RESUMEN
BACKGROUND: Considering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants. RESEARCH DESIGN AND METHODS: Part 1 involved 60 participants, receiving 50-800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states. RESULTS: ASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (Tmax: 1.00-2.00 h) and decreased (t1/2: 1.10-3.04 h) without accumulation. The Cmax and area under the plasma concentration - time curve (AUC) of ASC10-A increased dose-dependently (50-800 mg BID) over 5.5 days, with no accumulation. The Tmax was slightly delayed in the fed state; however, the Cmax and AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%). CONCLUSION: ASC10 was demonstrated to be safe and well tolerated and exhibited dose-proportional exposure and minimal food effects. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier is NCT05523141.
Asunto(s)
Antivirales , Profármacos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Administración Oral , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/farmacocinética , Área Bajo la Curva , Pueblo Asiatico , China , COVID-19 , Tratamiento Farmacológico de COVID-19 , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/análogos & derivados , Citidina/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Profármacos/efectos adversos , Profármacos/administración & dosificaciónRESUMEN
OBJECTIVE: This proof-of-principle pharmacovigilance study used Electronic Health Record (EHR) data to examine the safety of sotrovimab, paxlovid and molnupiravir in prehospital treatment of Covid-19. METHOD: With NHS England approval, we conducted an observational cohort study using OpenSAFELY-TPP, a secure software-platform which executes analyses across EHRs for 24 million people in England. High-risk individuals with Covid-19 eligible for prehospital treatment were included. Adverse events (AEs) were categorised into events in the drug's Summary of Product Characteristics (SmPC), drug-reactions and immune-mediated. Cox models compared risk across treatments. A pre-pandemic record analysis was performed for comparative purposes. RESULTS: Between 2021-2023, 37,449 patients received sotrovimab, paxlovid or molnupiravir whilst 109,647 patients made up an eligible-but-untreated population. The 28-day rates of AEs were low: SmPC 0.34 per 1000 patient-years (95% CI 0.32-0.36); drug-reactions 0.01 (95% CI 0.01-0.02) and immune-mediated 0.03 (95% CI 0.03-0.04), and similar or lower than the pre-pandemic period. Compared with the eligible but untreated population, sotrovimab and paxlovid associated with a risk of SmPC AE [adjHR 1.36 (95% CI 1.15-1.62) and 1.28 (95% CI 1.05-1.55), respectively], whilst sotrovimab associated with a risk of drug-reactions [adjHR 2.95 (95% CI 1.56-5.55)] and immune-mediated events [adjHR 3.22 (95% CI 1.86-5.57)]. CONCLUSION: Sotrovimab, paxlovid and molnupiravir demonstrate acceptable safety profiles. Although the risk of AEs was greatest with sotrovimab, event rates were lower than comparative pre-pandemic period.
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Antivirales , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Humanos , Antivirales/uso terapéutico , Antivirales/efectos adversos , Masculino , Femenino , Persona de Mediana Edad , Anciano , SARS-CoV-2/inmunología , Adulto , COVID-19/epidemiología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Neutralizantes/sangre , Inglaterra/epidemiología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Estudios de Cohortes , Anciano de 80 o más Años , Citidina/análogos & derivados , Citidina/uso terapéutico , Citidina/efectos adversos , Adulto Joven , HidroxilaminasRESUMEN
OBJECTIVES: Evaluate and compare the efficacy and safety of molnupiravir and favipiravir in outpatients with mild to moderate COVID-19 and at risk of severe COVID-19. METHODS: In an open-label, parallel-group, multicenter trial in Thailand, participants with moderate COVID-19 and at least one factor associated with severe COVID-19 were randomly assigned 1:1 to receive oral molnupiravir or oral favipiravir (standard of care). Phone calls for remote symptom assessment were made on Days 6, 15, and 29. Participants with worsening symptoms were instructed to return to the hospital. The primary endpoint was pulmonary involvement by Day 29, as evidenced by ≥2 of the following: dyspnea, oxygen saturation <92% or imaging. RESULTS: Nine hundred seventy-seven participants (487 molnupiravir, 490 favipiravir) were enrolled from 8 July 2022 to 19 January 2023. 98% had received ≥1 dose of COVID-19 vaccine and 83% ≥3 doses. By Day 29, pulmonary involvement occurred in 0% (0/483) in molnupiravir arm versus 1% (5/482) in favipiravir arm (-1.0%; Newcombe 95.2% CI: -2.4% to -0.0%; P = 0.021); all-cause death in 0% (0/483) and <1% (1/482); COVID-19 related hospitalization in <1% (1/483) and 1% (3/482); treatment-related adverse event in 1% (5/483) and 1% (4/486); and serious adverse event in 1% (4/483) and 1% (4/486). CONCLUSIONS: Favipiravir and molnupiravir had a similar efficacy and safety profile. Whether either of the two reduced the risk of complications during the omicron era in this population with a low risk of pulmonary involvement and a high vaccine coverage remains unclear. There were no differences in any of the safety endpoints. THAI CLINICAL TRIALS REGISTRY ID: TCTR20230111009.
