作者: Labardini-Méndez, Juan ; Candelaria, Myrna ; Espinoza-Zamora, Jose Ramiro ; López-González, Celia ; Toledano-Cuevas, Diana Vanesa ; Vieyra-García, Magnolia ; Zapata-Canto, Nidia ; Lozano-Zavaleta, Valentin ; Sosa-Espinoza, Alejandro ; Cervera, Eduardo ; Dueñas-González, Alfonso

OBJECTIVESTo evaluate the activity and safety of hydralazine and valproate (Transkrip) in cutaneous T-cell lymphoma (CTCL).METHODSPreviously untreated and progressive/refractory CTCL patients received hydralazine at 83 mg or 182 mg/day for slow and rapid acetylators respectively plus magnesium valproate at a total dose of 30 mg/Kg t.i.d daily in continuous 28-day cycles in this phase II study. The primary objective was overall response rate (ORR) measured by the modified severity weighted assessment tool (m-SWAT), secondary end-points were time to response (TTR), time to progression (TTP), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety.RESULTSFourteen patients were enrolled (7 untreated and 7 pretreated). ORR was 71% with 50% complete and 21% partial. Two had stable disease and two progressed. At a median follow-up of 36 months (5-52), median TTR was 2 months (1-4); median DOR was 28 months (5-45); median PFS 36 and not reached for OS. There were no differences in median TTR, DOR, and PFS between treated and pretreated patients. Pruritus relieve was complete in 13 out of 14 patients. No grade 3 or 4 toxicities were observed.CONCLUSIONThe combination of hydralazine and valproate is safe, very well tolerated and effective in CTCL.

2014-10-01·Expert Opinion on Drug Metabolism & Toxicology

Hydralazine–valproate: a repositioned drug combination for the epigenetic therapy of cancer

Review

作者: Lucely Cetina ; Lucia Taja-Chayeb ; Jaime Coronel ; Alfonso Dueñas-Gonzalez ; Alma Chavez-Blanco ; Aurora González-Fierro

INTRODUCTIONDNA methylation (DNMTi) and histone deacetylase inhibitors (HDACi) are in development for cancer therapy. So far, four epigenetic drugs are approved for myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma (CTCL). The combination of hydralazine-valproate (TRANSKRIP(™)) is being repositioned as an oral DNMT and HDAC inhibitor.AREAS COVEREDBrief discussion on the current status of epigenetic drugs and studies published on the preclinical and clinical development of the hydralazine-valproate combination.EXPERT OPINIONDrug repositioning is a strategy for prompt and cost-efficient drug discovery. There is evidence that combining DNMTi with HDACi would be more efficacious than administering each agent on its own. Hydralazine-valproate is safe when used alone or in combination with chemotherapy or chemoradiation. The fact that both drugs are orally administered is another advantage over current epigenetic drugs. This combination is promising but larger studies are needed. Among these, the randomized Phase III trials in advanced and in locally advanced cervical cancer combined with chemotherapy and cisplatin-radiation respectively, would eventually confirm its efficacy. Studies on MDS and CTCL would also eventually prove the efficacy of hydralazine valproate so that in the coming years hydralazine-valproate could have a role in cancer epigenetic therapy.

2011-04-01·Annals of Hematology3区 · 医学

Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial

3区 · 医学

Article

作者: Catalina Trejo-Becerril ; Lucía Taja-Chayeb ; Enrique Pérez-Cárdenas ; Eduardo Cervera ; Silvia Vidal ; Erick de la Cruz-Hernández ; Aquileo Herrera ; Juan Labardini ; Alfonso Dueñas-Gonzalez ; Daymi Arias-Bofill ; Myrna Candelaria ; Aurora González-Fierro

Decitabine and azacitidine, two DNA methyltransferase (DNMT) inhibitors, are the current standard of treatment for myelodysplastic syndrome (MDS). Histone deacetylase (HDAC) inhibitors are also being tested against MDS. Both drug classes synergize in their gene reactivating and anticancer activities. The combination of hydralazine and valproate (Transkrip®), a DNMT and HDAC inhibitor, respectively), has been developed as epigenetic therapy under the drug repositioning concept. To evaluate the clinical efficacy and safety of hydralazine and valproate against MDS, an open phase-II study for previously treated patients with MDS was conducted. The hydralazine dose was given according with the acetylator phenotype, and valproate was dosed at 30 mg/kg/day. Response was graded with International Working Group criteria. Toxicity was evaluated by the Common Toxemia Criteria-National Cancer Institute version 3 scale. From November 2007 to January 2010, 12 patients were included. Median age±SD was 53±19.78 years (range, 23-79 years); median time from diagnosis to inclusion in the study was 7.9 months (range 2.6-36.1 months). Median of previous treatment was 2 (range, 1-6). Refractory cytopenia with multilineage dysplasia was diagnosed in ten cases, and refractory anemia with excess of blasts in two. Overall response was documented in six (50%) of 12 cases, including one CR, one PR, and four hematological improvements of the erythroid series. Two patients (16.6%) progressed to acute myeloid leukemia. Hemoglobin increased from 7.4 to 10.3 g/dL (in 13 weeks), neutrophils, from 1.1 to 2.0 (in 3 weeks), and platelets, from 66×10(9) to 72×10(9)/L (in 2 weeks). Transfusional requirements decreased from 2.3 to 0 U bi-monthly for red blood cells and from 0.5 to 0 U bi-monthly for platelets in responding patients. Main toxicities were mild, including somnolence and nausea. Preliminary results of this phase-II study suggest that the combination of hydralazine and valproate is a promising non-toxic and effective therapy for MDS.

100 项与丙戊酸镁/盐酸肼屈嗪相关的药物交易

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