Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.542
Filtrar
1.
Life Sci ; 240: 117105, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31786196

RESUMO

AIMS: To investigate whether Rac1 inhibition can alleviate radiation-induced intestinal injury (RIII), meanwhile exist no protection on tumors. MATERIALS AND METHODS: Rac1 inhibition was achieved by its specific inhibitor, NSC23766. Mice were pretreated with different intraperitoneal injections, which were normal saline for NS group (N = 9), and 2.5 mg/kg and 5 mg/kg of NSC23766 for Low-Dose group (N = 9) and High-Dose group (N = 9), respectively. After total body irritation (10Gy), small intestinal tissues were collected for Hematoxylin-Eosin (H&E) staining and Terminal-deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling (TUNEL). Intestinal epithelial and tumor cell lines, namely MODE-k and CT-26, were used to further study the role of Rac1 inhibition on radiation damage. Flow cytometry was used to detect changes in reactive oxygen species production, cell cycles and mitochondrial membrane potential, the latter was also checked by fluorescence microscope. Changes of protein-expression associated with apoptosis and cell cycles were detected by Western blotting to explain the possible molecular mechanism. KEY FINDINGS: Height of intestine villi and depth of crypt were higher (P < 0.01) and apoptosis ratio lower (P < 0.01) in High-Dose group compared with those in NS group. After radiation, Rac1 inhibition pre-treatment improved the vitality (P < 0.01) and reduced the apoptosis (P < 0.01) in MODE-k while yielded opposite results in CT-26, and reduced ROS production of MODE-k (P < 0.01) while had little effect on that of CT-26. Rac1 inhibition differently affected the cell cycles of normal cells and that of tumor cells. SIGNIFICANCE: Inhibition of Rac1 could alleviate RIII, meanwhile assist the killing effect of radiation on tumor cells.


Assuntos
Aminoquinolinas/uso terapêutico , Neoplasias Intestinais/radioterapia , Intestinos/lesões , Neuropeptídeos/antagonistas & inibidores , Pirimidinas/uso terapêutico , Lesões Experimentais por Radiação/tratamento farmacológico , Protetores contra Radiação/uso terapêutico , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio , Irradiação Corporal Total
2.
MMWR Morb Mortal Wkly Rep ; 68(46): 1062-1068, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31751320

RESUMO

An estimated 219 million cases of malaria occurred worldwide in 2017, causing approximately 435,000 deaths (1). Malaria is caused by intraerythrocytic protozoa of the genus Plasmodium transmitted to humans through the bite of an infective Anopheles mosquito. Five Plasmodium species that regularly cause illness in humans are P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi (2). The parasite first develops in the liver before infecting red blood cells. Travelers to areas with endemic malaria can prevent malaria by taking chemoprophylaxis. However, most antimalarials do not kill the liver stages of the parasite, including hypnozoites that cause relapses of disease caused by P. vivax or P. ovale. Therefore, patients with these relapsing species must be treated with two medications: one for the acute infection, and another to treat the hypnozoites (antirelapse therapy). Until recently, primaquine was the only drug available worldwide to kill hypnozoites. Tafenoquine, a long-acting 8-aminoquinoline drug related to primaquine, was approved by the Food and Drug Administration (FDA) on July 20, 2018, for antirelapse therapy (Krintafel) and August 8, 2018, for chemoprophylaxis (Arakoda) (3,4). This report reviews evidence for the efficacy and safety of tafenoquine and provides CDC guidance for clinicians who prescribe chemoprophylaxis for travelers to areas with endemic malaria and treat malaria.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Malária/prevenção & controle , Guias de Prática Clínica como Assunto , Prevenção Secundária , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medicina de Viagem , Estados Unidos
3.
Nursing ; 49(8): 24-32, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31268951
4.
Int Health ; 11(1): 7-14, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30184203

