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1.
Clin Infect Dis ; 74(1): 133-135, 2022 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-32472675

RESUMO

Calls for adherence to evidence-based medicine have emerged during the initial wave of the COVID-19 pandemic but reports of outcomes are lacking. This retrospective study of an institutional cohort including 135 patients with confirmed COVID-19 demonstrates positive outcomes when organizational standards of care consist of evidence-based supportive therapies.


Assuntos
COVID-19 , Estudos de Coortes , Humanos , Pandemias , Estudos Retrospectivos , SARS-CoV-2
2.
Malar J ; 15: 453, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27599723

RESUMO

BACKGROUND: The US Army designed artelinate/lysine salt (AL) to overcome the instability of sodium artesunate in aqueous solution (AS). To select the most efficacious artemisinin treatment, direct comparison was performed in an uncomplicated non-human primate malaria model. METHODS: Splenectomized rhesus monkeys were inoculated with Plasmodium coatneyi and on day six, single equimolar loading dose of IV AL (11.8 mg kg(-1)) or IV AS (8 mg kg(-1)) were administered followed by 1/2 the first dose once daily for 2 more days. Blood smear were performed twice daily and the number of parasites were counted microscopically. Blood samples were obtained after the first dose within 6 h for pharmacokinetic (PK) and ex vivo pharmacodynamic evaluation by simultaneously measuring plasma drug concentration and anti-malarial activity against Plasmodium falciparum in vitro. RESULTS: The anti-P. coatneyi in vivo activity of both compounds were comparable, but the ex vivo anti-P. falciparum potency of the IV AS regimen as administered was sevenfold higher than that of IV AL. Comparing in vivo pharmacodynamics of AL and AS, daily assessed parasite counts showed comparable 99 % parasite clearance times (PC99: 2.03, 1.84 day), parasite clearance rates (5.34, 4.13 per min) and clearance half-life (PCt1/2: 7.79, 10.1 h). This study showed strong and significant inverse correlation between PCt1/2 and t1/2 of AS + DHA, and AUC0-∞ of DHA, and correlated with Vz of AS (r(2) > 0.7, p ≤ 0.002). Lastly, following IV AL, there was a modest inverse correlation between PCt1/2 and Cmax (r(2) 0.6, p ≤ 0.04). Although all tested monkeys recrudesced subsequently, two died following AL regimen before parasite clearance. While the aetiology of those deaths could not be definitively determined, pathologic evidence favoured a sepsis-like syndrome and suggested that severe malaria was more likely than drug toxicity. CONCLUSION: The model demonstrated that both AS and DHA contributed to the anti-malarial activity of IV AS, while IV AL activity was largely restricted to the parent drug. Parasite clearance was strongly and linearly dependent on drug exposure for both artemisinin regimens. However, IV AS had higher ex vivo potency against P. falciparum, leading to an IND filing for GMP manufactured AS in the United States.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/farmacocinética , Artemisininas/farmacologia , Artemisininas/farmacocinética , Malária/tratamento farmacológico , Animais , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Artesunato , Modelos Animais de Doenças , Macaca mulatta , Esplenectomia , Resultado do Tratamento , Estados Unidos
3.
Malar J ; 13: 281, 2014 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-25047305

RESUMO

BACKGROUND: Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya. METHODS: The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA. RESULTS: The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng · h/mL vs 3,543 ng · h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS. CONCLUSIONS: Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.


Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Malária Falciparum/tratamento farmacológico , Ativação Metabólica , Adulto , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/sangue , Antimaláricos/provisão & distribuição , Antimaláricos/uso terapêutico , Artemisininas/administração & dosagem , Artemisininas/efeitos adversos , Artemisininas/sangue , Artemisininas/provisão & distribuição , Artemisininas/uso terapêutico , Artesunato , Atovaquona/uso terapêutico , Cromatografia Líquida , Combinação de Medicamentos , Composição de Medicamentos/normas , Monitoramento de Medicamentos , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Quênia , Malária Falciparum/sangue , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Proguanil/uso terapêutico , Reticulócitos/efeitos dos fármacos , Adulto Jovem
4.
Mil Med ; 178(2): e255-9, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23764334

