RESUMO
BACKGROUND: Given the lack of evidence for survival benefit in patients with metastatic renal cell carcinoma from the addition of radiation therapy to tyrosine kinase inhibitor therapy, this Bayesian network meta-analysis aimed to evaluate survival outcomes in patients receiving radiation therapy plus tyrosine kinase inhibitor therapy. METHODS: The preferred reporting items for systematic reviews and meta-analyses reporting guidelines were followed to conduct this study. The electronic databases of PubMed, Cochrane Library, EMBASE, and Web of Science were searched from the inception to August 2021. All phase III clinical trials that reported the outcomes of tyrosine kinase inhibitor with radiation therapy compared with those of tyrosine kinase inhibitor or radiation therapy alone for patients with metastatic renal cell carcinoma were considered eligible for inclusion in this meta-analysis. Overall survival as the primary outcome of interest, and adverse events as secondary outcome of interest were recorded for meta-analysis. RESULTS: A Bayesian network meta-analysis is an appropriate statistical method to compare all treatment options by statistically simulating the estimated results of a comprehensive trial, and to compare treatments by common and associated comparators. In addition, Bayesian network meta-analysis can produce ranking probabilities of treatments, which may contribute to clinicians' clinical decision-making.
Assuntos
Protocolos Clínicos , Quimioterapia Combinada/normas , Pirazóis/normas , Pirimidinas/normas , Radioterapia/normas , Teorema de Bayes , Carcinoma de Células Renais/terapia , Humanos , Metanálise em Rede , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Radioterapia/métodos , Revisões Sistemáticas como AssuntoRESUMO
A rapid, simple, precise and accurate high performance liquid chromatographic (HPLC) analytical method was developed and validated for the determination of the active substances (a.s.) azoxystrobin, topramezone, acetamiprid, fluometuron and folpet in their respective commercially available formulations. The method was used for the analysis of samples under the frame of the national quality control program of plant protection products in the Greek market. Chromatographic separation of the active substances from additives and co-formulants is achieved using isocratic elution with acetonitrile and 0.1% phosphoric acid solution (60:40 v/v) at a flow rate of 0.4 mL min-1 on a C18 monolithic column (Chromolith Performance-RP18e 100 × 4.6 mm) and UV detection at 230 nm. Validation parameters of the method fulfilled acceptability criteria. Recovery of all individual compounds was in the range 97.8-100.9%. Precision expressed as relative standard deviation was lower than the theoretical values of the modified Horwitz equation. Correlation coefficients of linearity of response were better than 0.999. The benefits of the proposed method are significant reduction in analysis time and total cost since all analytes were determined with the same extraction procedures and chromatographic system. Analysis of real samples for all active ingredients confirmed fitness for purpose of the suggested method.
Assuntos
Cromatografia Líquida de Alta Pressão , Praguicidas/análise , Praguicidas/química , Grécia , Compostos de Metilureia/análise , Compostos de Metilureia/normas , Neonicotinoides/análise , Neonicotinoides/normas , Praguicidas/normas , Ftalimidas/análise , Ftalimidas/normas , Pirazóis/análise , Pirazóis/normas , Pirimidinas/análise , Pirimidinas/normas , Controle de Qualidade , Estrobilurinas/análise , Estrobilurinas/normasAssuntos
Antagonistas dos Receptores de Orexina/normas , Antagonistas dos Receptores de Orexina/uso terapêutico , Piridinas/normas , Piridinas/uso terapêutico , Pirimidinas/normas , Pirimidinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Currículo , Educação Médica Continuada , Humanos , Guias de Prática Clínica como Assunto , Distúrbios do Início e da Manutenção do Sono/diagnósticoRESUMO
For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open-label, multicenter study to investigate an intrapatient nilotinib dose-escalation strategy for patients with newly diagnosed chronic-phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty-three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207-736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5 . The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non-AE related reasons. Four of these patients achieved MR4.5 . The MR4.5 rate by 24 months was 45.7%. The progression-free, overall and event-free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML-CP.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Pirimidinas/normas , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Leucemia Mieloide de Fase Crônica/patologia , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Taxa de Sobrevida , Adulto JovemRESUMO