RESUMO

Glucose-6-phosphate dehyrdgoenase (G6PD) deficiency is a common X-linked genetic trait, with an associated enzyme phenotype, whereby males are either G6PD deficient or normal, but females exhibit a broader range of G6PD deficiencies, ranging from severe deficiency to normal. Heterozygous females typically have intermediate G6PD activity. G6PD deficiency has implications for the safe treatment for Plasmodium vivax malaria. Individuals with this deficiency are at greater risk of serious adverse events following treatment with the only curative class of anti-malarials, 8-aminoquinolines, such as primaquine. Quantitative diagnostic tests for G6PD deficiency are complex and require sophisticated laboratories. The commonly used qualitative tests, do not discriminate intermediate G6PD activities. This has resulted in poor understanding of the epidemiology of G6PD activity in females and its corresponding treatment ramifications. New simple-to-use quantitative tests, and a momentum to eliminate malaria, create an opportunity to address this knowledge gap. While this will require additional resources for clinical studies, adequate operational research, and appropriate pharmacovigilance, the health benefits from this investment go beyond the immediate intervention for which the G6PD status is first diagnosed.


Assuntos
Deficiência de Glucosefosfato Desidrogenase , Conhecimentos, Atitudes e Prática em Saúde , África , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Feminino , Humanos , Malária Vivax/tratamento farmacológico , Masculino , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Fatores de Risco , Fatores Sexuais
5.
Exp Parasitol ; 195: 78-86, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30385267

RESUMO

Currently, available treatment options for leishmaniasis are limited and unsatisfactory. In a previous study, a quinoline derivative (AMQ-j), exhibited a strong effect against Leishmania amazonensis and its antileishmanial activity was preliminarily associated with mitochondrial dysfunction. The present study further explores the antileishmanial effect of this compound against L. amazonensis, as well as determines the main cellular processes involved in the death of the parasite. Moreover, this study evaluated the in vivo effect of the AMQ-j in BALB/c mice experimentally infected by L. amazonensis. The results showed that the compound AMQ-j induces a set of morphological and biochemical features that could correlate with both autophagy-related and apoptosis-like processes, indicating intense mitochondrial swelling, a collapse of the mitochondrial membrane potential, an abnormal chromatin condensation, an externalization of phosphatidylserine, an accumulation of lipid bodies, a disorganization of cell cycle, a formation of autophagic vacuoles, and an increase of acidic compartments. Treatment with AMQ-j through an intralesional route was effective in reducing the parasite burden and size of the lesion. No significant increase in the serum levels of hepatic or renal damage toxicity markers was observed. These findings contribute to the understanding of the mode of action of quinoline derivatives involved in the death of Leishmania parasites and encourage new studies in other experimental models of Leishmania infection.


Assuntos
Aminoquinolinas/farmacologia , Antiprotozoários/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Aminoquinolinas/toxicidade , Animais , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Ciclo Celular/efeitos dos fármacos , Creatinina/metabolismo , Orelha Externa/parasitologia , Orelha Externa/patologia , Feminino , Concentração Inibidora 50 , Rim/efeitos dos fármacos , Leishmania mexicana/citologia , Leishmania mexicana/crescimento & desenvolvimento , Leishmania mexicana/ultraestrutura , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , Células Vero
6.
J Travel Med ; 25(1)2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30380095

