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Journal of Travel Medicine May 2023Perceived adverse effects of antimalarial chemoprophylaxis can be difficult to distinguish from travel-related illness and are often cited as important reasons for...
BACKGROUND
Perceived adverse effects of antimalarial chemoprophylaxis can be difficult to distinguish from travel-related illness and are often cited as important reasons for non-adherence or refusal of antimalarial chemoprophylaxis. We aimed to investigate the occurrence of symptoms of illness in travellers with and without chemoprophylaxis in a cross-sectional study after travel and to identify risk factors for non-adherence to prophylaxis.
METHODS
We enrolled 458 travellers to Africa and South America during their pre-travel medical consultation at the travel clinic of the University Medical Centre Hamburg-Eppendorf and conducted post-travel interviews on symptoms of illness and intake of malaria prophylaxis.
RESULTS
Eleven percent (49/437) of the participants reported symptoms of illness during travel. In total, 36% (160/448) of the participants reported prescription of chemoprophylaxis, the vast majority of these travelled to Africa (98%) and received atovaquone/proguanil (93%). Frequency of symptoms did not differ significantly between participants without prophylaxis and those taking atovaquone/proguanil. Non-adherence to prophylaxis was frequent (20%), but only 3% (4/149) of the participants stopped the medication early because of perceived side effects. Risk factors associated with non-adherence to prophylaxis included age under 30 years, travel to West or Central Africa and travel duration greater than 14 days.
CONCLUSIONS
Symptoms of illness during travel occurred at similar frequencies irrespective of intake of chemoprophylaxis. Travellers should be informed about chemoprophylaxis in a balanced way, without raising fear of side effects, especially among groups at higher risk for incorrect use of prophylaxis.
Topics: Humans; Adult; Antimalarials; Proguanil; Atovaquone; Travel; Malaria; Cross-Sectional Studies; Travel-Related Illness; Risk Factors; Prescriptions; Drug-Related Side Effects and Adverse Reactions; Germany
PubMed: 37098163
DOI: 10.1093/jtm/taad055 -
Biomedicine & Pharmacotherapy =... Jun 2023The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved...
The continuing heavy toll of the COVID-19 pandemic necessitates development of therapeutic options. We adopted structure-based drug repurposing to screen FDA-approved drugs for inhibitory effects against main protease enzyme (Mpro) substrate-binding pocket of SARS-CoV-2 for non-covalent and covalent binding. Top candidates were screened against infectious SARS-CoV-2 in a cell-based viral replication assay. Promising candidates included atovaquone, mebendazole, ouabain, dronedarone, and entacapone, although atovaquone and mebendazole were the only two candidates with IC50s that fall within their therapeutic plasma concentration. Additionally, we performed Mpro assays on the top hits, which demonstrated inhibition of Mpro by dronedarone (IC50 18 µM), mebendazole (IC50 19 µM) and entacapone (IC50 9 µM). Atovaquone showed only modest Mpro inhibition, and thus we explored other potential mechanisms. Although atovaquone is Dihydroorotate dehydrogenase (DHODH) inhibitor, we did not observe inhibition of DHODH at the respective SARS-CoV-2 IC50. Metabolomic profiling of atovaquone treated cells showed dysregulation of purine metabolism pathway metabolite, where ecto-5'-nucleotidase (NT5E) was downregulated by atovaquone at concentrations equivalent to its antiviral IC50. Atovaquone and mebendazole are promising candidates with SARS-CoV-2 antiviral activity. While mebendazole does appear to target Mpro, atovaquone may inhibit SARS-CoV-2 viral replication by targeting host purine metabolism.
Topics: Humans; Antiviral Agents; SARS-CoV-2; COVID-19; Dihydroorotate Dehydrogenase; Drug Repositioning; Dronedarone; Pandemics; Atovaquone; Mebendazole; Purines; Molecular Docking Simulation; Protease Inhibitors; Molecular Dynamics Simulation
PubMed: 37068330
DOI: 10.1016/j.biopha.2023.114614 -
Reproduction (Cambridge, England) Jun 2023Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study...
IN BRIEF
Developing novel therapies to cure and manage endometriosis is a major unmet need that will benefit over 180 million women worldwide. Results from the current study suggest that inhibitors of oxidative phosphorylation may serve as novel agents for the treatment of endometriosis.
