RESUMEN
Filoviruses are emerging pathogens and causative agents of viral haemorrhagic fever. Case fatality rates of filovirus disease outbreaks are among the highest reported for any human pathogen, exceeding 90% (ref. 1). Licensed therapeutic or vaccine products are not available to treat filovirus diseases. Candidate therapeutics previously shown to be efficacious in non-human primate disease models are based on virus-specific designs and have limited broad-spectrum antiviral potential. Here we show that BCX4430, a novel synthetic adenosine analogue, inhibits infection of distinct filoviruses in human cells. Biochemical, reporter-based and primer-extension assays indicate that BCX4430 inhibits viral RNA polymerase function, acting as a non-obligate RNA chain terminator. Post-exposure intramuscular administration of BCX4430 protects against Ebola virus and Marburg virus disease in rodent models. Most importantly, BCX4430 completely protects cynomolgus macaques from Marburg virus infection when administered as late as 48 hours after infection. In addition, BCX4430 exhibits broad-spectrum antiviral activity against numerous viruses, including bunyaviruses, arenaviruses, paramyxoviruses, coronaviruses and flaviviruses. This is the first report, to our knowledge, of non-human primate protection from filovirus disease by a synthetic drug-like small molecule. We provide additional pharmacological characterizations supporting the potential development of BCX4430 as a countermeasure against human filovirus diseases and other viral diseases representing major public health threats.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/farmacología , Infecciones por Filoviridae/prevención & control , Infecciones por Filoviridae/virología , Filoviridae/efectos de los fármacos , Nucleósidos de Purina/farmacología , Adenina/análogos & derivados , Administración Oral , Animales , Antivirales/administración & dosificación , Antivirales/química , Antivirales/farmacocinética , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , ARN Polimerasas Dirigidas por ADN/metabolismo , Modelos Animales de Enfermedad , Ebolavirus/efectos de los fármacos , Filoviridae/enzimología , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/virología , Humanos , Inyecciones Intramusculares , Macaca fascicularis/virología , Enfermedad del Virus de Marburg/prevención & control , Enfermedad del Virus de Marburg/virología , Marburgvirus/efectos de los fármacos , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacocinética , Pirrolidinas , ARN/biosíntesis , Factores de TiempoRESUMEN
Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.
Asunto(s)
Linfoma de Células T Periférico/tratamiento farmacológico , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Administración Oral , Adulto , Anciano , Femenino , Humanos , Linfoma de Células T Periférico/sangre , Masculino , Persona de Mediana Edad , Nucleósidos de Purina/efectos adversos , Pirimidinonas/efectos adversos , RecurrenciaRESUMEN
New nucleoside derivatives with nitrogen substitution at the C-6 position were prepared and screened initially for their in vitro anticancer bioactivity against human epithelial cancer cells (liver Huh7, colon HCT116, breast MCF7) by the NCI-sulforhodamine B assay. N6-(4-trifluoromethylphenyl)piperazine analog (27) exhibited promising cytotoxic activity. The compound 27 was more cytotoxic (IC50â¯=â¯1-4⯵M) than 5-FU, fludarabine on Huh7, HCT116 and MCF7 cell lines. The most potent nucleosides (11, 13, 16, 18, 19, 21, 27, 28) were further screened for their cytotoxicity in hepatocellular cancer cell lines. The compound 27 demonstrated the highest cytotoxic activity against Huh7, Mahlavu and FOCUS cells (IC50â¯=â¯1, 3 and 1⯵M respectively). Physicochemical properties, drug-likeness, and drug score profiles of the molecules showed that they are estimated to be orally bioavailable. The results pointed that the novel derivatives would be potential drug candidates.
Asunto(s)
Antineoplásicos/farmacología , Nucleósidos de Purina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Cladribina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/farmacología , Humanos , Estructura Molecular , Nucleósidos de Purina/síntesis química , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacocinética , Vidarabina/análogos & derivados , Vidarabina/farmacologíaRESUMEN
BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ngâ¢h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.