RESUMO

OBJECTIVE: Operation Onward Liberty is the current U.S. military mentorship program working with the Armed Forces of Liberia, training their national army. Throughout West Africa, and Liberia in particular, malaria remains a serious health concern. This is a critical concern to all U.S. Forces deployed in areas endemic with malaria. In January 2011, a new protocol was instituted among Operation Onward Liberty members using short message service (SMS) technology to ensure 100% daily accountability. METHODS: Beginning in January 2011, SMS was used to report completion of daily ingestion of malaria chemoprophylaxis by U.S. Forces in Liberia. RESULTS: Since then, there were no cases of malaria identified by both Binax rapid diagnostic test and thin smear. The previous year (2010) saw 12 cases of malaria among U.S. Forces in Liberia (9 during the same 6-month period), with 3 evacuations for malaria, costing an estimated 1.5 million dollars. CONCLUSIONS: Although directly observed therapy is still the gold standard of malaria chemoprophylaxis, use of cellular telephone texting technology, or SMS, for communicating ingestion may be the best alternative for reasonable accountability in the deployed setting, especially considering the highly decentralized nature of this and other deployment locations.


Assuntos
Antimaláricos/uso terapêutico , Quimioprevenção/métodos , Terapia Diretamente Observada/métodos , Malária/prevenção & controle , Militares , Humanos , Incidência , Malária/epidemiologia , Estudos Retrospectivos , Viagem , Estados Unidos/epidemiologia
5.
Fed Pract ; 40(Suppl 3): S24-S34, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38021095

RESUMO

Background: Erlotinib and gefitinib are epidermal growth factor receptor-tyrosine kinase inhibitors approved for non-small cell lung cancer treatment by the US Food and Drug Administration. Drug-drug interactions (DDIs) with these agents are vague and poorly understood. Because DDIs can have an effect on clinical outcomes, we aimed to identify drugs that interact with erlotinib or gefitinib and describe their clinical manifestations. Methods: A retrospective analysis was performed on the health records of patients in the US Department of Defense Cancer Registry (retrieved September 2021), Comprehensive Ambulatory/Professional Encounter Records, and Pharmacy Data Transaction Service database (both retrieved May 2022). Patients' medical history, diagnoses, and demographics were extracted and analyzed for differences in adverse effects when these agents were used alone vs concomitantly with other prescription drugs. Patients' diagnoses and prescription drug use were extracted to compare completed vs discontinued treatment groups, identify medications commonly co-administered with erlotinib or gefitinib, and evaluate DDIs with antidepressants. Results: Of 387 patients using erlotinib, 264 completed treatments; 28 of 33 patients using gefitinib completed treatment. The P value for erlotinib discontinuation when used alone vs concomitantly was < .001, and the P value for gefitinib discontinuation was .06. Patients who took erlotinib or gefitinib concomitantly with a greater number of prescription drugs had a higher rate of treatment discontinuation than those who received fewer medications. Patients in the completed group received 1 to 75 prescription drugs, and those in the completed group were prescribed 3 to 103. Those who discontinued treatment had more diagnosed medical issues than those who completed treatment. Conclusions: This review cannot conclude that concomitant use with prescription drug(s) resulted in erlotinib or gefitinib discontinuation. There were no significant DDIs determined between erlotinib or gefitinib and antidepressants.

6.
Malar J ; 11: 255, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22853818

RESUMO

BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. METHODS: Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. RESULTS: Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (C(max)) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and C(max) values of AS and DHA were increased proportionally to the AS climbing multiple doses. DISCUSSION: The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.


Assuntos
Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Artemisininas/efeitos adversos , Artemisininas/farmacocinética , Adulto , África , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Artesunato , Resinas Compostas , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Estados Unidos , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-35756846

