RESUMO
PURPOSE: To describe the clinical studies, chemistry manufacturing and controls, and clinical pharmacology and toxicology that led to Food and Drug Administration approval of nelarabine (Arranon) for the treatment of T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma. EXPERIMENTAL DESIGN: Two phase 2 trials, one conducted in pediatric patients and the other in adult patients, were reviewed. The i.v. dose and schedule of nelarabine in the pediatric and adult studies was 650 mg/m2/d daily for 5 days and 1,500 mg/m2 on days 1, 3, and 5, respectively. Treatments were repeated every 21 days. Study end points were the rates of complete response (CR) and CR with incomplete hematologic or bone marrow recovery (CR*). RESULTS: The pediatric efficacy population consisted of 39 patients who had relapsed or had been refractory to two or more induction regimens. CR to nelarabine treatment was observed in 5 (13%) patients and CR+CR* was observed in 9 (23%) patients. The adult efficacy population consisted of 28 patients. CR to nelarabine treatment was observed in 5 (18%) patients and CR+CR* was observed in 6 (21%) patients. Neurologic toxicity was dose limiting for both pediatric and adult patients. Other severe toxicities included laboratory abnormalities in pediatric patients and gastrointestinal and pulmonary toxicities in adults. CONCLUSIONS: On October 28, 2005, the Food and Drug Administration granted accelerated approval for nelarabine for treatment of patients with relapsed or refractory T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma after at least two prior regimens. This use is based on the induction of CRs. The applicant will conduct postmarketing clinical trials to show clinical benefit (e.g., survival prolongation).
Assuntos
Arabinonucleosídeos/uso terapêutico , Aprovação de Drogas , Leucemia-Linfoma de Células T do Adulto/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , United States Food and Drug Administration , Animais , Arabinonucleosídeos/efeitos adversos , Arabinonucleosídeos/síntese química , Arabinonucleosídeos/farmacologia , Cães , Aprovação de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Haplorrinos , Humanos , Taxa de Depuração Metabólica , Camundongos , Modelos Biológicos , Coelhos , Ratos , Estados UnidosRESUMO
Different arabinosides and ribosides, viz. Ara-DDA or 9(1-beta-D-arabinofuranosyl) 1,3-dideazaadenine (6), Ara-NDDP or 9(1-beta-D-arabinofuranosyl) 4-nitro-1,3-dideazapurine (7), Ara-DKP or 1(1-beta-D-arabinofuranosyl) diketopiperazine (8), Ribo-DDA or 9(1-beta-D-ribofuranosyl) 1,3-dideazaadenine (9) and Ribo-NDDP or 9(1-beta-D-ribofuranosyl) 4-nitro-1,3-dideazapurine (10) have been synthesized as probable antiviral agents. The arabinosides have been synthesized using the catalyst TDA-1 that causes stereospecific formation of beta-nucleosides while a one-pot synthesis procedure was adopted for the synthesis of the ribonucleosides where beta-anomers were obtained in higher yields. All the five nucleoside analogs have been screened for antiviral property against HIV-1 (IIIB), HSV-1 and 2, parainfluenza-3, reovirus-1 and many others. It was observed that arabinosides had greater inhibitory action than ribosides. The compound 7 or Ara-NDDP has shown maximum inhibition of HIV-1 replication than the rest of the molecules with an IC50 of 79.4 microg/mL.
Assuntos
Adenina , Adenina/análogos & derivados , Antivirais/síntese química , Arabinonucleosídeos/síntese química , Nitrocompostos , Piperazinas/síntese química , Purinas , Ribonucleosídeos/síntese química , Adenina/síntese química , Adenina/química , Adenina/farmacologia , Animais , Antivirais/química , Antivirais/farmacologia , Arabinonucleosídeos/química , Arabinonucleosídeos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Dicetopiperazinas , Avaliação Pré-Clínica de Medicamentos , Células HeLa/citologia , Células HeLa/efeitos dos fármacos , Células HeLa/virologia , Humanos , Nitrocompostos/síntese química , Nitrocompostos/química , Nitrocompostos/farmacologia , Conformação de Ácido Nucleico , Piperazinas/química , Piperazinas/farmacologia , Purinas/síntese química , Purinas/química , Purinas/farmacologia , Ribonucleosídeos/química , Ribonucleosídeos/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Células Vero/citologia , Células Vero/efeitos dos fármacos , Células Vero/virologia , Vírus/efeitos dos fármacosRESUMO
The synthesis of hypoxanthine, 2-chlorohypoxanthine, and 2-methylhypoxanthine arabinoside by an enzymatic transarabinosylation and their chemical conversion to biologically interesting purine arabinosides are described. Some of the synthesized compounds were tested for the inhibition of DNA synthesis in cultured tumor cells.