Asunto(s)
Linfoma de Células T/tratamiento farmacológico , Células T Asesinas Naturales/patología , Nucleósidos de Purina/uso terapéutico , Pirimidinonas/uso terapéutico , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos/efectos de los fármacos , Exantema/inducido químicamente , Femenino , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Linfoma de Células T Periférico/tratamiento farmacológico , Linfopenia/inducido químicamente , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Micosis Fungoide/tratamiento farmacológico , Nucleósidos de Purina/efectos adversos , Nucleósidos de Purina/farmacocinética , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Recurrencia , Neoplasias Cutáneas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Forodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 x 10(9)/L and median serum beta2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300 nM and did not reach desired 2 microM level. PNP inhibition ranged from 57% to 89% and steady-state 2'-deoxyguanosine (dGuo) concentration median was 1.8 microM. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6 microM to 10 microM. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 microM dGuo and forodesine (2 microM) resulted in accumulation of higher levels of dGTP (40-250 microM) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population.
Asunto(s)
Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/farmacocinética , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Vidarabina/análogos & derivados , Administración Oral , Anciano , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Esquema de Medicación , Quimioterapia Combinada , Inhibidores Enzimáticos/sangre , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Recuento de Linfocitos , Linfocitos/citología , Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Monoéster Fosfórico Hidrolasas/metabolismo , Nucleósidos de Purina/sangre , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Purina-Nucleósido Fosforilasa/metabolismo , Pirimidinonas/sangre , Índice de Severidad de la Enfermedad , Vidarabina/administración & dosificaciónRESUMEN
A series of 2'-C-methyl branched purine and pyrimidine C-nucleosides were prepared. Their anti-HCV activity and pharmacological properties were profiled, and compared with known 2'-C-Me N-nucleoside counterparts. In particular, 2'-C-Me 4-aza-7,9-dideazaadenosine C-nucleoside (2) was found to have potent and selective anti-HCV activity in vitro as well as a favorable pharmacokinetic profile and in vivo potential for enhanced potency over the corresponding N-nucleoside.
Asunto(s)
Antivirales/síntesis química , Compuestos Aza/síntesis química , Hepacivirus/efectos de los fármacos , Nucleósidos de Purina/síntesis química , Nucleósidos de Pirimidina/síntesis química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Proteínas no Estructurales Virales/antagonistas & inhibidores , Administración Oral , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Línea Celular , Cricetinae , Perros , Hepacivirus/enzimología , Hepacivirus/crecimiento & desarrollo , Hepatocitos/efectos de los fármacos , Hepatocitos/virología , Humanos , Inyecciones Intravenosas , Cultivo Primario de Células , Nucleósidos de Purina/farmacocinética , Nucleósidos de Purina/farmacología , Nucleósidos de Pirimidina/farmacocinética , Nucleósidos de Pirimidina/farmacología , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Proteínas no Estructurales Virales/metabolismoRESUMEN
Amdoxovir (AMDX) inhibits HIV-1 containing the M184V/I mutation and is rapidly absorbed and deaminated to its active metabolite, beta-D-dioxolane guanosine (DXG). DXG is synergistic with zidovudine (ZDV) in HIV-1-infected primary human lymphocytes. A recent in silico pharmacokinetic (PK)/enzyme kinetic study suggested that ZDV at 200 mg twice a day (b.i.d.) may reduce toxicity without compromising efficacy relative to the standard 300-mg b.i.d. dose. Therefore, an intense PK clinical study was conducted using AMDX/placebo, with or without ZDV, in 24 subjects randomized to receive oral AMDX at 500 mg b.i.d., AMDX at 500 mg plus ZDV at 200 or 300 mg b.i.d., or ZDV at 200 or 300 mg b.i.d. for 10 days. Full plasma PK profiles were collected on days 1 and 10, and complete urine sampling was performed on day 9. Plasma and urine concentrations of AMDX, DXG, ZDV, and ZDV-5'-O-glucuronide (GZDV) were measured using a validated liquid chromatography-tandem mass spectrometry method. Data were analyzed using noncompartmental methods, and multiple comparisons were performed on the log-transformed parameters, at steady state. Coadministration of AMDX with ZDV did not significantly change either of the plasma PK parameters or percent recovery in the urine of AMDX, DXG, or ZDV/GZDV. Larger studies with AMDX/ZDV, with a longer duration, are warranted.
