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2.
Inn Med (Heidelb) ; 64(5): 415-425, 2023 May.
Artigo em Alemão | MEDLINE | ID: mdl-37140630

RESUMO

The current influx of refugees and the high rate of immigration increase the prevalence and impact of infectious diseases in Europe. Infections may be detected at first contact, as a result of systematic screening or as part of general medical care. Diagnosis and treatment require special expertise and, in some cases, special precautions. The spectrum of imported infections is determined by the countries of origins of the migrants and the circumstances associated with their escape to Germany. In this article, diagnosis and treatment of the most important infectious diseases will be presented. As far as infectious diseases are concerned, refugees and migrants are not a threat to the host population, but instead have to be perceived and cared for as a highly vulnerable group.


Assuntos
Doenças Transmissíveis , Migrantes , Humanos , Doenças Transmissíveis/diagnóstico , Alemanha , Europa (Continente)/epidemiologia , Emigração e Imigração
3.
Front Cell Infect Microbiol ; 12: 1047281, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36760233

RESUMO

Background: Little is known about knowledge, attitudes and behaviors concerning Chagas disease (CD) among Latin American migrants in Germany to inform public health decision making. Methods: A cross-sectional, questionnaire-based study was conducted between March 2014 and October 2019 among Latin American migrants in six cities in Germany to obtain information on migration history, socioeconomic and insurance status, knowledge about CD, potential risk factors for Trypanosoma cruzi infection, and willingness to donate blood or organs. Results: 168 participants completed the questionnaire. The four countries with the highest proportion of participants contributing to the study population were Colombia, Mexico, Peru and Ecuador. Before migrating to Europe, the majority of the study population resided in an urban setting in houses made of stone or concrete, had higher academic education and was integrated into the German healthcare and healthcare insurance system. The majority of all study participants were also willing to donate blood and organs and a quarter of them had donated blood previously. However, many participants lacked basic knowledge about symptoms and modes of transmission of Chagas disease. One out of 56 serologic tests (1.8%) performed was positive. The seropositive female participant born in Argentina had a negative PCR test and no signs of cardiac or other organ involvement. Conclusions: The study population does not reflect the population structure at risk for T. cruzi infection in endemic countries. Most participants had a low risk profile for infection with T. cruzi. Although the sample size was small and sampling was not representative of all persons at risk in Germany, the seroprevalence found was similar to studies previously conducted in Europe. As no systematic screening for T. cruzi in Latin American blood and organ donors as well as in women of child-bearing age of Latin American origin is implemented in Germany, a risk of occasional transmission of T. cruzi remains.


Assuntos
Doença de Chagas , Trypanosoma cruzi , Humanos , Feminino , Estudos Transversais , América Latina/epidemiologia , Estudos Soroepidemiológicos , Cidades , Conhecimentos, Atitudes e Prática em Saúde , Doença de Chagas/epidemiologia , Alemanha/epidemiologia
4.
Viruses ; 13(6)2021 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067381

RESUMO

After more than one year of the COVID-19 pandemic, antiviral treatment options against SARS-CoV-2 are still severely limited. High hopes that had initially been placed on antiviral drugs like remdesivir have so far not been fulfilled. While individual case reports provide striking evidence for the clinical efficacy of remdesivir in the right clinical settings, major trials failed to demonstrate this. Here, we highlight and discuss the key findings of these studies and underlying reasons for their failure. We elaborate on how such shortcomings should be prevented in future clinical trials and pandemics. We suggest in conclusion that any novel antiviral agent that enters human trials should first be tested in a post-exposure setting to provide rapid and solid evidence for its clinical efficacy before initiating further time-consuming and costly clinical trials for more advanced disease. In the COVID-19 pandemic this might have established remdesivir early on as an efficient antiviral agent at a more suitable disease stage which would have saved many lives, in particular in large outbreaks within residential care homes.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/uso terapêutico , Alanina/uso terapêutico , COVID-19/epidemiologia , Humanos , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Resultado do Tratamento , Replicação Viral/efeitos dos fármacos
5.
J Clin Microbiol ; 59(8): e0031921, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-33962959

