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1.
Dtsch Med Wochenschr ; 149(8): 454-457, 2024 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-38565119

RESUMO

HISTORY: A 42-year-old female presented with a two-day history of vomiting, diarrhea, fever and chills. Two weeks before she had returned to Germany from a Safari in Tanzania. She had disregarded the recommendation to take antimalarial chemoprophylaxis. CLINICAL FINDINGS AND DIAGNOSIS: The thin blood film showed Plasmodium falciparum-parasitized erythrocytes, and Plasmodium falciparum malaria was diagnosed. The full blood count showed thrombocytopenia and ultrasound imaging revealed splenomegaly. Initially the criteria for complicated malaria were not fulfilled. THERAPY AND COURSE: We started oral therapy with atovaquone/proguanil. The patient vomited the tablets twice. Therefore therapy was switched to intravenous artesunate. Subsequently, parasitemia dropped from 2.8 to 1.0 % within 22 hours. After 3 days of artesunate i. v., treatment could then be completed with oral atovaquone/proguanil, and the symptoms resolved. CONCLUSIONS: Patients with malaria and persistent vomiting should be treated intravenously and monitored closely, as severe gastrointestinal symptoms may reflect impending organ failure. We therefore propose including persistent vomiting in the list of criteria for complicated malaria.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Feminino , Humanos , Adulto , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Artesunato/uso terapêutico , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Malária Falciparum/complicações , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Combinação de Medicamentos , Vômito/etiologia
2.
Infect Disord Drug Targets ; 24(2): e201023222469, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37881078

RESUMO

BACKGROUND: The concern about the global spread of resistant malaria has made the researchers not focus only on the treatment of established infections but relatively more on the prevention of the disease. OBJECTIVE: This study evaluates the chemopreventive activity of ketoconazole in a murine malarial model. METHOD: Five out of seven groups of mice were pretreated for five days with proguanil (PRG), sulfadoxine/ pyrimethamine (SP), 10, 20, and 40 mg/kg body weight (b.w) of ketoconazole (KET10, KET20, and KET40), before being infected (on the sixth day) with Plasmodium berghei. Two other groups were infected-not-treated (INT) and not-infected-nor-treated (NINT). At 72 hours postinfection, five out of ten mice in each group were sacrificed to assess parasitemia, chemoprevention, hematologic, hepatic, and renal parameters. The remaining mice were observed for 28 days to determine their mean survival day post-infection (SDPI). RESULTS: All ketoconazole groups, except KET10, demonstrated 100% chemoprevention and significantly higher mean SDPI (p<0.001) in relation to INT (negative control). There was no significant difference in the mean SDPI observed in KET20 in relation to PRG or NINT (healthy control). A dose-related increase (p<0.01) in the mean plasma urea was observed when ketoconazole groups were compared to one another: KET10 versus KET20 (p<0.01) and KET20 versus KET40 (p<0.01). Sulfadoxine/pyrimethamine demonstrated significantly reduced mean plasma urea (p<0.001) and creatinine (p<0.05) in relation to INT and NINT, respectively. While PRG demonstrated significantly higher mean red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT) in relation to INT. CONCLUSION: Ketoconazole possesses prophylactic antimalarial activity with associated dose-related renal impairment. Sulfadoxine/pyrimethamine demonstrated renoprotective potentials, while PRG prevented malaria-associated anemia.


Assuntos
Anemia , Antimaláricos , Malária Falciparum , Malária , Animais , Camundongos , Pirimetamina/uso terapêutico , Proguanil/uso terapêutico , Sulfadoxina/uso terapêutico , Cetoconazol/uso terapêutico , Antimaláricos/uso terapêutico , Malária/complicações , Malária/tratamento farmacológico , Malária/prevenção & controle , Anemia/tratamento farmacológico , Anemia/prevenção & controle , Rim , Ureia/uso terapêutico
3.
Drug Metab Pharmacokinet ; 54: 100537, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38086197