Asunto(s)
Fármacos Anti-VIH/farmacocinética , Dioxolanos/farmacocinética , Interacciones Farmacológicas , Infecciones por VIH/tratamiento farmacológico , Nucleósidos de Purina/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Zidovudina/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Dioxolanos/administración & dosificación , Esquema de Medicación , Femenino , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Nucleósidos de Purina/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Resultado del Tratamiento , Adulto Joven , Zidovudina/administración & dosificaciónRESUMEN
A sensitive and specific liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method has been developed and validated for the quantification of metacavir in rat plasma using tinidazole as an internal standard (I.S.). Following ethyl acetate extraction, the analytes were separated on a Shim-pack ODS (4.6 microm, 150 mm x 2.0 mm I.D.) column and analyzed in selected ion monitoring (SIM) mode with a positive ESI interface using the respective [M+H](+) ions, 266 for metacavir and 248 for tinidazole. The method was validated over the concentration range of 1-600 ng/mL for metacavir. Between and within-batch precisions (R.S.D.%) were all within 15% and accuracy (%) ranged from 92.2 to 105.8%. The lower limit of quantification (LLOQ) was 1 ng/mL. The extraction recovery was on average 89.8%. The validated method was used for the pharmacokinetic study of metacavir in rats.
Asunto(s)
Antivirales/sangre , Cromatografía Liquida/métodos , Nucleósidos de Purina/sangre , Espectrometría de Masa por Ionización de Electrospray/métodos , Animales , Antivirales/farmacocinética , Estabilidad de Medicamentos , Nucleósidos de Purina/farmacocinética , Ratas , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The search for more effective and safer anti-leukemia therapies has led to the identification of several new agents that show activity against specific types of acute lymphoblastic leukemia (ALL). Recently, three novel purine nucleoside analogues (nelarabine, clofarabine, and forodesine) have shown promising activity in patients with relapsed or refractory ALL. Of these, nelarabine has shown clinically meaningful benefit in patients with T-cell ALL, with overall response rates ranging from 33% to 60%, the induction of durable complete remissions, and an overall 1-year survival rate of 28% in adults. Clofarabine has also shown promising clinical activity in pediatric patients, with an overall response rate of 30%, and some patients are able to proceed to allogeneic hematopoietic cell transplantation. Forodesine is the most recent novel agent, with a unique mechanism that has shown single-agent activity in relapsed and refractory T- and B-cell leukemias and cutaneous lymphomas. Although clinical experience is limited, treatment-related toxicities appear to be mild. The rationale, pharmacology, and clinical experience to date with these agents in the treatment of patients with refractory acute leukemia are reviewed, with a highlight on ALL.
Asunto(s)
Nucleótidos de Adenina/farmacología , Antineoplásicos/farmacología , Arabinonucleósidos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Nucleósidos de Purina/farmacología , Purina-Nucleósido Fosforilasa/efectos de los fármacos , Pirimidinonas/farmacología , Nucleótidos de Adenina/farmacocinética , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Arabinonucleósidos/farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Clofarabina , Humanos , Nucleósidos de Purina/farmacocinética , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirimidinonas/farmacocinéticaRESUMEN
Purine nucleoside phosphorylase (PNP) was recognized more than 30 years ago as a potential target for the treatment of patients with T-cell malignancies when an inherited deficiency of PNP was reported to be associated with a profound T-cell lymphopenia. The biochemical basis for this T-cell deficiency was subsequently shown to be related to the accumulation of plasma 2'-deoxyguanosine (dGuo) and intracellular dGuo triphosphate (dGTP). These observations have led to a search for PNP inhibitors that would be useful clinically in the management of T cell-derived malignancies. The most potent inhibitor of PNP described to date is forodesine, a rationally designed, transition-state analogue inhibitor. The preclinical and clinical pharmacology of forodesine showed its effectiveness in inhibiting PNP and augmenting dGuo levels in plasma. Increased dGTP concentrations in leukemia cells of different lineages provides strong support for the potential use of this agent in the treatment of patients with hematologic malignancies of both T- and B-cell origin.
