Minoxidil use in dermatology, side effects and recent patents

Minoxidil, a vasodilator medication known for its ability to slow or stop hair loss and promote hair regrowth, was first introduced, exclusively as an oral drug, to treat high blood pressure. It was however discovered to have the important side-effect of increasing growth or darkening of fine body hairs; this led to the development of a topical formulation as a 2% concentration solution for the treatment of female androgenic alopecia or 5% for treating male androgenic alopecia. Measurable changes disappear within months after discontinuation of treatment. The mechanism by which it promotes hair growth is not fully understood. Minoxidil is a potassium channel opener, causing hyperpolarization of cell membranes and it is also a vasodilator, it is speculated that, by widening blood vessels and opening potassium channels, it allows more oxygen, blood and nutrients to the follicle. This can also cause follicles in the telogen phase to shed, usually soon to be replaced by new, thicker hairs in a new anagen phase. It needs to be applied regularly, once or twice daily, for hair gained to be maintained, and side effects are common. The most common adverse reactions of the topical formulation are limited to irritant and allergic contact dermatitis on the scalp. There have been cases of allergic reactions to the nonactive ingredient propylene glycol, which is found in some topical solution especially if they are galenic. Increased hair loss which can occur during Minoxidil use, is due to the synchronization of the hair cycle that the treatment induces. In this review, we described its mechanism of action, use in dermatology and some patents related to alternative treatment of allergic reactions due to its use.     

Topical minoxidil. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in alopecia areata and alopecia androgenetica

When minoxidil is administered orally for periods in excess of 1 month, hypertrichosis occurs as a side effect in a majority of patients. Consequently, topical minoxidil has been developed to try to improve hair growth in patients with alopecia areata and alopecia androgenetica. Preliminary studies have shown that topical minoxidil promotes cosmetically acceptable hair regrowth in a variable proportion of patients with alopecia areata. Data from a large multicentre trial indicate that cosmetically worthwhile results are achieved in about one-third of subjects with alopecia androgenetica after 1 year of treatment. A much higher proportion (about 80%) of patients with alopecia androgenetica exhibited some non-vellus hair regrowth after 1 year, and whether more of these patients would develop a cosmetically acceptable result with a longer treatment period is an important area of future investigation. Initial indications suggest that less severe disease is a predictor of likely response. Thus, topical minoxidil would seem to be a useful treatment modality for patients with alopecia androgenetica--a disease for which no other safe and effective drug therapy exists. Results from treating patients with alopecia areata with topical minoxidil, although encouraging, have been more variable and require further evaluation. Even though a number of questions remain to be answered about topical minoxidil (as would be expected at this stage in its development), it would seem to be the first available drug with the potential to promote substantial hair regrowth in these divergent diseases.     

Preparation and in vivo evaluation of lecithin-based microparticles for topical delivery of minoxidil

Minoxidil is widely used for treatment of androgenic alopecia. Commercial products containing minoxidil are usually in solution form. Repeated applications of minoxidil solution can lead to adverse effects such as skin irritation and horniness. The aims of this study were to prepare lecithin-based microparticle in minoxidil solution for enhancement of minoxidil topical delivery and skin protection and evaluate the ability of lecithin on in vitro delivery, in vivo hair growth, and skin trouble improvement compared to commercial minoxidil solution. In in vitro skin permeation study, minoxidil solution containing lecithin microparticle showed higher skin penetration rate and higher retention of drug inside the skin compared to minoxidil solution without lecithin. After topical application of minoxidil solutions with or without lecithin to C57BL/6 mice, minoxidil 5% solution containing lecithin microparticle showed hair re-growth as efficient as commercial product of minoxidil 5% solution. It also significantly improved skin troubles while commercial product presented horny substance and crust formation. Therefore, the lecithin-based microparticle in minoxidil 5% solution has good ability to promote hair growth without adverse effects.     