RESUMO

Background: Endemic malaria occurring across much of the globe threatens millions of exposed travelers. While unknown numbers of them suffer acute attacks while traveling, each year thousands return from travel and become stricken in the weeks and months following exposure. This represents perhaps the most serious, prevalent and complex problem faced by providers of travel medicine services. Since before World War II, travel medicine practice has relied on synthetic suppressive blood schizontocidal drugs to prevent malaria during exposure, and has applied primaquine for presumptive anti-relapse therapy (post-travel or post-diagnosis of Plasmodium vivax) since 1952. In 2018, the US Food and Drug Administration approved the uses of a new hepatic schizontocidal and hypnozoitocidal 8-aminoquinoline called tafenoquine for the respective prevention of all malarias and for the treatment of those that relapse (P. vivax and Plasmodium ovale). Methods: The evidence and rationale for tafenoquine for the prevention and treatment of malaria was gathered by means of a standard search of the medical literature along with the package inserts for the tafenoquine products Arakoda™ and Krintafel™ for the prevention of all malarias and the treatment of relapsing malarias, respectively. Results: The development of tafenoquine-an endeavor of 40 years-at last brings two powerful advantages to travel medicine practice against the malaria threat: (i) a weekly regimen of causal prophylaxis; and (ii) a single-dose radical cure for patients infected by vivax or ovale malarias. Conclusions: Although broad clinical experience remains to be gathered, tafenoquine appears to promise more practical and effective prevention and treatment of malaria. Tafenoquine thus applied includes important biological and clinical complexities explained in this review, with particular regard to the problem of hemolytic toxicity in G6PD-deficient patients.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Controle de Infecções/métodos , Malária Vivax/tratamento farmacológico , Malária/prevenção & controle , Viagem , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Malária/tratamento farmacológico , Masculino , Estados Unidos , United States Food and Drug Administration
8.
Drugs ; 78(16): 1751-1755, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30341682

RESUMO

Pyrotinib is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor developed for the treatment of HER2-positive advanced solid tumours. Based on positive results in a phase II trial, the drug recently received conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy. This article summarizes the milestones in the development of pyrotinib leading to this first global approval for the treatment of HER2-positive advanced breast cancer.


Assuntos
Acrilamidas , Aminoquinolinas , Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases , Receptor ErbB-2/antagonistas & inibidores , Acrilamidas/administração & dosagem , Acrilamidas/efeitos adversos , Acrilamidas/uso terapêutico , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antraciclinas/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Taxoides/farmacologia
9.
Drugs ; 78(14): 1517-1523, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30229442

RESUMO

Tafenoquine (Krintafel™, Arakoda™), an orally-active 8-aminoquinoline anti-malarial drug, is a long-acting analogue of primaquine with activity against pre-erythrocytic (liver) and erythrocytic (asexual) forms as well as gametocytes of Plasmodium species that include Plasmodium vivax (P. vivax) and Plasmodium falciparum. It has been developed by GlaxoSmithKline (formerly SmithKline Beecham) for the radical cure of P. vivax malaria and by 60 Degrees Pharmaceuticals for the prophylaxis of malaria. The exact mechanism(s) of action underlying the anti-Plasmodium activity of tafenoquine are unknown, although it may exert its effect by inhibiting haematin polymerization and, additionally, by inducing mitochondrial dysfunction leading to the apoptotic-like death of the organism. In July 2018, tafenoquine was approved in the USA for the radical cure of P. vivax malaria in patients aged ≥ 16 years who are receiving appropriate antimalarial therapy for acute P. vivax malaria. Subsequently, in August 2018, tafenoquine was approved in the USA for the prophylaxis of malaria in patients aged ≥ 18 years. This article primarily summarizes the milestones in the development of tafenoquine leading to its first global approval for the radical cure of P. vivax malaria.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Aprovação de Drogas , Humanos , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration
10.
Biochem Biophys Res Commun ; 503(4): 2517-2523, 2018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30208520