Asunto(s)
Nucleósidos de Purina/farmacología , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirimidinonas/farmacología , Linfocitos T/efectos de los fármacos , Vías Biosintéticas/efectos de los fármacos , Ensayos Clínicos como Asunto , Nucleótidos de Desoxiguanina/metabolismo , Desoxiguanosina/metabolismo , Humanos , Leucemia de Células T/tratamiento farmacológico , Nucleósidos de Purina/farmacocinética , Purina-Nucleósido Fosforilasa/efectos de los fármacos , Pirimidinonas/farmacocinéticaRESUMEN
Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine. Forodesine (BCX-1777, Immucillin H, 1-(9-deazahypoxanthin)-1,4-dideoxy-1,4-imino-D-ribitol) has carbon-carbon linkage between a cyclic amine moiety that replaces ribose and 9-deaza-hypixanthine. The drug is a novel T-cell selective immunosuppressive agent which in the presence of 2'-deoxyguanosine (dGuo) inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2), mixed lymphocyte reaction and phytohemagglutinin. In the mechanism of forodesine action two enzymes are involved: PNP and deoxycytidine kinase (dCK). PNP catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-1-phosphate, whereas dCK converts dGuo to deoxyguanosino-5'-monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP by high dCK activity, which leads to inhibition of ribonucleotide reductase (RR), an enzyme required for DNA synthesis and cell replication, which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders and it is undergoing phase II clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, which includes cutaneous T-cell lymphoma (CTCL). Moreover, recent preclinical and clinical data showed activity of forodesine in B-cell acute lympholastic leukemia (ALL).
Asunto(s)
Inhibidores Enzimáticos/farmacología , Nucleósidos de Purina/farmacología , Purina-Nucleósido Fosforilasa/antagonistas & inhibidores , Pirimidinonas/farmacología , Animales , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Humanos , Nucleósidos de Purina/farmacocinética , Nucleósidos de Purina/uso terapéutico , Pirimidinonas/farmacocinética , Pirimidinonas/uso terapéuticoRESUMEN
BMS-068645 is a selective adenosine 2A agonist that contains a methyl ester group which undergoes esterase hydrolysis to its acid metabolite. To permit accurate determinations of circulating BMS-068645 and its acid metabolite, blood samples must be rapidly stabilized at the time of collection. A sensitive, rapid and specific liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of BMS-068645 and its acid metabolite in human plasma has been developed and validated using diisopropyl fluorophosphate (DFP) as the esterase inhibitor to prevent BMS-068645 from converting to its acid metabolite. The D(5)-stable isotope labeled analogs of BMS-068645 and its metabolite were used as the internal standards (IS). Analytes and IS in plasma containing 20 mM DFP were acidified and extracted into methyl tert-butyl ether. The liquid-liquid extraction effectively eliminated the strong matrix effect caused by the esterase inhibitor. The chromatographic separation was achieved on a Waters Atlantis C18 column with a run time of 4 min. Detection was performed on a Sciex API 4000 with positive ion electrospray mode (ESI/MS/MS), monitoring the ion transitions m/z 487>314 and 473>300 for BMS-068645 and its acid metabolite, respectively. The method was validated over the range from 0.020 to 10.0 ng/mL for BMS-068645 and 0.050 to 10.0 ng/mL for its acid metabolite. Inter- and intra-run precision for the quality control samples during validation were less than 8.7% and 4.0%, respectively, for the two analytes. The assay accuracy was within +/-5.4% of the nominal values. The esterase inhibitor effectively stabilized BMS-068645 during blood collection and storage. Blood collection tubes containing DFP were easily prepared and used at the clinical sites and could be stored at -30 degrees C for 3 months. This method demonstrated adequate sensitivity, specificity, accuracy, precision, stability and ruggedness to support the analysis of human plasma samples in pharmacokinetic studies.
