Systemic Toxic Effects Associated With High-Dose Verapamil Infusion and Chemotherapy Administration

Abstract

Aside from its more conventional uses as a cardiovascular drug, the calcium channel blocker verapamil has recently been added to chemotherapeutic regimens to reduce drug resistance in B-cell and other neoplasms that express the P-glycoprotein. We recently treated patients with continuous-infusion verapamil (0.15 mg/kg per hour to 0.60 mg/kg per hour) over a 5-day period in combination with continuous-infusion vincristine and doxorubicin plus oral dexamethasone. Seventy-one courses involving 35 hospitalized patients were prospectively studied for cardiovascular and other side effects. Cardiovascular side effects were observed most frequently and consisted of first-degree heart block, hypotension, sinus bradycardia, and junctional rhythms. We observed higher degree heart block, but the QRS interval remained narrow and the ventricular escape rate remained relatively normal. Effects on mean arterial pressure, heart rate, and PR interval were both time and dose related. Severe, symptomatic congestive heart failure was rarely observed. The most common noncardiovascular side effects were constipation, peripheral edema, and weight gain. All systemic toxic effects observed were easily treated or disappeared with either temporary or permanent discontinuation of the verapamil infusion or by a decrease in the dose of verapamil. We conclude that the cardiovascular side effects associated with continuous, high-dose intravenous verapamil therapy are significant and dose limiting but are rapidly reversible. Less cardiotoxic chemosensitizers are needed to reverse multidrug resistance in cancer.

Expresión de proteínas relacionadas con resistencia a múltiples drogas (MDR-proteínas) y resistencia a la quimioterapia en el cáncer de pulmón

“…La edad media de los 99 pacientes fue de 64 ± 10,2, con una media de edad de 64 ± 9,7 años y de 61 ± 13 para las mujeres Presentaban tumores con histología no célula pequeña, 93 pacientes (49 carcinomas escamosos, 37 …”

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

“…[35][36][37] For example, the calcium channelblocking agent verapamil was observed to induce transient complete heart block, congestive heart failure and severe hypotension. 38 However, cardiovascular toxicity can be distinguished from P-glycoprotein inhibition, as demonstrated with verapamil chiral enantiomers 39,40 and several other MDR-reversing drugs. 33,34 Preclinical studies performed in rats and dogs did not anticipate the prolonged cardiac repolarization observed in most patients who received cinchonine.…”

Phase II trial of dexverapamil and epirubicin in patients with non-responsive metastatic breast cancer

“…Higher relative plasma concentrations of nor-dexverapamil have also been found in other clinical studies of dexverapamil (Scheithauer et al, 1993;Motzer et al, 1995) whereas, with racemic verapamil, the verapamil to norverapamil ratio has usually been . 1 (Pennock et al, 1991;Mross et al, 1993b). Norverapamil is known to have only 20% of the cardiovascular activity of the parent compound, when using the racemic mixture of verapamil (Neugebauer, 1978).…”

“…In clinical studies with verapamil, the cardiac effects of this calcium-channel blocker have limited dose escalation and thus the plasma levels have usually remained well below the concentrations needed for effective P-gp inhibition (Ozols et al, 1987;Pennock et al, 1991). The formulation of verapamil used in those studies has been a racemic mixture of R-and S-verapamil.…”