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Therapeutic Advances in Infectious... 2021Malaria, a parasitic disease caused by protozoa belonging to the genus , continues to represent a formidable public health challenge. Despite being a preventable... (Review)
Review
Malaria, a parasitic disease caused by protozoa belonging to the genus , continues to represent a formidable public health challenge. Despite being a preventable disease, cases reported among travelers have continued to increase in recent decades. Protection of travelers against malaria, a potentially life-threatening disease, is of paramount importance, and it is therefore necessary for healthcare professionals to be up to date with the most recent recommendations. The present review provides an update of the existent measures for malaria prevention among travelers.
PubMed: 34484736
DOI: 10.1177/20499361211040690 -
Reviews in Endocrine & Metabolic... Dec 2021Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications,... (Review)
Review
Hyperkalemia is a common and potentially life-threatening complication following kidney transplantation that can be caused by a composite of factors such as medications, delayed graft function, and possibly potassium intake. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs, and can be a cause of multiple hospital admissions and barriers to patient discharge. Medications used routinely after kidney transplantation are considered the most frequent culprit for post-transplant hyperkalemia in recipients with a well-functioning graft. These include calcineurin inhibitors (CNIs), pneumocystis pneumonia (PCP) prophylactic agents, and antihypertensives (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers). CNIs can cause hyperkalemic renal tubular acidosis. When hyperkalemia develops following transplantation, the potential offending medication may be discontinued, switched to another agent, or dose-reduced. Belatacept and mTOR inhibitors offer an alternative to calcineurin inhibitors in the event of hyperkalemia, however should be prescribed in the appropriate patient. While trimethoprim/sulfamethoxazole (TMP/SMX) remains the gold standard for prevention of PCP, alternative agents (e.g. dapsone, atovaquone) have been studied and can be recommend in place of TMP/SMX. Antihypertensives that act on the Renin-Angiotensin-Aldosterone System are generally avoided early after transplant but may be indicated later in the transplant course for patients with comorbidities. In cases of mild to moderate hyperkalemia, medical management can be used to normalize serum potassium levels and allow the transplant team additional time to evaluate the function of the graft. In the immediate post-operative setting following kidney transplantation, a rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Patiromer and sodium zirconium cyclosilicate (ZS-9) may play an important role in the management of chronic hyperkalemia in kidney transplant patients, although additional long-term studies are necessary to confirm these effects.
Topics: Humans; Hyperkalemia; Kidney Transplantation; Renin-Angiotensin System; Trimethoprim, Sulfamethoxazole Drug Combination
PubMed: 34292479
DOI: 10.1007/s11154-021-09677-7 -
International Journal of Molecular... May 2021A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through...
A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.
Topics: Animals; Anti-Infective Agents; Antigen Presentation; Apoptosis; Atovaquone; Cell Proliferation; Cytokines; Female; Humans; Immunosuppression Therapy; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Myeloid-Derived Suppressor Cells; T-Lymphocytes, Regulatory; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 34068008
DOI: 10.3390/ijms22105150 -
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 -
Expert Opinion on Drug Discovery Sep 2022is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for...
INTRODUCTION
is a prolific apicomplexan parasite that infects human and nonhuman animals worldwide and can cause severe brain and eye disease. Safer, more effective therapies for toxoplasmosis are needed. Cytochrome inhibitors are remarkably effective against toxoplasmosis and other apicomplexan-caused diseases.
AREAS COVERED
This work reviews cytochrome inhibitors. Emphasis is placed on the structure-activity relationships of these inhibitors with regard to efficacy, pharmacokinetics, selectivity of cytochrome over host, safety, and potential therapeutic strategies.
EXPERT OPINION
Cytochrome inhibitors are highly promising compounds for toxoplasmosis that have been effective in clinical and preclinical studies. Clinical experience with atovaquone previously validated cytochrome as a tractable drug target and, over the past decade, optimization of cytochrome inhibitors has resulted in improved bioavailability, metabolic stability, potency, blood-brain barrier penetration, and selectivity for the cytochrome over the mammalian . Recent studies have demonstrated preclinical safety, identified novel therapeutic strategies for toxoplasmosis using synergistic combinations or long-acting administration and provided insight into their role in chronic infection. This research has identified drug candidates that are more effective than clinically used drugs in preclinical measures of efficacy.
Topics: Animals; Antiprotozoal Agents; Atovaquone; Cytochromes; Humans; Structure-Activity Relationship; Toxoplasma; Toxoplasmosis
PubMed: 35772172
DOI: 10.1080/17460441.2022.2096588 -
Travel Medicine and Infectious Disease 2019The combination of Atovaquone and Proguanil (Malarone™) has been widely used for treatment and prevention of Plasmodium falciparum malaria. Transient elevation of... (Review)
Review
The combination of Atovaquone and Proguanil (Malarone™) has been widely used for treatment and prevention of Plasmodium falciparum malaria. Transient elevation of liver enzymes is a recognized side effect of the medication. The association of Vanishing bile duct syndrome (VBDS) with the use of Atovaqoune/Proguanil was not previously reported. We describe a case of a 62-year-old male with no history of liver disease who presented with painless jaundice after receiving malaria prophylaxis with Atovaquone-proguanil for 25 days. The patient developed severe hepatitis with Vanishing bile duct syndrome. This case highlights a serious side effect of a usually well-tolerated medication.