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Amidas , Antivirales , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Pirazinas , SARS-CoV-2 , Humanos , Amidas/uso terapéutico , Masculino , Pirazinas/uso terapéutico , Pirazinas/efectos adversos , Pirazinas/administración & dosificación , Femenino , Tailandia , Antivirales/uso terapéutico , Antivirales/efectos adversos , Antivirales/administración & dosificación , Persona de Mediana Edad , Adulto , Citidina/uso terapéutico , Citidina/efectos adversos , Citidina/administración & dosificación , Hidroxilaminas/uso terapéutico , Hidroxilaminas/efectos adversos , Hidroxilaminas/administración & dosificación , Anciano , Resultado del Tratamiento , COVID-19 , Pacientes AmbulatoriosAsunto(s)
Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Hidroxilaminas/uso terapéutico , Antivirales/efectos adversos , COVID-19/diagnóstico , COVID-19/virología , Citidina/efectos adversos , Citidina/uso terapéutico , Aprobación de Drogas , Interacciones Farmacológicas , Humanos , Hidroxilaminas/efectos adversos , Resultado del Tratamiento , Estados Unidos , United States Food and Drug AdministrationRESUMEN
[Figure: see text].
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Antivirales/farmacología , Citidina/análogos & derivados , Hidroxilaminas/farmacología , Mutagénesis , Virus ARN/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/efectos adversos , Antivirales/uso terapéutico , COVID-19/virología , Citidina/efectos adversos , Citidina/metabolismo , Citidina/farmacología , Citidina/uso terapéutico , Citidina/toxicidad , ADN/biosíntesis , Evolución Molecular , Genoma Viral , Humanos , Hidroxilaminas/efectos adversos , Hidroxilaminas/metabolismo , Hidroxilaminas/uso terapéutico , Pruebas de Mutagenicidad , Fosforilación , Infecciones por Virus ARN/tratamiento farmacológico , Infecciones por Virus ARN/virología , Virus ARN/genética , ARN Viral/biosíntesis , ARN Viral/genética , Ribonucleósidos/metabolismo , SARS-CoV-2/genética , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND AND AIMS: Molnupiravir is a newer oral antiviral drug that has recently received emergency use authorization (EUA) in USA, UK and India. We aim to conduct an update on our previous systematic review to provide practical clinical guideline for using molnupiravir in patients with COVID-19. METHODS: We systematically searched the electronic database of PubMed, MedRxiv and Google Scholar until January 5, 2022, using key MeSH keywords. RESULTS: Final result of phase 3 study in 1433 non-hospitalized COVID-19 patients showed a significant reduction in composite risk of hospital admission or death (absolute risk difference, -3.0% [95% confidence interval {CI}, -5.9 to -0.1%]; 1-sided P = 0.02) although with a non-significant 31% relative risk reduction (RRR). RRR for death alone was 89% (95% CI, 14 to 99; P-value not reported). Number needed to treat to prevent 1 death or 1 hospitalization or death composite appears to be closely competitive to other agents having EUA in people with COVID-19. However, cost-wise molnupiravir is comparatively cheaper compared to all other agents. CONCLUSION: Molnupiravir could be a useful agent in non-pregnant unvaccinated adults with COVID-19 who are at increased risk of severity including hospitalization. However, it is effective only when used within 5-days of onset of symptoms. A 5-days course seems to be safe without any obvious short-term side effects.
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Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Hidroxilaminas/uso terapéutico , SARS-CoV-2 , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/uso terapéutico , Anciano , Alanina/análogos & derivados , Alanina/uso terapéutico , Animales , COVID-19/mortalidad , Vacunas contra la COVID-19 , Citidina/efectos adversos , Citidina/uso terapéutico , Método Doble Ciego , Aprobación de Drogas , Combinación de Medicamentos , Femenino , Hospitalización , Humanos , Hidroxilaminas/efectos adversos , Lactamas/uso terapéutico , Leucina/uso terapéutico , Masculino , Persona de Mediana Edad , Nitrilos/uso terapéutico , Prolina/uso terapéutico , Ritonavir/uso terapéutico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, ß-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.