ABSTRACT
Current therapeutic strategies for endometriosis focus on symptom management and are not curative. Here, we provide evidence supporting the inhibition of oxidative phosphorylation (OXPHOS) as a novel treatment strategy for endometriosis. Additionally, we report an organotypic organ-on-a-chip luminal model for endometriosis. The OXPHOS inhibitors, curcumin, plumbagin, and the FDA-approved anti-malarial agent, atovaquone, were tested against the endometriosis cell line, 12Z, in conventional as well as the new organotypic model. The results suggest that all three compounds inhibit proliferation and cause cell death of the endometriotic cells by inhibiting OXPHOS and causing an increase in intracellular oxygen radicals. The oxidative stress mediated by curcumin, plumbagin, and atovaquone causes DNA double-strand breaks as indicated by the elevation of phospho-γH2Ax. Mitochondrial energetics shows a significant decrease in oxygen consumption in 12Z cells. These experiments also highlight differences in the mechanism of action as curcumin and plumbagin inhibit complex I whereas atovaquone blocks complexes I, II, and III. Real-time assessment of cells in the lumen model showed inhibition of migration in response to the test compounds. Additionally, using two-photon lifetime imaging, we demonstrate that the 12Z cells in the lumen show decreased redox ratio (NAD(P)H/FAD) and lower fluorescence lifetime of NAD(P)H in the treated cells confirming major metabolic changes in response to inhibition of mitochondrial electron transport. The robust chemotoxic responses observed with atovaquone suggest that this anti-malarial agent may be repurposed for the effective treatment of endometriosis.
Topics: Female; Humans; Curcumin; Atovaquone; Antimalarials; Oxidative Phosphorylation; Endometriosis; NAD; Antineoplastic Agents; Cell Proliferation
PubMed: 37068140
DOI: 10.1530/REP-22-0265 -
Ticks and Tick-borne Diseases Jul 2023In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several...
In the present study, the effect of a combination therapy consisting of diminazene aceturate (DA) and imidocarb dipropionate (ID) on the in vitro growth of several parasitic piroplasmids, and on Babesia microti in BALB/c mice was evaluated using a fluorescence-based SYBR Green I test. We evaluated the structural similarities between the regularly used antibabesial medications, DA and ID, and the recently found antibabesial drugs, pyronaridine tetraphosphate, atovaquone, and clofazimine, using atom pair fingerprints (APfp). The Chou-Talalay approach was used to determine the interactions between the two drugs. A Celltac MEK-6450 computerized hematology analyzer was used to detect hemolytic anemia every 96 hours in mice infected with B. microti and in those treated with either mono- or combination therapy. According to the APfp results, DA and ID have the most structural similarities (MSS). DA and ID had synergistic and additive interactions against the in vitro growth of Babesia bigemina and Babesia bovis, respectively. Low dosages of DA (6.25 mg kg) and ID (8.5 mg kg) in conjunction with each other inhibited B. microti growth by 16.5 %, 32 %, and 4.5 % more than 25 mg kg DA, 6.25 mg kg DA, and 8.5 mg kg ID monotherapies, respectively. In the blood, kidney, heart, and lung tissues of mice treated with DA/ID, the B. microti small subunit rRNA gene was not detected. The obtained findings suggest that DA/ID could be a promising combination therapy for treating bovine babesiosis. Also, such combination may overcome the potential problems of Babesia resistance and host toxicity induced by utilizing full doses of DA and ID.
Topics: Animals; Mice; Babesiosis; Theileria; Babesia; Imidocarb
PubMed: 37011497
DOI: 10.1016/j.ttbdis.2023.102145 -
Infection and Drug Resistance 2023Currently, atovaquone is not recommended for treating severe pneumonia (PCP) due to insufficient evidence in clinical studies. This report describes a case of severe...
Currently, atovaquone is not recommended for treating severe pneumonia (PCP) due to insufficient evidence in clinical studies. This report describes a case of severe PCP in a human immunodeficiency virus (HIV)-negative immunosuppressed patient who was successfully treated with oral atovaquone and corticosteroids. A 63-year-old Japanese woman complained of fever and dyspnea for 3 days. She had been treated with oral prednisolone (30 mg/day) for interstitial pneumonia for 3 months without PCP prophylaxis. Although we could not confirm from the respiratory specimen, a diagnosis of PCP was indicated by marked elevation of serum beta-D-glucan levels and bilateral ground-glass opacities in the lung fields. Based on the arterial blood gas test results (alveolar-arterial oxygen difference >45 mmHg), the disease status of PCP was defined as severe. Trimethoprim-sulfamethoxazole (SXT) is the first-line drug for treating severe PCP. However, given the patient's history of SXT-induced toxic epidermal necrolysis, she was administered atovaquone instead of SXT. Her clinical symptoms and respiratory condition gradually improved, with a 3-week treatment showing a good clinical course. Previous clinical studies on atovaquone have only been conducted in HIV-positive patients with mild or moderate PCP. Accordingly, the clinical efficacy of atovaquone for severe PCP cases or PCP in HIV-negative patients remains unclear. There is a rising incidence of PCP among HIV-negative patients, given the increasing number of patients receiving immunosuppressive medications; moreover, atovaquone has less severe side effects than SXT. Therefore, there is a need for further clinical investigation to confirm the efficacy of atovaquone in cases of severe PCP, especially among HIV-negative patients. In addition, it also remains unclear whether corticosteroids are beneficial for severe PCP in non-HIV patients. Thus, the use of corticosteroids in cases of severe PCP in non-HIV patients should also be investigated.