RESUMO

Objective: To evaluate drug-drug interactions (DDIs) between gefitinib with/without losartan and selective serotonin reuptake inhibitors (SSRIs). Methods: In vitro supersomes were used to identify CYP isoenzymes (CYP1A2, 2C9, 2C19, 2D6, and 3A4) involved in drug metabolism, and in vitro pooled cryopreserved primary human hepatocytes were employed to investigate DDIs. Results: The isoenzymes that showed drug degradation are listed in parentheses beside the respective drug: gefitinib (CYP2D6, 3A4, 1A2, 2C9, and 2C19), losartan (CYP2C9 and 3A4), citalopram (CYP2D6, 2C19, 3A4, and 2C9), fluoxetine (CYP2D6, 2C9, and 2C19), fluvoxamine (CYP2D6, 2C9, and 2C19), paroxetine (CYP2D6, 3A4, and 2C9), sertraline (CYP2D6, 2C9, 2C19, 1A2, and 3A4), and venlafaxine (CYP2D6 and 2C19).DDIs from human hepatocytes assays revealed that gefitinib had significant metabolic changes in (1:1) combination with paroxetine or sertraline (p-value â€‹= â€‹0.042 and 0.025 respectively) and (1:1:1) combination with losartan and fluoxetine, fluvoxamine, paroxetine, or sertraline (p-value â€‹= â€‹0.009, 0.027, 0.048, and 0.037 respectively). Losartan showed significant changes in (1:1:1) combination with gefitinib and fluoxetine or sertraline (p-value â€‹= â€‹0.026 and 0.008 respectively). Fluoxetine, fluvoxamine, and paroxetine underwent significant changes in (1:1:1) combination with gefitinib and losartan (p-value â€‹= â€‹0.003, 0.022, and 0.046 respectively). Sertraline had significant changes within all combinations: DDIs with gefitinib alone and in combination with gefitinib and losartan (p-value â€‹= â€‹0.009 and 0.008 respectively). Citalopram and venlafaxine appeared to be unaffected by any combination. Conclusion: The study provides a clear proof-of concept for in vitro metabolic DDI testing. While identifying compounds by their inhibition potential can help better predict their metabolism, it cannot resolve problems that arise from DDIs since the overall degree of effectiveness is unknown. As shown in this study, gefitinib has been identified as a weak CYP2C19 and 2D6 inhibitor, however, gefitinib can have significant DDIs with sertraline. Furthermore, multiple drug combinations (1:1:1) can change the significance of previously determined DDIs in (1:1) combination. Thus, in vitro assays can potentially provide better guidance for multidrug regimens with minimal risk for DDIs.

8.
Mil Med ; 2022 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-35277723

RESUMO

BACKGROUND: Evidence has emerged showing potential benefit of Remdesivir and dexamethasone in severe coronavirus disease 2019 (COVID-19) but results from large randomized control trials are conflicting. While initial data for dexamethasone indicated a mortality benefit, the impact of Remdesivir was best demonstrated in decreased time to recovery. Despite extensive disease burden throughout the world efficacy data of individual interventions is lacking in part due to extensive concurrent use of confounding investigational therapeutics. MATERIALS AND METHODS: We performed a retrospective analysis of the impact of Remdesivir and dexamethasone on real-world outcomes in severe COVID-19. All patients admitted to our community hospital between March 2020 and December 31, 2020 were included, and all patients admitted before national guidelines endorsed Remdesivir and dexamethasone outside of clinical trials were treated with only supportive care and used as historical controls. No other investigational therapeutics were utilized. This study was reviewed and approved by the Fort Belvoir Community Hospital IRB. RESULTS: 58 hospitalized patients met criteria for severe COVID-19 as confirmed by RT-PCR, and 14 (25%) were used as historical controls. Baseline demographics and overall mortality rate (7.1%) did not significantly differ between the groups. The median length of stay was 7 days and 6 days in the historical control group and interventional group, respectively (P = 0.55). CONCLUSIONS: We did not observe an appreciable impact on the duration of hospitalization when Remdesivir and dexamethasone were added to supportive care in a community hospital. This study was not sufficiently powered to detect the previously described mortality benefit of dexamethasone.

9.
Am J Bioeth ; 16(8): 38-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27366846
10.
Curr Res Toxicol ; 2: 217-224, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345864

