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Frontiers in Pharmacology 2023
PubMed: 37767402
DOI: 10.3389/fphar.2023.1282233 -
Viruses Aug 2023The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic...
The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.
Topics: Animals; Mice; SARS-CoV-2; COVID-19; Atovaquone; Endoribonucleases; Coronavirus OC43, Human
PubMed: 37766247
DOI: 10.3390/v15091841 -
Emerging Infectious Diseases Oct 2023A 55-year-old man sought treatment for an uncomplicated febrile illness after returning to Canada from the Philippines. A suspected diagnosis of Plasmodium knowlesi... (Review)
Review
A 55-year-old man sought treatment for an uncomplicated febrile illness after returning to Canada from the Philippines. A suspected diagnosis of Plasmodium knowlesi infection was confirmed by PCR, and treatment with atovaquone/proguanil brought successful recovery. We review the evolving epidemiology of P. knowlesi malaria in the Philippines, specifically within Palawan Island.
Topics: Male; Humans; Middle Aged; Philippines; Plasmodium knowlesi; Malaria; Canada; Polymerase Chain Reaction
PubMed: 37735805
DOI: 10.3201/eid2910.230809 -
Journal of Cellular and Molecular... Oct 2023The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by...
The widespread emergence of antimalarial drug resistance has created a major threat to public health. Malaria is a life-threatening infectious disease caused by Plasmodium spp., which includes Apicoplast DNA polymerase and Plasmodium falciparum cysteine protease falcipain-2. These components play a critical role in their life cycle and metabolic pathway, and are involved in the breakdown of erythrocyte hemoglobin in the host, making them promising targets for anti-malarial drug design. Our current study has been designed to explore the potential inhibitors from haplopine derivatives against these two targets using an in silico approach. A total of nine haplopine derivatives were used to perform molecular docking, and the results revealed that Ligands 03 and 05 showed strong binding affinity compared to the control compound atovaquone. Furthermore, these ligand-protein complexes underwent molecular dynamics simulations, and the results demonstrated that the complexes maintained strong stability in terms of RMSD (root mean square deviation), RMSF (root mean square fluctuation), and Rg (radius of gyration) over a 100 ns simulation period. Additionally, PCA (principal component analysis) analysis and the dynamic cross-correlation matrix showed positive outcomes for the protein-ligand complexes. Moreover, the compounds exhibited no violations of the Lipinski rule, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions yielded positive results without indicating any toxicity. Finally, density functional theory (DFT) and molecular electrostatic potential calculations were conducted, revealing that the mentioned derivatives exhibited better stability and outstanding performance. Overall, this computational approach suggests that these haplopine derivatives could serve as a potential source for developing new, effective antimalarial drugs to combat malaria. However, further in vitro or in vivo studies might be conducted to determine their actual effectiveness.
PubMed: 37724615
DOI: 10.1111/jcmm.17940 -
The American Journal of Tropical... Oct 2023Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million...
Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million infections each year. We sought to evaluate patient and provider acceptability of malaria chemoprevention in a long-acting formulation. We administered questionnaires to patients and providers in malaria endemic districts in Kenya and Zambia. Questions explored preferences and concerns around long-acting antimalarial formulations compared with oral formulations. We recruited 202 patient respondents (Kenya, n = 102; Zambia, n = 100) and 215 provider respondents (Kenya, n = 105; Zambia, n = 110). Long-acting injection was preferred to oral pills, whereas oral pills were preferred to implant or transdermal administration by patient respondents. Of 202 patient respondents, 80% indicated that they 'definitely would try' malaria chemoprevention offered by injection instead of oral pills. Of parents or guardians, 84% of 113 responded that they 'definitely would' have their child age < 12 years and 90% of 88 'definitely would' have their child ≥12 years receive an injection for malaria prevention. Provider respondents indicated that they would be more likely to prescribe a long-acting injectable product compared with an oral product for malaria chemoprevention in adults (70%), adolescents ages 12 years and older (67%), and children <12 years (81%). Potential for prolonged adverse effects with long-acting products was the highest concern for patient respondents, while higher medication-related cost was cited as the most concerning barrier to implementation by providers. Overall, these findings indicate enthusiasm for the development of long-acting injectable antimalarials to provide individual delivery method options across age groups.
Topics: Child; Adult; Adolescent; Humans; Antimalarials; Malaria; Chemoprevention; Zambia; Injections
PubMed: 37604474
DOI: 10.4269/ajtmh.23-0245 -
Veterinary World Jun 2023New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved...
