The hydroxypropyl‐β‐cyclodextrin‐minoxidil inclusion complex improves the cardiovascular and proliferative adverse effects of minoxidil in male rats: Implications in the treatment of alopecia

The efficacy of minoxidil (MXD) ethanolic solutions (1%-5% w/v) in the treatment of androgenetic alopecia is limited by adverse reactions. The toxicological effects of re- peated topical applications of escalating dose (0.035%-3.5% w/v) and of single and twice daily doses (3.5% w/v) of a novel hydroxypropyl-β-cyclodextrin MXD GEL for- mulation (MXD/HP-β-CD) and a MXD solution were investigated in male rats. The cardiovascular effects were evaluated by telemetric monitoring of ECG and arterial pressure in free-moving rats. Ultrasonographic evaluation of cardiac morphology and function, and histopathological and biochemical analysis of the tissues, were per- formed. A pharmacovigilance investigation was undertaken using the EudraVigilance database for the evaluation of the potential cancer-related effects of topical MXD. Following the application of repeated escalating doses of MXD solution, cardiac hypertrophy, hypotension, enhanced serum natriuretic peptides and K+-ion levels, serum liver biomarkers, and histological lesions including renal cancer were observed. In addition, the administration of a twice daily dose of MXD solution, at SF rat vs human = 311, caused reductions in the systolic, diastolic, and mean blood pressure of the rats (−30.76 ± 3%, −28.84 ± 4%, and −30.66 ± 5%, respectively, vs the baseline; t test P < .05). These effects were not reversible following washout of the MXD solu- tion. Retrospective investigation showed 32 cases of cancer associated with the use of topical MXD in humans. The rats treated with MXD HP-β-CD were less severely af- fected. MXD causes proliferative adverse effects. The MXD HP-β-CD inclusion com- plex reduces these adverse effects.