Treatments for androgenetic alopecia and alopecia areata: current options and future prospects

Androgenetic alopecia and alopecia areata are common disorders of the hair follicle which may heavily influence self esteem and self image. Androgenetic alopecia is caused by the heightened sensitivity of scalp follicles to dihydro- testosterone whereas alopecia areata is induced by an autoimmune reaction. Current drug treatment approaches include the use of regrowth stimulators such as topical minoxidil and oral finasteride for androgenetic alopecia, as well as topical minoxidil, dithranol (anthralin), corticosteroids, contact sensitisers, and psoralen plus ultraviolet A irradiation (PUVA) therapy for alopecia areata. Combination regimens are also proposed. However, extreme cases of either type of alopecia do not generally respond well to these existing treatments. For this reason, new therapeutic strategies are directed towards both improving the targeting of existing agents, as well as the development of novel hypertrichotic modalities.     

Simultaneous effects of tocopheryl polyethylene glycol succinate (TPGS) on local hair growth promotion and systemic absorption of topically applied minoxidil in a mouse model

In this study, topical minoxidil solutions supplemented with TPGS in cosolvent systems of various compositions consisting of water, alcohol, and polyethylene glycol 400 were designed to evaluate the efficacy of promoting hair growth after topical application and the safety in terms of the amount of minoxidil absorbed through the skin into the circulation using C57BL/6J mice as a model. The commercial product of 2% Regaine) was used as the positive control. The role, which sulfotransferase activity plays in hair growth with treatment using minoxidil, was determined as well. The results revealed that the addition of 0.5% TPGS was able to enhance the proliferation of hair, but an increase in the amount of TPGS to 2% led to deterioration in the enhancement of hair growth. At the higher added amount (2.0%) of TPGS, the promotion of hair growth was slightly reduced for both cosolvent formulations F1 (100% water) and F3 (100% PEG 400), whereas it was reduced to a greater extent for the cosolvent formulations F8-F10. In comparison, the influences of cosolvent compositions with TPGS amounts of 0.0 and 2.0% on the promotion of hair growth were similar. On the contrary, variability in the promotion of hair growth by different solvent formulations was minimal when the added amount of TPGS was 0.5%. In general, a relationship between hair growth and sulfotransferase activities after topical application of 2% Regaine and minoxidil formulations containing various amounts of TPGS was not demonstrated. Plasma concentrations of minoxidil with 2% Regaine were found to be greater than those of 2% minoxidil in those cosolvent formulations containing various amounts of TPGS, while showing insignificant differences among those 10 cosolvent formulations with a fixed amount of TPGS. A tendency for the plasma concentration of minoxidil to increase after the topical administration of minoxidil formulations containing the higher amount of TPGS (2%) was noted.     

New drugs under investigation for the treatment of alopecias

Introduction: Alopecia is a very common complaint in medical practice, which usually has a large psychological impact in patients. Treatment of alopecia is often difficult and frustrating for patients and clinicians owing to the slow growth rate of the hair, long treatment terms, limited efficacy, and possible adverse side effects.

Areas covered: This paper reviews the new and emerging treatments for two of the most common forms of alopecia, known as androgenetic alopecia and alopecia areata. A literature search of PubMed/MEDLINE and ClinicalTrial.gov was performed to gather information about active research on new treatments for alopecias. Websites of companies sponsoring clinical trials were also searched for interim result data.

Expert opinion: Many new therapies in two of the most common forms of hair loss have been developed and are currently being studied with encouraging results. In alopecia areata, JAK inhibitors are promising. The discovery of JAK inhibitors has prompted the research and identification of new molecules. In androgenetic alopecia, we are still looking for a topical treatment that is superior to topical minoxidil. However, stem-cell research is advancing and the goal to create new follicles or refresh dormant follicles may be realized in the near future.     