The main goal of the present study was to determine and validate an aquatic Maximum Acceptable Concentration-Environmental Quality Standard (MAC-EQS) value for the agricultural fungicide azoxystrobin (AZX). Assessment factors were applied to short-term toxicity data using the lowest EC50 and after the Species Sensitivity Distribution (SSD) method. Both ways of EQS generation were applied to a freshwater toxicity dataset for AZX based on available data, and to marine toxicity datasets for AZX and Ortiva® (a commercial formulation of AZX) obtained by the present study. A high interspecific variability in AZX sensitivity was observed in all datasets, being the copepoda Eudiaptomus graciloides (LC50,48h = 38 µg L-1) and the gastropod Gibbula umbilicalis (LC50,96h = 13 µg L-1) the most sensitive freshwater and marine species, respectively. MAC-EQS values derived using the lowest EC50 (≤0.38 µg L-1) were more protective than those derived using the SSD method (≤3.2 µg L-1). After comparing the MAC-EQS values estimated in the present study to the smallest AA-EQS available, which protect against the occurrence of prolonged exposure of AZX, the MAC-EQS values derived using the lowest EC50 were considered overprotective and a MAC-EQS of 1.8 µg L-1 was validated and recommended for AZX for the water column. This value was derived from marine toxicity data, which highlights the importance of testing marine organisms. Moreover, Ortiva affects the most sensitive marine species to a greater extent than AZX, and marine species are more sensitive than freshwater species to AZX. A risk characterization ratio higher than one allowed to conclude that AZX might pose a high risk to the aquatic environment. Also, in a wider conclusion, before new pesticides are approved, we suggest to improve the Tier 1 prospective Ecological Risk Assessment by increasing the number of short-term data, and apply the SSD approach, in order to ensure the safety of aquatic organisms.
Assuntos
Fungicidas Industriais/normas , Metacrilatos/normas , Pirimidinas/normas , Poluentes Químicos da Água/normas , Animais , Organismos Aquáticos , Copépodes , Ecologia , Água Doce , Fungicidas Industriais/toxicidade , Metacrilatos/toxicidade , Praguicidas , Estudos Prospectivos , Pirimidinas/toxicidade , Medição de Risco , Estrobilurinas , Testes de Toxicidade , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidadeRESUMO
BACKGROUND: Riociguat (BAY 63-2521) is an oral NO-independent as well as NO-synergistic stimulator of soluble guanylate cyclase (sGC) for the treatment of pulmonary hypertension. BAY 60-4552 (M-1) is its pharmacologically active major metabolite. An isotope dilution LC-ESI-MS/MS method has been developed and validated for the simultaneous determination of riociguat and M-1 in lithium heparinized human plasma. RESULTS: The validated concentration range covers 0.500 µg/l (LLOQ) to 100 µg/l (ULOQ) for both analytes. Interassay accuracy and precision (%CV) for both analytes ranged from 92.7 to 111% and from 2.61 to 9.89%, respectively. CONCLUSION: The method proved to be selective, specific, sufficiently sensitive, highly reproducible and robust for the analysis of large numbers of samples.
Assuntos
Análise Química do Sangue/métodos , Pirazóis/sangue , Pirimidinas/sangue , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Humanos , Marcação por Isótopo , Pirazóis/metabolismo , Pirazóis/normas , Pirimidinas/metabolismo , Pirimidinas/normas , Controle de Qualidade , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/normasRESUMO
Nanocarriers may provide interesting delivery platforms for microbicide drugs and their characterization should be addressed early in development. Differently surface-engineered dapivirine-loaded, poly(epsilon-caprolactone) (PCL)-based nanoparticles (NPs) were obtained by nanoprecipitation using polyethylene oxide (PEO), sodium lauryl sulfate (SLS), or cetyltrimethylammonium bromide (CTAB) as surface modifiers. Physical-chemical properties of NP aqueous dispersions were evaluated upon storage at -20-40 °C for one year. NPs presented 170-200 nm in diameter, roundish-shape, low polydispersity index (≤0.18), and high drug association efficiency (≥97%) and loading (≥12.7%). NPs differed in zeta potential, depending on surface modifier (PEO: -27.9 mV; SLS: -54.7 mV; CTAB: +42.4 mV). No interactions among formulation components were detected by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), except for SLS-PCL NPs. Colloidal properties of NPs were lost at -20 °C storage. Negatively charged NPs were stable up to one year at 5-40°C; as for CTAB-PCL NPs, particle aggregation was observed from 30 to 90 days of storage depending on temperature. Colloidal instability affected the in vitro drug release of CTAB-PCL NPs after 360 days. In any case, no degradation of dapivirine was apparent. Overall, PEO-PCL and SLS-PCL NPs presented suitable properties as nanocarriers for dapivirine. Conversely, CTAB-PCL NPs require additional strategies in order to increase stability.