RESUMO

We previously reported that repeated oral administration of vonoprazan (VPZ) followed by oral administration of proguanil (PG) in healthy adults increased blood concentration of PG and decreased blood concentration of its metabolite cycloguanil (CG) compared with administration of PG alone. In this study, we investigated whether this interaction can be quantitatively explained by VPZ inhibition of PG metabolism. In an in vitro study using human liver microsomes, VPZ inhibited CG formation from PG in a concentration-dependent manner, and the inhibition was enhanced depending on preincubation time. Then, a physiologically based pharmacokinetic (PBPK) model analysis was performed incorporating the obtained inhibition parameters. By fitting the blood concentration profiles of VPZ and PG/CG after VPZ and PG were orally administered alone to our PBPK model, parameters were obtained which can reproduce their concentration profiles. In contrast, when the VPZ inhibition parameters for CG formation from the in vitro study were incorporated, the predicted blood PG and CG concentrations were unchanged; the apparent dissociation constant had to be set to about 1/23 of the obtained in vitro value to reproduce the observed interaction. Further comprehensive evaluation is required, including the possibility that mechanisms other than metabolic inhibition may be involved.


Assuntos
Proguanil , Pirróis , Sulfonamidas , Triazinas , Adulto , Humanos , Proguanil/farmacocinética , Ativação Metabólica , Pirróis/farmacologia
4.
J Travel Med ; 31(3)2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38157311

RESUMO

BACKGROUND: Failure of artemisinin-based combination therapy is increasingly reported in patients with Plasmodium falciparum malaria in sub-Saharan Africa. We aimed to describe the clinical and genomic characteristics of recent cases of P. falciparum malaria failing artemether-lumefantrine in Belgium. METHODS: Travel-related cases of malaria confirmed at the national reference laboratory of the Institute of Tropical Medicine, Antwerp, Belgium, were reviewed. All cases for which attending clinicians reported persistence (beyond Day 3 post-treatment initiation, i.e. early failure) or recrudescence (from Day 7 to 42, i.e. late failure) of P. falciparum parasites despite adequate drug intake were analysed. Both initial and persistent/recurrent samples were submitted to next generation sequencing to investigate resistance-conferring mutations. RESULTS: From July 2022 to June 2023, eight P. falciparum cases of failure with artemether-lumefantrine therapy were reported (early failure = 1; late failure = 7). All travellers were returning from sub-Saharan Africa, most (6/8) after a trip to visit friends and relatives. PfKelch13 (PF3D7_1343700) mutations associated with resistance to artemisinin were found in two travellers returning from East Africa, including the validated marker R561H in the patient with early failure and the candidate marker A675V in a patient with late failure. Additional mutations were detected that could contribute to decreased susceptibility to artemisinin in another three cases, lumefantrine in six cases and proguanil in all eight participants. Various regimens were used to treat the persistent/recrudescent cases, with favourable outcome. CONCLUSION: Within a 12-month period, we investigated eight travellers returning from sub-Saharan Africa with P. falciparum malaria and in whom artemether-lumefantrine failure was documented. Mutations conferring resistance to antimalarials were found in all analysed blood samples, especially against lumefantrine and proguanil, but also artemisinin. There is a pressing need for systematic genomic surveillance of resistance to antimalarials in international travellers with P. falciparum malaria, especially those experiencing treatment failure.


Assuntos
Antimaláricos , Artemisininas , Malária Falciparum , Malária , Humanos , Antimaláricos/uso terapêutico , Proguanil/uso terapêutico , Viagem , Bélgica , Artemeter/uso terapêutico , Combinação Arteméter e Lumefantrina/uso terapêutico , Doença Relacionada a Viagens , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Artemisininas/uso terapêutico , Lumefantrina/uso terapêutico , Malária/tratamento farmacológico , Genômica , Plasmodium falciparum/genética , Combinação de Medicamentos
5.
Int J Antimicrob Agents ; 63(2): 107065, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38122947

RESUMO

The emergence of Acinetobacter baumannii infections as a significant healthcare concern in hospital settings, coupled with their association with poorer clinical outcomes, has prompted extensive investigation into novel therapeutic agents and innovative treatment strategies. Proguanil and chlorhexidine, both categorized as biguanide compounds, have displayed clinical efficacy as antimalarial and topical antibacterial agents, respectively. In this study, we conducted an investigation to assess the effectiveness of combining proguanil and chlorhexidine with clarithromycin or rifampicin against both laboratory strains and clinical isolates of A. baumannii. The combination therapy demonstrated rapid bactericidal activity against planktonic multidrug-resistant A. baumannii, exhibiting efficacy in eradicating mature biofilms and impeding the development of antibiotic resistance in vitro. Additionally, when administered in conjunction with clarithromycin or rifampicin, proguanil enhanced the survival rate of mice afflicted with intraperitoneal A. baumannii infections, and chlorhexidine expedited wound healing in mice with skin infections. These findings are likely attributable to the disruption of A. baumannii cell membrane integrity by proguanil and chlorhexidine, resulting in heightened membrane permeability and enhanced intracellular accumulation of clarithromycin and rifampicin. Overall, this study underscores the potential of employing proguanil and chlorhexidine in combination with specific antibiotics to effectively combat A. baumannii infections and improve treatment outcomes in clinically challenging scenarios.


Assuntos
Acinetobacter baumannii , Rifampina , Animais , Camundongos , Rifampina/farmacologia , Rifampina/uso terapêutico , Clorexidina/farmacologia , Clorexidina/uso terapêutico , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Proguanil/farmacologia , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana Múltipla
6.
Antimicrob Agents Chemother ; 67(6): e0170922, 2023 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-37154745

RESUMO

Atovaquone-proguanil (AP) is used as treatment for uncomplicated malaria, and as a chemoprophylactic agent against Plasmodium falciparum. Imported malaria remains one of the top causes of fever in Canadian returning travelers. Twelve sequential whole-blood samples before and after AP treatment failure were obtained from a patient diagnosed with P. falciparum malaria upon their return from Uganda and Sudan. Ultradeep sequencing was performed on the cytb, dhfr, and dhps markers of treatment resistance before and during the episode of recrudescence. Haplotyping profiles were generated using three different approaches: msp2-3D7 agarose and capillary electrophoresis, and cpmp using amplicon deep sequencing (ADS). A complexity of infection (COI) analysis was conducted. De novo cytb Y268C mutants strains were observed during an episode of recrudescence 17 days and 16 h after the initial malaria diagnosis and AP treatment initiation. No Y268C mutant reads were observed in any of the samples prior to the recrudescence. SNPs in the dhfr and dhps genes were observed upon initial presentation. The haplotyping profiles suggest multiple clones mutating under AP selection pressure (COI > 3). Significant differences in COI were observed by capillary electrophoresis and ADS compared to the agarose gel results. ADS using cpmp revealed the lowest haplotype variation across the longitudinal analysis. Our findings highlight the value of ultra-deep sequencing methods in the understanding of P. falciparum haplotype infection dynamics. Longitudinal samples should be analyzed in genotyping studies to increase the analytical sensitivity.


Assuntos
Antimaláricos , Malária Falciparum , Humanos , Plasmodium falciparum/genética , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Sefarose/uso terapêutico , Canadá , Proguanil/farmacologia , Proguanil/uso terapêutico , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Malária Falciparum/prevenção & controle , Combinação de Medicamentos , Falha de Tratamento , Tetra-Hidrofolato Desidrogenase , Sequenciamento de Nucleotídeos em Larga Escala , Recidiva
7.
Travel Med Infect Dis ; 54: 102590, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37209974

RESUMO

BACKGROUND: Hair analysis to identify substance use is an established methodology. This could also be a method to monitor adherence to antimalarial drugs. We aimed to establish a methodology to determine hair concentrations of atovaquone, proguanil and mefloquine in travellers using chemoprophylaxis. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous analysis of the antimalarial drugs -atovaquone (ATQ), proguanil (PRO) and mefloquine (MQ), in human hair. The hair samples from five volunteers were used for this proof-of-concept analysis. Three volunteers were taking daily atovaquone/proguanil (ATQ/PRO) chemoprophylaxis and two volunteers were using weekly mefloquine (MQ) chemoprophylaxis. RESULTS: With this proof-of-principle analysis, we could show that ATQ/PRO and MQ are integrated into the hair matrix. Chemoprophylaxis could be quantified with the established method. In hair segments, maximal concentrations of 3.0 ng/mL/20 mg hair proguanil, 1.3 ng/mL/20 mg hair atovaquone and 78.3 ng/mL/20 mg hair mefloquine were measured. Moreover, malaria drug concentration changes correlated with the time interval since finishing the chemoprophylaxis regimen. CONCLUSIONS: The validated method was used successfully for the analysis of antimalarial-drug positive hair samples containing atovaquone, proguanil or mefloquine. This research shows that hair can be used for adherence monitoring of chemoprophylaxis and paves the way for larger studies and optimized procedures.