RESUMO

Acute kidney injury induced by renal ischemia-reperfusion (IR) is a prominent risk factor in the development towards renal fibrosis. Ras-related C3 botulinum toxin substrate 1(Rac1) has been involved in the pathophysiology of fibrotic disorders. But the role of Rac1 in the pathogenesis of IR-induced renal fibrosis is still unknown. Here, we examined the effects of NSC23766, an inhibitor of Rac1, on the progression of renal fibrosis after IR injury. In mice, IR induced Rac1 activation in kidneys. Rac1 inhibition alleviated renal damage and dysfunction. Mice treated with NSC23766 displayed diminished collagen area in the kidneys compared with IR controls, which was associated with reduction of extracellular matrix (ECM) proteins and α-SMA. Furthermore, Rac1 inhibition reduced profibrotic molecules levels in the kidneys of mice with IR. Finally, Rac1 inhibition impaired the accumulation of bone marrow-derived M2 macrophages and the transition of M2 macrophages to myofibroblasts. In cultured mouse monocytes, IL-4 treatment activated Rac1, which was abrogated by NSC23766. Moreover, application with IL-4 induced polarization of monocytes to M2 phenotype and increased the levels of ECM proteins and α-SMA, which was abolished by NSC23766. In summary, Rac1 plays a crucial role in the pathogenesis of renal fibrosis after IR via regulation of expressions of profibrotic molecules, bone-marrow derived M2 macrophages recruitment, and M2 macrophages-myofibroblasts transition.


Assuntos
Fibrose/etiologia , Neuropeptídeos/fisiologia , Traumatismo por Reperfusão/complicações , Proteínas rac1 de Ligação ao GTP/fisiologia , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Nefropatias/patologia , Macrófagos , Camundongos , Miofibroblastos , Neuropeptídeos/antagonistas & inibidores , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores
11.
Artigo em Inglês | MEDLINE | ID: mdl-30201820

RESUMO

Tafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acute Plasmodium vivax malaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/F and Q/F, respectively), apparent volume of distribution for central and peripheral compartments (V 2/F and V 3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka ), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/F and 915 liters for V 2/F in P. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.


Assuntos
Aminoquinolinas/farmacocinética , Antimaláricos/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Disponibilidade Biológica , Ensaios Clínicos como Assunto , Feminino , Humanos , Malária Vivax/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto Jovem
12.
Am Surg ; 84(8): 1319-1325, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30185309

RESUMO

The significance and management of melanoma in situ (MIS) at the margin of excision of invasive melanoma is debated. Patients undergoing excision of invasive melanoma from 2000 to 2016 with MIS at the margin were identified. A cohort without MIS was matched for age, gender, location, and Breslow depth. Thirty-two patients with 33 cases of MIS at the margin were identified. Melanoma was located on the head/neck (66.7%), extremities (24.2%), and trunk (9.1%). Median Breslow depth was 1.0 mm (range 0.25-10.80). Margin treatment included re-excision (45.5%), re-excision plus imiquimod (3.0%), imiquimod alone (9.1%), and observation alone (42.4%). At a median follow-up of 91 months (range 28-126), five patients (15.2%) with a median Breslow depth of 4.75 mm (range 1.10-6.70) developed local recurrence (LR). Three underwent re-excision of the positive margin and two were observed. Intervention for positive margins did not decrease LR compared with observation (P = 0.905, OR = 1.125, 95% confidence interval [CI] 0.162-7.824). All five patients with LR were alive at the last follow-up. There were two recurrences in the matched cohort (6.1%); both were alive at the last follow-up. Risk of LR is higher with MIS at the margin, but this does not seem to impact survival. Larger studies may elucidate predictive factors and interventions that decrease risk for LR.


Assuntos
Melanoma/patologia , Melanoma/cirurgia , Recidiva Local de Neoplasia/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminoquinolinas/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Imiquimode , Masculino , Margens de Excisão , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Neoplasias Cutâneas/tratamento farmacológico
13.
PLoS One ; 13(9): e0202436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30208056

RESUMO

Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Reposicionamento de Medicamentos , Neovascularização Retiniana/tratamento farmacológico , Aminoquinolinas/química , Aminoquinolinas/farmacocinética , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Animais , Antimaláricos/química , Antimaláricos/farmacocinética , Apelina/metabolismo , Receptores de Apelina/antagonistas & inibidores , Receptores de Apelina/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Neovascularização de Coroide/tratamento farmacológico , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Feminino , Humanos , Lasers , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Retiniana/patologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico , Distribuição Tecidual , Fator A de Crescimento do Endotélio Vascular/metabolismo
15.
Cutis ; 101(6): 466-468, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30063776