Assuntos
Fenômenos Químicos , Nanopartículas/química , Polímeros/química , Pirimidinas/química , Portadores de Fármacos/química , Portadores de Fármacos/normas , Estabilidade de Medicamentos , Nanopartículas/normas , Polímeros/normas , Pirimidinas/normasRESUMO
Imatimib mesylate is a drug for the treatment of gastrointestinal stroma tumor and chronic myelogenous leukemia. In this study, capillary electrophoretic analysis of imatinib mesylate and related compounds was developed. The optimized separation condition was NaH(2)PO(4) (10 mM) aqueous solution containing 5 mM of 2-hydroxypropyl-ß-cyclodextrin at a pH of 2.0. The separation could be obtained in less than 20 min when the separation voltage was 20 kV. To enhance the sensitivity, field amplified sample stacking combining with large volume sample injection was adopted. The optimal injection conditions were obtained by using methanol containing 0.5 mM HCl as the sample dilution solution and performing injection at a voltage of 15 kV for 60 s. The linearity ranges of ima amine, N-desmethyl imatinib and imatinib mesylate were 0.005-0.500 µg/ml, and 4-chloromethyl-N-(4-methyl-3-((4-(pyridin-3-yl) pyrimidin-2-yl) amino) phenyl) benzamide was 0.010-0.500 µg/ml, with good linear correlation coefficients (r(2)>0.9900). The intra-day and inter-day relative standard deviations of peak areas were satisfactory. Under the optimized condition, five batches of the synthesized samples were detected and ima amine was found in all the batches. Due to its simplicity, effectiveness and low price, the developed method can be used for quality control analysis of imatinib mesylate.
Assuntos
Antineoplásicos/análise , Eletroforese Capilar/métodos , Piperazinas/análise , Inibidores de Proteínas Quinases/análise , Pirimidinas/análise , 2-Hidroxipropil-beta-Ciclodextrina , Antineoplásicos/normas , Benzamidas , Soluções Tampão , Contaminação de Medicamentos , Concentração de Íons de Hidrogênio , Hidrólise , Mesilato de Imatinib , Fosfatos/química , Piperazinas/normas , Inibidores de Proteínas Quinases/normas , Pirimidinas/normas , Controle de Qualidade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solventes/química , beta-Ciclodextrinas/químicaRESUMO
A simple, precise, accurate stability-indicating gradient reverse phase ultra-performance liquid chromatographic (RP-UPLC) method was developed for quantitative determination of purity of Imatinib Mesylate (IMM) drug substance and drug products in the presence of its process related impurities, and degradation products. The proposed RP-UPLC method utilizes Acquity UPLC BEH 50-mm, 2.1mm and 1.7 µm C-18 column at 30 °C, with a gradient program of 9.0 min at a flow rate of 0.3 mL/min. The compounds of interest were monitored at 237 nm. Resolution for Imatinib and eight related components was found to be greater than 1.5 for any pair of components. The correlation coefficients (r(2)>0.9990) obtained indicate clear correlations between the concentrations and their peak areas for the investigated compounds. RSD obtained for the repeatability and intermediate precision experiments, was less than 5.0%. Accuracy of the method was further ascertained by performing recovery studies through spiking experiments. The drug substance was subjected to hydrolytic, oxidative, photolytic and thermal stress conditions as per ICH. The developed method was validated according to the current ICH guidelines for specificity, limit of detection, limit of quantitation, linearity, accuracy, precision, ruggedness and robustness. The method is also suitable for the assay determination of IMM in pharmaceutical dosage forms.
