 , Doenças do Cão , Animais , Animais Domésticos , COVID-19/veterinária , Doenças do Gato , Gatos , Doenças do Cão/epidemiologia , Doenças do Cão/prevenção & controle , Cães , Georgia , Humanos , SARS-CoV-2/genética
11.
Virol J ; 8: 313, 2011 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-21689420

RESUMO

The prevalence of North American orthopoxviruses in nature is unknown and may be more difficult to ascertain due to wide spread use of vaccinia virus recombinant vaccines in the wild. A real time PCR assay was developed to allow for highly sensitive and specific detection of North American orthopoxvirus DNA in animal tissues and bodily fluids. This method is based on the amplification of a 156 bp sequence within a myristylated protein, highly conserved within the North American orthopoxviruses but distinct from orthologous genes present in other orthopoxviruses. The analytical sensitivity was 1.1 fg for Volepox virus DNA, 1.99 fg for Skunkpox virus DNA, and 6.4 fg for Raccoonpox virus DNA with a 95% confidence interval. Our assay did not cross-react with other orthopoxviruses or ten diverse representatives of the Chordopoxvirinae subfamily. This new assay showed more sensitivity than tissue culture tests, and was capable of differentiating North American orthopoxviruses from other members of Orthopoxvirus. Thus, our assay is a promising tool for highly sensitive and specific detection of North American orthopoxviruses in the United States and abroad.


Assuntos
Orthopoxvirus/genética , Orthopoxvirus/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , Infecções por Poxviridae/veterinária , Virologia/métodos , Animais , Reações Cruzadas , América do Norte , Infecções por Poxviridae/virologia , Sensibilidade e Especificidade
12.
mSphere ; 6(1)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536322

RESUMO

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [Cmax]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.


Assuntos
Citosina/análogos & derivados , Monkeypox virus/efeitos dos fármacos , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Varíola/tratamento farmacológico , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Citosina/farmacocinética , Citosina/farmacologia , Modelos Animais de Doenças , Cães , Feminino , Isoindóis/farmacocinética , Isoindóis/farmacologia , Masculino , Vírus da Varíola/efeitos dos fármacos
13.
Vaccines (Basel) ; 8(3)2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32698399

RESUMO

The protection provided by smallpox vaccines when used after exposure to Orthopoxviruses is poorly understood. Postexposu re administration of 1st generation smallpox vaccines was effective during eradication. However, historical epidemiological reports and animal studies on postexposure vaccination are difficult to extrapolate to today's populations, and 2nd and 3rd generation vaccines, developed after eradication, have not been widely tested in postexposure vaccination scenarios. In addition to concerns about preparedness for a potential malevolent reintroduction of variola virus, humans are becoming increasingly exposed to naturally occurring zoonotic orthopoxviruses and, following these exposures, disease severity is worse in individuals who never received smallpox vaccination. This study investigated whether postexposure vaccination of prairie dogs with 2nd and 3rd generation smallpox vaccines was protective against monkeypox disease in four exposure scenarios. We infected animals with monkeypox virus at doses of 104 pfu (2× LD50) or 106 pfu (170× LD50) and vaccinated the animals with IMVAMUNE® or ACAM2000® either 1 or 3 days after challenge. Our results indicated that postexposure vaccination protected the animals to some degree from the 2× LD50, but not the 170× LD5 challenge. In the 2× LD50 challenge, we also observed that administration of vaccine at 1 day was more effective than administration at 3 days postexposure for IMVAMUNE®, but ACAM2000® was similarly effective at either postexposure vaccination time-point. The effects of postexposure vaccination and correlations with survival of total and neutralizing antibody responses, protein targets, take formation, weight loss, rash burden, and viral DNA are also presented.

14.
Viruses ; 12(12)2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317132

RESUMO

Akhmeta virus is a zoonotic Orthopoxvirus first identified in 2013 in the country of Georgia. Subsequent ecological investigations in Georgia have found evidence that this virus is widespread in its geographic distribution within the country and in its host-range, with rodents likely involved in its circulation in the wild. Yet, little is known about the pathogenicity of this virus in rodents. We conducted the first laboratory infection of Akhmeta virus in CAST/EiJ Mus musculus to further characterize this novel virus. We found a dose-dependent effect on mortality and weight loss (p < 0.05). Anti-orthopoxvirus antibodies were detected in the second- and third-highest dose groups (5 × 104 pfu and 3 × 102 pfu) at euthanasia by day 10, and day 14 post-infection, respectively. Anti-orthopoxvirus antibodies were not detected in the highest dose group (3 × 106 pfu), which were euthanized at day 7 post-infection and had high viral load in tissues, suggesting they succumbed to disease prior to mounting an effective immune response. In order of highest burden, viable virus was detected in the nostril, lung, tail, liver and spleen. All individuals tested in the highest dose groups were DNAemic. Akhmeta virus was highly pathogenic in CAST/EiJ Mus musculus, causing 100% mortality when ≥3 × 102 pfu was administered.


