RESUMO
Finasteride and minoxidil are medicaments commonly prescribed for treating benign prostatic hyperplasia (BPA), hypertension, and/or androgenetic alopecia (AGA). The mechanism of action of finasteride is based on the interference in androgenic pathways, which may lead to fertility-related disorders in men. Minoxidil, however, can act in multiple ways, and there is no consensus that its use can adversely affect male fertility. Since finasteride and minoxidil could be risk factors for male fertility, we aimed to compare their impact on the two reproductive organs testis and epididymis of adult murine models, besides testis/epididymis-related cells, and describe the mechanism of action involved. For such, we used the PRISMA guideline. We included 31 original studies from a structured search on PubMed/MEDLINE, Scopus, and Web of Science databases. For in vivo studies, the bias analysis and the quality of the studies were assessed as described by SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation). We concluded that finasteride and minoxidil act as hormone disruptors, causing oxidative stress and morphological changes mainly in the testis. Our results also revealed that finasteride treatment could be more harmful to male reproductive health because it was more associated with reproductive injuries, including damage to the epididymis, erectile dysfunction, decreased libido, and reduced semen volume. Thus, this study contributes to the global understanding of the mechanisms by which medicaments used for alopecia might lead to male reproductive disorders. We hope that our critical analysis expedites clinical research and reduces methodological bias. The registration number on the Prospero platform is CRD42022313347.
Assuntos
Minoxidil , Hiperplasia Prostática , Adulto , Masculino , Humanos , Animais , Camundongos , Minoxidil/toxicidade , Minoxidil/uso terapêutico , Finasterida/toxicidade , Alopecia/induzido quimicamente , Alopecia/tratamento farmacológico , Administração Oral , Hiperplasia Prostática/induzido quimicamente , Resultado do TratamentoRESUMO
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 repeated 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-ß-cyclodextrin MXD GEL formulation (MXD/HP-ß-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 performed. 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 solution. Retrospective investigation showed 32 cases of cancer associated with the use of topical MXD in humans. The rats treated with MXD HP-ß-CD were less severely affected. MXD causes proliferative adverse effects. The MXD HP-ß-CD inclusion complex reduces these adverse effects.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Pressão Sanguínea/efeitos dos fármacos , Minoxidil/administração & dosagem , Neoplasias/induzido quimicamente , Administração Tópica , Alopecia/tratamento farmacológico , Animais , Eletrocardiografia , Excipientes/química , Feminino , Géis , Humanos , Masculino , Minoxidil/toxicidade , Soluções Farmacêuticas , Farmacovigilância , Ratos , Ratos Wistar , Estudos RetrospectivosRESUMO
PURPOSE: To evaluate the inhibitory effect of minoxidil on cultured proliferating lens epithelial cells (LECs) versus cytotoxic effect over corneal endothelial cells in culture, because minimum side effects over anterior chamber structures and particularly on corneal endothelium are required for successful therapy and prevention of posterior capsular opacification (PCO). METHODS: New Zealand Rabbit LECs and corneal endothelium were cultured in DMEM at 35 degrees C in 5% CO2 in multiwells during 7 days. Both types of cells were exposed to minoxidil (1, 2 and 4 mM) for 1 and 24 hours. Control group and balanced salt solution group were included. After seven days multiwells were processed for light microscopy study. Morphometric study of cellular population of LECs and corneal endothelium cells were done using a computed planimetry system. RESULTS: Dose-dependent effect on LECs proliferation was noted and non-confluent colonies of cells were observed on all treated groups. Morphologic changes in normal appearance of corneal endothelial cells after 1 hour of minoxidil treatment was observed and intracellular alterations were confirmed even with the lowest dose exposure. CONCLUSIONS: Although effectiveness of minoxidil suppressing in vitro LECs proliferation could be suggest as a useful therapeutic agent to prevent PCO, however the inhibitory effect of different concentrations on corneal endothelial cells conditioned its possible use on ocular surgery.
Assuntos
Anti-Hipertensivos/farmacologia , Cristalino/efeitos dos fármacos , Minoxidil/farmacologia , Vasodilatadores/farmacologia , Animais , Anti-Hipertensivos/toxicidade , Catarata/prevenção & controle , Células Cultivadas/efeitos dos fármacos , Córnea/citologia , Córnea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/toxicidade , Cristalino/citologia , Minoxidil/toxicidade , Coelhos , Vasodilatadores/toxicidadeRESUMO
To investigate whether during cardiac hypertrophy changes occur in contractile protein composition and in mechanical and energetic properties of the myocardium, contractile protein composition, isometric force and adenosine triphosphate (ATP) consumption were studied in control and hypertrophied guinea-pig hearts. Cardiac hypertrophy was induced by adding minoxidil (120 or 200 mg/l) to the drinking water. Protein analysis was performed by one-dimensional gel electrophoresis. The myosin heavy-chain (MHC) composition was determined in an enzyme-linked immunosorbent assay (ELISA). ATP consumption and force development were simultaneously measured during isometric contraction in chemically skinned trabeculae. Histochemical analysis of cross-sectional area of cardiomyocytes and interstitial space was performed on the left ventricular tissue of 200 mg/l minoxidil-treated and control guinea pigs. Minoxidil treatment (120 and 200 mg/l) significantly increased left ventricular dry weight normalized for body weight by 19 +/- 4 and 24 +/- 4%, respectively. No significant differences were found in the cellular cross-sectional area, while interstitial space was slightly decreased in minoxidil-treated hearts. In left ventricular trabeculae of 200 mg/l minoxidil-treated guinea pigs, ATPase activity was slightly less than in those of control guinea pigs, whereas force did not differ significantly. Calcium sensitivity of force and ATPase activity were not affected by minoxidil treatment. Gel electrophoresis revealed no difference in contractile protein composition, but a tendency towards a lower amount of alpha-MHC in the minoxidil-treated hearts was found in ELISA.
Assuntos
Cardiomegalia/induzido quimicamente , Minoxidil/toxicidade , Vasodilatadores/toxicidade , Trifosfato de Adenosina/metabolismo , Animais , Cálcio/farmacologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Proteínas Contráteis/metabolismo , Feminino , Cobaias , Histocitoquímica , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Cadeias Pesadas de Miosina/metabolismo , Tamanho do Órgão/efeitos dos fármacosRESUMO
Minoxidil (MNX), like several other vasoactive drugs, causes cardiovascular toxicity in dogs by undetermined mechanisms. We studied the mechanism of cardiovascular toxicity of MNX [an adenosine triphosphate (ATP)-sensitive potassium channel opener] by blocking its pharmacologic effects with glyburide (an ATP-sensitive potassium channel blocker) in groups of 5 female beagle dogs treated orally for 2 days with 1.0 mg/kg/day of MNX alone or with glyburide given in 5 or 6 divided doses of 300 mg/kg at 2 hr before and after each dose of MNX and at 3-6-hr intervals thereafter. A third group of 5 dogs received glyburide alone in the same dosing regimen as in the combination group. Mean arterial pressure (MAP), heart rate (HR), the pharmacokinetics of MNX, and gross and microscopic changes in the heart were evaluated. Glyburide did not influence the pharmacokinetics of MNX but prevented or markedly attenuated the MNX-induced cardiovascular lesions (right atrial hemorrhagic lesions, subendocardial necrosis, or coronary arteritis) occurred in dogs whose MNX-induced hemodynamic effects were effectively blocked by glyburide. In conclusion, the cardiovascular toxicity of MNX in dogs is not caused by a direct toxic effect of MNX on the heart but apparently is related to the exaggerated pharmacologic/profound hemodynamic effects it elicits in the dog.
Assuntos
Coração/efeitos dos fármacos , Minoxidil/toxicidade , Vasodilatadores/toxicidade , Animais , Análise Química do Sangue , Pressão Sanguínea/efeitos dos fármacos , Cães , Feminino , Glibureto/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Minoxidil/antagonistas & inibidores , Minoxidil/farmacocinética , Miocárdio/patologia , Canais de Potássio/efeitos dos fármacos , Relação Estrutura-Atividade , Vasodilatadores/antagonistas & inibidores , Vasodilatadores/farmacocinéticaRESUMO
A 1-cm2 area on the back of CD1 mice was prepared for topical application of minoxidil, N-methyl-N-nitrosourea (MNU), or cyclophosphamide (CY) by clipping or plucking hair from a patch of skin. Plucking stimulates hair follicle cell division while clipping does not. Minoxidil was topically administered for 8 consecutive days. CY or MNU was administered topically once on the eighth day postplucking. The incidence of nuclear aberrations and mitotic figures were measured in hair follicles while frequency of micronuclei and the ratio of RBC/PCE were measured in the bone marrow. Results with minoxidil showed no increase in either nuclear aberrations in the hair follicle or micronuclei in the bone marrow. These results suggest that topically applied minoxidil is not genotoxic. In contrast, a dose-dependent effect of MNU on the incidence of nuclear aberrations in the hair follicle was seen. CY induced a dose-dependent increase in the incidence of micronuclei in the bone marrow and in nuclear aberrations in the hair follicle after topical application. Minoxidil applied to clipped mice significantly increased the incidence of mitotic figures above that seen in both the clipped and plucked controls. This suggests that minoxidil is a mitogenic agent in the hair follicle. These findings are consistent with the success of topically applied minoxidil in the treatment of alopecia areata.
Assuntos
Medula Óssea/efeitos dos fármacos , Cabelo/efeitos dos fármacos , Minoxidil/toxicidade , Administração Tópica , Animais , Ciclofosfamida/toxicidade , Avaliação Pré-Clínica de Medicamentos , Metilnitrosoureia/toxicidade , CamundongosRESUMO
The authors studied the effects of vasodilator treatment with either hydralazine or minoxidil on gas exchange and lung water accumulation over a 5-h period in canine oleic acid-induced pulmonary edema. Thirty dogs were given intravenous oleic acid 1 day prior to study to produce a stable, diffuse lung injury. On the day of study, one group of animals was given minoxidil, a potent systemic and pulmonary vasodilator. A second group was given hydralazine, a potent systemic vasodilator but weak pulmonary vasodilator, and a third group was not treated. Hemodynamic and gas exchange variables were assessed prior to treatment, and again after 5 h of treatment. Both drugs caused an increase in cardiac output and a decrease in peripheral vascular resistance. Minoxidil increased venous admixture from 17 +/- 4 to 55 +/- 6% (P less than 0.05), whereas hydralazine-treated dogs had a smaller increase, from 26 +/- 5 to 47 +/- 6% (P less than 0.05), and untreated animals did not show a significant change. Lung water increased 27 +/- 12% in the untreated animals over the course of the study, 43 +/- 18% in the hydralazine animals, and 60 +/- 16% (P less than 0.05 vs. untreated) in the minoxidil animals. The authors conclude that adverse effects may result from peripheral vasodilators in animals with permeability pulmonary edema, but the extent and severity of these effects may vary, depending on the drugs' effects on the pulmonary circulation.