Abstract
Background
Washington State served as the initial epicenter of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States. An understanding of the risk ...factors and clinical outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) may provide guidance for management.
Methods
All laboratory-confirmed COVID-19 cases in adults admitted to an academic medical center in Seattle, Washington, between 2 March and 26 March 2020 were included. We evaluated individuals with and without severe disease, defined as admission to the intensive care unit or death.
Results
One hundred five COVID-19 patients were hospitalized. Thirty-five percent were admitted from a senior home or skilled nursing facility. The median age was 69 years, and half were women. Three or more comorbidities were present in 55% of patients, with hypertension (59%), obesity (47%), cardiovascular disease (38%), and diabetes (33%) being the most prevalent. Most (63%) had symptoms for ≥5 days prior to admission. Only 39% had fever in the first 24 hours, whereas 41% had hypoxia at admission. Seventy-three percent of patients had lymphopenia. Of 50 samples available for additional testing, no viral coinfections were identified. Severe disease occurred in 49%. Eighteen percent of patients were placed on mechanical ventilation, and the overall mortality rate was 33%.
Conclusions
During the early days of the COVID-19 epidemic in Washington State, the disease had its greatest impact on elderly patients with medical comorbidities. We observed high rates of severe disease and mortality in our hospitalized patients.
In this case series of 105 consecutively hospitalized COVID-19 patients, the median age was 69 years, and 55% had 3 or more comorbidities. Severe disease occurred in 49% of patients, and overall mortality was 33%.
An estimated 8 million persons, mainly in Latin America, are infected with Trypanosoma cruzi, the etiologic agent of Chagas disease. Existing antiparasitic drugs for Chagas disease have significant ...toxicities and suboptimal effectiveness, hence new therapeutic strategies need to be devised to address this neglected tropical disease. Due to the high research and development costs of bringing new chemical entities to the clinic, we and others have investigated the strategy of repurposing existing drugs for Chagas disease. Screens of FDA-approved drugs (described in this paper) have revealed a variety of chemical classes that have growth inhibitory activity against mammalian stage Trypanosoma cruzi parasites. Aside from azole antifungal drugs that have low or sub-nanomolar activity, most of the active compounds revealed in these screens have effective concentrations causing 50% inhibition (EC50's) in the low micromolar or high nanomolar range. For example, we have identified an antihistamine (clemastine, EC50 of 0.4 µM), a selective serotonin reuptake inhibitor (fluoxetine, EC50 of 4.4 µM), and an antifolate drug (pyrimethamine, EC50 of 3.8 µM) and others. When tested alone in the murine model of Trypanosoma cruzi infection, most compounds had insufficient efficacy to lower parasitemia thus we investigated using combinations of compounds for additive or synergistic activity. Twenty-four active compounds were screened in vitro in all possible combinations. Follow up isobologram studies showed at least 8 drug pairs to have synergistic activity on T. cruzi growth. The combination of the calcium channel blocker, amlodipine, plus the antifungal drug, posaconazole, was found to be more effective at lowering parasitemia in mice than either drug alone, as was the combination of clemastine and posaconazole. Using combinations of FDA-approved drugs is a promising strategy for developing new treatments for Chagas disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid ...parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Cutaneous leishmaniasis (CL) is often caused by Leishmania braziliensis (L. braziliensis) in South America. Because of the risk for mucocutaneous leishmaniasis, L. braziliensis is frequently treated ...with parenteral or oral medications. Here, we present a case of a young woman with L. braziliensis (CL) that did not respond to miltefosine but eventually experienced spontaneous resolution. This case highlights the potential for treatment failure and the importance of clinical monitoring in the setting of cutaneous leishmaniasis caused by L. braziliensis.
Chagas disease is one of the major neglected diseases of the world. Existing drug therapies are limited, ineffective, and highly toxic. We describe a novel strategy of drug discovery of adapting an ...existing clinical compound with excellent pharmaceutical properties to target a pathogenic organism. The protein farnesyltransferase (PFT) inhibitor tipifarnib, now in phase III anticancer clinical trials, was previously found to kill Trypanosoma cruzi by blocking sterol 14α-demethylase (14DM). We rationally developed tipifarnib analogues that display reduced affinity for human PFT to reduce toxicity while increasing affinity for parasite 14DM. The lead compound has picomolar activity against cultured T. cruzi and is efficacious in a mouse model of acute Chagas disease.