PubMed: 36969941
DOI: 10.2147/IDR.S406904 -
Avicenna Journal of Medicine Jan 2023pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has... (Review)
Review
pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has been a decline in pneumonia incidence in HIV since the introduction of antiretroviral medications. However, its incidence is increasing in non-HIV immunocompromised patients including those with solid organ transplantation, hematopoietic stem cell transplantation, solid organ tumors, autoimmune deficiencies, and primary immunodeficiency disorders. We aim to review and summarize the etiology, epidemiology, clinical presentation, diagnosis, and management of pneumonia in HIV, and non-HIV patients. HIV patients usually have mild-to-severe symptoms, while non-HIV patients present with a rapidly progressing disease. Induced sputum or bronchoalveolar lavage fluid can be used to make a definitive diagnosis of pneumonia. Trimethoprim-sulfamethoxazole is considered to be the first-line drug for treatment and has proven to be highly effective for pneumonia prophylaxis in both HIV and non-HIV patients. Pentamidine, atovaquone, clindamycin, and primaquine are used as second-line agents. While several diagnostic tests, treatments, and prophylactic regimes are available at our disposal, there is need for more research to prevent and manage this disease more effectively.
PubMed: 36969352
DOI: 10.1055/s-0043-1764375 -
Open Forum Infectious Diseases Mar 2023We report genomic sequences with multiple mutations in the atovaquone-target region of cytochrome b, including a newly identified Y272S mutation, plus 1 mutation of...
We report genomic sequences with multiple mutations in the atovaquone-target region of cytochrome b, including a newly identified Y272S mutation, plus 1 mutation of undetermined significance in the azithromycin-associated ribosomal protein L4. The parasite was sequenced from an immunocompromised patient on prophylactic atovaquone for pneumonia before diagnosis of babesiosis.
PubMed: 36968958
DOI: 10.1093/ofid/ofad097 -
Malaria Journal Mar 2023New anti-malarial drugs are needed urgently to address the increasing challenges of drug-resistant falciparum malaria. Two rhinacanthin analogues containing a...
BACKGROUND
New anti-malarial drugs are needed urgently to address the increasing challenges of drug-resistant falciparum malaria. Two rhinacanthin analogues containing a naphthoquinone moiety resembling atovaquone showed promising in-vitro activity against a P. falciparum laboratory reference strain (K1). The anti-malarial activity of these 2 compounds was further evaluated for P. falciparum field isolates from an area of multi-drug resistance in Northeast Thailand.
METHODS
Using a pLDH enzyme-linked immunosorbent assay, four P. falciparum isolates from Northeast Thailand in 2018 were tested for in vitro sensitivity to the two synthetic rhinacanthin analogues 1 and 2 as well as established anti-malarials. Mutations in the P. falciparum cytochrome b gene, a marker for atovaquone (ATQ) resistance, were genotyped in all four field isolates as well as 100 other clinical isolates from the same area using PCR-artificial Restriction Fragment Length Polymorphisms. Pfkelch13 mutations, a marker for artemisinin (ART) resistance, were also examined in all isolates.
RESULTS
The 50% inhibitory concentrations (IC) of P. falciparum field isolates for rhinacanthin analogue 1 was 321.9-791.1 nM (median = 403.1 nM). Parasites were more sensitive to analogue 2: IC 48.6-63.3 nM (median = 52.2 nM). Similar results were obtained against P. falciparum reference laboratory strains 3D7 and W2. The ART-resistant IPC-5202 laboratory strain was more sensitive to these compounds with a median IC 45.9 and 3.3 nM for rhinacanthin analogues 1 and 2, respectively. The ATQ-resistant C2B laboratory strain showed high-grade resistance towards both compounds (IC > 15,000 nM), and there was a strong positive correlation between the IC values for these compounds and ATQ (r = 0.83-0.97, P < 0.001). There were no P. falciparum cytochrome b mutations observed in the field isolates, indicating that P. falciparum isolates from this area remained ATQ-sensitive. Pfkelch13 mutations and the ring-stage survival assay confirmed that most isolates were resistant to ART.