Asunto(s)
Alquinos/sangre , Cromatografía Liquida/métodos , Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Isoflurofato/química , Nucleósidos de Purina/sangre , Agonistas del Receptor Purinérgico P1 , Espectrometría de Masas en Tándem/métodos , Alquinos/farmacocinética , Calibración , Ésteres , Humanos , Nucleósidos de Purina/farmacocinética , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
More recently, three novel purine nucleoside analogs, including clofarabine, nelarabine and immucillin H, have been introduced into clinical trials. These agents have different metabolic properties, novel mechanism of action, and are undergoing phase I-II clinical studies for the treatment of hematopoietic malignancies. Pharmacology and anticancer activity of PNA are the subjects of this review.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Nucleósidos de Purina/farmacología , Nucleósidos de Purina/uso terapéutico , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Humanos , Nucleósidos de Purina/farmacocinéticaRESUMEN
The purine nucleoside analogues (PNAs), fludarabine (FA), 2-CdA (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) represent a group of cytotoxic agents with high activity in lymphoid and myeloid malignancies. PNAs share similar chemical structure and mechanism of action. Several mechanisms could be responsible for their cytotoxicity both in proliferating and quiescent cells, such as inhibition of DNA synthesis, inhibition of DNA repair and accumulation of DNA strand breaks. Induction of apoptosis through the mitochondrial pathway, direct binding to apoptosome or modulation of p53 expression all lead to apoptosis, which is the main end-point of PNA action. However, individual PNAs exhibit significant differences, especially in their interaction with enzymes involved in adenosine and deoxyadenosine metabolism. Synergistic interactions between PNAs and other cytotoxic agents (alkylating agents, anthracycline antitumor antibiotics, cytarabine, monoclonal antibodies) have been demonstrated in both preclinical and clinical studies. PNAs are highly effective in chronic lymphoid leukemias and low grade B- and T-cell non-Hodgkin's lymphomas, including Waldenström's macroglobulinemia. DCF and 2-CdA are currently the drugs of choice in hairy cell leukemia. Moreover, clinical studies have confirmed the efficacy of PNAs alone or in combination protocols in the treatment of acute myeloid leukemia and myelodysplastic syndromes. Finally, PNAs, especially FA, play an important role in non-myeloablative conditioning regimens for allogenic stem cell transplantation in high-risk patients. The toxicity profiles of PNAs are similar for all agents and consist mainly of dose-limiting myelotoxicity and prolonged immunosuppression. Three other compounds: clofarabine, nelarabine and immucillin-H are currently being evaluated clinically.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Hematológicas/tratamiento farmacológico , Nucleósidos de Purina/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Humanos , Nucleósidos de Purina/efectos adversos , Nucleósidos de Purina/farmacocinética , Nucleósidos de Purina/farmacologíaRESUMEN
Spicamycin (SPM), produced by Streptomyces alanosinicus, induces potent differentiation in a human leukemia cell line, HL60. One of the derivatives of SPM (SPM-D), KRN5500, has a wide range of antitumor activity against human cancer cell lines. We examined the cytotoxicity of SPM-D in small and non-small cell lung cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony assays. SPM-D was active against a wide range of lung cancer cell lines. All three cisplatin (CDDP)-resistant cell lines established in our laboratory (PC-9/CDDP, PC-14/CDDP, and H69/CDDP) showed collateral sensitivity to SPM-D with relative resistance values of 0.43, 0.34, and 0.32, respectively. Intracellular SPM-D in PC-14/CDDP was 35% higher than that for PC-14 suggesting that intracellular accumulation can explain the collateral sensitivity to SPM-D at least in PC-14/CDDP. On the other hand, in PC-9/CDDP cells, no increase of intracellular SPM-D accumulation was observed, but the conversion ratio of a metabolite (the amino nucleoside moiety of spicamycin binding with glycine, SAN-G) from SPM-D evaluated by TLC was higher as compared with that of parental PC-9 cells (45.5% versus 37%; PC-9/CDDP versus PC-9). The increased intracellular metabolism of SPM-D could explain the mechanism of collateral sensitivity in PC-9/CDDP cisplatin-resistant cell lines. To elucidate the determinant of the SPM-D-induced cytotoxicity, we established SPM-D-resistant cell lines, PC-9/SPM-D, PC-14/SPM-D, and H69/SPM-D, by exposing cells to stepwise increases in SPM-D concentration. The relative resistances of these sublines were more than 5000, 46.6, and 37.8 times those of the parental cell lines, respectively. The intracellular concentration of the active metabolite, SAN-G, was found to be decreased in the SPM-D-resistant sublines. This result indicates that the intracellular metabolism of SPM-D to SAN-G is one of the determinants of cellular sensitivity to SPM-D in these SPM-D-resistant cell lines. In conclusion, both drug accumulation and metabolism may contribute to the sensitivity/resistance to SPM-D and both may merit investigation.
