RESUMO
Orally delivered drugs offer significant benefits in the fight against viral infections, and cost-effective production is critical to their impact on pandemic response in low- and middle-income countries. One example, molnupiravir, a COVID-19 therapy developed by Emory, Ridgeback, and Merck & Co., had potential to benefit from significant cost of goods (COGs) reductions for its active pharmaceutical ingredient (API), including starting materials. A holistic approach to identifying, developing, and evaluating optimized synthetic routes, which includes detailed COGs modeling, provides a rapid means to increase the availability, uptake and application of molnupiravir and other antivirals in global markets. Identification and development of alternate processes for the synthesis of molnupiravir has been conducted by the Medicines for All Institute at Virginia Commonwealth University (M4ALL) and the Green and Turner Labs at the University of Manchester. Both groups developed innovative processes based on synthetic route design and biocatalysis aimed at lowering costs and improving global access. The authors then performed COGs modeling to assess cost saving opportunities. This included a focus on manufacturing environments and facilities amenable to global public health and the identification of key parameters using sensitivity analyses. While all of the evaluated routes provide efficiency benefits, the best options yielded 3-6 fold API COGs reductions leading to treatment COGs as low as <$3/regimen. Additionally, key starting materials and cost drivers were quantified to evaluate the robustness of the savings. Finally, COGs models can continue to inform the focus of future development efforts on the most promising routes for additional cost savings. While the full price of a treatment course includes other factors, these alternative API synthetic approaches have significant potential to help facilitate broader access in low- and middle-income countries. As other promising therapeutics are developed, a similar process could enable rapid cost reductions while enhancing global access.
RESUMO
Asiatic schistosomiasis caused by Schistosoma japonicum is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from S. japonicum (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antígenos de Helmintos/farmacologia , Desenvolvimento de Medicamentos , Vacinas Protozoárias/farmacologia , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/prevenção & controle , Drogas Veterinárias/farmacologia , Adjuvantes Imunológicos/economia , Animais , Anticorpos Anti-Helmínticos/sangue , Antígenos de Helmintos/economia , Antígenos de Helmintos/imunologia , Bovinos , Análise Custo-Benefício , Modelos Animais de Doenças , Custos de Medicamentos , Feminino , Interações Hospedeiro-Patógeno , Imunogenicidade da Vacina , Camundongos Endogâmicos C57BL , Contagem de Ovos de Parasitas , Projetos Piloto , Vacinas Protozoárias/economia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/parasitologia , Esquistossomose Japônica/transmissão , Vacinação , Drogas Veterinárias/economiaRESUMO
Did Americans change following the September 11 terrorist attacks? We provide a tentative answer with respect to the positive traits included in the Values in Action Classification of Strengths and measured with a self-report questionnaire available on-line and completed by 4,817 respondents. When scores for individuals completing the survey in the 2 months immediately after September 11 were compared with scores for those individuals who completed the survey before September 11, seven character strengths showed increases: gratitude, hope, kindness, leadership, love, spirituality, and teamwork. Ten months after September 11, these character strengths were still elevated, although to a somewhat lesser degree than immediately following the attacks.
Assuntos
Aeronaves , Caráter , Inventário de Personalidade/estatística & dados numéricos , Valores Sociais , Terrorismo/psicologia , Adulto , District of Columbia , Feminino , Seguimentos , Humanos , Masculino , Cidade de Nova Iorque , Psicometria , Religião e Psicologia , EspiritualidadeRESUMO
PURPOSE: This study investigated the use of private prayer among middle-aged and older patients as a way of coping with cardiac surgery and prayer's relationship to optimism. DESIGN AND METHODS: The measure of prayer included three aspects: (a) belief in the importance of private prayer, (b) faith in the efficacy of prayer on the basis of previous experiences, and (c) intention to use prayer to cope with the distress associated with surgery. The sample was 246 patients awaiting cardiac surgery. The first in-person interview was administered 2 weeks before surgery and optimism was measured the day before surgery by telephone. RESULTS: Private prayer predicted optimism, along with older age, better socioeconomic resources, and healthier affect. Neither measures of general religiosity nor any type of prayers used by patients were associated with optimism. IMPLICATIONS: Suggestions were made for clinicians to improve spiritual assessment and care, and for researchers to address spiritual coping in clinical situations.