RESUMO

Imiquimod is a topical immunomodulating medication approved by the US Food and Drug Administration for the treatment of condyloma acuminata, actinic keratoses (AKs), and superficial basal cell carcinoma (BCC). Imiquimod commonly is used off label for its antiviral and antitumoral effects. We present a case of a 51-year-old man with vitiligolike depigmentation following treatment of periungual verruca vulgaris with imiquimod therapy.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Aminoquinolinas/efeitos adversos , Hipopigmentação/induzido quimicamente , Paroniquia/tratamento farmacológico , Dermatopatias Virais/tratamento farmacológico , Verrugas/tratamento farmacológico , Adjuvantes Imunológicos/uso terapêutico , Aminoquinolinas/uso terapêutico , Humanos , Imiquimode , Masculino , Pessoa de Meia-Idade
16.
Artigo em Inglês | MEDLINE | ID: mdl-29987144

RESUMO

New prophylactic drugs against malaria infections are urgently needed. We conducted randomized, double-blind, placebo-controlled, phase 2 trials of a new antimalarial drug combination, naphthoquine-azithromycin (NQAZ), to determine its safety and protective efficacy in a low-endemicity area of Southeast Asia. In the first trial, 127 healthy volunteers were randomized to receive two single doses of either 400 mg of NQAZ (200 mg of each drug), 800 mg of NQAZ (400 mg of each drug), or placebo on day 0 and day 30. Weekly follow-ups were performed for 2 months, and physical and clinical laboratory exams were done during the second and eighth week. Both drug regimens were well tolerated, without any serious adverse events. Four adverse events (transient and slight elevations of serum transaminase concentrations) were found only in the two drug-treated groups and thus might be drug-related. In the second trial, 353 volunteer villagers were randomized into the same three groups as in the first trial, and malaria infections were followed for a month. For the intention-to-treat analysis, both regimens offered greater than 90% prophylactic efficacies against all malaria infections. When the analysis was done according to parasite species, 400 mg and 800 mg NQAZ provided 81.63 and 90.59% prophylactic efficacies, respectively, against Plasmodium falciparum infections, whereas both offered 100% prophylactic efficacy against Plasmodium vivax and Plasmodium ovale These trials showed that NQAZ had a good safety profile, and monthly single doses of 400 mg or 800 mg for adults offered excellent prophylaxis against malaria infections, especially the two relapsing species.


Assuntos
1-Naftilamina/análogos & derivados , Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , 1-Naftilamina/efeitos adversos , 1-Naftilamina/uso terapêutico , Adolescente , Adulto , Aminoquinolinas/efeitos adversos , Antimaláricos/efeitos adversos , Azitromicina/efeitos adversos , Quimioprevenção/métodos , Criança , China , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Voluntários Saudáveis , Humanos , Malária Falciparum/tratamento farmacológico , Malária Vivax/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/efeitos dos fármacos , Plasmodium ovale/efeitos dos fármacos , Plasmodium vivax/efeitos dos fármacos , Adulto Jovem
17.
Drugs ; 78(9): 861-879, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29802605

RESUMO

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel-ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.


Assuntos
Antimaláricos/química , Antimaláricos/uso terapêutico , Malária/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Artemisininas/uso terapêutico , Descoberta de Drogas , Resistência a Múltiplos Medicamentos , Compostos Ferrosos/uso terapêutico , Humanos , Imidazóis/uso terapêutico , Lumefantrina/uso terapêutico , Malária/prevenção & controle , Metalocenos , Piperazinas/uso terapêutico , Transdução de Sinais , Resultado do Tratamento
18.
PLoS One ; 13(5): e0196716, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29738562