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Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/toxicidad , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/metabolismo , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Carcinoma de Células Pequeñas/metabolismo , División Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cisplatino/farmacología , Digitonina/farmacología , Resistencia a Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Líquido Intracelular/metabolismo , Neoplasias Pulmonares/metabolismo , Nucleósidos de Purina/metabolismo , Nucleósidos de Purina/farmacocinética , Nucleósidos de Purina/toxicidad , Células Tumorales Cultivadas/químicaRESUMEN
The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.
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Amidas/farmacocinética , Antivirales/farmacocinética , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , Nucleósidos de Purina/farmacocinética , Pirazinas/farmacocinética , Adenina/análogos & derivados , Adenosina/análogos & derivados , Amidas/farmacología , Amidas/uso terapéutico , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Brotes de Enfermedades/prevención & control , Ebolavirus/efectos de los fármacos , Voluntarios Sanos , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Modelos Animales , Nucleósidos de Purina/farmacología , Nucleósidos de Purina/uso terapéutico , Pirazinas/farmacología , Pirazinas/uso terapéutico , PirrolidinasRESUMEN
PURPOSE: The spicamycin analogue KRN5500 is a nucleoside-like antibiotic with broad spectrum activity against human solid tumor models. It appears to possess a novel mechanism of action directed against the endoplasmic reticulum and Golgi apparatus with effects on protein processing. A Phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities, and pharmacokinetic behavior of KRN5500 given as a 1-h i.v. infusion for 5 consecutive days every 3 weeks. EXPERIMENTAL DESIGN: Adult patients with refractory solid tumors, good performance status, and normal to near normal renal, hepatic, and hematological function were eligible for the study. At least three patients were evaluated at each dose level, and a modified Fibonacci algorithm was used for dose escalation. The MTD was based on the occurrence of severe toxicity during the first cycle of therapy. The plasma pharmacokinetics of KRN5500 was characterized during the first week of dosing. RESULTS: Characteristics of the 26 patients entered into the study were as follows: 13 males and 13 females; median age, 54.5 years (range, 40-70 years); and Eastern Cooperative Oncology Group performance status 0-1. A majority had refractory colorectal carcinoma (17 of 26 patients) with at least two prior regimens of therapy. The dose of KRN5500 was escalated from 0.8 to 4.9 mg/m(2)/day in five dose levels, and the MTD was 2.9 mg/m(2)/day. All dose-limiting toxicities were nonhematological and included pulmonary toxicities, hyperglycemia, fatigue, hepatotoxicity, and ataxia, with one fatality due to interstitial pneumonitis. Clinically significant toxicities occurring in multiple patients that were not dose-limiting included nausea/vomiting, diarrhea, fatigue, neurological symptoms, hyperbilirubinemia, hyperglycemia, lymphopenia, and thrombocytopenia. There were no objective responses, although 3 of 17 evaluable patients exhibited disease stabilization for 5-6 cycles. The pharmacokinetics for the first dose of KRN5500 was biexponential and linear across all five dose levels. Mean values of pharmacokinetic parameters were as follows: total plasma clearance, 6.15 +/- 2.37 liters/h/m(2); apparent volume of distribution at steady state, 6.56 +/- 1.98 liters/m(2); biological half-life, 1.29 +/- 0.37 h; and mean residence time, 1.07 +/- 0.31 h. Clearance was significantly lower (P = 0.011) in the eight patients who were at least 65 years old (4.6 +/- 1.6 liters/h/m(2)) as compared with the 18 younger patients (7.1 +/- 2.3 liters/h/m(2)). Peak plasma concentrations of KRN5500 in the cohort receiving the MTD ranged from 350 to 400 ng/ml. CONCLUSIONS: The MTD of KRN5500, when given as a 1-h i.v. infusion for 5 consecutive days, was 2.9 mg/m(2)/day. The only suggestion of therapeutic activity observed in this study was disease stabilization in three patients with chemorefractory colorectal cancer. Administering KRN5500 as a continuous i.v. infusion with the objective of prolonging systemic exposure to potentially cytotoxic concentrations of the drug should be considered.