RESUMO

For the control of immunity in COVID-19 survivors and vaccinated subjects, there is an urgent need for reliable and rapid serological assays. Based on samples from 63 COVID-19 survivors up to 7 months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performances of three commercial immunoassays for the detection of SARS-CoV-2 IgA and IgG antibodies (Euroimmun SARS-COV-2 IgA/IgG, Mikrogen recomWell SARS-CoV-2 IgA/IgG, and Serion ELISA agile SARS-CoV-2 IgA/IgG) and three rapid lateral flow (immunochromatographic) tests (Abbott PanBio COVID-19 IgG/IgM, Nadal COVID-19 IgG/IgM, and Cleartest Corona 2019-nCOV IgG/IgM) with a 50% plaque-reduction neutralization test (PRNT50) representing the gold standard. Fifty-seven out of 63 PCR-confirmed COVID-19 patients (90%) showed neutralizing antibodies. The sensitivity of the seven assays ranged from 7.0% to 98.3%, and the specificity ranged from 86.0% to 100.0%. Only one commercial immunoassay showed a sensitivity and specificity of greater than 98%.


Assuntos
COVID-19 , SARS-CoV-2 , Anticorpos Antivirais , Humanos , Imunoensaio , Imunoglobulina M , Pandemias , Sensibilidade e Especificidade
6.
Dtsch Med Wochenschr ; 146(6): 399-402, 2021 03.
Artigo em Alemão | MEDLINE | ID: mdl-33735926

RESUMO

INTRODUCTION: Tuberculosis is an often underestimated infectious disease which can lead to manifest infections even after years of latency. Pulmonary manifestations are by far the most frequent, although any other organ can be equally affected. HISTORY: A 95-year old patient presented with a localized painful swelling of the right foot for further investigation. Despite her advanced age there were no pre-existing medical conditions, except for a club foot existing since early childhood. FINDINGS AND DIAGNOSIS: On physical examination we found a hyperemic fluctuant swelling of 5 cm diameter at the arch of the right foot. The X-ray showed a complete destruction of the regular osseous structures from the upper ankle joint to the proximal metatarsal bones. THERAPY AND COURSE: Intraoperatively the suspicion of an abscess was confirmed and material was obtained for microbiological investigation. Liquid cultures grew Mycobacterium tuberculosis. In an MRI-scan, involvement of the tarsal and metatarsal bones could not be excluded, thus the duration of the standard antituberculose treatment was set to 9 months. CONCLUSIONS: Tuberculosis, primary or reactivated, should always be considered as a potential cause of unclear infections; especially in patients with anticipated immunosenescence.


Assuntos
Imunossenescência , Tuberculose Latente , Tuberculose Osteoarticular , Idoso de 80 Anos ou mais , Feminino , Ossos do Pé/diagnóstico por imagem , Ossos do Pé/patologia , Humanos
7.
BMC Infect Dis ; 20(1): 395, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32503443

RESUMO

BACKGROUND: Tanzania has a high prevalence (7.17%) of chronic hepatitis B infection. Mother to Child transmission is very common, resulting in high rate of chronic infections. Currently, there is no screening program for HBV in pregnant women. This study investigated the prevalence and risk factors for chronic HBV infection in pregnant women in a tertiary hospital in Mwanza, Tanzania. METHODS: Seven hundred and forty-three women attending antenatal care and/or delivering at the Bugando Medical Centre were enrolled. All answered a questionnaire on sociodemographic and other risk factors and were tested for HBsAg using a rapid test. In HBsAg positive mothers, maternal blood and umbilical cord blood samples collected after delivery were analyzed for serological (HBsAg, HBeAg and anti-HBe) and virologic (HBV-DNA viral load and genotype) markers. All their babies were vaccinated within 24 h of delivery. The children were followed up at 3 years of age. Data was analyzed using the Mann-Whitney U-test, independent sample T-test and logistic regression. RESULTS: Of the 743 participants, 22 (3%) were positive for HBsAg, and 2 (9%) had detectable HBe-antigen. Low condom use was the only statistically significant risk factor for chronic HBV infection (OR = 3.514, 95%CI = 1.4-8.0). Of 14 maternal blood samples genotyped, 10 (71%) were genotype A and 4 (29%) were genotype D. HBV-DNA was detected in 21/22 samples, with a median of 241 IU/ml (range: 27.4-25.9 × 107 IU/ml). Five (33%) of 15 available cord blood samples were positive for HBsAg and 10 (67%) were negative. At follow-up, one child showed chronic HBV infection characteristics, one had anti-HBs level of 7 mIU/ml and 5/7(71%) had protective anti-HBs levels (> 10 mIU/ml). CONCLUSION: This cohort of pregnant women showed a lower-intermediate prevalence of HBV of 3%. In the 3 years follow-up only 1 out of 7 children showed evidence of chronic HBV infection. The child's mother with high viral load (25.9 × 107 IU/ml), was positive for HBeAg with a high degree of sequence similarity suggesting vertical transmission. These results highlight a need for improved diagnosis and treatment of HBV infection in pregnant women in Tanzania, in order to prevent vertical transmission.