Assuntos
Antimaláricos , Humanos , Antimaláricos/uso terapêutico , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Mefloquina/uso terapêutico , Cromatografia Líquida , Quimioterapia Combinada , Viagem , Espectrometria de Massas em Tandem , Combinação de Medicamentos
9.
J Travel Med ; 30(3)2023 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-37098163

RESUMO

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.


Assuntos
Antimaláricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Malária , Humanos , Adulto , Antimaláricos/efeitos adversos , Proguanil/uso terapêutico , Atovaquona/efeitos adversos , Viagem , Malária/tratamento farmacológico , Estudos Transversais , Doença Relacionada a Viagens , Fatores de Risco , Prescrições , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Alemanha
10.
Emergencias (Sant Vicenç dels Horts) ; 35(2): 139-141, abr. 2023.
Artigo em Espanhol | IBECS | ID: ibc-216464

RESUMO

Pregunta. ¿Cuáles son los beneficios y los riesgos de la atovacuona-proguanil para tratar los casos sin complicaciones de malaria provocada por el parásito Plasmodium falciparum?Fundamento. El tipo de malaria más común y grave es el causado por Plasmodium falciparum. En su forma menos agresiva (sin complicaciones), los síntomas son fiebre, dolores de cabeza, dolor muscular y vómitos. La enfermedad puede convertirse en grave y mortal si no se la trata con rapidez o con la medicación adecuada. Esta revisión tiene por objetivo descubrir si la atovacuona-proguanil es efectiva y segura para tratar los casos de malaria por Plasmodium falciparum sin complicaciones. El procedimiento fue comparar los resultados de estudios que comparaban la atovacuona-proguanil con otros tratamientos. Como mensajes clave destacamos que la atovacuona-proguanil es tan efectiva para tratar los casos sin complicación de malaria por Plasmodium falciparum como el artesunato-mefloquina. Puede resultar menos efectiva que el artemeter-lumefantrine, artesunato-amodiaquino y artesunato-atovacuona-proguanil, pero hacen falta evidencias más robustas para confirmarlo. Los efectos secundarios parecen similares con la atovacuona-proguanil.Fecha de investigación. Las evidencias de esta revisión están actualizadas hasta el 30 de enero de 2020. (AU)


Assuntos
Humanos , Atovaquona/uso terapêutico , Proguanil/uso terapêutico , Malária/tratamento farmacológico , Plasmodium falciparum
11.
Clin Pharmacokinet ; 62(4): 599-608, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36897544

RESUMO

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).


Assuntos
Esomeprazol , Proguanil , Humanos , Atovaquona , Estudos Cross-Over , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Interações Medicamentosas , Esomeprazol/farmacologia , Proguanil/farmacocinética , Substâncias Redutoras
12.
Am J Trop Med Hyg ; 108(4): 777-782, 2023 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-36878214

RESUMO

Atovaquone-proguanil is one of the most commonly prescribed malaria prophylactic drugs. However, sporadic mutations conferring resistance to atovaquone have been detected in recent years associated with single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum cytochrome b ( pfcytb) gene. Monitoring polymorphisms linked with resistance is essential in assessing the prevalence of drug resistance and may help in designing strategies for malaria control. Several approaches have been used to study genetic polymorphisms associated with antimalarial drug resistance. However, they either lack high throughput capacity or are expensive in time or money. Ligase detection reaction fluorescent microsphere assay (LDR-FMA) provides a high-throughput method to detect genetic polymorphisms in P. falciparum. In this study, we have created primers to detect SNPs associated with clinically relevant atovaquone resistance using LDR-FMA and validated them in clinical samples. Four SNPs from pfcytb gene were analyzed using LDR-FMA. The results were 100% consistent with DNA sequence data, indicating that this method has potential as a tool to detect genetic polymorphisms associated with atovaquone resistance in P. falciparum.