RESUMO

OBJECTIVE: To evaluate drug-drug interactions (DDIs) between gefitinib or erlotinib with fluoxetine, and/or losartan. METHODS: Human pooled microsomes, supersomes, and cryopreserved human hepatocytes were used to monitor DDIs in vitro. RED (Rapid Equilibrium Dialysis) protein binding was employed to investigate other pharmacokinetics. RESULTS: Gefitinib is significantly metabolized by Cytochrome P450 (CYP) 2D6 and CYP3A4, with less than 80% of the drug remaining. Erlotinib is significantly metabolized by CYP3A4, CYP2D6, and CYP1A2. Although gefitinib and erlotinib were metabolized by the same CYP isoenzymes, the metabolites formed from degradation of the two drugs were different.Fluoxetine inhibited CYP2D6 and CYP3A4 metabolism of gefitinib with an IC50 of 65.12 ± 1.88 µM and 4.11 ± 2.26 µM, respectively. Fluoxetine also inhibited CYP2D6 and CYP3A4 metabolism of erlotinib with an IC50 of 7.06 ± 1.54 µM and 4.57 ± 1.22 µM, respectively.For hepatocytes, fluoxetine affected the metabolism of gefitinib or erlotinib, while losartan had no effect. Gefitinib and erlotinib inhibited the metabolism of fluoxetine and losartan. Two-drug combinations involving gefitinib or erlotinib with fluoxetine or losartan yielded insignificant (p-value ≥ 0.05) differences in metabolism. However, combinations involving three drugs yielded significant degrees of inhibition (p-value ≤ 0.05). Three drug combinations involving fluoxetine and losartan with gefitinib or erlotinib yielded significant degrees of inhibition of the metabolism of gefitinib, but not for that of erlotinib. CONCLUSION: As could be predicted by previous studies involving the inhibitory effect of fluoxetine on CYP3A4 and CYP2D6, and studies involving CYP metabolism of gefitinib and erlotinib, the tests performed here confirmed that fluoxetine has an inhibitory effect on metabolism of gefitinib or erlotinib by the main CYP isoenzymes involved. This study suggests a variable inhibitory effect of fluoxetine particularly on CYP2D6 activity towards gefitinib or erlotinib; erlotinib metabolism is less affected. Likewise, the combination of fluoxetine and losartan does not significantly affect hepatocyte metabolism of erlotinib, but does for that of gefitinib. The results presented in this study thus indicate a need for DDI assays to involve multiple drugs to properly study multidrug regimens.

11.
Molecules ; 15(12): 8747-68, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-21124272

RESUMO

Artesunate (AS) is a potent antimalarial that is used worldwide for the treatment of malaria. A simple method with a total run time of 12 min was developed and validated for the quantification of AS and dihydroartemisinin (DHA), its active metabolite, in human (heparinized) plasma based on one-step protein precipitation in acetonitrile using artemisinin (ARN) as an internal standard, followed by liquid chromatography with a single quadrupole mass spectrometry system connected to a C18 column. Peak area ratio responses were fitted to the 2nd-order curve type, polynomial equation with weighting (1/concentration) over a quantification range between 3.20/5.33-3,000/5,000 nM (1.23/1.52-1153/1422 ng/mL) of AS/DHA showing linearity with very good correlation (r2>0.999). Single ion recordings of 5 µL injections of plasma extracts allowed for limits of detection of 1.02 nM (0.39 ng/mL) for AS and 0.44 nM (0.13 ng/mL) for DHA. The inter-assay and intra-assay accuracy and precision of the method was very good with an inaccuracy of ±12.4% and coefficients of variation of ≤10.7% at all tested concentrations. The recovery of the analytes from plasma was ≥95%. Other commonly used antimalarials including mefloquine, quinine, and chloroquine, did not interfere with the analysis. Post-preparative tests over 24 h in an autosampler (10 °C) showed that the DHA response was only 2.1% of AS from auto-hydrolysis, and ß-DHA was the major, stable epimer that was used for quantification of DHA. In contrast, α-DHA increased steadily up to 600%. Artesunate and DHA in plasma were stable through three freeze/thaw cycles for up to 6 h at room temperature and up to one year at -80 °C.


Assuntos
Antimaláricos/análise , Artemisininas/análise , Plasma/química , Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Artesunato , Cromatografia Líquida/métodos , Humanos , Espectrometria de Massas/métodos , Sensibilidade e Especificidade , Fatores de Tempo
12.
Mil Med ; 175(7 Suppl): 18-24, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23634474

RESUMO

The Combat Wound Initiative (CWI) program is a collaborative, multidisciplinary, and interservice public-private partnership that provides personalized, state-of-the-art, and complex wound care via targeted clinical and translational research. The CWI uses a bench-to-bedside approach to translational research, including the rapid development of a human extracorporeal shock wave therapy (ESWT) study in complex wounds after establishing the potential efficacy, biologic mechanisms, and safety of this treatment modality in a murine model. Additional clinical trials include the prospective use of clinical data, serum and wound biomarkers, and wound gene expression profiles to predict wound healing/failure and additional clinical patient outcomes following combat-related trauma. These clinical research data are analyzed using machine-based learning algorithms to develop predictive treatment models to guide clinical decision-making. Future CWI directions include additional clinical trials and study centers and the refinement and deployment of our genetically driven, personalized medicine initiative to provide patient-specific care across multiple medical disciplines, with an emphasis on combat casualty care.