Alopecia areata

Alopecia aerata (AA) is an autoimmune disease that presents as well defined patches of nonscarring hair loss with no overt epidermal changes. The life-time risk of AA in the general population is approximately 1.7%. As many as 60% of patients with AA have disease onset before 20 years of age. AA most commonly manifests as sudden loss of hair in well demarcated, localized area in the scalp. The hair loss is usually limited to a single patch. The lesion is usually round or oval. "Exclamation point hairs" are frequently seen at the periphery of the lesion. Because of the high rate of spontaneous recovery especially in those with small areas of hair loss or with a recent onset, not all patients require pharmacological treatment. A "watch-and-wait" approach is often recommended. Psychological support may be offered if necessary. For patients who actively desire treatment, topical corticosteroids and/or minoxidil are the treatment of choice. Interleukin (IL)-31 antibodies and 308-nm Excimer laser as novel treatment modalities appear promising in the armamentarium against this distressing disease. The review also outlined recent patents on the treatment of alopecia.     

加味二至丸联合外用米诺地尔酊治疗青年型男性脱发的临床观察

目的 探讨加味二至丸联合外用米诺地尔酊对青年型男性脱发的疗效.方法 选取男性型脱发患者126例,按随机数字表法分为三组,即西药组(米诺地尔酊外用)、中药组(加味二至丸)和联合治疗组(加味二至丸加米诺地尔酊外用),每组42例.超声仪检测三组患者治疗前后血流动力学特征变化;高分辨率扫描电子显微镜-X射线能谱仪测定秃发区微量元素Ca、Fe、Zn、Cu的含量;检测各组治疗后毛发生长速度、生长长度和毛囊状况,最后进行疗效判定.结果 与治疗前相比,三组患者治疗后血流阻力指数(RI)明显下降,流速时间积分(VT1)和峰值流速(Vmax)明显升高,且联合治疗组血流动力学改善效果较西药组和中药组明显(P＜0.05);联合治疗组发中微量元素Fe、Ca、Zn、Cu含量明显升高,且升高幅度大于单纯西药和中药组(P＜0.05);联合治疗组毛发生长速度为(12.605 ±3.271) ×10-2 mm·d-1,治疗后总有效率高达92.9％,明显高于单纯中药组(76.2％)和西药组(54.8％),且联合治疗组毛囊生长期较另外两组延长(P＜0.05).结论 加味二至丸联合外用米诺地尔酊对男性型脱发患者疗效确切,值得临床推广应用.     

The additive effects of minoxidil and retinol on human hair growth in vitro

Minoxidil enhances hair growth by prolonging the anagen phase and induces new hair growth in androgenetic alopecia (AGA), whereas retinol significantly improves scalp skin condition and promotes hair growth. We investigated the combined effects of minoxidil and retinol on human hair growth in vitro and on cultured human dermal papilla cells (DPCs) and epidermal keratinocytes (HaCaT). The combination of minoxidil and retinol additively promoted hair growth in hair follicle organ cultures. In addition, minoxidil plus retinol more effectively elevated phosphorylated Erk, phosphorylated Akt levels, and the Bcl-2/Bax ratio than minoxidil alone in DPCs and HaCaT. We found that the significant hair shaft elongation demonstrated after minoxidil plus retinol treatment would depend on the dual kinetics associated with the activations of Erk- and Akt-dependent pathways and the prevention of apoptosis by increasing the Bcl-2/Bax ratio.     

The physiological and pharmacological roles of prostaglandins in hair growth

Hair loss is a common status found among people of all ages. Since the role of hair is much more related to culture and individual identity, hair loss can have a great influence on well-being and quality of life. It is a disorder that is observed in only scalp patients with androgenetic alopecia (AGA) or alopecia areata caused by stress or immune response abnormalities. Food and Drug Administration (FDA)-approved therapeutic medicines such as finasteride, and minoxidil improve hair loss temporarily, but when they stop, they have a limitation in that hair loss occurs again. As an alternative strategy for improving hair growth, many studies reported that there is a relationship between the expression levels of prostaglandins (PGs) and hair growth. Four major PGs such as prostaglandin D2 (PGD₂), prostaglandin I2 (PGI₂), prostaglandin E2 (PGE₂), and prostaglandin F2 alpha (PGF₂α) are spatiotemporally expressed in hair follicles and are implicated in hair loss. This review investigated the physiological roles and pharmacological interventions of the PGs in the pathogenesis of hair loss and provided these novel insights for clinical therapeutics for patients suffering from alopecia.     