Assuntos
Hepatite B Crônica/diagnóstico , Adolescente , Adulto , Estudos Transversais , DNA Viral/genética , DNA Viral/metabolismo , Feminino , Genótipo , Anticorpos Anti-Hepatite B/sangue , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/epidemiologia , Hepatite B Crônica/virologia , Humanos , Lactente , Recém-Nascido , Masculino , Gravidez , Cuidado Pré-Natal , Prevalência , Tanzânia/epidemiologia , Centros de Atenção Terciária , Carga Viral , Adulto Jovem
8.
J Med Chem ; 61(8): 3350-3369, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29590750

RESUMO

Rhodesain (RD) is a parasitic, human cathepsin L (hCatL) like cysteine protease produced by Trypanosoma brucei ( T. b.) species and a potential drug target for the treatment of human African trypanosomiasis (HAT). A library of hCatL inhibitors was screened, and macrocyclic lactams were identified as potent RD inhibitors ( Ki < 10 nM), preventing the cell-growth of Trypanosoma brucei rhodesiense (IC50 < 400 nM). SARs addressing the S2 and S3 pockets of RD were established. Three cocrystal structures with RD revealed a noncovalent binding mode of this ligand class due to oxidation of the catalytic Cys25 to a sulfenic acid (Cys-SOH) during crystallization. The P-glycoprotein efflux ratio was measured and the in vivo brain penetration in rats determined. When tested in vivo in acute HAT model, the compounds permitted up to 16.25 (vs 13.0 for untreated controls) mean days of survival.


Assuntos
Catepsina L/antagonistas & inibidores , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Lactamas Macrocíclicas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Animais , Sítios de Ligação , Barreira Hematoencefálica/metabolismo , Linhagem Celular , Cisteína Endopeptidases/química , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Reposicionamento de Medicamentos , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacocinética , Ligantes , Masculino , Camundongos Endogâmicos C57BL , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Suínos , Tripanossomicidas/síntese química , Tripanossomicidas/química , Tripanossomicidas/farmacocinética
9.
Artigo em Alemão | MEDLINE | ID: mdl-29480365

RESUMO

BACKGROUND: In September 2014, the German government mandated the German Red Cross (GRC) and the German Armed Forces to support the international efforts to stop the epidemic of Ebola virus disease (EVD) in West-Africa. The GRC requested specific training from the Medical Mission Institute Wuerzburg (MI). OBJECTIVES: We describe and discuss the development, strategy, results, and evaluation of the program to formulate conclusions and recommendations for similar emergencies. METHODS: On 26 September 2014, it was agreed to establish a two-day training program to prepare Ebola aid workers for the treatment of EVD patients and infection protection in Ebola treatment centers (ETC) in the epidemic area. Course evaluation was based on protocoled discussions with participants and standardized questionnaires. RESULTS: The training started on 6 October 2014. By 24 February 2015, 214 trainees participated in 14 courses. Of 96 GRC staff deployed to West Africa, 90 (94%) participated in the training. Course content included containment strategy in filovirus outbreaks and practical exercises for standardized procedures in personal protective equipment (PPE). The average trainer-trainee ratio in PPE exercises was 1:3. "Excellent" or "good" ratings were received on 93% of the evaluations. CONCLUSION: Rapid implementation was possible by teaching a harmonized, and field-approved concept for infection protection and treatment. Realistic simulated scenarios and field-experienced trainers allowed transfer of knowledge as well as reassurance. Additional recommendations are further conversion of the training into a permanent program and, in the case of a crisis, interlocking of training with operational planning to allow rapid escalation and adaptation. Also, the concepts for training and interventions should be harmonized and developed further for additional challenges like airborne transmission and application of intensive-care medicine.