Assuntos
Doenças dos Animais/virologia , Infecção Laboratorial/veterinária , Orthopoxvirus/fisiologia , Infecções por Poxviridae/veterinária , Doenças dos Animais/diagnóstico , Doenças dos Animais/mortalidade , Animais , Feminino , Camundongos , Testes Sorológicos , Carga Viral
15.
Virology ; 544: 55-63, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32174514

RESUMO

Historic observations suggest that survivors of smallpox maintained lifelong immunity and protection to subsequent infection compared to vaccinated individuals. Although protective immunity by vaccination using a related virus (vaccinia virus (VACV) strains) was the key for smallpox eradication, it does not uniformly provide long term, or lifelong protective immunity (Heiner et al., 1971). To determine differences in humoral immune responses, mice were inoculated with VACV either systemically, using intranasal inoculation (IN), or locally by an intradermal (ID) route. We hypothesized that sub-lethal IN infections may mimic systemic or naturally occurring infection and lead to an immunodominance reaction, in contrast to localized ID immunization. The results demonstrated systemic immunization through an IN route led to enhanced adaptive immunity to VACV-expressed protein targets both in magnitude and in diversity when compared to an ID route using a VACV protein microarray. In addition, cytokine responses, assessed using a Luminex® mouse cytokine multiplex kit, following IN infection was greater than that stemming from ID infection. Overall, the results suggest that the route of immunization (or infection) influences antibody responses. The greater magnitude and diversity of response in systemic infection provides indirect evidence for anecdotal observations made during the smallpox era that survivors maintain lifelong protection. These findings also suggest that systemic or disseminated host immune induction may result in a superior response, that may influence the magnitude of, as well as duration of protective responses.


Assuntos
Imunidade Humoral , Vaccinia virus/imunologia , Vacínia/imunologia , Imunidade Adaptativa , Administração Intranasal , Animais , Anticorpos Neutralizantes , Anticorpos Antivirais , Injeções Intradérmicas , Camundongos , Camundongos Endogâmicos BALB C , Testes de Neutralização , Vacínia/virologia
16.
Virus Res ; 275: 197772, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31593747

RESUMO

Numerous animal models of systemic orthopoxvirus disease have been developed to evaluate therapeutics against variola virus (VARV), the causative agent of smallpox. These animal models do not resemble the disease presentation in human smallpox and most used surrogate Orthopoxviruses. A rodent model using VARV has a multitude of advantages, and previous investigations identified the CAST/EiJ mouse as highly susceptible to monkeypox virus infection, making it of interest to determine if these rodents are also susceptible to VARV infection. In this study, we inoculated CAST/EiJ mice with a range of VARV doses (102-106 plaque forming units). Some animals had detectable viable VARV from the oropharynx between days 3 and 12 post inoculation. Despite evidence of disease, the CAST/EiJ mouse does not provide a model for clinical smallpox due to mild signs of morbidity and limited skin lesions. However, in contrast to previous rodent models using VARV challenge (i.e. prairie dogs and SCID mice), a robust immune response was observed in the CAST/EiJ mice (measured by Immunoglobulin G enzyme-linked immunosorbent assay). This is an advantage of this model for the study of VARV and presents a unique potential for the study of the immunomodulatory pathways following VARV infection.


Assuntos
Modelos Animais de Doenças , Camundongos , Varíola/imunologia , Vírus da Varíola/imunologia , Vírus da Varíola/patogenicidade , Animais , Feminino , Humanos , Camundongos SCID , Varíola/fisiopatologia , Varíola/virologia
17.
J Am Assoc Lab Anim Sci ; 59(3): 305-309, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32213233

RESUMO

In veterinary and human medicine, gabapentin (a chemical analog of γ-aminobutyric acid) is commonly prescribed to treat postoperative and chronic neuropathic pain. This study explored the pharmacokinetics of oral and subcutaneous administration of gabapentin at high (80 mg/kg) and low (30 mg/kg) doses as a potential analgesic in black-tailed prairie dogs (Cynomys ludovicianus; n = 24). The doses (30 and 80 mg/kg) and half maximal effective concentration (1.4 to 16.7 ng/mL) for this study were extrapolated from pharmacokinetic efficacy studies in rats, rabbits, and cats. Gabapentin in plasma was measured by using an immunoassay, and data were evaluated using noncompartmental analysis. The peak plasma concentrations (mean ±1 SD) were 42.6 ±14.8 and 115.5 ±15.2 ng/mL, respectively, after 30 and 80 mg/kg SC and 14.5 ±3.5 and 20.7 ±6.1 ng/mL after the low and high oral dosages, respectively. All peak plasma concentrations of gabapentin occurred within 5 h of administration. Disappearance half-lives for the low and high oral doses were 7.4 ± 6.0 h and 5.0 ± 0.8 h, respectively. The results of this study demonstrate that oral administration of gabapentin at low (30 mg/kg) doses likely would achieve and maintain plasma concentrations at half maximum effective concentration for 12 h, making it a viable option for an every 12-h treatment.


Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Gabapentina/administração & dosagem , Gabapentina/farmacocinética , Sciuridae/metabolismo , Administração Oral , Analgésicos/sangue , Animais , Animais Selvagens , Feminino , Gabapentina/sangue , Injeções Subcutâneas , Masculino , Sciuridae/sangue , Sciuridae/classificação
18.
Viruses ; 12(2)2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32033253

RESUMO

Currently, no rabies virus-specific antiviral drugs are available. Ranpirnase has strong antitumor and antiviral properties associated with its ribonuclease activity. TMR-001, a proprietary bulk drug substance solution of ranpirnase, was evaluated against rabies virus in three cell types: mouse neuroblastoma, BSR (baby hamster kidney cells), and bat primary fibroblast cells. When TMR-001 was added to cell monolayers 24 h preinfection, rabies virus release was inhibited for all cell types at three time points postinfection. TMR-001 treatment simultaneous with infection and 24 h postinfection effectively inhibited rabies virus release in the supernatant and cell-to-cell spread with 50% inhibitory concentrations of 0.2-2 nM and 20-600 nM, respectively. TMR-001 was administered at 0.1 mg/kg via intraperitoneal, intramuscular, or intravenous routes to Syrian hamsters beginning 24 h before a lethal rabies virus challenge and continuing once per day for up to 10 days. TMR-001 at this dose, formulation, and route of delivery did not prevent rabies virus transit from the periphery to the central nervous system in this model (n = 32). Further aspects of local controlled delivery of other active formulations or dose concentrations of TMR-001 or ribonuclease analogues should be investigated for this class of drugs as a rabies antiviral therapeutic.


Assuntos
Antivirais/farmacologia , Vírus da Raiva/efeitos dos fármacos , Ribonucleases/farmacologia , Liberação de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Linhagem Celular , Células Cultivadas , Quirópteros , Cricetinae , Feminino , Fibroblastos/virologia , Mesocricetus , Camundongos , Raiva/prevenção & controle , Vírus da Raiva/fisiologia , Ribonucleases/administração & dosagem
19.
J Wildl Dis ; 55(3): 637-644, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30822210

RESUMO

The distribution of orthopoxviruses (OPXVs) across the North American continent is suggested to be widespread in a wide range of mammalian hosts on the basis of serosurveillance studies. To address the question of whether carnivores in northwestern Mexico are exposed to naturally circulating OPXVs, wild carnivores were collected by live trapping within four different habitat types during fall of 2013 and spring of 2014 within the Janos Biosphere Reserve in northwestern Chihuahua, Mexico. A total of 51 blood samples was collected for testing. Anti-OPXV immunoglobulin G enzymelinked immunosorbent assay, western blot, and rapid fluorescent focus inhibition test (RFFIT) assays were conducted. About 47% (24/51) of the carnivores tested were seropositive for anti-OPXV binding antibodies and had presence of immunodominant bands indicative of OPXV infection. All samples tested were negative for rabies virus neutralizing antibodies by RFFIT, suggesting that the OPXV antibodies were due to circulating OPXV, and not from exposure to oral rabies vaccine (vacciniavectored rabies glycoprotein vaccine) bait distributed along the US-Mexico border. Our results indicated that there may be one or more endemic OPXV circulating within six species of carnivores in northwestern Mexico.


Assuntos
Anticorpos Antivirais/sangue , Carnívoros/imunologia , Orthopoxvirus/imunologia , Infecções por Poxviridae/veterinária , Animais , Especificidade de Anticorpos , México , Infecções por Poxviridae/epidemiologia , Infecções por Poxviridae/imunologia , Infecções por Poxviridae/virologia , Prevalência
20.
Vaccines (Basel) ; 7(3)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31349649

RESUMO

Rabies is preventable through vaccination, but the need to mount annual canine vaccination campaigns presents major challenges in rabies control and prevention. The development of a rabies vaccine that ensures lifelong immunity and animal population management in one dose could be extremely advantageous. A nonsurgical alternative to spay/neuter is a high priority for animal welfare, but irreversible infertility in one dose has not been achieved. Towards this goal, we developed a rabies virus-vectored immunocontraceptive vaccine ERA-2GnRH, which protected against rabies virus challenge and induced >80% infertility in mice after three doses in a live, liquid-vaccine formulation (Wu et al., 2014). To improve safety and use, we formulated an inactivated vaccine in a thermo-responsive chitosan hydrogel for one-dose delivery and studied the immune responses in mice. The hydrogel did not cause any injection site reactions, and the killed ERA-2GnRH vaccine induced high and persistent rabies virus neutralizing antibodies (rVNA) in mice. The rVNA in the hydrogel group reached an average of 327.40 IU/mL, more than 200 times higher than the liquid vaccine alone. The Gonadotropin-releasing hormone (GnRH) antibodies were also present and lasted longer in the hydrogel group, but did not prevent fertility in mice, reflecting a possible threshold level of GnRH antibodies for contraception. In conclusion, the hydrogel facilitated a high and long-lasting immunity, and ERA-2GnRH is a promising dual vaccine candidate. Future studies will focus on rabies protection in target species and improving the anti-GnRH response.

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