2%米诺地尔酊剂外用辅治斑秃的疗效观察

目的观察2%米诺地尔酊剂外用辅治斑秃的临床疗效。方法将120例斑秃患者随机分为观察组和对照组各60例。对照组给予基础对症治疗;观察组在对照组治疗基础上加用2%米诺地尔酊剂,并用生姜汁及生蒜外擦患处,每天2次,1个月为1个疗程。治疗后比较2组疗效及不良反应。结果观察组总有效率为93.3%高于对照组的75.0%,差异有统计学意义(P<0.01)。观察组出现头晕1例,对照组出现下肢水肿1例,经调整用药后均改善。结论 2%米诺地尔酊剂外用辅治斑秃可提高治疗效果,值得临床推广应用。     

Topical minoxidil in the treatment of male pattern alopecia

Male pattern hair loss (androgenetic alopecia) is a common problem. In fact, it affects nearly all males to some degree. Expression of the disorder is variable, and while it is never life-threatening, it often becomes a major source of consternation. The biology of the process is poorly understood, and no current therapy can halt or reverse the process. Only cosmetic surgery, which is painful, time consuming, and expensive, has been effective. In the past 7 years, since it was noted that a patient taking minoxidil for hypertension had reversal of male pattern hair loss, awareness of a possible therapeutic role for topical minoxidil in the management of this disorder has grown among physicians, scientists, and the general public. It can be concluded from available data that topical application of minoxidil is effective in providing cosmetically satisfying thickening of hair in a select group of individuals with male pattern hair loss. The drug's mechanism of action remains obscure. No serious side effects have been demonstrated with its use, however, and it is therefore advised in selected patients.     

Nongenotoxicity of minoxidil in murine hair follicles as determined by the nuclear aberration assay

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.     

Drug-induced hair disorders

Drugs may induce hair loss, stimulate hair growth or, more rarely, induce changes in the hair shape and colour. Drug-induced hair loss is usually completely reversible and is, in most cases, a consequence of a toxic effect of the drug on the hair follicle matrix. In rare cases alopecia may be permanent. Depending on type of drug, dosage and patient susceptibility, hair loss presents as telogen effluvium, anagen effluvium or both. Telogen effluvium is also commonly observed after discontinuation of drugs that prolong anagen, such as topical minoxidil and oral contraceptives. Although a large number of drugs have been occasionally reported to produce hair loss, only for a few drugs the relation between drug intake and hair loss has been proven.     

Safety concerns when using novel medications to treat alopecia

ABSTRACT

Introduction: Alopecia is often a cause of great concern to patients for cosmetic and psychologic reasons. The aim of treating non-scarring alopecias is to reduce hair loss and, to some extent, enhance hair regrowth. However, therapies for scarring alopecias are limited and aiming to halt disease progression. Nonetheless, available modalities of treatment come with numerous side effects.

Areas covered: Many new treatments for non-scarring alopecias have been introduced in recent years. This review summarizes the safety concerns when using novel therapeutic modalities such as JAK inhibitors, hair transplantation, mesotherapy, oral minoxidil, platelet-rich plasma, microneedling, and 5α-reductase inhibitors for treating hair loss. A broad literature search was performed using PubMed and Google Scholar in April 2018 to compile published articles that reported the adverse effects of new therapeutic modalities for alopecia.

Expert opinion: Although emerging therapeutic modalities for alopecia have demonstrated efficacy in hair regrowth and treating established disease, their safety profiles vary widely. When considering the new treatments for alopecia, physicians should weigh the potential benefits and risks of each treatment or combination treatment to ensure safe and successful outcomes.     