RESUMO

INTRODUCTION: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in the human population affecting an estimated 8% of the world population, especially those living in areas of past and present malaria endemicity. Decreased G6PD enzymatic activity is associated with drug-induced hemolysis and increased risk of severe neonatal hyperbilirubinemia leading to brain damage. The G6PD gene is on the X chromosome therefore mutations cause enzymatic deficiency in hemizygote males and homozygote females while the majority of heterozygous females have an intermediate activity (between 30-80% of normal) with a large distribution into the range of deficiency and normality. Current G6PD qualitative tests are unable to diagnose G6PD intermediate activities which could hinder wide use of 8-aminoquinolines for Plasmodium vivax elimination. The aim of the study was to assess the diagnostic performances of the new Carestart G6PD quantitative biosensor. METHODS: A total of 150 samples of venous blood with G6PD deficient, intermediate and normal phenotypes were collected among healthy volunteers living along the north-western Thailand-Myanmar border. Samples were analyzed by complete blood count, by gold standard spectrophotometric assay using Trinity kits and by the latest model of Carestart G6PD biosensor which analyzes both G6PD and hemoglobin. RESULTS: Bland-Altman comparison of the CareStart normalized G6PD values to that of the gold standard assay showed a strong bias in values resulting in poor area under-the-curve values for both 30% and 80% thresholds. Performing a receiver operator curve identified threshold values for the CareStart product equivalent to the 30% and 80% gold standard values with good sensitivity and specificity values, 100% and 92% (for 30% G6PD activity) and 92% and 94% (for 80% activity) respectively. CONCLUSION: The Carestart G6PD biosensor represents a significant improvement for quantitative diagnosis of G6PD deficiency over previous versions. Further improvements and validation studies are required to assess its utility for informing radical cure decisions in malaria endemic settings.


Assuntos
Técnicas Biossensoriais , Ensaios Enzimáticos Clínicos/instrumentação , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Glucosefosfato Desidrogenase/sangue , Sistemas Automatizados de Assistência Junto ao Leito , Adulto , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Área Sob a Curva , Doenças Endêmicas , Grupos Étnicos/genética , Feminino , Genótipo , Deficiência de Glucosefosfato Desidrogenase/epidemiologia , Deficiência de Glucosefosfato Desidrogenase/etnologia , Deficiência de Glucosefosfato Desidrogenase/genética , Hemoglobinometria , Humanos , Malária Vivax/tratamento farmacológico , Malária Vivax/epidemiologia , Masculino , Metemoglobinemia/induzido quimicamente , Metemoglobinemia/genética , Metemoglobinemia/prevenção & controle , Mianmar/epidemiologia , Gravidez , Complicações Hematológicas na Gravidez/diagnóstico , Complicações Hematológicas na Gravidez/epidemiologia , Primaquina/efeitos adversos , Primaquina/uso terapêutico , Curva ROC , Espectrofotometria Ultravioleta
19.
PLoS Negl Trop Dis ; 12(4): e0006440, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29677199

RESUMO

BACKGROUND: The 8-aminoquinoline antimalarials, the only drugs which prevent relapse of vivax and ovale malaria (radical cure), cause dose-dependent oxidant haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Patients with <30% and <70% of normal G6PD activity are not given standard regimens of primaquine and tafenoquine, respectively. Both drugs are currently considered contraindicated in pregnant and lactating women. METHODS: Quantitative G6PD enzyme activity data from 5198 individuals were used to estimate the proportions of heterozygous females who would be ineligible for treatment at the 30% and 70% activity thresholds, and the relationship with the severity of the deficiency. This was used to construct a simple model relating allele frequency in males to the potential population coverage of tafenoquine and primaquine under current prescribing restrictions. FINDINGS: Independent of G6PD deficiency, the current pregnancy and lactation restrictions will exclude ~13% of females from radical cure treatment. This could be reduced to ~4% if 8-aminoquinolines can be prescribed to women breast-feeding infants older than 1 month. At a 30% activity threshold, approximately 8-19% of G6PD heterozygous women are ineligible for primaquine treatment; at a 70% threshold, 50-70% of heterozygous women and approximately 5% of G6PD wild type individuals are ineligible for tafenoquine treatment. Thus, overall in areas where the G6PDd allele frequency is >10% more than 15% of men and more than 25% of women would be unable to receive tafenoquine. In vivax malaria infected patients these proportions will be lowered by any protective effect against P. vivax conferred by G6PD deficiency. CONCLUSION: If tafenoquine is deployed for radical cure, primaquine will still be needed to obtain high population coverage. Better radical cure antimalarial regimens are needed.


Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Deficiência de Glucosefosfato Desidrogenase/genética , Malária Vivax/tratamento farmacológico , Plasmodium vivax/efeitos dos fármacos , Primaquina/uso terapêutico , Adolescente , Adulto , Feminino , Heterozigoto , Humanos , Lactação , Masculino , Gravidez , Adulto Jovem
20.
Actas dermo-sifiliogr. (Ed. impr.) ; 109(3): 248-253, abr. 2018. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-172830

RESUMO

Introducción y objetivos: El imiquimod es un excelente tratamiento para las queratosis actínicas, sin embargo, su pauta prolongada de 4 semanas y la reacción local que produce pueden limitar su utilización. Los objetivos del estudio son demostrar la eficacia del imiquimod al 5% para las queratosis actínicas aplicado en una pauta continuada de 12 días y correlacionar el grado de reacción local con la eficacia. Pacientes y métodos: Se incluyeron pacientes con al menos 8 queratosis actínicas que se trataron con imiquimod en crema al 5% durante 12 días seguidos. Se evaluó la reacción local como leve, moderada o intensa. El estudio estadístico de la correlación entre la reacción local y la respuesta clínica se realizó con la prueba χ2 de Pearson y el test de correlación rho de Spearman. Resultados: Un total de 65 pacientes completaron el estudio. Se obtuvo un 52,3% de respuestas completas y un 75,4% de respuestas parciales. Encontramos una asociación estadísticamente significativa entre el grado de reacción local y la respuesta al tratamiento tanto en la prueba χ2 de Pearson como en el test de correlación rho de Spearman. Conclusiones: La pauta continuada de imiquimod al 5% aplicado durante 12 días es eficaz para el tratamiento de las queratosis actínicas. El grado de reacción local durante el tratamiento se correlaciona con la respuesta clínica


Introduction and objectives: Imiquimod is an excellent option for patients with actinic keratosis, although its use may be limited by the long course of treatment required (4 weeks) and the likelihood of local skin reactions. The objectives of the present study were to demonstrate the effectiveness of a 12-day course of imiquimod 5% for the treatment of actinic keratosis and to examine the association between treatment effectiveness and severity of local reactions. Patients and methods: We included patients with at least 8 actinic keratoses treated with imiquimod 5% cream for 12 consecutive days. Local reactions were classified as mild, moderate, or severe. The statistical analysis of the association between local reactions and clinical response was based on the Pearson chi cuadrado test and the Spearman rank correlation test. Results: Sixty-five patients completed the study. Complete response was recorded in 52.3% and partial response in 75.4%. We found a statistically significant association between severity of the local reaction and response to treatment in both the Pearson chi cuadrado test and the Spearman rank correlation test. Conclusions: A 12-day course of imiquimod 5% proved effective for the treatment of actinic keratosis. Severity of local reactions during treatment was correlated with clinical response


Assuntos
Humanos , Masculino , Feminino , Idoso , Ceratose Actínica/diagnóstico , Ceratose Actínica/tratamento farmacológico , Aminoquinolinas/uso terapêutico , Administração Tópica , Resultado do Tratamento , Ceratose Actínica/complicações , Aminoquinolinas/farmacologia , Couro Cabeludo , Couro Cabeludo/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA