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Journal of Korean Medical Science Jun 2024Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the...
Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per μL of blood (p/μL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/μL. However, at follow-up, parasite density increased to 7,630 p/μL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Topics: Humans; Malaria, Falciparum; Ghana; Antimalarials; Middle Aged; Male; Plasmodium falciparum; Proguanil; Atovaquone; Travel; Artemisinins; Artesunate; Parasitemia; Doxycycline; Drug Combinations; Treatment Failure; Artemether, Lumefantrine Drug Combination
PubMed: 38859743
DOI: 10.3346/jkms.2024.39.e186 -
Cancer Medicine Jun 2024We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion...
BACKGROUND
We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment.
METHODS
Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components.
RESULTS
Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci.
CONCLUSIONS
The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.
Topics: Animals; Humans; Mice; Sulfonamides; Cell Line, Tumor; Pyrimidines; Female; Indazoles; Neoplasm Metastasis; Molybdenum; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Pancreatic Neoplasms; Xenograft Model Antitumor Assays
PubMed: 38826119
DOI: 10.1002/cam4.7291 -
Microbiology Spectrum May 2024Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials...
UNLABELLED
Naphthoquine is a promising candidate for antimalarial combination therapy. Its combination with artemisinin has demonstrated excellent efficacy in clinical trials conducted across various malaria-endemic areas. A co-formulated combination of naphthoquine and azithromycin has also shown high clinical efficacy for malaria prophylaxis in Southeast Asia. Developing new combination therapies using naphthoquine will provide additional arsenal responses to the growing threat of artemisinin resistance. Furthermore, due to its long half-life, the possible interaction of naphthoquine with other drugs also needs attention. However, studies on its pharmacodynamic interactions with other drugs are still limited. In this study, the interactions of naphthoquine with ivermectin, atovaquone, curcumin, and ketotifen were evaluated in the asexual stage of 3D7. By using the combination index analysis and the SYBR Green I-based fluorescence assay, different interaction patterns of selected drugs with naphthoquine were revealed. Curcumin showed a slight but significant synergistic interaction with naphthoquine at lower effect levels, and no antagonism was observed across the full range of effect levels for all tested ratios. Atovaquone showed a potency decline when combined with naphthoquine. For ivermectin, a significant antagonism with naphthoquine was observed at a broad range of effect levels below 75% inhibition, although no significant interaction was observed at higher effect levels. Ketotifen interacted with naphthoquine similar to ivermectin, but significant antagonism was observed for only one tested ratio. These findings should be helpful to the development of new naphthoquine-based combination therapy and the clinically reasonable application of naphthoquine-containing therapies.
IMPORTANCE
Pharmacodynamic interaction between antimalarials is not only crucial for the development of new antimalarial combination therapies but also important for the appropriate clinical use of antimalarials. The significant synergism between curcumin and naphthoquine observed in this study suggests the potential value for further development of new antimalarial combination therapy. The finding of a decline in atovaquone potency in the presence of naphthoquine alerts to a possible risk of treatment or prophylaxis failure for atovaquone-proguanil following naphthoquine-containing therapies. The observation of antagonism between naphthoquine and ivermectin raised a need for concern about the applicability of naphthoquine-containing therapy in malaria-endemic areas with ivermectin mass drug administration deployed. Considering the role of atovaquone-proguanil as a major alternative when first-line artemisinin-based combination therapy is ineffective and the wide implementation of ivermectin mass drug administration in malaria-endemic countries, the above findings will be important for the appropriate clinical application of antimalarials involving naphthoquine-containing therapies.
PubMed: 38780257
DOI: 10.1128/spectrum.00630-24 -
Case Reports in Infectious Diseases 2024We report a challenging case of persistent relapsing babesiosis in an immunocompromised host that was successfully managed with atovaquone-proguanil (Malarone)....
We report a challenging case of persistent relapsing babesiosis in an immunocompromised host that was successfully managed with atovaquone-proguanil (Malarone). Malignant B-cell transformation and immunosuppressants, such as rituximab, deplete normal B-cells which normally produce antibodies to combat Babesia infection. Treatment can be prolonged and challenging in immunocompromised hosts. Atovaquone-proguanil (Malarone) is a novel therapy that can be used as part of a salvage regimen in case antimicrobial resistance or failure exists. Weighing the risks and benefits of continuing cancer therapy treatment or reducing the level of immunosuppression may aid in treatment. These are just as important as the choice of antimicrobial therapy for effective treatment and eradication of Babesia infection, especially in immunocompromised hosts.
PubMed: 38774593
DOI: 10.1155/2024/7168928 -
Cancer & Metabolism May 2024Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS)...
BACKGROUND
Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP) to preferentially target cancer cell's mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia.
METHODS
B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system.
RESULTS
Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24 h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors.
CONCLUSIONS
We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy.
PubMed: 38702787
DOI: 10.1186/s40170-024-00342-6 -
Materials Today. Bio Jun 2024The hypoxic tumor microenvironment (TME) of osteosarcoma (OS) is the Achilles' heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are...
Dual regulation of osteosarcoma hypoxia microenvironment by a bioinspired oxygen nanogenerator for precise single-laser synergistic photodynamic/photothermal/induced antitumor immunity therapy.
The hypoxic tumor microenvironment (TME) of osteosarcoma (OS) is the Achilles' heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the hypoxia. Herein, we proposed a "reducing expenditure of O and broadening sources" dual-strategy and constructed ultrasmall IrO@BSA-ATO nanogenerators (NGs) for decreasing the O-consumption and elevating the O-supply simultaneously. As O NGs, the intrinsic catalase (CAT) activity could precisely decompose the overexpressed HO to produce O in situ, enabling exogenous O infusion. Moreover, the cell respiration inhibitor atovaquone (ATO) would be at the tumor sites, effectively inhibiting cell respiration and elevating oxygen content for endogenous O conservation. As a result, IrO@BSA-ATO NGs systematically increase tumor oxygenation in dual ways and significantly enhance the antitumor efficacy of PDT. Moreover, the extraordinary photothermal conversion efficiency allows the implementation of precise photothermal therapy (PTT) under photoacoustic guidance. Upon a single laser irradiation, this synergistic PDT, PTT, and the following immunosuppression regulation performance of IrO@BSA-ATO NGs achieved a superior tumor cooperative eradicating capability both and . Taken together, this study proposes an innovative dual-strategy to address the serious hypoxia problem, and this microenvironment-regulable IrO@BSA-ATO NGs as a multifunctional theranostics platform shows great potential for OS therapy.
PubMed: 38633865
DOI: 10.1016/j.mtbio.2024.101054 -
Malaria Journal Apr 2024To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis...
Superior protection in a relapsing Plasmodium cynomolgi rhesus macaque model by a chemoprophylaxis with sporozoite immunization regimen with atovaquone-proguanil followed by primaquine.
BACKGROUND
To gain a deeper understanding of protective immunity against relapsing malaria, this study examined sporozoite-specific T cell responses induced by a chemoprophylaxis with sporozoite (CPS) immunization in a relapsing Plasmodium cynomolgi rhesus macaque model.
METHODS
The animals received three CPS immunizations with P. cynomolgi sporozoites, administered by mosquito bite, while under two anti-malarial drug regimens. Group 1 (n = 6) received artesunate/chloroquine (AS/CQ) followed by a radical cure with CQ plus primaquine (PQ). Group 2 (n = 6) received atovaquone-proguanil (AP) followed by PQ. After the final immunization, the animals were challenged with intravenous injection of 10 P. cynomolgi sporozoites, the dose that induced reliable infection and relapse rate. These animals, along with control animals (n = 6), were monitored for primary infection and subsequent relapses. Immunogenicity blood draws were done after each of the three CPS session, before and after the challenge, with liver, spleen and bone marrow sampling and analysis done after the challenge.
RESULTS
Group 2 animals demonstrated superior protection, with two achieving protection and two experiencing partial protection, while only one animal in group 1 had partial protection. These animals displayed high sporozoite-specific IFN-γ T cell responses in the liver, spleen, and bone marrow after the challenge with one protected animal having the highest frequency of IFN-γ CD8, IFN-γ CD4, and IFN-γ γδ T cells in the liver. Partially protected animals also demonstrated a relatively high frequency of IFN-γ CD8, IFN-γ CD4, and IFN-γ γδ T cells in the liver. It is important to highlight that the second animal in group 2, which experienced protection, exhibited deficient sporozoite-specific T cell responses in the liver while displaying average to high T cell responses in the spleen and bone marrow.
CONCLUSIONS
This research supports the notion that local liver T cell immunity plays a crucial role in defending against liver-stage infection. Nevertheless, there is an instance where protection occurs independently of T cell responses in the liver, suggesting the involvement of the liver's innate immunity. The relapsing P. cynomolgi rhesus macaque model holds promise for informing the development of vaccines against relapsing P. vivax.
Topics: Animals; Primaquine; Sporozoites; Macaca mulatta; Plasmodium cynomolgi; Immunization; Malaria Vaccines; Chemoprevention; CD8-Positive T-Lymphocytes; Proguanil; Drug Combinations; Atovaquone
PubMed: 38632607
DOI: 10.1186/s12936-024-04933-y -
PloS One 2024Tropical theileriosis is a fatal leukemic-like disease of cattle caused by the tick-transmitted protozoan parasite Theileria annulata. The economics of cattle meat and...
