RESUMO
The classification of smallpox by the U.S. Centers for Disease Control and Prevention (CDC) as a Category A Bioterrorism threat agent has resulted in the U.S. Government investing significant funds to develop and stockpile a suite of medical countermeasures to ameliorate the consequences of a smallpox epidemic. This stockpile includes both vaccines for prophylaxis and antivirals to treat symptomatic patients. In this manuscript, we describe the path to approval for the first therapeutic against smallpox, identified during its development as ST-246, now known as tecovirimat and TPOXX®, a small-molecule antiviral compound sponsored by SIGA Technologies to treat symptomatic smallpox. Because the disease is no longer endemic, the development and approval of TPOXX® was only possible under the U.S. Food and Drug and Administration Animal Rule (FDA 2002). In this article, we describe the combination of animal model studies and clinical trials that were used to satisfy the FDA requirements for the approval of TPOXX ® under the Animal Rule.
Assuntos
Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Desenvolvimento de Medicamentos , Isoindóis/uso terapêutico , Varíola/tratamento farmacológico , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Estados Unidos , United States Food and Drug Administration , Vírus da Varíola/efeitos dos fármacosRESUMO
The human population is currently faced with the potential use of natural or recombinant variola and monkeypox viruses as biological weapons. Furthermore, the emergence of human monkeypox in Africa and its expanding environs poses a significant natural threat. Such occurrences would require therapeutic and prophylactic intervention with antivirals to minimize morbidity and mortality of exposed populations. Two orally-bioavailable antivirals are currently in clinical trials; namely CMX001, an ether-lipid analog of cidofovir with activity at the DNA replication stage and ST-246, a novel viral egress inhibitor. Both of these drugs have previously been evaluated in the ectromelia/mousepox system; however, the trigger for intervention was not linked to a disease biomarker or a specific marker of virus replication. In this study we used lethal, intranasal, ectromelia virus infections of C57BL/6 and hairless SKH1 mice to model human disease and evaluate exanthematous rash (rash) as an indicator to initiate antiviral treatment. We show that significant protection can be provided to C57BL/6 mice by CMX001 or ST-246 when therapy is initiated on day 6 post infection or earlier. We also show that significant protection can be provided to SKH1 mice treated with CMX001 at day 3 post infection or earlier, but this is four or more days before detection of rash (ST-246 not tested). Although in this model rash could not be used as a treatment trigger, viral DNA was detected in blood by day 4 post infection and in the oropharyngeal secretions (saliva) by day 2-3 post infection - thus providing robust and specific markers of virus replication for therapy initiation. These findings are discussed in the context of current respiratory challenge animal models in use for the evaluation of poxvirus antivirals.
Assuntos
Benzamidas/administração & dosagem , Biomarcadores Farmacológicos/análise , Citosina/análogos & derivados , Ectromelia Infecciosa/tratamento farmacológico , Isoindóis/administração & dosagem , Monkeypox virus/efeitos dos fármacos , Organofosfonatos/administração & dosagem , Varíola/tratamento farmacológico , Animais , Linhagem Celular , Citosina/administração & dosagem , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Vírus da Ectromelia/efeitos dos fármacos , Vírus da Ectromelia/fisiologia , Ectromelia Infecciosa/genética , Ectromelia Infecciosa/virologia , Feminino , Humanos , Camundongos , Camundongos Pelados , Camundongos Endogâmicos C57BL , Monkeypox virus/fisiologia , Varíola/virologia , Vírus da Varíola/efeitos dos fármacos , Vírus da Varíola/genética , Vírus da Varíola/fisiologia , Replicação Viral/efeitos dos fármacosRESUMO
In the nineteenth century, smallpox ravaged through the United States and Canada. At this time, a botanical preparation, derived from the carnivorous plant Sarracenia purpurea, was proclaimed as being a successful therapy for smallpox infections. The work described characterizes the antipoxvirus activity associated with this botanical extract against vaccinia virus, monkeypox virus and variola virus, the causative agent of smallpox. Our work demonstrates the in vitro characterization of Sarracenia purpurea as the first effective inhibitor of poxvirus replication at the level of early viral transcription. With the renewed threat of poxvirus-related infections, our results indicate Sarracenia purpurea may act as another defensive measure against Orthopoxvirus infections.