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Antineoplásicos/farmacocinética , Recurrencia Local de Neoplasia/metabolismo , Neoplasias/metabolismo , Nucleósidos de Purina/farmacocinética , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Área Bajo la Curva , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias/tratamiento farmacológico , Nucleósidos de Purina/administración & dosificación , Nucleósidos de Purina/toxicidad , Terapia RecuperativaRESUMEN
In order to enhance the brain delivery of 2'-F-ara-ddI,2'-F-ara-ddP 6 was synthesized and its in vitro and in vivo bioconversion reaction studied. For the study, a new efficient synthetic method for 2'-F-ara-ddP 6 was developed from 5-benzoyl-1,2-O-isopropylidene-3-deoxyribose 1. For in vitro study 2'-F-ara-ddP was incubated in pH 2, mouse liver homogenate, and mouse serum at 37 degrees C. No degradation was observed in pH 2 and serum, while in liver homogenate 2'-F-ara-ddP was almost completely converted to 2'-F-ara-ddI within 20 min (t1/2 = 3.54 min). In order to determine the role of xanthine oxidase in the conversion of 2'-F-ara-ddP to 2'-F-ara-ddI, in vitro studies were conducted in phosphate buffer (pH 7.4) in the presence or absence of allopurinol, in which the half-lives of 2'-F-ara-ddP were 7.4 and 3.4 h, respectively, indicating the conversions were catalyzed by the xanthine oxidase. A similar experiment with aldehyde oxidase isolated from the human liver did not affect the biotransformation. The biotransformation was also detected in the brain homogenate, although the rate of conversion was low and incomplete. In order to assess the bioconversion in vivo, pharmacokinetic studies of 2'-F-ara-ddP and 2'-F-ara-ddI were conducted in mice. The maximum serum concentrations of 2'-F-ara-ddI administered itself and as 2'-F-ara-ddP reached 48.1 +/- 10.00 and 89.3 +/- 26.0 microM and were observed in 1 and 0.25 h, respectively. The data indicate that 2'-F-ara-ddI is absorbed at a slower rate than that of 2'-F-raa-ddP. The bioavailability of the prodrug after oral administration was 60.7%. The concentration of 2'-F-ara-ddI following oral administration of 2'-ara-ddI was close to the detection limits while 2'-F-ara-ddI was detected at significantly higher concentrations in the brain after oral administration of 2'-F-ara-ddP. From this study, we have administered the enhanced brain delivery of anti-HIV nucleoside utilizing an in vivo biotransformation system.