BACKGROUND AND AIM
New anticancer drugs are being developed to avoid the toxicity and chemoresistance of the currently available drugs. The Food and Drug Administration-approved anti-malarial drug atovaquone is known to act as a selective oxidative phosphorylation inhibitor in the mitochondria by competing with CO Q10 (mitochondrial complex II and III). This study aimed to investigate the effect of atovaquone by examining the Na/K-ATPase (NKA) activity in various canine cell lines.
MATERIALS AND METHODS
Canine cell lines were treated with various concentrations (2.5, 5, 10, 15, and 20 μM) of atovaquone for 24, 48, and 72 h. Human cell lines were used as a control to validate the canine cancer cell lines. The activities of the drugs against the cancer cell lines were measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromideassay. The cell metabolic activity was determined by measuring the activities of the nicotinamide adenine dinucleotide phosphate-dependent cellular oxidoreductase enzymes. The NKA activity was measured using the single-cell patch clamping assay.
RESULTS
Atovaquone-induced apoptosis by elevating the concentration of reactive oxygen species (ROS) in the tumor cells, leading to cell death. Treatment of canine cancer cells with N-acetylcysteine (ROS inhibitor) reduced the activity of the drug. Furthermore, atovaquone inhibited more than 45% of the NKA ion current.
CONCLUSION
This study demonstrated effects of atovaquone against canine cancer cell lines. The data may prove beneficial in repurposing the drug as a new anticancer agent in canine clinical trials, which might aid in fighting human cancer.
PubMed: 37577204
DOI: 10.14202/vetworld.2023.1185-1192 -
Case Reports in Infectious Diseases 2023Babesiosis is a tick-borne condition that causes hemolytic anemia and manifests with flu-like symptoms such as fevers, chills, fatigue, and anorexia. Very few case...
Babesiosis is a tick-borne condition that causes hemolytic anemia and manifests with flu-like symptoms such as fevers, chills, fatigue, and anorexia. Very few case reports have documented babesiosis infection associated with a false-positive HIV test. In this case report, we add to the current literature by describing a patient admitted for treatment of babesiosis who had a preliminary positive HIV test on admission and a negative repeat HIV test after one week of treatment for babesiosis. A 60-year-old male with a past medical history of high cholesterol presented to the Emergency Department after having abnormal laboratory tests with his primary care doctor. He reported fever, fatigue, anorexia, and worsening jaundice for three weeks. He was hypotensive and febrile on admission. A blood smear showed Babesia species with 1-2% infected red blood cells. He was admitted to the intensive care unit and received treatment with plasmapheresis, atovaquone, and antibiotics. The fourth-generation HIV 1/2 antigen/antibody test was initially positive but after treatment, HIV testing was negative. A misdiagnosis of HIV can greatly impact a patient's quality of life as antiretroviral therapy has multiple deleterious side effects. Clinicians must consider further evaluation of patients with acute babesiosis who also test positive for HIV.
PubMed: 37528903
DOI: 10.1155/2023/6271710 -
PloS One 2023Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying...
Assessment of the transmission blocking activity of antimalarial compounds by membrane feeding assays using natural Plasmodium falciparum gametocyte isolates from West-Africa.
Antimalarial drugs that can block the transmission of Plasmodium gametocytes to mosquito vectors would be highly beneficial for malaria elimination efforts. Identifying transmission-blocking drugs currently relies on evaluation of their activity against gametocyte-producing laboratory parasite strains and would benefit from a testing pipeline with genetically diverse field isolates. The aims of this study were to develop a pipeline to test drugs against P. falciparum gametocyte field isolates and to evaluate the transmission-blocking activity of a set of novel compounds. Two assays were designed so they could identify both the overall transmission-blocking activity of a number of marketed and experimental drugs by direct membrane feeding assays (DMFA), and then also discriminate between those that are active against the gametocytes (gametocyte killing or sterilizing) or those that block development in the mosquito (sporontocidal). These DMFA assays used venous blood samples from naturally infected Plasmodium falciparum gametocyte carriers and locally reared Anopheles gambiae s.s. mosquitoes. Overall transmission-blocking activity was assessed following a 24 hour incubation of compound with gametocyte infected blood (TB-DMFA). Sporontocidal activity was evaluated following addition of compound directly prior to feeding, without incubation (SPORO-DMFA); Gametocyte viability was retained during 24-hour incubation at 37°C when gametocyte infected red blood cells were reconstituted in RPMI/serum. Methylene-blue, MMV693183, DDD107498, atovaquone and P218 showed potent transmission-blocking activity in the TB-DMFA, and both atovaquone and the novel antifolate P218 were potent inhibitors of sporogonic development in the SPORO-DMA. This work establishes a pipeline for the integral use of field isolates to assess the transmission-blocking capacity of antimalarial drugs to block transmission that should be validated in future studies.