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Antivirales/efectos adversos , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Daño del ADN/efectos de los fármacos , Hidroxilaminas/efectos adversos , Nucleósidos/efectos adversos , SARS-CoV-2/genética , Amidas/efectos adversos , Amidas/uso terapéutico , Antivirales/uso terapéutico , Citidina/efectos adversos , Citidina/uso terapéutico , Desoxiuridina/efectos adversos , Desoxiuridina/análogos & derivados , Desoxiuridina/uso terapéutico , Genoma Humano/efectos de los fármacos , Humanos , Hidroxilaminas/uso terapéutico , Mutagénesis/efectos de los fármacos , Nucleósidos/uso terapéutico , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Ribavirina/efectos adversos , Ribavirina/uso terapéutico , SARS-CoV-2/efectos de los fármacosRESUMEN
BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).
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Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Hidroxilaminas/uso terapéutico , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antivirales/efectos adversos , COVID-19/virología , Citidina/efectos adversos , Citidina/uso terapéutico , Método Doble Ciego , Femenino , Humanos , Hidroxilaminas/efectos adversos , Masculino , Persona de Mediana Edad , SARS-CoV-2/aislamiento & purificación , Resultado del Tratamiento , Carga Viral , Adulto JovenAsunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Citidina/análogos & derivados , Hidroxilaminas/uso terapéutico , SARS-CoV-2/genética , Adenosina Monofosfato/uso terapéutico , Administración Oral , Alanina/uso terapéutico , Antiinflamatorios/uso terapéutico , Antivirales/administración & dosificación , Antivirales/efectos adversos , COVID-19/prevención & control , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/uso terapéutico , Evolución Molecular , Hospitalización/estadística & datos numéricos , Humanos , Hidroxilaminas/administración & dosificación , Hidroxilaminas/efectos adversos , Mutagénesis/efectos de los fármacos , Medición de Riesgo , Tiempo de Tratamiento , Eficacia de las Vacunas , Carga Viral , Replicación Viral/efectos de los fármacosRESUMEN
Mutagenic ribonucleosides can act as broad-based antiviral agents. They are metabolized to the active ribonucleoside triphosphate form and concentrate in genomes of RNA viruses during viral replication. ß-d-N4-hydroxycytidine (NHC, initial metabolite of molnupiravir) is >100-fold more active than ribavirin or favipiravir against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with antiviral activity correlated to the level of mutagenesis in virion RNA. However, NHC also displays host mutational activity in an animal cell culture assay, consistent with RNA and DNA precursors sharing a common intermediate of a ribonucleoside diphosphate. These results indicate highly active mutagenic ribonucleosides may hold risk for the host.
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Antivirales/farmacología , Citidina/análogos & derivados , Mutágenos/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/efectos adversos , Células CHO/efectos de los fármacos , Células Cultivadas , Cricetulus , Citidina/efectos adversos , Citidina/farmacología , Relación Dosis-Respuesta a Droga , Mutagénesis/efectos de los fármacos , Mutágenos/efectos adversos , SARS-CoV-2/genética , Replicación Viral/efectos de los fármacosRESUMEN
The purpose of this study was to determine the plasma pharmacokinetics (PK) and toxicity of zebularine, an oral cytidine analog with demethylating activity, in dogs. Plasma zebularine concentrations were determined by HPLC-MS/MS following an oral zebularine dose of 8 or 4 mg kg-1 . Plasma zebularine clearance was constant. Mean maximum concentration (Cmax ) was 23 ± 4.8 and 8.6 ± 1.4 µM following 8 and 4 mg kg-1 , respectively. Mean half-life was 5.7 ± 0.84 and 7.1 ± 2.1 following 8 and 4 mg kg-1 , respectively. A single 8 mg kg-1 dose was well tolerated. Daily 4 mg kg-1 treatment in three laboratory dogs resulted in grade 4 neutropenia (n = 3), grade 1 anorexia (n = 2) and grade 1 or 2 dermatologic changes (n = 2). All adverse events resolved with supportive care. A 4 mg kg-1 dose every 21 days was well tolerated. A follow-up dose escalation study is in progress with a lower starting dose.