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Antivirales/síntesis química , Arabinonucleósidos/síntesis química , Encéfalo/metabolismo , Didanosina/análogos & derivados , Profármacos/síntesis química , Nucleósidos de Purina/síntesis química , Xantina Oxidasa/fisiología , Administración Oral , Animales , Antivirales/química , Antivirales/farmacocinética , Arabinonucleósidos/metabolismo , Arabinonucleósidos/farmacocinética , Biotransformación , Encéfalo/enzimología , Didanosina/síntesis química , Didanosina/química , Didanosina/farmacocinética , Femenino , Humanos , Hígado/metabolismo , Ratones , Profármacos/metabolismo , Profármacos/farmacocinética , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacocinéticaRESUMEN
(-)-beta-D-Dioxolane guanine (DXG) is a nucleoside analog possessing potent activity against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), and hepatitis B virus (HBV) in vitro. Owing to the limited aqueous solubility of DXG, (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), a more water-soluble prodrug of DXG, is being developed for clinical use. The purpose of this study was to characterize the pharmacokinetics of DXG after administration of DXG and DAPD to rats and monkeys. After intravenous administration of DXG, plasma concentrations of the nucleoside declined in a biexponential manner, with a terminal-phase half-life of 0.44 +/- 0.14 hr (mean +/- SD) in rats and 2.3 hr in monkeys. Total clearance of DXG was 4.28 +/- 0.99 liters/hr/kg in rats and 0.72 liters/hr/kg in monkeys. Renal excretion of unchanged DXG accounted for approximately 50% of total clearance in both species. Steady state volume of distribution of DXG was 2.30 liters/kg in rats and 1.19 liters/kg in monkeys. After intravenous administration of DAPD to rats, prodrug concentrations declined with a half-life of 0.37 +/- 0.11 hr. DXG was rapidly generated from DAPD, with approximately 61% of the dose of DAPD being converted to DXG. After administration of DAPD to monkeys, only concentrations of metabolite DXG could be determined owing to rapid conversion of DAPD to DXG during sample collection. The half-lives of DAPD and DXG after intravenous administration determined from urinary excretion data were 0.8 +/- 0.4 and 1.6 +/- 0.2 hr, respectively. Oral bioavailability of DAPD was estimated to be approximately 30%.
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Fármacos Anti-VIH/farmacocinética , Dioxolanos/farmacocinética , Guanosina/análogos & derivados , Macaca mulatta/metabolismo , Profármacos/farmacocinética , Nucleósidos de Purina/farmacocinética , Ratas/metabolismo , Administración Oral , Animales , Antivirales/farmacocinética , Disponibilidad Biológica , Biotransformación , Dioxolanos/sangre , Dioxolanos/orina , Guanosina/sangre , Guanosina/farmacocinética , Guanosina/orina , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Estructura Molecular , Nucleósidos de Purina/sangre , Nucleósidos de Purina/orina , Ratas Sprague-Dawley , Especificidad de la Especie , Distribución TisularRESUMEN
PURPOSE: KRN5500, a novel spicamycin derivative, shows the greatest activity against a human tumor xenograft model and the highest therapeutic index among spicamycin derivatives. KRN5500 is currently under clinical development in Japan and the United States. The objective of this study was to develop a population pharmacokinetic model that describes the KRN5500 plasma concentration versus time data. METHODS: Data were collected from 18 patients entered in a phase 1 study. These patients received KRN5500 3-21 mg/m2 as a 2-h infusion. A total of 219 concentration measurements were available. The data were analyzed using the nonlinear mixed effect model (NONMEM) program. In addition, the basic and final population pharmacokinetic models were evaluated using bootstrapping resampling. RESULTS: The basic model selected was a two-compartment model with a combination of additive and constant coefficient of variation error models. The basic model fitted well not only the original data, but also 100 bootstrap replicates generated from the original data set. With regard to the effect of covariates selected by generalized additive modeling analysis, gender (SEX) and performance status were found to be possible determinants of the volume of central compartment by NONMEM analysis. The final regression model for V1 was V1 = theta V1 (1--SEX x theta SEX), where V1 is the typical population value of the volume of central compartment, and SEX = 0 if the patient is male, otherwise SEX = 1. The final model was fitted to the 200 bootstrapped samples. The mean parameter estimates were within 15% of those obtained with the original data set. CONCLUSIONS: The KRN5500 plasma concentration versus time data obtained from the phase 1 study were well described by the population pharmacokinetic model. Further evaluation by bootstrapping showed that the population pharmacokinetic model was stable.