PubMed: 31238106
DOI: 10.1016/j.tmaid.2019.06.010 -
Journal of Mass Spectrometry and... Nov 2022Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability...
BACKGROUND
Atovaquone has traditionally been used as an antiparasitic and antifungal agent, but recent studies have shown its potential as an anticancer agent. The high variability in atovaquone bioavailability highlights the need for therapeutic drug monitoring, especially in pediatric patients. The goal of our study was to develop and validate the performance of an assay to quantify atovaquone plasma concentrations collected from pediatric cancer patients using LC-MS/MS.
METHODS
Atovaquone was extracted from a 10 µL volume of K-EDTA human plasma using a solution consisting of ACN: EtOH: DMF (8:1:1 v:v:v), separated using reverse-phase chromatography, and detected using a SCIEX 5500 QTrap MS system. LC-MS/MS assay performance was evaluated for precision, accuracy, carryover, sensitivity, specificity, linearity, and interferences.
RESULTS
Atovaquone and its deuterated internal standard were analyzed using a gradient chromatographic method that had an overall cycle-time of 7.4 min per injection, and retention times of 4.3 min. Atovaquone was measured over a dynamic concentration range of 0.63 - 80 µM with a deviation within ≤ ± 5.1 % of the target value. Intra- and inter-assay precision were ≤ 2.7 % and ≤ 8.4 %, respectively. Dilutional, carryover, and interference studies were also within acceptable limits.
CONCLUSIONS
Our studies have shown that our LC-MS/MS-based method is both reliable and robust for the quantification of plasma atovaquone concentrations and can be used to determine the effective dose of atovaquone for pediatric patients treated for AML.
PubMed: 36388060
DOI: 10.1016/j.jmsacl.2022.09.004 -
Journal of Crohn's & Colitis Apr 2023Pneumocystis jirovecii pneumonia [PJP] is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including...
BACKGROUND AND AIM
Pneumocystis jirovecii pneumonia [PJP] is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including patients with inflammatory bowel disease [IBD]. Our aim was to describe immunosuppressive treatment exposure as well as the outcome in IBD patients with PJP.
METHODS
PJP cases were retrospectively collected through the COllaborative Network For Exceptionally Rare case reports of the European Crohn's and Colitis Organisation. Clinical data were provided through a case report form.
RESULTS
In all, 18 PJP episodes were reported in 17 IBD patients [10 ulcerative colitis and seven Crohn's disease]. The median age at PJP diagnosis was 55 years (interquartile range [IQR], 40-68 years]. Two PJP [11.1%] occurred in patients on triple immunosuppression, 10 patients [55.6%] had double immunosuppressive treatment, four patients [22.2%] had monotherapy and two PJP occurred in absence of immunosuppressive treatment [one in a human immunodeficiency virus patient and one in a patient with a history of autologous stem cell transplantation]. Immunosuppressive therapies included steroids [n = 12], thiopurines [n = 10], infliximab [n = 4], ciclosporin [n = 2], methotrexate [n = 1], and tacrolimus [n = 1]. None of the patients diagnosed with PJP had received prophylaxis. All patients were treated by trimethoprim/sulphamethoxazole or atovaquone and an intensive care unit [ICU] stay was required in seven cases. Two patients [aged 71 and 32 years] died, and one patient had a recurrent episode 16 months after initial treatment. Evolution was favourable for the others.
CONCLUSION
This case series reporting potentially fatal PJP highlights the need for adjusted prophylactic therapy in patients with IBD on immunosuppressive therapy.
Topics: Humans; Adult; Middle Aged; Aged; Pneumonia, Pneumocystis; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Pneumocystis carinii; Transplantation, Autologous; Immunosuppressive Agents; Inflammatory Bowel Diseases; Crohn Disease
PubMed: 36223253
DOI: 10.1093/ecco-jcc/jjac153 -
The Lancet. Infectious Diseases May 2023Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the...
BACKGROUND
Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS.
METHODS
VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332.
FINDINGS
Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection.
INTERPRETATION
CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases.
FUNDING
National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Topics: Adult; Animals; Humans; Antibodies, Monoclonal; Malaria, Falciparum; Antimalarials; Plasmodium falciparum; Malaria Vaccines
PubMed: 36708738
DOI: 10.1016/S1473-3099(22)00793-9 -
Advanced Science (Weinheim,... Apr 2022Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased...
Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria-targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria-targeted atovaquone treatment led to significant reductions of both granulocytic myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria-targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic-myeloid-derived suppressor cells and regulatory T cells, which may lead to death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. Mitochondria-targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic-myeloid-derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic-myeloid-derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor-infiltrating CD4 T cells. Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.
Topics: Atovaquone; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Tumor Microenvironment; Vaccination
PubMed: 35243806
DOI: 10.1002/advs.202101267