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Citidina/análogos & derivados , Enfermedades de los Perros/tratamiento farmacológico , Neoplasias/veterinaria , Administración Oral , Aldehído Oxidasa/metabolismo , Animales , Cromatografía Líquida de Alta Presión/veterinaria , Citidina/efectos adversos , Citidina/farmacocinética , Citosol , Metilación de ADN , Perros , Femenino , Semivida , Indiana , Hígado/metabolismo , Macrólidos , Masculino , Neoplasias/tratamiento farmacológico , Neutropenia/inducido químicamente , Neutropenia/veterinaria , Facultades de Medicina VeterinariaAsunto(s)
Antineoplásicos/efectos adversos , Citidina/efectos adversos , Antineoplásicos/uso terapéutico , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/uso terapéutico , Citarabina/efectos adversos , Citarabina/análogos & derivados , Citarabina/uso terapéutico , Citidina/uso terapéutico , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , GemcitabinaRESUMEN
BACKGROUND: TAS-106 was designed to inhibit RNA synthesis by blocking RNA polymerases I, II, and III. METHODS: This was a single-center, open-label, phase I study to identify the maximum tolerated dose (MTD), pharmacokinetics, and biologic effects of the combination of TAS-106 and carboplatin, following a standard 3 + 3 design. This phase I trial was comprised of a regimen of a 60-min IV infusion of carboplatin on day 1 of each 21-day cycle followed by a 24-h infusion of TAS-106, also on day 1 of each cycle. RESULTS: 39 patients were treated (21 male, 18 female, median age 62 years, range 21-80 years). Median number of prior therapies was 4. Maximum Tolerated Dose (MTD) was 3 mg/m(2) TAS-106 with AU 4 carboplatin. Dose-limiting toxicities were neutropenia and thrombocytopenia, with and without growth factor support. While no patients achieved a complete or partial response, four patients had stable disease lasting ≥4 months, including one patient each with ovarian, non-small cell lung, basal cell and colorectal cancer. CONCLUSIONS: In summary, the combination of TAS-106 and carboplatin was well-tolerated, and further studies in non-small cell lung and ovarian cancer are warranted to assess the efficacy of this drug combination.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Citidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/efectos adversos , Carboplatino/farmacocinética , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/farmacocinética , Citidina/uso terapéutico , Demografía , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/metabolismo , Neoplasias/patología , Sistema Nervioso/patología , Adulto JovenRESUMEN
TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m(2) over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0-99.0 days) and 48 days (95% CI 41.0-83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0-234.0 days) and 280 days (95% CI 107.0-462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Citidina/análogos & derivados , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Anciano , Carcinoma , Citidina/efectos adversos , Citidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de SupervivenciaRESUMEN
BACKGROUND: The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. PATIENTS AND METHODS: Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. RESULTS: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. CONCLUSION: Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
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Antineoplásicos/administración & dosificación , Citidina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.
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Antineoplásicos/administración & dosificación , Citidina/análogos & derivados , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Neoplasias/tratamiento farmacológico , ARN Polimerasa III/antagonistas & inhibidores , ARN Polimerasa II/antagonistas & inhibidores , ARN Polimerasa I/antagonistas & inhibidores , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Área Bajo la Curva , Biotransformación , Citidina/administración & dosificación , Citidina/efectos adversos , Citidina/farmacocinética , Esquema de Medicación , Inhibidores Enzimáticos/efectos adversos , Estudios de Factibilidad , Femenino , Semivida , Humanos , Infusiones Intravenosas , Estimación de Kaplan-Meier , Masculino , Dosis Máxima Tolerada , Tasa de Depuración Metabólica , Persona de Mediana Edad , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , ARN Polimerasa I/metabolismo , ARN Polimerasa II/metabolismo , ARN Polimerasa III/metabolismo , Texas , Resultado del TratamientoRESUMEN
Malignant tumors of childhood represent a rather heterogeneous group of neoplasms originating from virtually any anatomical structure. Despite major improvements in the clinical management including timely diagnosis, advanced supportive care and refined multimodality treatment, prognosis remains grim for certain risk groups. Aberrant epigenetic regulation, i.e. changes in gene transcription not due to DNA sequence alterations, is now increasingly recognized as a fundamental process in malignant transformation, tumor progression and drug resistance. The molecular mechanisms involve aberrant activity of enzymes controlling the packaging and transcriptional regulation of the genome. Two major protein families are involved in this process, DNA methyltransferases and histone deacetylases. With the availability of small molecule inhibitors targeting the aberrant epigenetic machinery in cancer cells, these compounds are evaluated in several clinical trials.
