Disease relevance of Dexverapamil

• EPOCH and dexverapamil were well tolerated, but compared with EPOCH alone, produced more hematologic toxicity [1].
• Controlled trial of dexverapamil, a modulator of multidrug resistance, in lymphomas refractory to EPOCH chemotherapy [1].
• The maximum-tolerated dose of dexverapamil was 900 mg/m2/d. Among 41 NHL patients (excluding mycosis fungoides), there were three complete responses (CRs) and two partial responses (PRs) (12%) and five minor responses (MRs); two of 10 HD patients achieved PRs [1].
• Phase II study of dexverapamil plus anthracycline in patients with metastatic breast cancer who have progressed on the same anthracycline regimen [2].
• Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it [2].

High impact information on Dexverapamil

• Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy [3].
• Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions [3].
• Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients [3].
• The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred [3].
• The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity [3].

Chemical compound and disease context of Dexverapamil

• Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer [4].
• To determine whether the chemotherapy resistance of non-small cell lung cancer could be modified by oral dexverapamil, the D-isomer of verapamil, 54 patients were entered into a randomised phase II study of oral dexverapamil plus chemotherapy (vindesine/etoposide) (arm B) versus chemotherapy (arm A) alone in January 1994 [5].

Biological context of Dexverapamil

• The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly [2].
• Modulation of vincristine cytotoxicity by dexverapamil in sensitive and resistant HL-60 cell lines as a function of extracellular protein binding [6].

Anatomical context of Dexverapamil

• The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change [3].

Associations of Dexverapamil with other chemical compounds

• In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil [3].
• Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition [2].
• In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02) [4].
• In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine [7].
• Multidrug resistance modulation in vivo: the effect of cyclosporin A alone or with dexverapamil on idarubicin pharmacokinetics in acute leukemia [8].

Gene context of Dexverapamil

• Brain uptake was increased approximately 12-fold in mice lacking P-gp in the BBB, but the P-gp inhibitor dexverapamil did not increase uptake in P-gp-competent mice [7].
• The purpose of this study was to determine the maximum tolerated dose (MTD) of a cytotoxic regimen consisting of the second-generation chemosensitizer dexverapamil (DVPM), high dose epirubicin, and recombinant human granulocyte-macrophage-colony stimulating factor (GM-CSF) in pancreatic carcinoma [9].
• Among 6 patients with MDR-1 > 15, 3 responded to dexverapamil whereas only 1/8 patients with MDR-1 < 15 responded [10].
• We conducted a controlled trial of dexverapamil, an inhibitor of Pgp, in 45 Hodgkin's (HD) and 154 Non-Hodgkin's (NHL) lymphomas refractory to EPOCH chemotherapy [10].

Analytical, diagnostic and therapeutic context of Dexverapamil

• RESULTS: Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy [3].
• Dexverapamil was escalated eight dose levels, from 240 to 1,200 mg/m2/d. When possible, serial biopsies were obtained to measure mdr-1 expression by quantitative polymerase chain reaction (PCR) [1].
• In a cross-over design, dexverapamil was added to EPOCH after disease stabilization or progression occurred [11].
• Injectable and infusion formulations of dexverapamil are evaluated for their potential to produce phlebitis [12].

References