Assuntos
Antimaláricos , Malária Falciparum , Humanos , Atovaquona/uso terapêutico , Plasmodium falciparum/genética , Polimorfismo de Nucleotídeo Único , Ligases/genética , Proguanil/uso terapêutico , Antimaláricos/uso terapêutico , Malária Falciparum/tratamento farmacológico , Combinação de Medicamentos , Primers do DNA , Resistência a Medicamentos/genética , Citocromos b/genética
13.
Biochemistry ; 62(3): 710-721, 2023 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-36657084

RESUMO

Over one and a half million people die of tuberculosis (TB) each year. Multidrug-resistant TB infections are especially dangerous, and new drugs are needed to combat them. The high cost and complexity of drug development make repositioning of drugs that are already in clinical use for other indications a potentially time- and money-saving avenue. In this study, we identified among existing drugs five compounds: azelastine, venlafaxine, chloroquine, mefloquine, and proguanil as inhibitors of acetyltransferase Eis from Mycobacterium tuberculosis, a causative agent of TB. Eis upregulation is a cause of clinically relevant resistance of TB to kanamycin, which is inactivated by Eis-catalyzed acetylation. Crystal structures of these drugs as well as chlorhexidine in complexes with Eis showed that these inhibitors were bound in the aminoglycoside binding cavity, consistent with their established modes of inhibition with respect to kanamycin. Among three additionally synthesized compounds, a proguanil analogue, designed based on the crystal structure of the Eis-proguanil complex, was 3-fold more potent than proguanil. The crystal structures of these compounds in complexes with Eis explained their inhibitory potencies. These initial efforts in rational drug repositioning can serve as a starting point in further development of Eis inhibitors.


Assuntos
Acetiltransferases , Mycobacterium tuberculosis , Tuberculose , Humanos , Acetiltransferases/antagonistas & inibidores , Antituberculosos/farmacologia , Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Canamicina/farmacologia , Canamicina/química , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Proguanil/metabolismo , Tuberculose/tratamento farmacológico
14.
BMJ Mil Health ; 169(2): 146-151, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33257519

RESUMO

OBJECTIVES: Military deployments to the tropics are associated with specific infection risks. To add to the available epidemiological information, infectious disease risks in German military personnel returning from predominantly tropical deployments were assessed. METHODS: Since 2006, German soldiers returning from predominantly tropical deployments have been offered the opportunity of returnee screenings at the Department of Tropical Medicine and Infectious Diseases of the Bundeswehr Hospital Hamburg. Case files and diagnostic results recorded between 2006 and 2018 were retrospectively assessed to identify deployment-associated infectious disease risks. RESULTS: Along with high enteric colonisation rates with apathogenic protozoa and resistant Enterobacteriaceae, direct or indirect proof of infections among the 764 assessed cases comprised Plasmodium spp (n=37), Giardia duodenalis (n=21), Schistosoma spp (n=14), Yersinia enterocolitica (n=5), Strongyloides stercoralis (n=3), Campylobacter jejuni (n=1), Leishmania spp (n=1) and Salmonella enterica (n=1), as well as latent infections with Mycobacterium tuberculosis complex (n=8). The infections were mainly imported from the African region and Eastern Mediterranean region and high proportions of cases lacked typical symptoms. Reported side effect rates of antimalarial chemoprophylaxis for mefloquine (n=121), atovaquone/proguanil (n=49) and doxycycline (n=6) were 36.3%, 19.3% and 11.8%, respectively, while non-compliance rates were 12.9%, 13.0% and 5.9%, respectively. CONCLUSIONS: Considerable rates of infections with sometimes atypical or absent symptoms confirm a need for returnee screenings after tropical deployments. High reported side effect rates for mefloquine support its replacement by atovaquone/proguanil or doxycycline for antimalarial chemoprophylaxis.


Assuntos
Antimaláricos , Doenças Transmissíveis , Militares , Humanos , Antimaláricos/uso terapêutico , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Mefloquina/uso terapêutico , Doxiciclina/uso terapêutico , Estudos Retrospectivos
15.
Travel Med Infect Dis ; 52: 102520, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36526126

RESUMO

According to current guidelines, atovaquone-proguanil (AP) malaria chemoprophylaxis should be taken once daily starting one day before travel and continued for seven days post-exposure. However, drug-sparing regimens, including discontinuing AP after leaving malaria-endemic areas are cost-saving and probably more attractive to travelers, and may thus enhance adherence. AP has causal prophylactic effects, killing malaria parasites during the hepatic stage. If early hepatic stages were already targeted by AP, AP could possibly be discontinued upon return. Pharmacokinetic data and studies on drug-sparing AP regimens suggest this to be the case. Nevertheless, the evidence is weak and considered insufficient to modify current recommendations. Field trials require large numbers of travelers and inherently suffer from the lack of a control group. Safely-designed controlled human malaria infection trials could significantly reduce study participant numbers and safely establish an effective AP abbreviated regimen which we propose as the optimal trial design to test this concept.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Humanos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Proguanil/farmacologia , Proguanil/uso terapêutico , Atovaquona/farmacologia , Atovaquona/uso terapêutico , Malária/tratamento farmacológico , Malária/prevenção & controle , Combinação de Medicamentos , Viagem , Malária Falciparum/tratamento farmacológico , Malária Falciparum/prevenção & controle
16.
BMC Med ; 20(1): 439, 2022 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-36357883

RESUMO

BACKGROUND: Individuals with a family history of colorectal cancer (CRC) are at a high risk of developing CRC. Preclinical studies suggest that the anti-malaria drug proguanil and atovaquone might play a role in preventing CRC, but population-based evidence is still lacking. METHODS: By accessing a couple of nationwide Swedish registers, we performed a cohort study to explore whether using proguanil and atovaquone might associate with a lower risk of CRC by adopting a new-user study design. Adults who have 1 or more first-degree relatives (parents or siblings) diagnosed with CRC were identified and linked with the Prescribed Drug Register to evaluate their administration history of proguanil and atovaquone. Survival analysis of the time to CRC diagnosis with Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: A total of 16,817 incident proguanil/atovaquone users were identified and matched with 168,170 comparisons, who did not use proguanil/atovaquone, on the ratio of 1:10. We found a significant negative association between proguanil/atovaquone use and risk of CRC (adjusted HR, 0.76; 95% CI, 0.62-0.93). Test for trend showed significant dose- and duration-response correlations (P < 0.001). The association was more pronounced in CRC diagnosed at an advanced stage than at an early stage (adjusted HR, 0.69 vs.0.81). CONCLUSIONS: This national-wide population-based cohort study showed that the use of proguanil and atovaquone was associated with a reduced risk of CRC among individuals with a family history of CRC.


Assuntos
Antimaláricos , Neoplasias Colorretais , Malária Falciparum , Adulto , Humanos , Proguanil/uso terapêutico , Atovaquona/uso terapêutico , Estudos de Coortes , Combinação de Medicamentos , Antimaláricos/efeitos adversos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/prevenção & controle , Malária Falciparum/tratamento farmacológico
17.
PLoS Med ; 19(10): e1004104, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36215323

RESUMO

BACKGROUND: Children with sickle cell anemia (SCA) in areas of Africa with endemic malaria transmission are commonly prescribed malaria chemoprevention. Chemoprevention regimens vary between countries, and the comparative efficacy of prevention regimens is largely unknown. METHODS AND FINDINGS: We enrolled Kenyan children aged 1 to 10 years with homozygous hemoglobin S (HbSS) in a randomized, open-label trial conducted between January 23, 2018, and December 15, 2020, in Homa Bay, Kenya. Children were assigned 1:1:1 to daily Proguanil (the standard of care), monthly sulfadoxine/pyrimethamine-amodiaquine (SP-AQ), or monthly dihydroartemisinin-piperaquine (DP) and followed monthly for 12 months. The primary outcome was the cumulative incidence of clinical malaria at 12 months, and the main secondary outcome was the cumulative incidence of painful events by self-report. Secondary outcomes included other parasitologic, hematologic, and general events. Negative binomial models were used to estimate incidence rate ratios (IRRs) per patient-year (PPY) at risk relative to Proguanil. The primary analytic population was the As-Treated population. A total of 246 children were randomized to daily Proguanil (n = 81), monthly SP-AQ (n = 83), or monthly DP (n = 82). Overall, 53.3% (n = 131) were boys and the mean age was 4.6 ± 2.5 years. The clinical malaria incidence was 0.04 episodes/PPY; relative to the daily Proguanil group, incidence rates were not significantly different in the monthly SP-AQ (IRR: 3.05, 95% confidence interval [CI]: 0.36 to 26.14; p = 0.39) and DP (IRR: 1.36, 95% CI: 0.21 to 8.85; p = 0.90) groups. Among secondary outcomes, relative to the daily Proguanil group, the incidence of painful events was not significantly different in the monthly SP-AQ and DP groups, while monthly DP was associated with a reduced rate of dactylitis (IRR: 0.47; 95% CI: 0.23 to 0.96; p = 0.038). The incidence of Plasmodium falciparum infection relative to daily Proguanil was similar in the monthly SP-AQ group (IRR 0.46; 95% CI: 0.17 to 1.20; p = 0.13) but reduced with monthly DP (IRR 0.21; 95% CI: 0.08 to 0.56; p = 0.002). Serious adverse events were common and distributed between groups, although compared to daily Proguanil (n = 2), more children died receiving monthly SP-AQ (n = 7; hazard ratio [HR] 5.44; 95% CI: 0.92 to 32.11; p = 0.064) but not DP (n = 1; HR 0.61; 95% CI 0.04 to 9.22; p = 0.89), although differences did not reach statistical significance for either SP-AQ or DP. Study limitations include the unexpectedly limited transmission of P. falciparum in the study setting, the high use of hydroxyurea, and the enhanced supportive care for trial participants, which may limit generalizability to higher-transmission settings where routine sickle cell care is more limited. CONCLUSIONS: In this study with limited malaria transmission, malaria chemoprevention in Kenyan children with SCA with monthly SP-AQ or DP did not reduce clinical malaria, but DP was associated with reduced dactylitis and P. falciparum parasitization. Pragmatic studies of chemoprevention in higher malaria transmission settings are warranted. TRIAL REGISTRATION: clinicaltrials.gov (NCT03178643). Pan-African Clinical Trials Registry: PACTR201707002371165.


Assuntos
Anemia Falciforme , Antimaláricos , Artemisininas , Malária Falciparum , Malária , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Amodiaquina/uso terapêutico , Anemia Falciforme/tratamento farmacológico , Antimaláricos/uso terapêutico , Artemisininas/uso terapêutico , Quimioprevenção , Combinação de Medicamentos , Hidroxiureia , Quênia/epidemiologia , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Proguanil/uso terapêutico , Pirimetamina/uso terapêutico , Sulfadoxina/uso terapêutico
18.
Microb Drug Resist ; 28(12): 1065-1070, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36255442

RESUMO

Efflux by resistance nodulation cell division transporters, such as AcrAB-TolC in Escherichia coli, substantially contributes to the development of Gram-negative multidrug resistance. Therefore, the finding of compounds that counteract efflux is an urgent goal in the fight against infectious diseases. Previously, an efflux inhibitory activity of the antimalarials mefloquine and artesunate was reported. In this study, we have investigated further antimalarials regarding efflux by AcrB, the pumping part of AcrAB-TolC, and their drug-enhancing potency in E. coli. We show that 10 of the 24 drugs tested are substrates of the multidrug efflux pump AcrB. Among them, tafenoquine and proguanil, when used at subinhibitory concentrations, caused an at least 4- and up to 24-fold enhancement in susceptibility to 6 and 14 antimicrobial agents, respectively. Both antimalarials are able to increase the intracellular accumulation of Hoechst 33342, with proguanil showing similar effectiveness as the efflux inhibitor 1-(1-naphthylmethyl)piperazine. In the case of proguanil, AcrB-dependent efflux inhibition could also be demonstrated in a real-time efflux assay. In addition to presenting new AcrB substrates, our study reveals two previously unknown efflux inhibitors among antimalarials. Particularly proguanil appears as a promising candidate and its chemical scaffold might be further optimized for repurposing as antimicrobial drug enhancer.


Assuntos
Anti-Infecciosos , Antimaláricos , Farmacorresistência Bacteriana Múltipla , Proteínas de Escherichia coli , Mefloquina , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proguanil , Anti-Infecciosos/farmacologia , Antimaláricos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/farmacologia , Proguanil/farmacologia , Mefloquina/farmacologia
19.
PLoS One ; 17(8): e0273357, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35984838

RESUMO

Despite ongoing efforts to control malaria infection, progress in lowering the number of deaths and infections appears to have stalled. The continued high incidence of malaria infection and mortality is in part due to emergence of parasites resistant to frontline antimalarials. This highlights the need for continued identification of novel protein drug targets. Mitochondrial functions in Plasmodium falciparum, the deadliest species of human malaria parasite, are targets of validated antimalarials including atovaquone and proguanil (Malarone). Thus, there has been great interest in identifying other essential mitochondrial proteins as candidates for novel drug targets. Garnering an increased understanding of the proteomic landscape inside the P. falciparum mitochondrion will also allow us to learn about the basic biology housed within this unique organelle. We employed a proximity biotinylation technique and mass spectrometry to identify novel P. falciparum proteins putatively targeted to the mitochondrion. We fused the leader sequence of a mitochondrially targeted chaperone, Hsp60, to the promiscuous biotin ligase TurboID. Through these experiments, we generated a list of 122 "putative mitochondrial" proteins. To verify whether these proteins were indeed mitochondrial, we chose five candidate proteins of interest for localization studies using ectopic expression and tagging of each full-length protein. This allowed us to localize four candidate proteins of unknown function to the mitochondrion, three of which have previously been assessed to be essential. We suggest that phenotypic characterization of these and other proteins from this list of 122 could be fruitful in understanding the basic mitochondrial biology of these parasites and aid antimalarial drug discovery efforts.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Biotinilação , Combinação de Medicamentos , Humanos , Malária/parasitologia , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proguanil/uso terapêutico , Proteômica
20.
Travel Med Infect Dis ; 49: 102365, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35661741

RESUMO

BACKGROUND: Atovaquone/proguanil (AP) is a highly effective malaria chemoprophylaxis combination. According to current guidelines, AP is taken once daily during, and continued for seven days post exposure. A systematic review by Savelkoel et al. summarised data up to 2017 on abbreviated AP regimens, and concluded that discontinuing AP upon return may be effective, although the available data was insufficient to modify current recommendations. The same applies to other studies evaluating during-travel dose-sparing regimens. METHODS: A literature search in Pubmed and Embase was performed including search terms related to AP prophylaxis and pharmacokinetics to search for recent studies on abbreviated AP regimens published since 2017. RESULTS: Since the 2017 review, no new studies assessing discontinuing AP ad-hoc post-exposure prophylaxis have been published. Two new studies were identified assessing other abbreviated AP regimens; one investigated a twice-weekly AP regimen in 32 travellers, and one a three-day AP course in therapeutic dose (1000/400 mg) prior to exposure in 215 travellers. No malaria cases were detected in the study participants adhering to these regimens. CONCLUSIONS: Further research would be needed if the research question is considered of sufficient importance to facilitate evidence-based decision-making to modify current guidelines, as efficacy studies in travellers are fraught with confounders. We recommend human challenge trials to study abbreviated AP regimens pertaining to malaria chemoprophylaxis as they allow for rational, subject number, time- and cost-saving trial designs.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Antimaláricos/uso terapêutico , Atovaquona/uso terapêutico , Combinação de Medicamentos , Humanos , Malária/tratamento farmacológico , Malária/prevenção & controle , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Proguanil/uso terapêutico , Viagem
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