Assuntos
Ondas de Choque de Alta Energia/uso terapêutico , Militares , Pesquisa Translacional Biomédica , Ferimentos e Lesões/terapia , Biomarcadores , Queimaduras/terapia , Ensaios Clínicos como Assunto , Humanos , Neovascularização Fisiológica , Parcerias Público-Privadas , Estados Unidos , Guerra , Cicatrização
13.
Malar J ; 8: 112, 2009 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-19470172

RESUMO

BACKGROUND: Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans. METHODS: Pharmacokinetics, tissue distribution, mass balance, and elimination of [14C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma. Drug concentrations were obtained up to 192 hr from measurements of total radioactivity and drug concentration to determine the contribution by the parent and metabolites to the total dose of drug injected from whole blood, plasma, urine and faecal samples. RESULTS: Drug was widely distributed after 1 hr and rapidly declined at 24 hr in all tissues except spleen until 96 hrs. Only 0.81% of the total radioactivity was detected in rat brain tissue. DHA revealed a high binding capacity with both rat and human plasma proteins (76-82%). The concentration of total radioactivity in the plasma fraction was less than 25% of that in blood total. Metabolism of DHA was observed with high excretion via bile into intestines and approximately 89-95% dose of all conjugations were accounted for in blood, urine and faeces. However, the majority of elimination of [14C] DHA was through urinary excretion (52% dose). The mean terminal half-lives of plasma and blood radioactivity (75.57-122.13 h) were significantly prolonged compared with that of unchanged DHA (1.03 h). CONCLUSION: In rat brain, the total concentration of [14C] was 2-fold higher than that in plasma, indicating the radioactivity could easily penetrate the brain-blood barrier. Total radioactivity distributed in RBC was about three- to four-fold higher than that in plasma, suggesting that the powerful anti-malarial potency of DHA in the treatment of blood stage malaria may relate to the high RBC binding. Biliary excretion and multiple concentration peaks of DHA have been demonstrated with high urinary excretion due to a most likely drug re-absorption in the intestines (enterohepatic circulation). The long lasting metabolites of DHA (> 192 hr) in the rats may be also related to the enterohepatic circulation.


Assuntos
Antimaláricos/farmacocinética , Artemisininas/farmacocinética , Animais , Antimaláricos/metabolismo , Área Sob a Curva , Artemisininas/metabolismo , Barreira Hematoencefálica , Radioisótopos de Carbono/metabolismo , Radioisótopos de Carbono/farmacocinética , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Injeções Intravenosas , Masculino , Taxa de Depuração Metabólica , Metaboloma/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Distribuição Tecidual
14.
Molecules ; 15(1): 40-57, 2009 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-20110870

RESUMO

Preclinical studies in rodents have demonstrated that artemisinins, especially injectable artesunate, can induce fetal death and congenital malformations at a low dose range. The embryotoxicity can be induced in those animals only within a narrow window in early embryogenesis. Evidence was presented that the mechanism by which embryotoxicity of artemisinins occurs seems to be limited to fetal erythropoiesis and vasculogenesis/ angiogenesis on the very earliest developing red blood cells, causing severe anemia in the embryos with higher drug peak concentrations. However, this embryotoxicity has not been convincingly observed in clinical trials from 1,837 pregnant women, including 176 patients in the first trimester exposed to an artemisinin agent or artemisinin-based combination therapy (ACT) from 1989 to 2009. In the rodent, the sensitive early red cells are produced synchronously over one day with single or multiple exposures to the drug can result in a high proportion of cell deaths. In contrast, primates required a longer period of treatment of 12 days to induce such embryonic loss. In humans only limited information is available about this stage of red cell development; however, it is known to take place over a longer time period, and it may well be that a limited period of treatment of 2 to 3 days for malaria would not produce serious toxic effects. In addition, current oral intake, the most commonly used route of administration in pregnant women with an ACT, results in lower peak concentration and shorter exposure time of artemisinins that demonstrated that such a concentration-course profile is unlikely to induce the embryotoxicity. When relating the animal and human toxicity of artemisinins, the different drug sensitive period and pharmacokinetic profiles as reviewed in the present report may provide a great margin of safety in the pregnant women.