Assuntos
Surtos de Doenças/prevenção & controle , Pessoal de Saúde , Doença pelo Vírus Ebola/epidemiologia , Cooperação Internacional , Militares , Equipamento de Proteção Individual , Socorro em Desastres , África Ocidental , Alemanha , Humanos , Cruz Vermelha
10.
Bioorg Med Chem ; 25(16): 4526-4531, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28698054

RESUMO

Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.


Assuntos
Tacrina/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade , Tacrina/química , Trypanosoma brucei brucei/citologia
11.
Am J Trop Med Hyg ; 97(2): 567-574, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28722637

RESUMO

Schistosomiasis remains one of the most prevalent parasitic diseases worldwide and the infection is frequently found in travelers and migrants. The European Network for Tropical Medicine and Travel Health conducted a sentinel surveillance study on imported schistosomiasis between 1997 and 2010. This report summarizes epidemiological and clinical data from 1,465 cases of imported schistosomiasis. Direct pathogen detection and serology were the main diagnostic tools applied. Of these, 486 (33%) cases were identified among European travelers, 231 (16%) among long-term expatriates, and 748 (51%) among non-European immigrants. Overall, only 18.6% of travelers had received pretravel advice; 95% of infections were acquired in the African region. On species level, Schistosoma mansoni was identified in 570 (39%) and Schistosoma haematobium in 318 (22%) cases; 57.5% of patients were symptomatic. Acute symptoms were reported in 27% of patients leading to earlier presentation within 3 months. Praziquantel was used in all patients to treat schistosomiasis. Many infections were detected in asymptomatic patients. In 47.4% of asymptomatic patients infection was detected by microscopy and in 39% by serology or antigen testing. Schistosomiasis remains a frequent infection in travelers and migrants to Europe. Travelers should be made aware of the risk of schistosomiasis infection when traveling to sub-Saharan Africa. Posttravel consultations particularly for returning expatriates are useful given the high potential for detecting asymptomatic infections.


Assuntos
Anti-Helmínticos/uso terapêutico , Praziquantel/uso terapêutico , Esquistossomose/diagnóstico , Adolescente , Adulto , África Subsaariana/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Animais , Criança , Pré-Escolar , Europa (Continente)/epidemiologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Esquistossomose/tratamento farmacológico , Esquistossomose/epidemiologia , Migrantes/estatística & dados numéricos , Viagem/estatística & dados numéricos , Adulto Jovem
12.
J Trop Pediatr ; 62(6): 436-445, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27318113

RESUMO

BACKGROUND: It is unclear whether algorithms with evidence-based interventions are used in a setting where the work load is high and qualified staff is scarce to identify neonates with life-threatening conditions. METHODS: The nurse-midwives' knowledge and opinion about the World Health Organization (WHO) guide on postpartum newborn care were assessed in a hospital in Tanzania before and after training. Their adherence to this guide was evaluated by analysing 100 neonatal records. RESULTS: Before training, 44% of the nurse-midwives were familiar with the WHO guide. All nurse-midwives supported the implementation of the guide. In all, 21% of the postpartum record forms were fully completed. Risk factors for illness were missed in 27%. CONCLUSION: Nurse-midwives' expertise in the WHO guide on postpartum newborn care cannot be taken for granted. The complexity of this guide demands expertise and makes its use time-consuming and thus its practicability disputable in a setting with limited resources.