Assuntos
Fitoterapia/história , Fitoterapia/métodos , Extratos Vegetais/farmacologia , Sarraceniaceae/química , Varíola/tratamento farmacológico , Vírus da Varíola/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Animais , Canadá , Linhagem Celular , Cidofovir , Citosina/análogos & derivados , Citosina/uso terapêutico , Imunofluorescência , Células HeLa , História do Século XIX , Humanos , Técnicas In Vitro , Organofosfonatos/uso terapêutico , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Varíola/história , Estados UnidosRESUMO
SIGA Technologies, Inc. is a small biotech company committed to developing novel products for the prevention and treatment of serious viral diseases, with an emphasis on products to combat outbreaks that could result from bioterrorism. With government support, SIGA has developed the necessary infrastructure to successfully advance new antiviral drugs from the discovery stage through to licensing. Currently, there is a need to develop safe and effective inhibitors for poxvirus-induced diseases such as smallpox caused by variola, which is a potential biological warfare agent. Likewise emerging zoonotic infections due to cowpox virus and monkeypox virus require the development of effective countermeasures. Tecovirimat, also known as ST-246, has shown efficacy in all small animal and nonhuman primate prophylaxis and therapeutic efficacy models of poxvirus-induced disease tested to date. Phase I clinical trials and new drug application-enabling toxicology studies have been completed with tecovirimat. A phase II clinical study is being run and SIGA has initiated commercial scale-up manufacturing and preparation for the pivotal safety and efficacy studies. SIGA is committed to getting approval for tecovirimat and supplying it to the Strategic National Stockpile, the Department of Defense and global health authorities.
Assuntos
Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Isoindóis/uso terapêutico , Varíola/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Guerra Biológica , Ensaios Clínicos como Assunto , Ensaios de Uso Compassivo , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoindóis/efeitos adversos , Isoindóis/farmacologia , Varíola/prevenção & controle , Varíola/virologiaRESUMO
Since the eradication of naturally occurring smallpox in 1980, the fear that variola virus could be used as a biological weapon has become real. Over the last 10 years, emergency preparedness programs have been launched to protect populations against a smallpox outbreak or the possible emergence in humans of other orthopoxvirus infections, such as monkeypox. Vaccination against smallpox was responsible for its eradication, but was linked with high rates of adverse events and contraindications. In this context, intensive research in the poxvirus field has led to the development of safer vaccines and to an increase in the number of anti-poxvirus agents in the pipeline. SIGA Technologies Inc, under license from ViroPharma Inc, is developing tecovirimat (ST-246). Tecovirimat is a novel antiviral that inhibits the egress of orthopoxviruses by targeting viral p37 protein orthologs. The development of tecovirimat during the last 5 years for the treatment of smallpox and for its potential use as adjunct to smallpox vaccine is reviewed here.
Assuntos
Antivirais/uso terapêutico , Benzamidas/uso terapêutico , Isoindóis/uso terapêutico , Varíola/tratamento farmacológico , Vírus da Varíola/efeitos dos fármacos , Proteínas do Envelope Viral/antagonistas & inibidores , Animais , Antivirais/efeitos adversos , Antivirais/farmacocinética , Antivirais/provisão & distribuição , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Benzamidas/provisão & distribuição , Guerra Biológica , Defesa Civil , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoindóis/efeitos adversos , Isoindóis/farmacocinética , Isoindóis/provisão & distribuição , Patentes como Assunto , Varíola/prevenção & controle , Varíola/virologia , Vacina Antivariólica/provisão & distribuição , Resultado do Tratamento , Vírus da Varíola/crescimento & desenvolvimento , Vírus da Varíola/patogenicidadeRESUMO
Variola virus and other members of the genus Orthopoxviruses constitute a prominent bioterrorism and public health threat. Treatment with the anti-viral drug cidofovir inhibits replication of orthopoxviruses in vitro and in vivo. In this study, we visualized the effect of cidofovir on viral kinetics in orthopoxvirus infected mice by using whole-body fluorescence imaging (FI). We engineered a cowpox virus (CPV) expressing the enhanced green fluorescent protein (GFP). Single-step growth curves and calculated 50% lethal doses (LD(50)) of wild-type CPX (Wt-CPV) and GFP-expressing CPX (GFP-CPV) were comparable. Whole-body FI first detected GFP fluorescence in the mesenteric tissue of untreated animals on post-infection day (PID) 1. On PID 3 GFP signal was detected throughout the mesentery, in all abdominal organs by PID 5 and in most major organs, except for the heart and brain by PID 6. Infected animals treated with 25mg/kg of cidofovir also began showing signs of viral replication on PID 1, however, the fluorescent signal was limited only to discrete foci throughout the course of the infection. This work describes the first use of an established Orthopox model of infection to evaluate drug efficacy and track virus progression on a macroscopic level.