米诺地尔凝胶治疗斑秃的多中心随机双盲安慰剂对照临床试验

目的 评价2.2%米诺地尔凝胶（抗斑秃药）治疗斑秃的疗效和安全性.方法 用随机双盲安慰剂对照多中心研究,选择脱发＜40%头皮面积、病程在1年以内的患者,随机进入米诺地尔凝胶试验组（66例）或凝胶基质对照组（62例）,分别给予米诺地尔凝胶或基质,每日2次,外用,共3个月.结果 在毛发开始生长时间、生长长度、脱发面积减少和综合评价,试验组均优于对照组;2组药物不良反应发生率分别为7.58%,6.45%（P＞0.05）.结论 米诺地尔凝胶治疗斑秃安全、有效.     

RU 58841-myristate--prodrug development for topical treatment of acne and androgenetic alopecia

Acne and androgenetic alopecia are linked to androgen effects and therefore should improve following topical application of antiandrogens. We present a new antiandrogen prodrug, RU 58841-myristate (RUM) for topical therapy. Almost devoid of affinity to the androgen receptor, as derived from investigations in the mouse fibroblast cell line 29 +/GR +, RUM is rapidly metabolised to the potent antiandrogen RU 58841 by cultured human foreskin fibroblasts and keratinocytes, male occipital scalp skin dermal papilla cells, and by cells of the sebaceous gland cell line SZ95. In order to improve a specific targeting of the hair follicle, RUM was loaded on solid lipid nanoparticles (SLN), which are already known to support dermal targeting effects. Physically stable RUM loaded SLN were produced by hot homogenization. Penetration/permeation studies carried out using the Franz diffusion cell proved only negligible permeation of reconstructed epidermis and excised porcine skin within 6 h, implying a more topical action of the drug. Targeting to the hair follicle using SLN was visualised by fluorescence microscopy, following the application of Nile Red labelled SLN to human scalp skin. Transmission electron microscopy (TEM) allowed to detect intact silver labelled SLN in porcine hair follicles of preparations applied to the skin for 24 h. RUM loaded SLN should be considered for topical antiandrogen therapy of acne and androgenetic alopecia.     

Liposomes and niosomes as potential carriers for dermal delivery of minoxidil

The aim of this work was to formulate minoxidil loaded liposome and niosome formulations to improve skin drug delivery. Multilamellar liposomes were prepared using soy phosphatidylcholine at different purity degrees (Phospholipon 90, 90% purity, soy lecithin (SL), 75% purity) and cholesterol (Chol), whereas niosomes were made with two different commercial mixtures of alkylpolyglucoside (APG) surfactants (Oramix NS10, Oramix CG110), Chol and dicetylphosphate. Minoxidil skin penetration and permeation experiments were performed in vitro using vertical diffusion Franz cells and human skin treated with either drug vesicular systems or propylene glycol-water-ethanol solution (control). Penetration of minoxidil in epidermal and dermal layers was greater with liposomes than with niosomal formulations and the control solution. These differences might be attributed to the smaller size and the greater potential targeting to skin and skin appendages of liposomal carriers, which enhanced globally the skin drug delivery. The greatest skin accumulation was always obtained with non-dialysed vesicular formulations. No permeation of minoxidil through the whole skin thickness was detected in the present study irrespective of the existence of hair follicles. Alcohol-free liposomal formulations would constitute a promising approach for the topical delivery of minoxidil in hair loss treatment.     

Case reports: alopecia universalis: hair growth following initiation of simvastatin and ezetimibe therapy

Alopecia areata is an organ specific autoimmune disease in which hair is lost in various patterns. Its most extreme form, alopecia universalis, is the total loss of all scalp and body hair. This form of the condition is very resistant to treatment and spontaneous remission is quite rare. The following is a case of a 54-year-old male with longstanding alopecia universalis who began to grow dense hair on his scalp as well as patchy hair growth on his face, pubic and axillary areas one month after starting a course of simvastatin 40 mg and ezetimibe 10 mg daily prescribed for his hyperlipidemia. For 2 years prior to starting the combination drug, he had taken simvastatin 40 mg alone without evidence of any hair growth. The combination of simvastatin and ezetimibe has previously demonstrated synergistic immunomodulatory effects, which most likely accounts for the clinical response in this case.