RESUMO
In spring 1987, British pharmaceutical company Wellcome PLC released azidothymidine (AZT) sold under trade name Retrovir, the first successful treatment for AIDS. In the context of a global public health emergency and with no competing products, Wellcome invested heavily in upfront costs to bring Retrovir to market, reflected in the original launch price of $188 (US dollars), applied to all other markets. Retrovir subsequently faced backlash in the United States for its high cost and Wellcome's profits became a target of debates about prescription drugs in the American healthcare system. As a result, the company agreed to two price reductions within the first two years of market release. Events in the US had global impact, discouraging the company from providing AZT via commercial channels in African countries. Drawing from new archival material, this article explores how Retrovir's pricing reflected the uncertainties of the global AIDS crisis as well as the unique risks Wellcome faced as a foreign company in its most important market of the US. It argues that, contrary to critical opinion, Wellcome's pricing of Retrovir did reflect an underlying principle regarding the appropriate role of for-profit research-intensive pharmaceutical companies during an unprecedented pandemic.
Assuntos
Síndrome da Imunodeficiência Adquirida , Zidovudina , Humanos , Estados Unidos , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Custos e Análise de Custo , Internacionalidade , Preparações Farmacêuticas , Indústria FarmacêuticaRESUMO
The fundamental biological function of nucleoside diphosphate kinase (NDK) is to catalyze the reversible exchange of the γ-phosphate between nucleoside triphosphate (NTP) and nucleoside diphosphate (NDP). This kinase also has functions that extend beyond its canonically defined enzymatic role as a phosphotransferase. However, the role of NDK in filamentous fungi, especially in Aspergillus flavus (A. flavus), is not yet known. Here we report that A. flavus has two NDK-encoding gene copies as assessed by qPCR. Using gene-knockout and complementation experiments, we found that AfNDK regulates spore and sclerotia development and is involved in plant virulence as assessed in corn and peanut seed-based assays. An antifungal test with the inhibitor azidothymidine suppressed AfNDK activity in vitro and prevented spore production and sclerotia formation in A. flavus, confirming AfNDK's regulatory functions. Crystallographic analysis of AfNDK, coupled with site-directed mutagenesis experiments, revealed three residues (Arg-104, His-117, and Asp-120) as key sites that contribute to spore and sclerotia development. These results not only enrich our knowledge of the regulatory role of this important protein in A. flavus, but also provide insights into the prevention of A. flavus infection in plants and seeds, as well as into the structural features relevant for future antifungal drug development.
Assuntos
Aspergillus flavus/enzimologia , Proteínas Fúngicas , Núcleosídeo-Difosfato Quinase , Esporos Fúngicos/enzimologia , Fatores de Virulência , Arachis/microbiologia , Cristalografia por Raios X , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Núcleosídeo-Difosfato Quinase/química , Núcleosídeo-Difosfato Quinase/metabolismo , Sementes/microbiologia , Fatores de Virulência/química , Fatores de Virulência/metabolismo , Zea mays/microbiologiaRESUMO
Dry Eye Disease (DED) is a very common disorder that can result in severe disability and vision loss. Although the pathogenesis of DED is not fully understood, hyperosmolarity, inflammation, and tear film instability are recognized as hallmarks of DED. Recently, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a class of medication used to treat HIV, have been shown to inhibit inflammation in a mouse model of retinal atrophy. In this study, we investigated whether Zidovudine (AZT) can inhibit human corneal epithelial cell (HCEC) inflammatory responses under hyperosmotic conditions. HCECs were cultured in hyperosmotic media containing AZT. Cell viability, cytokine production, and reactive oxygen species (ROS) production were measured. We found that AZT decreased nuclear factor kappa B (NF-κB) and Interleukin-6 (IL-6) levels, increased Superoxide Dismutase 1 (SOD1) production, decreased ROS production, and increased cell viability. These results support the novel use of AZT in the reduction of ocular surface inflammation and the promotion of corneal health in the context of DED.