Drug-related nephrotoxic and ototoxic reactions : a link through a predictive mechanistic commonality.

BACKGROUND: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that drugs that influence the transport of sodium and/or potassium change ionic homeostasis in the inner ear and, hence, induce functional disturbances such as hearing loss, tinnitus and vertigo. OBJECTIVES: To assess whether renal suspected adverse drug reactions (sADRs) have predictive value for ear and labyrinth adverse drug reactions (ADRs) and whether drug classes involved have influence ion transport systems. STUDY DESIGN: Data were obtained from the Netherlands Pharmacovigilance Centre Lareb. The study base comprised all reports of sADRs up until 1 January 2007. Cases were all sADRs for relevant renal disorders and all sADRs for relevant ear disorders. All other reported sADRs were selected as 'non-cases'. The relationship between drug classes and renal, ear and labyrinth sADRs was evaluated by calculating reporting odds ratios (RORs). An ROR > or = 1.50 was regarded as a cut-off value for an association. Drug classes were classified into four groups: (A) ROR kidney <1.50 and ROR ear <1.50 or no reports on ear sADRs (reference group); (B) ROR kidney <1.50 and ROR ear > or = 1.50; (C) ROR kidney > or = 1.50 and ROR ear <1.50 or no reports on ear sADRs; and (D) ROR kidney > or = 1.50 and ROR ear > or = 1.50. For each group, we calculated odds ratios (ORs) for the association between the group classification and the effect on ion channels/ion transport systems in kidney and ear tissues. RESULTS: Of 193 drug classes with relevant ADRs for renal disorders, 120 drug classes also had reports on ototoxic reactions. Fourteen out of 120 drug classes had an ROR > or = 1.50 for the association between the drug class and both renal and ear sADRs. Among these drug classes were several with a well known ability to induce renal (adverse) effects and ear and labyrinth disorders, such as loop diuretics, aminoglycosides and quinine. We found that one mechanistic commonality of the drug classes mentioned in the reports was the ability to affect ion transport systems. The percentage of drugs having this property differed between the four groups. The ORs for groups D and B were significantly higher compared with the reference group (OR 12.2, 95% CI 3.0, 30.5 and OR 8.7, 95% CI 2.4, 18.7, respectively), whereas there was no association for group C. CONCLUSION: Our data suggest that renal sADRs as such are not a marker for drug-induced ear and labyrinth disorders. However, the ability of drugs to act on ion channels or ion transport systems and, therefore, have an influence on ionic homeostasis in the kidney and ear might be a predictor for the possible occurrence of drug-related ototoxicity.

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

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellular accumulation of various anticancer drugs including anthracyclines and vinca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitro and in animal models. Here, we report an open phase I dose escalation trial in patients with refractory or relapsed malignant lymphoid diseases. Cinchonine dihydrochloride was administered by continuous i.v. infusion for 48 h and escalated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infusion started 24 h before i.v. doxorubicin (25 mg/m2), vinblastine (6 mg/m2), cyclophosphamide (600 mg/m2) and methylprednisolone (1 mg/kg/d) (CHVP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four patients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine administered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolarization was the main dose-limiting toxicity. No ventricular arrhythmia including 'torsade de pointes' was observed. An MDR reversing activity was identified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinchonine might be started 12 h before MDR-related chemotherapy infusion and requires continuous cardiac monitoring but no reduction of cytotoxic drug doses.