CONCLUSIONS
Two rhinacanthin analogues showed parasiticidal activity against multi-drug resistant P. falciparum isolates, although less potent than ATQ. Rhinacanthin analogue 2 was more potent than analogue 1, and can be a lead compound for further optimization as an anti-malarial in areas with multidrug resistance.
Topics: Humans; Antimalarials; Plasmodium falciparum; Atovaquone; Thailand; Cytochromes b; Malaria, Falciparum; Drug Resistance
PubMed: 36959593
DOI: 10.1186/s12936-023-04532-3 -
Clinical Pharmacokinetics Apr 2023CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates.... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND AND OBJECTIVE
CYP2C19-mediated drug interactions of acid-reducing agents are clinically important given the high possibility of concomitant administration with CYP2C19 substrates. This study aimed to evaluate the effect of tegoprazan on the pharmacokinetics (PK) of a CYP2C19 substrate, proguanil, compared with vonoprazan or esomeprazole.
METHODS
A two-part, randomized, open-label, two-sequence, three-period crossover study was conducted in 16 healthy CYP2C19 extensive metabolizers (eight subjects per part). In each period, a single oral dose of atovaquone/proguanil 250/100 mg was administered alone or co-administered with tegoprazan 50 mg, esomeprazole 40 mg (Part 1 only) or vonoprazan 20 mg (Part 2 only). The plasma and urine concentrations of proguanil and its metabolite, cycloguanil, were measured up to 48 h post-dose. PK parameters were calculated using a non-compartmental method and compared between administered alone and co-administered with tegoprazan, vonoprazan or esomeprazole.
RESULTS
Co-administration of tegoprazan did not significantly affect the systemic exposure of proguanil and cycloguanil. In contrast, co-administration of vonoprazan or esomeprazole increased proguanil systemic exposure and decreased cycloguanil systemic exposure, and the magnitude of the corresponding change was greater with esomeprazole co-administration than vonoprazan co-administration.
CONCLUSION
Tegoprazan, unlike vonoprazan and esomeprazole, exhibited negligible CYP2C19-mediated PK interaction. It suggests that as an alternative to other acid-reducing agents, tegoprazan can be used concomitantly with CYP2C19 substrates in clinical settings.
TRIAL REGISTRATION
Clinicaltrials.gov identifier: NCT04568772 (Registered on September 29, 2020).
Topics: Humans; Atovaquone; Cross-Over Studies; Cytochrome P-450 CYP2C19; Drug Interactions; Esomeprazole; Proguanil; Reducing Agents
PubMed: 36897544
DOI: 10.1007/s40262-023-01228-4 -
The Journal of Infectious Diseases Aug 2023Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects...
BACKGROUND
Mpox virus (MPXV) is a zoonotic orthopoxvirus and caused an outbreak in 2022. Although tecovirimat and brincidofovir are approved as anti-smallpox drugs, their effects in mpox patients have not been well documented. In this study, by a drug repurposing approach, we identified potential drug candidates for treating mpox and predicted their clinical impacts by mathematical modeling.
METHODS
We screened 132 approved drugs using an MPXV infection cell system. We quantified antiviral activities of potential drug candidates by measuring intracellular viral DNA and analyzed the modes of action by time-of-addition assay and electron microscopic analysis. We further predicted the efficacy of drugs under clinical concentrations by mathematical simulation and examined combination treatment.
RESULTS
Atovaquone, mefloquine, and molnupiravir exhibited anti-MPXV activity, with 50% inhibitory concentrations of 0.51-5.2 μM, which was more potent than cidofovir. Whereas mefloquine was suggested to inhibit viral entry, atovaquone and molnupiravir targeted postentry processes. Atovaquone was suggested to exert its activity through inhibiting dihydroorotate dehydrogenase. Combining atovaquone with tecovirimat enhanced the anti-MPXV effect of tecovirimat. Quantitative mathematical simulations predicted that atovaquone can promote viral clearance in patients by 7 days at clinically relevant drug concentrations.
CONCLUSIONS
These data suggest that atovaquone would be a potential candidate for treating mpox.
Topics: Humans; Atovaquone; Mefloquine; Monkeypox virus
PubMed: 36892247
DOI: 10.1093/infdis/jiad058