Assuntos
Animais de Laboratório/embriologia , Artemisininas/efeitos adversos , Artemisininas/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Embrião de Mamíferos/efeitos dos fármacos , Teratogênicos/toxicidade , Animais , Artemisininas/administração & dosagem , Artemisininas/farmacocinética , Feminino , Humanos , Gravidez
15.
PLoS Negl Trop Dis ; 13(5): e0007253, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31048871

RESUMO

BACKGROUND: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. METHODS: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. RESULTS: The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. CONCLUSIONS: Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.


Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Paromomicina/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Gentamicinas/administração & dosagem , Humanos , Leishmania major/efeitos dos fármacos , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tunísia , Adulto Jovem
16.
Trans R Soc Trop Med Hyg ; 102(2): 155-60, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18082863

RESUMO

A group of scientists and journal editors developed the STARD (Standards for Reporting of Diagnostic Accuracy) checklist to improve the reporting of diagnostic accuracy. This checklist provides a standardised framework to ensure all relevant information is considered and no potentially important parameters are inadvertently overlooked. Whilst the quality of reporting is crucial to the understanding of a test's potential performance characteristics, this checklist can and should be used not only to assess the reporting itself, but also to question any potential flaws in the assay inadvertently overlooked or not challenged by others. This article uses the STARD checklist to look at a recent report on a new assay for Chagas disease and examines the strength of this work against a standard review tool. Potential issues associated with the reporting of the work as well as potential issues with the assay are identified and additional questions are posed that might help clarify the issues identified.


Assuntos
Doença de Chagas/diagnóstico , Ensaio de Imunoadsorção Enzimática/normas , Editoração/normas , Projetos de Pesquisa/normas , Animais , Viés , Doença de Chagas/imunologia , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Trypanosoma cruzi/imunologia
17.
J Pharm Biomed Anal ; 48(3): 876-84, 2008 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-18762400

RESUMO

Quantitative whole-body autoradiography (QWBA) and liquid scintillation counting (LSC) have been conducted to determine the metabolic profiles and tissue distribution of [(14)C] labeled artesunate (AS) injection in rats. The QWBA technique showed more accurate results in the quantification of radioactivity in 40 organs and tissues, compared to 19 organs with the LSC technique. The benefit of QWBA was especially apparent on measurements of bile, bone marrow, and gland organs; however, the LSC method produced more relevant findings than QWBA. Particularly, the LSC method allowed access to the following distribution patterns that were unavailable via QWBA performance: such as pharmacokinetic evaluation of radiolabeled AS in blood and plasma, tissue/plasma partition coefficients, conversion pathway of AS to dihydroartemisinin (DHA, an active and major metabolite of AS), unchanged AS and DHA in plasma, mass balance assessment, urinary and faecal eliminations, drug pathway with conjugation, [(14)C] AS binding with RBC and plasma protein, and metabolites identification. Even though the each method has its own advantages, common profiles were obtained from the two processes as shown in the results of the biliary metabolism, long-lasting metabolites, tissue distribution profiles, and multiple concentration peaks, which indicate a [(14)C] AS enterohepatic circulation.


Assuntos
Artemisininas/farmacocinética , Dissecação/métodos , Compostos Radiofarmacêuticos/farmacocinética , Animais , Área Sob a Curva , Artesunato , Autorradiografia/métodos , Autorradiografia/estatística & dados numéricos , Calibragem , Radioisótopos de Carbono/farmacocinética , Coleta de Dados/estatística & dados numéricos , Injeções Intravenosas/métodos , Masculino , Guias de Prática Clínica como Assunto/normas , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Contagem de Cintilação/métodos , Equivalência Terapêutica , Distribuição Tecidual
18.
Birth Defects Res B Dev Reprod Toxicol ; 83(4): 435-45, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18636509