Tropical theileriosis is a fatal leukemic-like disease of cattle caused by the tick-transmitted protozoan parasite Theileria annulata. The economics of cattle meat and milk production is severely affected by theileriosis in endemic areas. The hydroxynaphtoquinone buparvaquone (BPQ) is the only available drug currently used to treat clinical theileriosis, whilst BPQ resistance is emerging and spreading in endemic areas. Here, we chronically exposed T. annulata-transformed macrophages in vitro to BPQ and monitored the emergence of drug-resistant parasites. Surviving parasites revealed a significant increase in BPQ IC50 compared to the wild type parasites. Drug resistant parasites from two independent cloned lines had an identical single mutation, M128I, in the gene coding for T. annulata cytochrome B (Tacytb). This in vitro generated mutation has not been reported in resistant field isolates previously, but is reminiscent of the methionine to isoleucine mutation in atovaquone-resistant Plasmodium and Babesia. The M128I mutation did not appear to exert any deleterious effect on parasite fitness (proliferation and differentiation to merozoites). To gain insight into whether drug-resistance could have resulted from altered drug binding to TaCytB we generated in silico a 3D-model of wild type TaCytB and docked BPQ to the predicted 3D-structure. Potential binding sites cluster in four areas of the protein structure including the Q01 site. The bound drug in the Q01 site is expected to pack against an alpha helix, which included M128, suggesting that the change in amino acid in this position may alter drug-binding. The in vitro generated BPQ resistant T. annulata is a useful tool to determine the contribution of the various predicted docking sites to BPQ resistance and will also allow testing novel drugs against theileriosis for their potential to overcome BPQ resistance.
Topics: Animals; Cattle; Theileriasis; Parasites; Theileria annulata; Cytochromes b; Isoleucine; Methionine; Antiprotozoal Agents; Mutation; Racemethionine; Antiparasitic Agents; Ticks; Naphthoquinones
PubMed: 38626086
DOI: 10.1371/journal.pone.0299002 -
Clinical Microbiology and Infection :... Jul 2024Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several... (Meta-Analysis)
Meta-Analysis Comparative Study Review
Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.
BACKGROUND
Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone.
OBJECTIVES
To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis.
METHODS
DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023.
STUDY ELIGIBILITY CRITERIA
Comparative randomized controlled trials (RCTs).
PARTICIPANTS
PWH.
INTERVENTIONS
Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo.
ASSESSMENT OF RISK OF BIAS
Cochrane risk-of-bias tool for RCTs 2.
METHODS OF DATA SYNTHESIS
Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed.
RESULTS
A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups.
CONCLUSIONS
TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.
Topics: Humans; Pneumonia, Pneumocystis; Randomized Controlled Trials as Topic; Network Meta-Analysis; Trimethoprim, Sulfamethoxazole Drug Combination; Pneumocystis carinii; HIV Infections; AIDS-Related Opportunistic Infections; Dapsone; Pentamidine; Atovaquone; Antifungal Agents; Treatment Outcome
PubMed: 38583518
DOI: 10.1016/j.cmi.2024.03.037 -
Immunity, Inflammation and Disease Apr 2024Chronic obstructive pulmonary disease (COPD) is a globally prevalent respiratory disease, and programmed cell death plays a pivotal role in the development of COPD....
BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a globally prevalent respiratory disease, and programmed cell death plays a pivotal role in the development of COPD. Disulfidptosis is a newly discovered type of cell death that may be associated with the progression of COPD. However, the expression and role of disulfidptosis-related genes (DRGs) in COPD remain unclear.
METHODS
The expression of DRGs was identified by analyzing RNA sequencing (RNA-seq) data in COPD. Further, COPD patients were classified into two subtypes by unsupervised cluster analysis to reveal their differences in gene expression and immune infiltration. Meanwhile, hub genes associated with disulfidptosis were screened by weighted gene co-expression network analysis. Subsequently, the hub genes were validated experimentally in cells and animals. In addition, we screened potential therapeutic drugs through the hub genes.
RESULTS
We identified two distinct molecular clusters and observed significant differences in immune cell populations between them. In addition, we screened nine hub genes, and experimental validation showed that CDC71, DOHH, PDAP1, and SLC25A39 were significantly upregulated in cigarette smoke-induced COPD mouse lung tissues and bronchial epithelial cells (BEAS-2B) treated with cigarette smoke extract. Finally, we predicted 10 potential small molecule drugs such as Atovaquone, Taurocholic acid, Latamoxef, and Methotrexate.
CONCLUSION
We highlighted the strong association between COPD and disulfidptosis, with DRGs demonstrating a discriminative capacity for COPD. Additionally, the expression of certain novel genes, including CDC71, DOHH, PDAP1, and SLC25A39, is linked to COPD and may aid in the diagnosis and assessment of this condition.
Topics: Humans; Animals; Mice; Pulmonary Disease, Chronic Obstructive; Apoptosis; Atovaquone; Cluster Analysis; Epithelial Cells; Intercellular Signaling Peptides and Proteins
PubMed: 38578019
DOI: 10.1002/iid3.1231