Advances in Chagas disease drug development: 2009–2010 Buckner, Frederick S; Navabi, Nazlee
Current opinion in infectious diseases,
2010-December, 2010-Dec, 2010-12-00, 20101201, Letnik:
23, Številka:
6
Journal Article
Recenzirano
Odprti dostop
PURPOSE OF REVIEWThe need for better drugs to treat patients with Chagas disease remains urgent. This review summarizes the advancements in drug development over the past 2 years.
RECENT FINDINGSDrug ...development efforts are almost exclusively occurring as preclinical research, although phase II studies for the antifungal drug, posaconazole, and a prodrug of ravuconazole are being planned. Several recent laboratory investigations demonstrate anti-Trypanosoma cruzi activity of novel small molecules in animal models. These include nonpeptidic cruzain inhibitors, novel inhibitors of the sterol 14α-demethylase enzyme, new compounds (arylimidamides) related to pentamidine, derivatives of nifurtimox, compounds using ruthenium complexes, and several natural products. The recent implementation of a high-throughput screen of more than 300 000 compounds against intracellular T. cruzi amastigotes done at the Broad Institute is an important development, yielding approximately 300 selective inhibitors, many of which may serve as leads for medicinal chemistry efforts.
SUMMARYProgress is slow, but recent advancements in both drug development and advocacy for research on neglected diseases are encouraging. Efforts to define a target product profile and to harmonize methodologies for testing drugs for Chagas disease are described herein.
Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent ...and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo1,2-apyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC50 = 0.077 μM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.
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• New drugs for Chagas disease are needed with improved safety and efficacy. • Sterol 14-demethylase (CYP51) is essential for de novo sterol biosynthesis. • Antifungal azole drugs ...kill Trypanosoma cruzi by inhibiting CYP51 activity. • Posaconazole and ravuconazole are in Phase II clinical trials for Chagas disease. • Investigational CYP51 inhibitors are being developed as alternatives.
The protozoan parasite, Trypanosoma cruzi, causes the most prevalent parasitic infection in the American continent. It gives rise to life-long infection in humans and results in severe cardiomyopathy or other life-threatening manifestations (Chagas disease) in ∼30% of those infected. Animal models and clinical studies indicate that etiological treatment of the infection reduces the risk of developing the disease manifestations. Unfortunately, the existing chemotherapeutics have suboptimal antiparasitic activity and cause significant side effects in many patients, thus better anti-trypanosomal drugs are greatly needed. The sterol biosynthesis pathway has received attention as a target for the development of new drugs for Chagas disease. In particular, inhibitors of sterol 14-demethylase (CYP51) are shown to be extremely active on T. cruzi in vitro and in animal models. Antifungal drugs (i.e. azoles) in clinical use or in clinical studies have been extensively tested preclinically on T. cruzi with posaconazole and ravuconazole demonstrating the most promising activity. As a result, posaconazole and a pro-drug of ravuconazole (E1224) are currently being evaluated in Phase II studies for Chagas disease. Additional CYP51 inhibitors that are specifically optimized for anti-T. cruzi activity are in development by academia. These represent an alternative to proprietary antifungal drugs if the latter fall short in clinical trials or are too expensive for widespread clinical use in disease endemic countries. The research over the next few years will help define the role of CYP51 inhibitors, alone or in combination with other drugs, for managing patients with Chagas disease.
A previous publication from this lab (Patrick, et al. Bioorg. Med. Chem. 2016, 24, 2451–2465 ) explored the antitrypanosomal activities of novel derivatives of 2-(2-benzamido)ethyl-4-phenylthiazole ...(1), which had been identified as a hit against Trypanosoma brucei, the causative agent of human African trypanosomiasis. While a number of these compounds, particularly the urea analogues, were quite potent, these molecules as a whole exhibited poor metabolic stability. The present work describes the synthesis of 65 new analogues arising from medicinal chemistry optimization at different sites on the molecule. The most promising compounds were the urea derivatives of 2-aryl-benzothiazol-5-amines. One such analogue, (S)-2-(3,4-difluorophenyl)-5-(3-fluoro-N-pyrrolidylamido)benzothiazole (57) was chosen for in vivo efficacy studies based upon in vitro activity, metabolic stability, and brain penetration. This compound attained 5/5 cures in murine models of both early and late stage human African trypanosomiasis, representing a new lead for the development of drugs to combat this neglected disease.
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