RESUMO

BACKGROUND: Injectable artesunate (AS) can cause fetal death and teratogenic effects in animals at levels below the human therapeutic dose. Similar toxicity has also been found for oral artemisinins in various animal species, but has not been found in humans. METHODS: Studies on tissue distribution (5 mg/kg) and toxicokinetics (TK, 30 mg/kg x 3) were conducted in pregnant (GD11-13) and non-pregnant rats. RESULTS: TK profiles of AS showed that the two groups of rats were similar after a single AS dose but were significantly different after multiple doses. Following a daily dose for 3 days, no change in AS concentration was found in the pregnant animals, but a significant concentration decline was seen in the non-pregnant rats on day 3. In addition, a higher conversion rate of AS to dihydroartemisinin (DHA) was detected in the pregnant rats after either single or multiple doses compared to non-pregnant controls. The ratios of AUC(DHA)/AUC(AS) were 0.99-1.02 for the pregnant rats and 0.42-0.48 for non-pregnant animals, resulting in a total AUC(DHA D1-3) that was about 3.7-fold higher in pregnant rats (15,049 ng.h/ml) than in non-pregnant rats (4,015 ng.h/ml). Furthermore, the tissue/blood partition coefficients demonstrated that the level of radiolabeled AS that was distributed into uterus, placenta, and ovary was 2-4-fold higher than in blood. CONCLUSIONS: TK data showed that unchanged AS and DHA in the blood of pregnant rats were 1.53- and 3.74-fold, respectively, higher than those of non-pregnant animals, which all likely relate to the severe embryotoxicity of AS, even with a low-dosage regimen in pregnant animals.


Assuntos
Artemisininas/farmacocinética , Artemisininas/toxicidade , Embrião de Mamíferos/efeitos dos fármacos , Animais , Artemisininas/administração & dosagem , Artemisininas/sangue , Artemisininas/química , Artesunato , Autorradiografia , Feminino , Injeções Intravenosas , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
19.
J Microbiol Methods ; 148: 46-48, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29289564

RESUMO

This work developed a simple empirical algorithm to distinguish three Leishmania species using MALDI-TOF mass spectrometry. It suggests that complicated computer algorithms may not always be necessary for clinically useful microbiology applications.


Assuntos
Leishmania braziliensis/química , Leishmania braziliensis/classificação , Leishmaniose Cutânea/parasitologia , Técnicas Microbiológicas/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Algoritmos , Humanos
20.
Trans R Soc Trop Med Hyg ; 101(2): 104-12, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16860356

RESUMO

A recent therapeutic index study in rats demonstrated that i.v. artesunate (AS) is safer than artelinate (AL). The present study of acute toxicity illustrated an LD(50) of 177 mg/kg and 488 mg/kg for AL and AS, respectively, following daily i.v. injection for 3 days in Plasmodium berghei-infected rats. In uninfected rats, the LD(50) values were 116 mg/kg and 351 mg/kg after a single dose of AL and AS, respectively. This study showed vascular necrosis in 50% of the animals at 13.5 mg/kg AL and at 42.8 mg/kg AS. Animals also showed moderate signs of renal failure at 40 mg/kg AL and 240 mg/kg AS (100 times higher than the therapeutic dose). Histopathological evaluation demonstrated mild to moderate tubular necrosis in uninfected rats treated with 40 mg/kg AL and 240 mg/kg AS; interestingly, fewer pathological lesions were observed in malaria-infected rats. Renal injury was reversible in all cases by Day 8 after cessation of dosing. No neurotoxicity was seen in any case with all i.v. regimens. In conclusion, AL and AS exhibit less toxic effects in P. berghei-infected rats than in uninfected rats. Both agents caused irreversible vascular irritation, reversible nephrotoxicity and no neurotoxicity at high doses. The data indicate that AS is three times safer than AL in rats.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Antimaláricos/toxicidade , Artemisininas/toxicidade , Encefalopatias/induzido quimicamente , Malária/tratamento farmacológico , Sesquiterpenos/toxicidade , Doenças Vasculares/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Artesunato , Encefalopatias/patologia , Relação Dose-Resposta a Droga , Dose Letal Mediana , Masculino , Necrose/induzido quimicamente , Necrose/patologia , Plasmodium berghei , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Cauda/irrigação sanguínea , Cauda/patologia , Doenças Vasculares/patologia
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