Assuntos
Antineoplásicos/análise , Cromatografia Líquida de Alta Pressão/métodos , Piperazinas/análise , Pirimidinas/análise , Antineoplásicos/normas , Benzamidas , Contaminação de Medicamentos , Estabilidade de Medicamentos , Guias como Assunto , Hidrólise , Mesilato de Imatinib , Limite de Detecção , Oxirredução , Piperazinas/normas , Pirimidinas/normas , Reprodutibilidade dos Testes , TemperaturaRESUMO
A simple, linear gradient, rapid, precise and stability-indicating analytical method was developed for the estimation of related substances and degradants of paliperidone API and tablets. The chromatographic separations were achieved using an Acquity ultra-performance liquid chromatograph (BEH 100 mm, 2.1 mm, 1.7 µm C-18 column) employing 0.01 M potassium dihydrogen phosphate buffer (pH 2.0) as mobile phase A and acetonitrile-water (9:1) as mobile phase B. A linear gradient (mobile phase A, mobile phase B in the ratio of 84:16) with a 0.45 mL/min flow rate was chosen. All six impurities were eluted within five minutes of run time. The column temperature was maintained at 25 °C and a detector wavelength of 238 nm was employed. Paliperidone was exposed to thermal, photolytic, hydrolytic and oxidative stress conditions. The stressed samples were analyzed by the proposed method. Considerable degradation of the analyte was observed when it was subjected to oxidative conditions and impurity F was found to be the major degradant. Peak homogeneity data of paliperidone obtained by photodiode array (PDA) detection demonstrated the specificity of the method in the presence of degradants. The method was validated with respect to linearity, precision, accuracy, ruggedness, robustness, limit of detection and limit of quantification.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Isoxazóis/análise , Pirimidinas/análise , Estabilidade de Medicamentos , Isoxazóis/química , Isoxazóis/normas , Limite de Detecção , Palmitato de Paliperidona , Pirimidinas/química , Pirimidinas/normas , Reprodutibilidade dos Testes , Comprimidos/química , Comprimidos/normasRESUMO
Viral replication and pathogenesis involves many cellular protein kinases, and many specific inhibitors of such kinase have been developed for the treatment of noninfectious diseases. As expected, such drugs have been repeatedly demonstrated to inhibit viral replication in cultured cells. Cellular protein kinases have thus been considered for several years as potentially valid targets for antiviral therapy. However, until recently there was no proof of such activity in vivo. The three papers discussed herein demonstrate that inhibitors of cellular protein kinases are indeed effective for the treatment of virus-induced disease in animal models and human clinical trials.
Assuntos
Antivirais/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Antivirais/normas , Benzamidas , Herpesvirus Humano 8/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Camundongos , Piperazinas/normas , Piperazinas/uso terapêutico , Poxviridae/efeitos dos fármacos , Inibidores de Proteínas Quinases/normas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/normas , Pirimidinas/uso terapêutico , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: Lowering low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of coronary heart disease. The introduction of a highly efficacious new statin, rosuvastatin, may enable more patients to be treated to LDL-C goal within a fixed budget. OBJECTIVES: To compare the cost-effectiveness of rosuvastatin 10 mg and atorvastatin 10 mg in lowering LDL-C and achieving guideline goals after 12 weeks of treatment. The LDL-C goals were those recommended by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III and the Third Joint European Task Force. METHODS: The analysis was performed on pooled data from three clinical trials. Efficacy was measured as the percent reduction in LDL-C and the proportion of patients who reached guideline LDL-C goals following the first 12 weeks of treatment, prior to dose titration. Costs comprised drug acquisition costs only. The cost-effectiveness measures were cost per 1% reduction in LDL-C and cost per patient treated to their LDL-C goal. RESULTS: Treatment with rosuvastatin 10 mg costs 1.85 per 1% reduction in LDL-C, compared with 2.37 per 1% reduction with atorvastatin 10 mg. The average costs per patient treated to the European LDL-C goals were 130.18 for rosuvastatin 10 mg and 242.44 for atorvastatin 10 mg. Treating to NCEP ATP III goals costs 115 per patient treated with rosuvastatin 10 mg vs. 163 per patient treated with atorvastatin 10 mg. CONCLUSIONS: Rosuvastatin has the same acquisition costs as and is more efficacious than atorvastatin in lowering LDL-C and treating patients to target LDL-C levels.
Assuntos
LDL-Colesterol/sangue , Fluorbenzenos/economia , Ácidos Heptanoicos/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Hipercolesterolemia/tratamento farmacológico , Pirimidinas/economia , Pirróis/economia , Sulfonamidas/economia , Adolescente , Adulto , Idoso , Anticolesterolemiantes/economia , Anticolesterolemiantes/normas , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Análise Custo-Benefício , Método Duplo-Cego , Europa (Continente) , Feminino , Fluorbenzenos/normas , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/normas , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/sangue , Masculino , Pessoa de Meia-Idade , América do Norte , Pirimidinas/normas , Pirimidinas/uso terapêutico , Pirróis/normas , Pirróis/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Rosuvastatina Cálcica , Sulfonamidas/normas , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
BACKGROUND: Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). METHODS AND RESULTS: A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). CONCLUSIONS: Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS.
