Minoxidil development

A 39-year-old man taking ciclosporin, whose second kidney transplant functioned subnormally, and who required treatment for hypertension with atenolol and minoxidil, developed ankle oedema, which was resistant to furosemide, despite doses of up to 750 mg daily. When metolazone 2.5 mg daily was added for 2 weeks his serum creatinine levels more than doubled, from 193 to 449 micromol/L. When metolazone was stopped the creatinine levels fell again. Ciclosporin serum levels were unchanged and neither graft rejection nor hypovolaemia occurred. ... 

Another potent peripheral vasodilator with hypotensive activity is minoxidil (U-10,858, XXXI). The drug was developed at the Upjohn Corporation, apparently as a follow-up of a previous clinical candidate, diallylmelamine -N-oxide (U-20,388, XXXII). The amine precursor, diallylmelamine (U-7720, XXXIII), is active in rats and dogs but not in man because the active... 

Patterson, S. C., Ramstad, T., and Mills, K. A. (2005). Development and validation of a procedure for the determination of minoxidil in hair-regrowth formulations using two variants of capillary zone electrophoresis. II Farmaco 60(6—7), 547—554. 

Despite these challenges, the area of K+ channel openers (PCOs) is emerging as an active area of drug design. Over the past 5-10 years, eight novel structural classes of PCOs have received systematic development benzopyrans (e.g., cromakalim, 7.27), cyanoguanidines (e.g., pinacidil, 7.28), thioformamides (e.g., aprikalim, 7.29), pyridyl nitrates (e.g., nicorandil, 7.30), benzothiadiazines (e.g., diazoxide, 7.31), pyrimidine sulphates (e.g., minoxidil sulphate, 7.32), tertiary carbinols, and dihydropyridines. These various classes have been subjected to analog preparation with compound optimization via structure-activity studies. 

N, N -Diallyl-pynmidine-2,4,6-triamine, U-7720 (23) was initially, developed as a potent antihypertensive agent. Later, its metabolite minoxidil (3) was found to be efficacious as both an antihypertensive orally and for hair growth topically. The systemic and local side effects of topical minoxidil (3) are essentially non-existent. 

This topic has been reviewed both generally [9], and specifically for variation in the benzopyran nucleus [10]. SARs have also formed part of several comprehensive and useful reports and reviews [11-15], while full details of lead and development KCAs are regularly updated in a useful compilation [16] devoted to modulators of K channels. Hence, this section will address recent advances, and those previously reported [9, 10], where further detail is now available. These are best presented in terms of the different series of KCAs based on the prototype molecules, cromakalim (1), RP 49356 (4), pinacidil (6), and nicorandil (7) that, together with the older compounds, minoxidil sulphate (8) and diazoxide (9), now recognized as KCAs, illustrate the widening range of structural types of this classification... 

A 57-year-old man developed a pigmented contact dermatitis after using topical minoxidil 5% for 2 years (12). Patch tests were negative with the European standard series and with a textile and finishes series, but positive with minoxidil 5% on days 3 and 7. However, withdrawal of the minoxidil did not lead to improvement after 10 months. 

A 26-year-old woman took 60 ml of minoxidil solution 5% and 1 hour later developed hypotension (75/ 40 mmHg) and tachycardia (130/minute). She was... 

As in the early phases of drug development, the identification of new indications for old drugs can be both rational and serendipitous. Rarely, even adverse events can be exploited as new indications, and the hair-growing properties of the antihypertensive drug called minoxidil is a famous example. 

In the discovery phase, metabolite identification is usually performed with a combination of in vitro and in vivo experiments using samples from different species in order to compare metabolite exposures. The structural identification of major circulating metabolites formed in nonclinical animal models as well as the metabolites formed in human in vitro systems is needed for the metabolites to be synthesized and their pharmacological activities and/or toxicological implications to be determined [25], In addition, metabolite identification can lead to the discovery of candidates with satisfactory clearance/PK properties and/or improved safety profile. Following are some examples of metabolites that were later developed as drugs desloratadine from loratadine, acetaminophen from phenacetin, morphine from codeine, minoxidil sulfate from minoxidil, fexofenadine from terfenadine, and oxazepam from diazepam. 

Liposomes were discovered by Dr. Alec Bangham in 1961. During his studies on phospholipids and blood clotting, he found that if he mixed phospholipids and water, tiny phospholipid bilayer sacs, called liposomes, would form spontaneously. Since that first observation, liposomes have been developed as efficient delivery systems for everything from antitumor and antiviral drugs, to the hair-loss therapy minoxidil ... 

Minoxidil (rogaine) was first developed as an antihypertensive agent (see Chapter 32) and was noted to be associated with hypertrichosis in some patients. A topical formulation of minoxidil... 

Minoxidil (6-amino-l,2-dihydro-l-hydroxy-imino-4-piperidino pyrimidine) has been shown to regrow hair with minimal side effects. This drug is a vasodilator and a potassium channel opener. It was originally developed... 

C. Minoxidil. Two adults developed profound hypotension (with tachycardia) requiring pressor support following 1.3-g and 3-g ingestions from topical minoxidil solutions. 

Sakr FM, Gado AM, Mohammed HR, and Adam AN. (2013). Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology A pilot study. Drug Design Development and Therapy, 1,413—423. 

Developments in clinically useful anti hypertensives - There has been a great deal of discussionis on work carried out to evaluate the therapeutic potential of combining a vasodilator with a 6-adrenoreceptor blocker in order to counteract the tachycardia associated with the former. The combination of hydralazine with propranolol (p.o.) is effective in hypertensive patients at doses which separately do not give a satisfactory hypotensive effect a similar situation holds for dihydralazine. Alprenolol (i.v.) also reduced the cardiac stimulation observed in normotensive and hypertensive patients after dihydralazine (i.v.). Minoxidil (PDP), in combination with propranolol and hydrochlorothiazide, appears to be more effective in refractory hypertensive patients than hydralazine. Practolol effectively blocks the tachycardia in normotensive dogs treated with hydralazine (i.v.) without potentiating the hypotensive effects, which suggests that tachycardia does not diminish the hypotensive effect of hydralazine. 

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