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Metilasas de Modificación del ADN/genética , Epigénesis Genética/genética , Neoplasias/genética , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Transformación Celular Neoplásica/genética , Niño , Citidina/efectos adversos , Citidina/análogos & derivados , Citidina/uso terapéutico , Metilasas de Modificación del ADN/antagonistas & inhibidores , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Drogas en Investigación/efectos adversos , Drogas en Investigación/uso terapéutico , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/genética , Humanos , Neoplasias/tratamiento farmacológico , Transcripción Genética/genéticaRESUMEN
In the present study, we investigated the cardiovascular effects of intravenously injected uridine or cytidine, and the role of adenosine receptors in mediating these effects, in conscious normotensive rats. Intravenous (i.v.) administration of uridine (124, 250, 500 mg/kg) dose-dependently decreased arterial pressure and heart rate. Cytidine (124, 250, 500 mg/kg; i.v.) produced slight dose-related hypotension without changing heart rate. Plasma uridine and cytidine concentrations increased time- and dose-dependently while plasma adenosine levels did not change after injection of the respective nucleosides. Pretreatment with intravenous caffeine (20 mg/kg), 8-phenyltheophylline (8-PT) (1 mg/kg), nonselective adenosine receptor antagonists, or 8-p-sulfophenyltheophylline (8-SPT) (20 mg/kg), a nonselective adenosine receptor antagonist which does not cross the blood-brain barrier, abolished the cardiovascular effects of uridine (250 mg/kg; i.v.) or cytidine (250 mg/kg; i.v.). Intracerebroventricular (i.c.v.) caffeine (200 microg) or 8-SPT (50 microg) pretreatment did not change the magnitude of the cardiovascular responses induced by nucleosides. Intravenous 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX) (5 mg/kg), a selective adenosine A(1) receptor antagonist, greatly attenuated the cardiovascular responses to uridine and cytidine. Pretreatment with 3,7,-dimethyl-1-propargylxanthine (DMPX) (2 mg/kg), an adenosine A(1)/A(2) receptor antagonist, attenuated hypotension induced by uridine and blocked the arterial pressure decrease in response to cytidine. Uridine-induced bradycardia was blocked by DMPX. 4-(2-[7-amino-2-(2-furyl[1,2,4]-triazolo[2,3-a[1,3,5]triazin-5-yl-aminoethyl)phenol (ZM241385) (1 mg/kg; i.v.), a selective adenosine A(2A) receptor antagonist, pretreatment produced an only very small blockade in the first minute of the hypotensive effects of uridine without affecting the bradycardia. ZM241385 pretreatment completely blocked cytidine's hypotensive effect. In Langendorff-perfused rat heart preparation, uridine (10(-3) M), but not cytidine, decreased the heart rate. Our results show that intravenously injected uridine or cytidine is able to decrease arterial pressure by activating peripheral adenosine receptors. The data also implicates that the mainly adenosine A(1) receptor activation is involved in the uridine-induced cardiovascular effects, while both adenosine A(1) and A(2A) receptor activations mediate the cytidine's effects.
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Agonistas del Receptor de Adenosina A1 , Agonistas del Receptor de Adenosina A2 , Antihipertensivos/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Arterias Carótidas/efectos de los fármacos , Citidina/administración & dosificación , Hipotensión/inducido químicamente , Uridina/administración & dosificación , Adenosina/sangre , Animales , Antihipertensivos/efectos adversos , Antihipertensivos/sangre , Cafeína/administración & dosificación , Arterias Carótidas/metabolismo , Arterias Carótidas/fisiopatología , Estado de Conciencia , Citidina/efectos adversos , Citidina/sangre , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Hipotensión/metabolismo , Hipotensión/fisiopatología , Inyecciones Intravenosas , Inyecciones Intraventriculares , Masculino , Ratas , Ratas Wistar , Receptor de Adenosina A1/metabolismo , Receptor de Adenosina A2A/metabolismo , Teobromina/administración & dosificación , Teobromina/análogos & derivados , Teofilina/administración & dosificación , Teofilina/análogos & derivados , Factores de Tiempo , Triazinas/administración & dosificación , Triazoles/administración & dosificación , Uridina/efectos adversos , Uridina/sangre , Función Ventricular Izquierda/efectos de los fármacos , Presión Ventricular/efectos de los fármacos , Xantinas/administración & dosificaciónRESUMEN
Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes.