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... Shortly after the reports on hypertrichosis in the 1970s, it became -as Bryan [22] put it -an "open secret" that oral minoxidil, an antihypertensive, promoted the growth of terminal hair. The commencement of trials that examined the therapeutic impact of topical minoxidil solution was buttressed by "promising" observations physicians encountered in clinical practice [22]: dermatologists observed that 40% of male patients on minoxidil experienced growth of terminal hair, while another 40% reported halting in hair loss; the remaining 20% of patients reported no impact on hair growth. ...
... Shortly after the reports on hypertrichosis in the 1970s, it became -as Bryan [22] put it -an "open secret" that oral minoxidil, an antihypertensive, promoted the growth of terminal hair. The commencement of trials that examined the therapeutic impact of topical minoxidil solution was buttressed by "promising" observations physicians encountered in clinical practice [22]: dermatologists observed that 40% of male patients on minoxidil experienced growth of terminal hair, while another 40% reported halting in hair loss; the remaining 20% of patients reported no impact on hair growth. Clinical trials that examined the efficacy of topical minoxidil solution on alopecia began around 1978 [22], and like, Heymann [7], many dermatologists were excited when the US FDA approved the treatment of AGA with 2% minoxidil solution for men (in 1988) and women (in 1992) [7]. ...
... The commencement of trials that examined the therapeutic impact of topical minoxidil solution was buttressed by "promising" observations physicians encountered in clinical practice [22]: dermatologists observed that 40% of male patients on minoxidil experienced growth of terminal hair, while another 40% reported halting in hair loss; the remaining 20% of patients reported no impact on hair growth. Clinical trials that examined the efficacy of topical minoxidil solution on alopecia began around 1978 [22], and like, Heymann [7], many dermatologists were excited when the US FDA approved the treatment of AGA with 2% minoxidil solution for men (in 1988) and women (in 1992) [7]. ...
Background:
Recently, low-dose oral minoxidil (LDOM) has entered the landscape of therapies for androgenetic alopecia (AGA). We determined whether using LDOM is associated with improving AGA in a dose-dependent manner; secondarily, we examined whether a dose-dependent association also exists for safety.
Methods:
Systematic searches were conducted in PubMed and Scopus to identify studies that would be eligible for our quantitative analyses; the logistics of our analyses was determined by the data we gathered.
Results:
Six studies were eligible for quantitative analyses; we conducted meta-regressions. We found that, for persons with AGA, increasing the dosage of LDOM by 1 mg/day was - after six months - significantly associated with an expected sex-adjusted increase in hair diameter (mean difference = 1.4 μm, p = 0.01), total hair density (mean difference = 47.1 hairs/cm2, p = 0.007), terminal hair density (mean difference = 9.1 hairs/cm2, p = 0.001), risk of hypertrichosis (mean difference = 17.9%, p = 0.006), and cardiovascular adverse events (mean difference = 4.8%, p = 0.004).
Conclusions:
Our study produced new evidence as our work is the first to show a positive dose-dependent association between the use of LDOM and change in hair diameter, hair density, risk of hypertrichosis, and cardiovascular adverse events for persons with AGA. Future randomized trials could produce causal evidence that would corroborate these dose-dependent associations.
... It was repurposed as a hair loss treatment when hypertensive patients on oral treatment experienced increased hair growth as a side effect. 42 Topical minoxidil is thought to dilate scalp blood vessels, promoting hair growth by improving nutrient delivery to hair follicles. 43 It is available in different forms, such as solutions, foam, and shampoo, with the 5% solution being more effective than the 2% solution. ...
Androgenetic alopecia (AGA) is the most common nonscarring alopecia and is characterised by distinct gradual patterned hair loss. AGA is mediated by genetic predisposition and excessive follicular sensitivity to androgens, mainly in males, leading to the progressive conversion of scalp terminal hair into vellus hair. Although highly prevalent, it is not fatal but may have a severe psychosocial impact, especially on females and younger males. Significant advances have been made in understanding AGA's epidemiology and pathophysiology, but only 2 drugs remain approved by the FDA - finasteride and minoxidil. Prolonged use of these drugs, is a prerequisite for enhanced treatment response. However, this leads to poor medication adherence and adverse effects from extended use eg, the “postfinasteride syndrome” which persists beyond stopping the drug. Hence, there is a need for research on more effective alternative treatments for AGA, with fewer side effects.
This paper reviewed recent advances in AGA pathophysiology and its treatment options. The recently characterized structure of type 2, 5-alpha reductase holds significance in comprehending present and prospective treatments of AGA.
... Minoxidil constitutes another example of a drug that was repurposed twice by serendipity: it was originally conceived to treat ulcers but, while conducting trials in dogs, it was observed that it elicited a sustained reduction in blood pressure. Later, while conducting clinical trials to validate its antihypertensive efficacy in humans, minoxidil demonstrated an unexpected effect against hair loss (Bryan, 2011). The drug was FDA-approved as antihypertensive medication in 1979, and almost a decade later it became the first FDA-approved therapy against androgenic alopecia. ...
Drug repurposing involves exploring new medical uses for existing drugs, including approved, discontinued, shelved and investigational therapeutics. As the new indication is built on already available safety, pharmacokinetic and manufacturing data, drug repurposing represents an expedited way to develop innovative medications, and has found especial interest in the fields of rare and neglected conditions. It is estimated that about one third of recent approvals correspond to repurposing examples, and different public initiatives have been launched to foster the exploration of repurposing opportunities.
The present chapter reviews classical and recent examples of off-label use, drug rescue and drug repositioning at different stages of the drug development process, from sildenafil to aspirin, from thalidomide to adalimumab, among many others. It also discusses challenges and opportunities of drug repurposing, from commercial and legal obstacles to expansion of the drug repurposing horizons in the context of precision medicine and polypharmacology. At last, modern approximations to explore repurposing prospects in a systematic manner are summarized.
... Indeed, pharmacologic openers of K ATP channels (KCOs) were administered as antihypertensive agents prior to understanding their mechanism of action. Minoxidil was approved in 1971 for the treatment of hypertension (Bryan, 2011) followed by the introduction of diazoxide in 1976 (Lexicomp, 2020). Although the prototypic KCO, cromakalim, was synthesized from a β-blocker skeleton in the 1980s (Mannhold, 2004), it was not until 1983 that Noma and colleagues discovered the K ATP channel in cardiomyocytes (Noma, 1983). ...
Pharmacological openers of ATP-sensitive potassium (KATP) channels are effective antihypertensive agents, but off-target effects, including severe peripheral edema, limit their clinical usefulness. It is presumed that the arterial dilation induced by KATP channel openers (KCOs) increases capillary pressure to promote filtration edema. However, KATP channels also are expressed by lymphatic muscle cells (LMCs), raising the possibility that KCOs also attenuate lymph flow to increase interstitial fluid. The present study explored the effect of KCOs on lymphatic contractile function and lymph flow. In isolated rat mesenteric lymph vessels (LVs), the prototypic KATP channel opener cromakalim (0.01–3 µmol/l) progressively inhibited rhythmic contractions and calculated intraluminal flow. Minoxidil sulfate and diazoxide (0.01–100 µmol/l) had similar effects at clinically relevant plasma concentrations. High-speed in vivo imaging of the rat mesenteric lymphatic circulation revealed that superfusion of LVs with cromakalim and minoxidil sulfate (0.01–10 µmol/l) maximally decreased lymph flow in vivo by 38.4% and 27.4%, respectively. Real-time polymerase chain reaction and flow cytometry identified the abundant KATP channel subunits in LMCs as the pore-forming Kir6.1/6.2 and regulatory sulfonylurea receptor 2 subunits. Patch-clamp studies detected cromakalim-elicited unitary K⁺ currents in cell-attached patches of LMCs with a single-channel conductance of 46.4 pS, which is a property consistent with Kir6.1/6.2 tetrameric channels. Addition of minoxidil sulfate and diazoxide elicited unitary currents of similar amplitude. Collectively, our findings indicate that KCOs attenuate lymph flow at clinically relevant plasma concentrations as a potential contributing mechanism to peripheral edema.
SIGNIFICANCE STATEMENT
ATP-sensitive potassium (KATP) channel openers (KCOs) are potent antihypertensive medications, but off-target effects, including severe peripheral edema, limit their clinical use. Here, we demonstrate that KCOs impair the rhythmic contractions of lymph vessels and attenuate lymph flow, which may promote edema formation. Our finding that the KATP channels in lymphatic muscle cells may be unique from their counterparts in arterial muscle implies that designing arterial-selective KCOs may avoid activation of lymphatic KATP channels and peripheral edema.
... Minoxidil was originally investigated to treat ulcers; while conducting trials in dogs, it was observed that the compound elicited a prolonged reduction in blood pressure. Later, while undergoing clinical trials to prove its efficacy as antihypertensive medication, the drug showed an unexpected positive effect on hair loss [15]. It gained US FDA approval as antihypertensive medication in 1979 and in 1988 it became the first FDA-approved drug for the treatment of androgenic alopecia. ...
http://www.tandfonline.com/eprint/n2ctySRjNmJCaEm3VY7h/full
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Introduction: Drug repositioning implies finding new medical uses for existing drugs. It represents a cost-efficient approach, since the new indications are built on the basis of available information on pharmacokinetics, safety and manufacturing. Whereas most of the pioneering drug repurposing stories arose from serendipitous observations and clever exploitation of side effects, the drug discovery community has lately addressed repurposing initiatives in a more systematic manner. Today, in the middle of the omics era, we have the tools to explore drug repurposing opportunities in a tailored, personalized manner.
Areas covered: After a brief discussion on modern approaches to drug repurposing, the author connects the philosophies of drug repurposing and personalized medicine through the well-known and extended practice of off-label prescription. The author also discusses which, among current systematic repurposing approaches, are more appropriate to be integrated with the field of precision medicine.
Expert commentary: Personalized drug repurposing is not a new concept at all: for years, it has been known as off-label prescription, a practice widely accepted especially in some branches of medicine. Whereas in the past such approach was in many cases supported by empiric knowledge, today omics technologies allow us to face novel personalized drug repurposing options in a systematic manner.
Drug repurposing is a cost-effective method of discovering new treatments for diseases than traditional drug development methods. It involves virtual screening of chemical candidates with the aid of computational methods like molecular docking. Drug Repurposing against SARS-CoV2 focuses on current trends in drug repurposing against the novel coronavirus strains. The book aims to give readers an overview of drug repurposing against COVID-19 and various techniques involved in the process. The book consolidates available information on the pathophysiology, drug targets, and drug repurposing against COVID-19 into a single, convenient resource. Key features -An up-to-date compilation of the evidence that supports the drug repurposing for COVID-19. -How to use repurposing of available drugs for disease therapy. -Provides an improved understanding of pathophysiology and SARS-CoV2 viral entry pathways. - Provides references for further reading
Synopsis
Topical application of minoxidil in bald scalps of stumptailed macaques successfully induced regrowth of terminal hairs. The rate and degree of hair growth by minoxidil are much greater in the early stage of baldness in adolescent and young adults. Minoxidil also prevented the development of baldness when applied on non‐bald scalps of peri‐adolescent animals. Morphometric analysis of hair follicles (folliculograms) has brought a new aspect in observing cyclic dynamics and growth (transformation) of hair follicles. Using this analytic method and autoradiographic observation of DNA synthesis of hair follicles, the action of minoxidil appears to be a potent mitotic stimulator of the follicular as well as peri‐follicular germinal (or reserve) cells, thus inducing an enlargement of vellus follicles through the process of cyclic growth and maintaining anagen follicles in the growing phases. Most importantly, minoxidil has no influence in epidermal keratinocytes, sebaceous glands and other dermal components. During almost 3 years of consecutive treatment, the animals showed no detectable local or systemic side effects when examined by laboratory tests of blood cells, chemistry, steroid hormones, measurement of blood pressure and EKG test.
Le macaque a queue courte: exemple de calvitie
By means of increasingly more penetrating research efforts, the pharmaceutical industry is acquiring ever greater insight into disease and other adverse processes. This results in the discovery and development of drugs with more highly complex actions. This, together with a more stringent surveillance by government regulatory agencies, has increased the time required to develop a newly discovered entity from a few years in the 1950s and early 1960s to as much as 10–12 years at the present time. In cases where serendipitous discovery of new opportunities results in added dimensions for pursuit, the time required is even greater. The development of minoxidil as an agent to reverse androgenetic alopecia, now being concluded after 27 years, characterizes this more elaborate process.
Fifty-eight men with Hamilton scale type III vertex or type IV male pattern baldness were studied to determine the dose-response activity of low concentrations of topical minoxidil in promoting hair growth. The patients were treated with topical minoxidil at doses of 0.01%, 0.1%, 1%, or 2% or placebo in a randomized double-blind design for 6 months. At the end of 6 months, patients using 0.1%, 1%, and 2% topical minoxidil solutions showed a significantly greater difference in the mean increase of nonvellus hair growth in comparison with those using 0.01% minoxidil or placebo. There was a clear dose-response correlation for the increase of nonvellus hairs in the 0.1%, 1%, and 2% minoxidil treatment groups. There was a statistically significant difference in patient's self-evaluation of overall hair growth and degree of decreased hair shedding in the 1% and 2% minoxidil groups when compared with the other study groups. From this study we conclude that significant increases in nonvellus hair counts occur with 0.1% and greater doses of minoxidil. However, only in patients treated with the 1% and 2% solutions of minoxidil was there clinically perceptible hair growth.
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.
The effect of topical minoxidil (5% and 2% solutions) on hair regrowth was studied in the frontal bald scalp of 18 adolescent and adult stump-tailed macaques (Macaca arctoides). Gross observation of the hairiness and folliculogram analysis of the skin biopsy specimens have shown that minoxidil induces the enlargement of vellus follicles to the size of middle to terminal follicles (regrowth of hair effect), minoxidil maintains the terminal follicles in the prebald scalp of periadolescent animals (prevention of baldness effect), enlarged follicles regress after minoxidil is withdrawn, and hair follicular growth is once again stimulated when treatment with minoxidil is reinstituted. Hair regrowth was more prominent in the early stage of baldness among younger macaques than in baldness of longer duration in older animals. An in vitro study of 3H thymidine uptake revealed that the hair follicles in minoxidil-treated macaque skin showed significant enhancement of deoxyribonucleic acid synthesis in the follicular and perifollicular cells but not in the epidermal keratinocytes. Furthermore, the uptake of 3H minoxidil and its conversion to minoxidil sulfate (the active metabolite producing vasodilation) was relatively higher in the hair follicles than in the epidermis and dermis. Serum concentration of minoxidil was fairly constant 2, 4, 6, 15, and 24 hours after a single application (averaging 15 ng/ml with 5% minoxidil). Minoxidil's essential action in hair follicular growth may be as a potent vasodilator. However, a direct action on the hair follicle cannot be ruled out considering uptake and conversion of the drug to minoxidil sulfate within the hair follicle itself.
The hypotensive efficacies of two vasodilators, hydralazine and minoxidil, were assessed as these drugs were used individually in combination with beta-adrenergic blockade and diuretics in 11 hypertensive patients in whom elevated blood pressure had not been adequately controlled previously by other antihypertensive therapy.
Control supine blood pressure fell from 191/128 mm Hg on propranolol and hydrochlorothiazide to 169/108 mm Hg on hydralazine, with a significantly greater reduction to 142/92 mm Hg on minoxidil. Although sodium retention and tachycardia were controlled by the use of concomitant diuretics and beta-blockade, an increment in each of these drugs was occasionally required to prevent these complications. Renal function was changed little with the decrease in blood pressure. Plasma renin increased from a standing control of 14.5 mµg/ml/hr to 35.9 and 31.1 mµg/ml/hr, respectively, on hydralazine and minoxidil. These data suggest the role of vasodilators used in combination with beta-blockers and diuretics and indicate the greater therapeutic efficacy of minoxidil.