Dexverapamil

Dexverapamil can be synthesized through various synthetic routes. One common method involves the resolution of racemic verapamil into its enantiomers. The reaction conditions typically involve the use of chiral resolving agents and chromatographic techniques to separate the ®-enantiomer from the (S)-enantiomer . Industrial production methods may involve large-scale resolution processes and purification steps to obtain high-purity this compound.

Dexverapamil undergoes several types of chemical reactions, including:

Oxidation: this compound can be oxidized to form various metabolites. Common reagents for oxidation include hydrogen peroxide and other oxidizing agents.

Reduction: Reduction reactions can convert this compound into its reduced forms. Reducing agents such as sodium borohydride are commonly used.

Substitution: this compound can undergo substitution reactions where functional groups are replaced by other groups. Common reagents include halogens and nucleophiles.

Hydrolysis: Hydrolysis reactions can break down this compound into its constituent parts.

Dexverapamil has a wide range of scientific research applications, including:

Chemistry: this compound is used as a chiral resolving agent in various chemical reactions and processes.

Biology: In biological research, this compound is used to study the mechanisms of multidrug resistance in cancer cells.

Medicine: this compound is investigated for its potential to enhance the efficacy of cancer chemotherapy by reversing multidrug resistance.

Industry: This compound is used in the pharmaceutical industry for the development of new drugs and formulations targeting multidrug resistance in cancer.

Dexverapamil exerts its effects by inhibiting the P-glycoprotein efflux pump (MDR-1), which is responsible for the multidrug resistance phenotype in cancer cells. By inhibiting this pump, this compound increases the intracellular concentration of chemotherapeutic agents, thereby enhancing their cytotoxic effects . The molecular targets of this compound include various ion channels and transporters involved in drug resistance pathways .

Racemic Verapamil

• Mechanistic Differences :
  • Verapamil (racemic mixture of R- and S-enantiomers) inhibits P-gp but causes dose-limiting cardiotoxicity (e.g., hypotension, bradycardia) due to the S-enantiomer’s high calcium channel activity. Dexverapamil retains 90% of P-gp inhibitory potency with 5–10-fold lower cardiac effects .
  • Pharmacokinetic Interaction :
• This compound reduces epirubicin AUC by 36% while enhancing its antitumor activity .

Cyclosporin A and PSC833

• Mechanistic Profile: Cyclosporin A and its analog PSC833 are potent P-gp inhibitors but non-specifically increase the AUC and toxicity of cytotoxic drugs (e.g., paclitaxel, etoposide) due to CYP3A4 inhibition . Clinical Outcomes:
• Cyclosporin A increases hematologic toxicity (e.g., neutropenia) by 30–50%, limiting its use.

Second-Generation P-gp Inhibitors

• Royleanone Derivatives: Non-competitive inhibitors (e.g., compound 4) with efficacy comparable to this compound in preclinical models but lacking clinical validation .

Other Chemosensitizers

• Quinidine and Mefloquine : First-generation inhibitors with low therapeutic indices. Mefloquine shows synergistic effects with this compound but causes neurotoxicity .
• Celastrol : A natural compound targeting HERG channels; preclinical data suggest synergy with this compound in prostate cancer .

Key Research Findings

Pharmacokinetic Interactions

• Epirubicin : this compound reduces epirubicin AUC (2968 → 1901 µg·ml⁻¹·h⁻¹) but increases the distribution volume and metabolite (epirubicin-glucuronide) exposure, enhancing tumor penetration .
• Doxorubicin : Unlike epirubicin, this compound increases doxorubicin steady-state concentrations by 50%, suggesting drug-specific interactions .

Clinical Efficacy

• Breast Cancer : 4/23 patients (17%) achieved partial responses with this compound + epirubicin, despite reduced AUC .
• Lymphomas: 12% response rate in EPOCH-resistant non-Hodgkin’s lymphoma, correlating with MDR1 overexpression .
• Renal Cell Carcinoma: Minimal activity (1 PR in 25 patients), highlighting tumor-type specificity .

Toxicity Profile

• Cardiac : Asymptomatic bradycardia (11% of patients) and first-degree AV block, reversible upon discontinuation .
• Hematologic : Comparable myelosuppression to chemotherapy alone (e.g., WBC nadir 2.05 vs. 2.03 ×10⁹/L) .

Dexverapamil, a stereoisomer of verapamil, is primarily recognized for its role as a modulator of multidrug resistance (MDR) in cancer therapy. This compound has garnered attention due to its potential to inhibit P-glycoprotein (Pgp), a key player in the efflux of chemotherapeutic agents from cancer cells, thereby enhancing the efficacy of various anticancer drugs. This article delves into the biological activity of this compound, presenting clinical trial data, mechanisms of action, and case studies that illustrate its therapeutic potential.

This compound functions as a Pgp inhibitor, which is crucial in overcoming drug resistance in cancers. Pgp overexpression is associated with reduced intracellular concentrations of chemotherapeutic agents, leading to treatment failure. By inhibiting Pgp, this compound increases the accumulation of these drugs within cancer cells, potentially restoring their cytotoxic effects.