Assuntos
Anticolesterolemiantes/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/normas , Atorvastatina , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Avaliação de Medicamentos , Europa (Continente) , Feminino , Fluorbenzenos/efeitos adversos , Fluorbenzenos/normas , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/efeitos adversos , Ácidos Heptanoicos/normas , Ácidos Heptanoicos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Hipercolesterolemia/epidemiologia , Japão , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pravastatina/efeitos adversos , Pravastatina/normas , Pravastatina/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/normas , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/normas , Pirróis/uso terapêutico , Grupos Raciais , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosuvastatina Cálcica , Sinvastatina/efeitos adversos , Sinvastatina/normas , Sinvastatina/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/normas , Sulfonamidas/uso terapêutico , Resultado do Tratamento , Estados UnidosAssuntos
Aprovação de Drogas/estatística & dados numéricos , Indústria Farmacêutica/estatística & dados numéricos , Fluorbenzenos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Publicações Periódicas como Assunto/normas , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Fluorbenzenos/efeitos adversos , Fluorbenzenos/normas , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/normas , Hiperlipidemias/tratamento farmacológico , Vigilância de Produtos Comercializados/estatística & dados numéricos , Pirimidinas/efeitos adversos , Pirimidinas/normas , Rosuvastatina Cálcica , Sulfonamidas/efeitos adversos , Sulfonamidas/normas , Reino UnidoAssuntos
Indústria Farmacêutica/ética , Fluorbenzenos/normas , Inibidores de Hidroximetilglutaril-CoA Redutases/provisão & distribuição , Marketing de Serviços de Saúde/ética , Pirimidinas/normas , Sulfonamidas/normas , Ensaios Clínicos como Assunto/estatística & dados numéricos , Indústria Farmacêutica/economia , Fluorbenzenos/economia , Fluorbenzenos/provisão & distribuição , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Marketing de Serviços de Saúde/métodos , Marketing de Serviços de Saúde/normas , Pirimidinas/economia , Pirimidinas/provisão & distribuição , Rosuvastatina Cálcica , Sulfonamidas/economia , Sulfonamidas/provisão & distribuição , Resultado do TratamentoRESUMO
The translocation (9;22) gives rise to the p190(Bcr-Abl) and p210(Bcr-Abl) tyrosine kinase proteins, considered sufficient for leukemic transformation. Philadelphia-positive (Ph(+)) acute leukemia patients failing to respond to initial induction therapy have a poor prognosis with few effective treatment options. Imatinib is an orally administered, potent inhibitor of the Bcr-Abl tyrosine kinase. We conducted a clinical trial in 56 patients with relapsed or refractory Ph(+) acute lymphoblastic leukemia (ALL; 48 patients) or chronic myelogenous leukemia in lymphoid blast crisis (LyBC; 8 patients). Imatinib was given once daily at 400 mg or 600 mg. Imatinib induced complete hematologic responses (CHRs) and complete marrow responses (marrow-CRs) in 29% of ALL patients (CHR, 19%; marrow-CR, 10%), which were sustained for at least 4 weeks in 6% of patients. Median estimated time to progression and overall survival for ALL patients were 2.2 and 4.9 months, respectively. CHRs were reported for 3 (38%) of the patients with LyBC (one sustained CHR). Grade 3 or 4 treatment-related nonhematologic toxicity was reported for 9% of patients; none of the patients discontinued therapy because of nonhematologic adverse reactions. Grade 4 neutropenia and thrombocytopenia occurred in 54% and 27% of patients, respectively. Imatinib therapy resulted in a clinically relevant hematologic response rate in relapsed or refractory Ph(+) acute lymphoid leukemia patients, but development of resistance and subsequent disease progression were rapid. Further studies are warranted to test the effects of imatinib in combination with other agents and to define the mechanisms of resistance to imatinib.
Assuntos
Antineoplásicos/administração & dosagem , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Adulto , Idoso , Antineoplásicos/normas , Antineoplásicos/toxicidade , Benzamidas , Crise Blástica/complicações , Crise Blástica/tratamento farmacológico , Crise Blástica/mortalidade , Feminino , Seguimentos , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Piperazinas/normas , Piperazinas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Pirimidinas/normas , Pirimidinas/toxicidade , Indução de Remissão/métodos , Terapia de Salvação , Análise de SobrevidaAssuntos
Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Adulto , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Masculino , Piperazinas/normas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pirimidinas/normas , Terapia de Salvação , Transplante de Células-Tronco , Transplante Homólogo , Resultado do TratamentoAssuntos
Antineoplásicos/uso terapêutico , Piperazinas/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/normas , Benzamidas , Resistência a Medicamentos , Proteínas de Fusão bcr-abl/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Piperazinas/administração & dosagem , Piperazinas/normas , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/administração & dosagem , Pirimidinas/normas , Resultado do TratamentoRESUMO
Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.