Assuntos
Fidelidade a Diretrizes , Conhecimentos, Atitudes e Prática em Saúde , Capacitação em Serviço/métodos , Enfermeiros Obstétricos/educação , Guias de Prática Clínica como Assunto , Padrões de Prática em Enfermagem , Adulto , Algoritmos , Atenção à Saúde/métodos , Avaliação Educacional , Feminino , Humanos , Recém-Nascido , Período Pós-Parto , Estudos Prospectivos , Qualidade da Assistência à Saúde , População Rural , Inquéritos e Questionários , Tanzânia , Organização Mundial da Saúde
13.
PLoS One ; 11(1): e0146678, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26812052

RESUMO

BACKGROUND: HIV-disease progression correlates with immune activation. Here we investigated whether corticosteroid treatment can attenuate HIV disease progression in antiretroviral-untreated patients. METHODS: Double-blind, placebo-controlled randomized clinical trial including 326 HIV-patients in a resource-limited setting in Tanzania (clinicaltrials.gov NCT01299948). Inclusion criteria were a CD4 count above 300 cells/µl, the absence of AIDS-defining symptoms and an ART-naïve therapy status. Study participants received 5 mg prednisolone per day or placebo for 2 years. Primary endpoint was time to progression to an AIDS-defining condition or to a CD4-count below 200 cells/µl. RESULTS: No significant change in progression towards the primary endpoint was observed in the intent-to-treat (ITT) analysis (19 cases with prednisolone versus 28 cases with placebo, p = 0.1407). In a per-protocol (PP)-analysis, 13 versus 24 study participants progressed to the primary study endpoint (p = 0.0741). Secondary endpoints: Prednisolone-treatment decreased immune activation (sCD14, suPAR, CD38/HLA-DR/CD8+) and increased CD4-counts (+77.42 ± 5.70 cells/µl compared to -37.42 ± 10.77 cells/µl under placebo, p < 0.0001). Treatment with prednisolone was associated with a 3.2-fold increase in HIV viral load (p < 0.0001). In a post-hoc analysis stratifying for sex, females treated with prednisolone progressed significantly slower to the primary study endpoint than females treated with placebo (ITT-analysis: 11 versus 21 cases, p = 0.0567; PP-analysis: 5 versus 18 cases, p = 0.0051): No changes in disease progression were observed in men. CONCLUSIONS: This study could not detect any significant effects of prednisolone on disease progression in antiretroviral-untreated HIV infection within the intent-to-treat population. However, significant effects were observed on CD4 counts, immune activation and HIV viral load. This study contributes to a better understanding of the role of immune activation in the pathogenesis of HIV infection. TRIAL REGISTRATION: ClinicalTrials.gov NCT01299948.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fatores Imunológicos/farmacologia , Prednisolona/farmacologia , Adulto , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Progressão da Doença , Método Duplo-Cego , Feminino , Infecções por HIV/epidemiologia , Humanos , Fatores Imunológicos/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Adesão à Medicação , Prednisolona/uso terapêutico , Resultado do Tratamento , Carga Viral
15.
J Korean Med Sci ; 30(11): 1584-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26539001

RESUMO

In North Korea, the prevalence of hepatitis B is high due to natural factors, gaps in vaccination, and the lack of antiviral treatment. Aid projects are urgently needed, however impeded by North Korea's political and economical situation and isolation. The feasibility of a joint North Korean and German humanitarian hepatitis B prevention program was assessed. Part 1: Hepatitis B vaccination catch-up campaign. Part 2: Implementation of endoscopic ligation of esophageal varices (EVL) by trainings in Germany and North Korea. By vaccinating 7 million children between 2010 and 2012, the hepatitis B vaccination gap was closed. Coverage of 99.23% was reached. A total of 11 hepatitis B-induced liver cirrhosis patients (mean age 41.1 yr) with severe esophageal varices and previous bleedings were successfully treated by EVL without major complications. A clinical standard operating procedure, a feedback system and a follow-up plan were developed. The bi-modal preventive strategy was implemented successfully. Parts of the project can serve as an example for other low-income countries, however its general transferability is limited due to the special circumstances in North Korea.


Assuntos
Varizes Esofágicas e Gástricas/embriologia , Varizes Esofágicas e Gástricas/cirurgia , Vacinas contra Hepatite B/administração & dosagem , Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Vacinação em Massa/estatística & dados numéricos , Adulto , Terapia Combinada/métodos , Terapia Combinada/estatística & dados numéricos , República Democrática Popular da Coreia/epidemiologia , Esofagoscopia/estatística & dados numéricos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Prevenção Secundária/métodos , Prevenção Secundária/estatística & dados numéricos , Resultado do Tratamento
16.
PLoS One ; 10(9): e0137353, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26340747

RESUMO

BACKGROUND: Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties. RESULTS: The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0±0.29 mM). The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions. CONCLUSION: Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the blood-brain-barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemolymphatic as well as neurological stages of sleeping sickness.


Assuntos
Proteínas de Protozoários/antagonistas & inibidores , Piruvato Quinase/antagonistas & inibidores , Piruvatos/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultura/química , Sistemas de Liberação de Medicamentos/métodos , Resistência a Medicamentos , Ensaios Enzimáticos , Cinética , Proteínas de Protozoários/metabolismo , Piruvato Quinase/metabolismo , Trypanosoma brucei brucei/enzimologia , Trypanosoma brucei brucei/crescimento & desenvolvimento
17.
Parasitol Res ; 114(2): 501-12, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25416330

RESUMO

Potent compounds do not necessarily make the best drugs in the market. Consequently, with the aim to describe tools that may be fundamental for refining the screening of candidates for animal and preclinical studies and further development, molecules of different structural classes synthesized within the frame of a broad screening platform were evaluated for their trypanocidal activities, cytotoxicities against murine macrophages J774.1 and selectivity indices, as well as for their ligand efficiencies and structural chemical properties. To advance into their modes of action, we also describe the morphological and ultrastructural changes exerted by selected members of each compound class on the parasite Trypanosoma brucei. Our data suggest that the potential organelles targeted are either the flagellar pocket (compound 77, N-Arylpyridinium salt; 15, amino acid derivative with piperazine moieties), the endoplasmic reticulum membrane systems (37, bisquaternary bisnaphthalimide; 77, N-Arylpyridinium salt; 68, piperidine derivative), or mitochondria and kinetoplasts (88, N-Arylpyridinium salt; 68, piperidine derivative). Amino acid derivatives with fumaric acid and piperazine moieties (4, 15) weakly inhibiting cysteine proteases seem to preferentially target acidic compartments. Our results suggest that ligand efficiency indices may be helpful to learn about the relationship between potency and chemical characteristics of the compounds. Interestingly, the correlations found between the physico-chemical parameters of the selected compounds and those of commercial molecules that target specific organelles indicate that our rationale might be helpful to drive compound design toward high activities and acceptable pharmacokinetic properties for all compound families.


Assuntos
Fumaratos/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/efeitos dos fármacos , Animais , Linhagem Celular , Cisteína Proteases/efeitos dos fármacos , Fumaratos/química , Concentração de Íons de Hidrogênio , Macrófagos/efeitos dos fármacos , Camundongos , Mitocôndrias/efeitos dos fármacos , Organelas/efeitos dos fármacos , Piperazina , Piperazinas/química , Piperidinas/química , Tripanossomicidas/química , Trypanosoma brucei brucei/ultraestrutura
18.
Clin Infect Dis ; 59(10): 1401-10, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25091309

RESUMO

BACKGROUND: Through 2 international traveler-focused surveillance networks (GeoSentinel and TropNet), we identified and investigated a large outbreak of acute muscular sarcocystosis (AMS), a rarely reported zoonosis caused by a protozoan parasite of the genus Sarcocystis, associated with travel to Tioman Island, Malaysia, during 2011-2012. METHODS: Clinicians reporting patients with suspected AMS to GeoSentinel submitted demographic, clinical, itinerary, and exposure data. We defined a probable case as travel to Tioman Island after 1 March 2011, eosinophilia (>5%), clinical or laboratory-supported myositis, and negative trichinellosis serology. Case confirmation required histologic observation of sarcocysts or isolation of Sarcocystis species DNA from muscle biopsy. RESULTS: Sixty-eight patients met the case definition (62 probable and 6 confirmed). All but 2 resided in Europe; all were tourists and traveled mostly during the summer months. The most frequent symptoms reported were myalgia (100%), fatigue (91%), fever (82%), headache (59%), and arthralgia (29%); onset clustered during 2 distinct periods: "early" during the second and "late" during the sixth week after departure from the island. Blood eosinophilia and elevated serum creatinine phosphokinase (CPK) levels were observed beginning during the fifth week after departure. Sarcocystis nesbitti DNA was recovered from 1 muscle biopsy. CONCLUSIONS: Clinicians evaluating travelers returning ill from Malaysia with myalgia, with or without fever, should consider AMS, noting the apparent biphasic aspect of the disease, the later onset of elevated CPK and eosinophilia, and the possibility for relapses. The exact source of infection among travelers to Tioman Island remains unclear but needs to be determined to prevent future illnesses.


Assuntos
Ilhas , Sarcocistose/epidemiologia , Viagem , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Surtos de Doenças , Eosinófilos , Feminino , Geografia , Humanos , Contagem de Leucócitos , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Músculos/parasitologia , Músculos/patologia , Músculos/ultraestrutura , Vigilância em Saúde Pública , Fatores de Risco , Sarcocystis/genética , Sarcocystis/isolamento & purificação , Sarcocistose/diagnóstico , Sarcocistose/transmissão , Adulto Jovem
19.
J Clin Virol ; 60(4): 387-91, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24929754

RESUMO

BACKGROUND: The high cost of commercial HIV-1 viral load tests for monitoring of patients on antiretroviral treatment limits their use in resource-constrained settings. Commercial genotypic antiretroviral resistance testing is even more costly, yet it provides important benefits. OBJECTIVES: We sought to determine the sensitivity and negative predictive value of a qualitative PCR targeting partial reverse transcriptase for detection of virologic failure when 5 patient specimens are pooled. STUDY DESIGN: A total of 300 South African routine patient samples were included and tested in 60 pools of 5 samples each. A qualitative nested PCR was optimised for testing pools and individual samples from positive pools. All positive samples were sequenced to detect drug resistance-associated mutations. Results were compared to those of conventional viral load monitoring. RESULTS: Twenty-two of 60 pools tested positive. Individual testing yielded 29 positive individual samples. Twenty-six patients had viral loads of above 1000 copies/ml. The pooling algorithm detected 24 of those 26 patients, resulting in a negative predictive value of 99.3%, and a positive predictive value of 89.7%. The sensitivity for detecting patients failing therapy was 92%, with a specificity of 98.9%. Of the patients failing first-line ART, 83.3% had NRTI and 91.7% NNRTI resistance mutations. CONCLUSIONS: The pooled testing algorithm presented here required 43% fewer assays than conventional viral load testing. In addition to offering a potential cost saving over individual viral load testing, it also provided drug resistance information which is not available routinely in resourced-limited settings.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Terapia Antirretroviral de Alta Atividade , Sequência de Bases , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Mutação , Reação em Cadeia da Polimerase/métodos , RNA Viral/genética , Inibidores da Transcriptase Reversa/uso terapêutico , Análise de Sequência de RNA , África do Sul , Carga Viral
20.
Parasitol Int ; 63(3): 557-60, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24613272

RESUMO

Human African trypanosomiasis (HAT), also referred to as "sleeping sickness", is caused by the parasite Trypanosoma brucei. Diagnosing imported HAT outside endemic areas is difficult and diagnosis is often delayed. We report a case of imported human African trypanosomiasis caused by Trypanosoma brucei gambiense with an unusually long incubation period of at least 7 years. A 33 year old male African patient, a former resident of Cameroon, presented with a 4-month history of progressive personality changes. A few weeks before presentation the patient had first been admitted to a psychiatric ward and received antidepressant treatment, until a lumbar puncture showed pleocytosis and then antibiotic treatment for suspected neuroborreliosis was initiated. The patient continued to deteriorate during antibiotic treatment and became increasingly lethargic. Under antiparasitic and anti-inflammatory treatment, the condition of the patient gradually improved over the following months and he recovered completely after 24 months of follow-up. This well-documented case illustrates typical difficulties in establishing the correct diagnosis outside endemic areas and provides an overview of typical clinical, neuropathological and neuroimaging findings in T. b. gambiense trypanosomiasis, guiding the clinician in establishing the correct diagnosis in this rare disease.


Assuntos
Neuroimagem , Trypanosoma brucei gambiense/isolamento & purificação , Tripanossomíase Africana/diagnóstico , Adulto , Anti-Inflamatórios/uso terapêutico , Camarões , Eflornitina/uso terapêutico , Alemanha , Humanos , Masculino , Resultado do Tratamento , Tripanossomicidas/uso terapêutico , Tripanossomíase Africana/tratamento farmacológico , Tripanossomíase Africana/parasitologia , Tripanossomíase Africana/patologia
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