Assuntos
Antivirais/uso terapêutico , Vírus da Varíola Bovina/efeitos dos fármacos , Varíola Bovina/tratamento farmacológico , Citosina/análogos & derivados , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/metabolismo , Organofosfonatos/uso terapêutico , Animais , Antivirais/administração & dosagem , Antivirais/farmacologia , Bioterrorismo , Chlorocebus aethiops , Cidofovir , Varíola Bovina/patologia , Varíola Bovina/virologia , Vírus da Varíola Bovina/genética , Vírus da Varíola Bovina/patogenicidade , Vírus da Varíola Bovina/fisiologia , Citosina/administração & dosagem , Citosina/farmacologia , Citosina/uso terapêutico , Replicação do DNA , Avaliação Pré-Clínica de Medicamentos , Feminino , Proteínas de Fluorescência Verde/genética , Humanos , Processamento de Imagem Assistida por Computador/métodos , Camundongos , Camundongos Endogâmicos BALB C , Microscopia de Fluorescência , Organofosfonatos/administração & dosagem , Organofosfonatos/farmacologia , Recombinação Genética , Varíola/tratamento farmacológico , Varíola/patologia , Varíola/virologia , Resultado do Tratamento , Células Vero , Replicação ViralAssuntos
Citosina/análogos & derivados , Avaliação Pré-Clínica de Medicamentos/métodos , Engenharia Genética/legislação & jurisprudência , Genoma Viral , Varíola/virologia , Vírus da Varíola/genética , Cidofovir , Citosina/uso terapêutico , Genes Reporter/genética , Humanos , Organofosfonatos/uso terapêutico , Varíola/tratamento farmacológico , Vacina Antivariólica/efeitos adversos , Vacina Antivariólica/genética , Vírus da Varíola/efeitos dos fármacos , Organização Mundial da SaúdeRESUMO
Smallpox is a disease that followed humanity for thousands of years up until 30 years ago. It was possible to eradicate, because an effective live vaccine from crossreacting vaccinia could be developed. Twenty years have passed since vaccinations stopped and very few people are protected against the disease today. Variola today has become an object of discussion due to the possibility that it can be used as a bioweapon. Due to the number of complications that can be expected a general vaccination is probably not possible. Research is ongoing to develop new vaccines. Many countries are improving their capabilities to respond to a renewed threat of a smallpox epidemic.
Assuntos
Bioterrorismo/tendências , Citosina/análogos & derivados , Organofosfonatos , Varíola , Antivirais/uso terapêutico , Guerra Biológica/tendências , Cidofovir , Citosina/uso terapêutico , Europa (Continente)/epidemiologia , História do Século XVI , História do Século XVIII , História do Século XX , História Antiga , História Medieval , Humanos , Compostos Organofosforados/uso terapêutico , Varíola/tratamento farmacológico , Varíola/história , Varíola/prevenção & controle , Varíola/virologia , Vacina Antivariólica/imunologia , Vacina Antivariólica/provisão & distribuição , U.R.S.S.Assuntos
Relações Interinstitucionais , Pesquisa/organização & administração , Varíola , Vírus da Varíola , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Bioterrorismo/tendências , Centers for Disease Control and Prevention, U.S. , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Variação Genética , Humanos , Macaca fascicularis/virologia , National Institutes of Health (U.S.) , Varíola/diagnóstico , Varíola/tratamento farmacológico , Varíola/prevenção & controle , Varíola/virologia , Vacina Antivariólica , Estados Unidos , Vírus da Varíola/efeitos dos fármacos , Vírus da Varíola/genética , Vírus da Varíola/fisiologia , Organização Mundial da SaúdeAssuntos
Analgésicos/administração & dosagem , Bem-Estar do Animal/normas , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Macaca fascicularis/virologia , Varíola/tratamento farmacológico , Animais , Centers for Disease Control and Prevention, U.S. , Avaliação Pré-Clínica de Medicamentos/normas , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudênciaAssuntos
Interferons/farmacologia , Leucócitos/imunologia , Animais , Cercopithecus , Embrião de Galinha , Avaliação Pré-Clínica de Medicamentos , Humanos , Interferons/isolamento & purificação , Interferons/toxicidade , Camundongos , Testes de Neutralização , Varíola/tratamento farmacológico , Suínos , Vírus da Varíola/efeitos dos fármacosAssuntos
Indutores de Interferon/farmacologia , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Encefalite/tratamento farmacológico , Oftalmopatias/tratamento farmacológico , Febre Aftosa/tratamento farmacológico , Humanos , Indutores de Interferon/administração & dosagem , Indutores de Interferon/uso terapêutico , Indutores de Interferon/toxicidade , Dose Letal Mediana , Raiva/tratamento farmacológico , Pesquisa , Infecções Respiratórias/tratamento farmacológico , Varíola/tratamento farmacológico , Viroses/tratamento farmacológicoRESUMO
A patient with chronic erosive gastritis and protein-losing gastropathy is reported. Presentation was with weight loss and abdominal discomfort. There were endoscopic and radiological features of erosive gastritis. Radioactive chromium studies confirmed that the low serum albumin was associated with fecal protein loss. No improvement occurred with bed rest or Caved S but coincided with DeNol therapy.