Topics: Animals; Humans; Plasmodium falciparum; Antimalarials; Atovaquone; Folic Acid Antagonists; Malaria, Falciparum; Africa, Western
PubMed: 37494413
DOI: 10.1371/journal.pone.0284751 -
Infectious Diseases of Poverty Jul 2023Human babesiosis is a worldwide disease caused by intraerythrocytic protozoa of the genus Babesia. It is transmitted by bites from ixodid ticks, and mechanically...
Successful treatment with doxycycline monotherapy for human infection with Babesia venatorum (Babesiidae, Sporozoa) in China: a case report and proposal for a clinical regimen.
BACKGROUND
Human babesiosis is a worldwide disease caused by intraerythrocytic protozoa of the genus Babesia. It is transmitted by bites from ixodid ticks, and mechanically transmitted by blood transfusion. It is primarily treated with quinine and/or atovaquone, which are not readily available in China. In this study, we developed a novel treatment regimen involving doxycycline monotherapy in a patient with severe Babesia venatorum infection as an alternative therapeutic medication. The aim of our study is to provide a guidance for clinical practice treatment of human babesiosis.
CASE PRESENTATION
A 73-year-old man who had undergone splenectomy and blood transfusion 8 years prior, presented with an unexplained fever, headache, and thrombocytopenia, and was admitted to the Fifth Medical Center of the PLA General Hospital. He was diagnosed with B. venatorum infection by morphological review of thin peripheral blood smears, which was confirmed by multi-gene polymerase chain reaction (PCR), and sequencing of the entire 18s rRNA and partial β-tubulin encoding genes, as well as isolation by animal inoculation. The doxycycline monotherapy regimen (peros, 0.1 g bisindie) was administered following pharmacological guidance and an effective outcome was observed. The patient recovered rapidly following the doxycycline monotherapy. The protozoan load in peripheral blood samples decreased by 88% in hematocrit counts after 8 days, and negative PCR results were obtained after 90 days of follow-up at the hospital. The treatment lasted for 3 months without any side effects or sequelae. The nine-month follow-up survey of the patient did not reveal any signs of recrudescence or anti-babesial tolerance.
CONCLUSIONS
We have reported a clinical case of successful doxycycline monotherapy for human babesiosis caused by B. venatorum, which provides an optional medical intervention for human babesiosis.
Topics: Male; Animals; Humans; Aged; Babesia; Babesiosis; Doxycycline; Ixodidae; China
PubMed: 37443058
DOI: 10.1186/s40249-023-01111-1 -
Heliyon Jun 2023Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe... (Review)
Review
Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe economic losses in livestock as well as in pet animals. A large number of dairy animals are imported in order to fulfill the demands of milk, milk, meat and its products. In addition, different pet animals are transported from Pakistan to various parts of the world, therefore, it is important to identify the current status and distribution of babesiosis throughout Pakistan in order to control the disease and draw attention for future research, diagnosis, treatment and control of this diseases. No work has been done on a complete review on up-to-date on blood protozoal disease burden in Pakistan. This article will provide about the complete background of babesiosis in ruminants, equines and pet animals, its current status, distribution, vectors in Pakistan and allopathic and ethnoveterinary treatments used against babesiosis. Babesiosis may be subclinical (apparently normal) and may be clinical with acute to chronic disease and sometimes fatal. Babesia is found and develops inside the erythrocytes (red blood cells). Clinically, it causes fever, fatigue, lethargy, pallor mucus membranes, malaise, cachexia, respiratory distress, jaundice, icterus, hemolytic anemia, hemoglobinuria, lymphadenopathy, chollangocytitis, hepatomegaly, and splenomegaly. Chemotherapy for babesiosis includes Imidocarb dipropionate, Diaminazine aceturate Atovaquone and Bupravaquone, Azithromycin, Quinuronium sulfate and Amicarbalidesio-thionate are most widely used. Supportive therapy includes multivitamins, fluid therapy, antipyretics intravenous fluids, and blood transfusions are used if necessary. In addition, there are certain ethnoveterinary (homeopathic) ingredients which having anti-babesial activity. As the resistance against these drugs is developing every day. New more specific long-lasting drugs should be developed for the treatment of Babesiosis. Further studies should be done on disease genome of different species of for vaccine development like malarial parasites.
PubMed: 37441378
DOI: 10.1016/j.heliyon.2023.e17172