1. This compound in Lymphomas

A controlled trial investigated the efficacy of this compound in patients with relapsed Hodgkin's and non-Hodgkin's lymphomas who were refractory to standard chemotherapy regimens (EPOCH). The study involved 154 patients, with a median age of 44 years. Key findings included:

• Response Rates : Among 41 non-Hodgkin lymphoma patients treated with this compound and EPOCH, there were three complete responses (CRs) and two partial responses (PRs), yielding a response rate of approximately 12% .
• Mdr-1 Expression : Serial biopsies indicated that mdr-1 levels increased significantly upon treatment, suggesting a correlation between mdr-1 expression and response to this compound .
• Toxicity Profile : The combination was well tolerated but resulted in increased hematologic toxicity compared to EPOCH alone .

2. This compound with Vinblastine

In another study involving advanced renal cell carcinoma (RCC), this compound was combined with vinblastine after resistance was established. The trial included 23 patients and revealed:

• Tolerability : The treatment was associated with mild toxicities such as hypotension and bradycardia, but no severe adverse effects were reported .
• Response Rates : Although no complete or partial responses were observed in RCC patients, the study highlighted this compound's potential for further exploration as an MDR reversal agent due to its favorable toxicity profile compared to racemic verapamil .

Case Study Overview

Several case studies have been documented to assess the clinical impact of this compound on drug-resistant cancers:

Detailed Findings

In a phase II study involving anthracycline-resistant tumors, this compound demonstrated modest activity with two partial responses noted among patients who had previously shown disease progression on anthracyclines. This suggests that while this compound may not be universally effective across all cancer types, it holds promise in specific contexts where Pgp-mediated resistance is a significant barrier to treatment efficacy .

Basic Research Questions

Q. What is the mechanistic role of Dexverapamil in reversing P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in cancer cells?

this compound, the R-enantiomer of verapamil, competitively inhibits P-gp, an ATP-dependent efflux pump overexpressed in drug-resistant cancers. Unlike racemic verapamil, it exhibits reduced calcium channel antagonism, minimizing cardiotoxicity while retaining chemosensitizing efficacy. Methodologically, researchers validate this mechanism via in vitro assays (e.g., calcein-AM efflux inhibition) and in vivo xenograft models comparing tumor response with/without this compound co-administration .

Q. What experimental models are optimal for evaluating this compound’s chemosensitizing effects?

• Preclinical:
  • In vitro: P-gp-overexpressing cell lines (e.g., MCF-7/ADR) treated with anthracyclines (e.g., epirubicin) ± this compound. Metrics include IC50 shifts and intracellular drug accumulation via flow cytometry.
  • In vivo: Murine xenograft models with pharmacokinetic (PK) profiling to assess drug retention.
• Clinical: Phase II trials using a two-stage design (e.g., initial monotherapy followed by combination therapy in refractory patients) to isolate this compound’s contribution .

Q. How is this compound dosed in combination therapies to balance efficacy and toxicity?

Clinical protocols often use oral this compound (300 mg every 6 hours × 13 doses) paired with cytotoxic agents like epirubicin (120 mg/m² IV). Preclinical studies employ dose-escalation designs to identify thresholds where P-gp inhibition outweighs off-target effects. PK monitoring (e.g., trough plasma levels of this compound and its metabolites) ensures therapeutic exposure .

Advanced Research Questions

Q. How should researchers resolve contradictions in this compound’s impact on cytotoxic drug pharmacokinetics?

Contradictory findings (e.g., reduced epirubicin AUC with this compound in some trials vs. increased retention in preclinical models) require:

• Intrapatient PK comparisons to control for interindividual variability.
• Mechanistic studies differentiating P-gp inhibition from cytochrome P450 interactions.
• Meta-analyses of trial designs (e.g., dosing schedules, patient selection criteria) to identify confounding variables .

Q. What methodologies optimize this compound’s synergy with novel cytotoxic agents in resistant tumors?

• High-throughput screening of compound libraries paired with this compound to identify synergistic partners.
• Transcriptomic profiling of tumors pre-/post-treatment to detect P-gp-independent resistance pathways (e.g., upregulated anti-apoptotic proteins).
• Computational modeling of drug-P-gp binding affinities to refine structure-activity relationships .

Q. How can researchers mitigate residual cardiotoxicity in long-term this compound regimens?

• Cardiac biomarkers : Troponin I and BNP monitoring during trials.
• Preclinical models : Langendorff perfused heart assays to quantify calcium channel blockade.
• Dose fractionation : Testing split doses to maintain P-gp inhibition while reducing peak plasma concentrations .

Q. Guidance for Addressing Research Challenges

• Contradictory Data : Apply the FINER framework (Feasible, Interesting, Novel, Ethical, Relevant) to refine hypotheses and prioritize replication studies .
• Ethical Reporting : Disclose limitations (e.g., small sample sizes in phase II trials) and avoid overgeneralizing findings .