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PubMed1994

The same enzymes catalyze sulfation of minoxidil, minoxidil analogs and catecholamines.

Rat liver sulfation of minoxidil and minoxidil analogs is described and the enzymes responsible are compared with those that sulfate catecholamines. Our study of minoxidil sulfation showed male-dominant sex dimorphism of the enzyme activity due to two enzymes that coelute with dopamine sulfotransferases. The most abundant isoform, in our routine assay, is minoxidil sulfotransferase 2 (P2). Sulfation ability by this enzyme parallels minoxidil analog antihypertensive ability. Minoxidil, analog and dopamine sulfotransferases were not separable by several different chromatographic methods, supporting their identity. The minoxidil sulfotransferase activity dropped in hypophysectomized males, due mostly to diminished levels of minoxidil sulfotransferase 2/dopamine sulfotransferase II, which appears to be aryl sulfotransferase IV. Its relationship to the minoxidil sulfotransferase reported by the Falany group is not clear. Here, we describe the exploration of rat liver sulfation of antihypertensive minoxidil (2,4-diamino-6-piperidinopyrimidine-3-oxide), and several minoxidil analogs. Minoxidil sulfation was first reported in rat and human liver cytosol by Johnson's group at Upjohn [1,2]. Our interest in the sulfation process arose because direct action of minoxidil sulfate had been implicated both in vivo [3,4] and in vitro [5] in blood pressure control processes.

Animals↗
PubMed1994

Stimulation of Cl conductance by minoxidil sulfate and K conductance by minoxidil in eccrine clear cells.

Minoxidil sulfate (MXS), an antihypertensive agent and hair growth promoter, has been reported to stimulate K channels in vascular smooth muscle cells. We now report that MXS stimulates whole cell Cl currents, whereas minoxidil (MX) stimulates K currents in dissociated eccrine clear cells. Using whole cell clamp techniques we observed that: 1) 1 mM MXS stimulated sweat secretion in vitro; 2) MXS depolarized the membrane potential by as much as 40 mV; 3) MXS stimulated membrane conductance, increased inward current and shifted the reversal potential to the right when physiological electrolyte solutions were used; 4) in symmetrical Cl (Cl/Cl) solutions without permeable cations, MXS induced outwardly rectifying current-voltage (I-V) relationships; 5) in the Cl/Cl solutions, the MXS-induced current responses to imposed voltage pulses showed time-dependent activation, especially at the depolarizing potentials; 6) the reversal potential of the MXS-stimulated I-V curves in the Cl/Cl solutions shifted to the right by 55 mV when [Cl] in the bath was decreased from 157 to 7 mM; 7) MXS did not elevate cytosolic Ca or cAMP, although prolonged exposure to a Ca-free solution abolished the effect of MXS and 8) MXS-stimulated conductance was partially inhibited by diphenylamine-2-carboxylic acid, a blocker of Cl channels. The data suggest that MXS stimulates Cl channels, most likely depolarization-activated, outwardly rectifying channels. In contrast, the parent compound MX hyperpolarized the membrane potential and stimulated outward current without elevating cytosolic Ca and was independent of extracellular Ca, suggesting that MX stimulates Ca-insensitive K currents.

Animals↗
PubMed1993

Topical minoxidil therapy for androgenic alopecia in the Middle East. The Middle-Eastern Topical Minoxidil Study Group.

BACKGROUND: A 48-week open label trial was conducted in five Middle-Eastern countries (Lebanon, Egypt, Saudi Arabia, Jordan, and the United Arab Emirates) to determine the safety and efficacy of 2% minoxidil in the treatment of early androgenic alopecia and to compare the response with Western countries. METHODS: One hundred and ninety-five men aged between 19 and 47 years were enrolled. The duration of their baldness varied from 6 months to 10 years, and they all showed a type III vertex or type IV of the modified Hamilton scale. Baldness pattern, diameter of the balding area, hair counting within a 2.5 cm bald patch as well as investigator's and patient's evaluation were regularly noted. RESULTS: No significant changes were observed in vital signs or laboratory parameters. Of the 161 patients considered evaluable at 48 weeks, 80% showed moderate to dense growth. The mean increase in nonvellus hair at 12 months was 234. CONCLUSIONS: The age of the patient and the type of baldness rather than its duration affected the final outcome.

Administration, Cutaneous↗
PubMed1990

Minoxidil sulfate is the active metabolite that stimulates hair follicles.

An important step in understanding minoxidil's mechanism of action on hair follicles was to determine the drug's active form. We used organ-cultured vibrissa follicles to test whether it is minoxidil or its sulfated metabolite, minoxidil sulfate, that stimulates hair growth. Follicles from neonatal mice were cultured with or without drugs and effects were assessed by measuring incorporation of radiolabeled cysteine in hair shafts of the treated follicles. Assays of minoxidil sulfotransferase activity indicated that vibrissae follicles metabolize minoxidil to minoxidil sulfate. Dose-response studies showed that minoxidil sulfate is 14 times more potent than minoxidil in stimulating cysteine incorporation in cultured follicles. Three drugs that block production of intrafollicular minoxidil sulfate were tested for their effects on drug-induced hair growth. Diethylcarbamazine proved to be a noncompetitive inhibitor of sulfotransferase and prevented hair growth stimulation by minoxidil but not by minoxidil sulfate. Inhibiting the formation of intracellular PAPS with chlorate also blocked the action of minoxidil but not of minoxidil sulfate. Acetaminophen, a potent sulfate scavenger blocked cysteine incorporation by minoxidil. It also blocked follicular stimulation by minoxidil sulfate apparently by directly removing the sulfate from the drug. Experiments with U-51,607, a potent minoxidil analog that also forms a sulfated metabolite, showed that its activity was inhibited by both chlorate and diethylcarbamazine. These studies show that sulfation is a critical step for hair-growth effects of minoxidil and that it is the sulfated metabolite that directly affects hair follicles.

Acetaminophen↗
PubMed1990

Immunohistochemical and autoradiographic findings suggest that minoxidil is not localized in specific cells of vibrissa, pelage, or scalp follicles.

Immunohistochemistry with a minoxidil antibody suggested that minoxidil-immunoreactivity is associated with the root sheaths, laterally orientated differentiating matrix cells, and dividing epithelial cells of cultured vibrissa follicles of pigmented and albino neonatal mice. The dermal papilla and connective tissue sheath were devoid of minoxidil-immunoreactivity. To verify that minoxodil-immunoreactivity in the follicles was specific, immunostaining was conducted with dissected whisker pads, formalin-fixed "dead" follicles, and sections of spleen, liver and kidney (non-haired organs) cultured with minoxidil. Microscopic examination revealed minoxidil-immunoreactivity in all of these tissues. Follicles and whisker pads cultured with minoxidil, then washed for one h in media were devoid of minoxidil-immunoreactivity. These data suggest that minoxidil-immunoreactivity in cultured vibrissa follicles is probably non-specific. Sections of skin from C3H and CF1 mice which were topically dosed with minoxidil (in vivo) showed no minoxidil-immunoreactivity. Autoradiography demonstrated that tritiated minoxidil was bound in vivo and in vitro only to melanin granules in pigmented follicles of rodent and human tissue. This is probably non-specific binding since melanin is known to accumulate several chemically and pharmacologically unrelated drugs. It is reasonable to conclude that, under the conditions of these experiments, minoxidil is not specifically localized in any cells of whisker, pelage or, scalp follicles.

Animals↗
PubMed1987

Action of topical minoxidil in the bald stump-tailed macaque.

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.

Administration, Topical↗
PubMed1987

Androgenetic alopecia: treatment results with topical minoxidil.

A double-blind 12-month trial was conducted to evaluate the safety and efficacy of topical minoxidil in patients with androgenetic alopecia. During the first 4 months of the study, patients applied a topical solution containing either 2% minoxidil, 3% minoxidil, or placebo to their scalps twice daily. At the end of the fourth month, patients taking placebo were crossed over to treatment with 3% minoxidil solution. Of 60 patients enrolled in the study, 43 were evaluable at month 12. Hairs were counted in a 1-inch target area and classified as vellus, indeterminate, and terminal; the latter two classifications were combined as nonvellus hairs for further statistical analysis. All three groups had significant increases in total, nonvellus, and terminal hair counts between baseline and month 4 and between month 4 and month 12. At month 4 the average total hair counts increased from a baseline mean of 158.2 to 270.2 in the 2% minoxidil group, from 156.6 to 287.0 in the 3% minoxidil group, and from 162.6 to 246.9 in the placebo group. At month 12 the means were 415.6, 448.5, and 471.1 in the 2% minoxidil, 3% minoxidil, and placebo-3% minoxidil crossover subjects, respectively. The increases from month 4 to month 12 were highly significant for each group (p = 0.0001). Average increases in nonvellus hair counts between months 4 and 12 were 216, 181, and 264 in the 2% minoxidil, 3% minoxidil, and placebo-to-3% minoxidil crossover groups, respectively, all highly significant differences from zero (p = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1995

The effect of minoxidil analogues and metabolites on the contraction of collagen lattices by human skin fibroblasts.

Minoxidil, in addition to its effect on hypertension and hair growth, has been proposed as a potential antifibrotic agent. Minoxidil inhibits the contraction of collagen lattices by human fibroblasts in vitro. However, the mechanism of inhibition is unknown. As minoxidil is metabolised in the body to minoxidil glucuronide and minoxidil sulphate, we investigated the potencies of these metabolites to inhibit collagen lattice contraction. We also studied selected analogues of minoxidil to assess the influence of certain functional groups in the inhibition. The major metabolite, minoxidil glucuronide, proved to be inactive, whereas minoxidil sulphate was considerably more active than minoxidil. In terms of the structural analogues, the substitution of one amino group by a methyl group resulted in loss of the inhibitory activity; removal of the nitroxide oxygen led to stronger inhibition than with minoxidil. Further studies are planned to learn more about a possible role for minoxidil in wound contraction.

Animals↗
PubMed1987

Long-term follow-up of men with male pattern baldness treated with topical minoxidil.

Forty-one men with male pattern baldness completed 132 study weeks (2 years 9 months) with topical minoxidil and had follow-up 1-inch target-area vertex scalp hair counts. Initially these men were treated with either twice-daily 2% topical minoxidil for 12 months or 3% topical minoxidil for 8 to 12 months (one third of the subjects received placebo for the first 4 months). After 12 months all subjects continued to apply 3% topical minoxidil twice daily for 1 more year, after which they were randomized to once- versus twice-daily topical minoxidil for an additional 9 months. Those subjects who changed to once-daily application of topical minoxidil at 2 years had a mean change from baseline nonvellus hair count at 1 year of 291.2 (range of hairs four to 553) and at 2 years 9 months of 235 (two to 592 hairs). Those subjects who continued with twice-daily application of topical minoxidil throughout the study had a mean change from baseline nonvellus hair count at 1 year of 323 (15 to 589 hairs) and 335 (13 to 808 hairs) at 2 years 9 months with maintenance topical minoxidil. There were subjects on both maintenance schedules of topical minoxidil who lost some of the nonvellus hair they had initially gained with topical minoxidil; however, there was a greater mean loss in those patients following the once-daily versus twice-daily topical minoxidil regimen (p = 0.05). No subject lost nonvellus target hair as compared with baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Topical↗
PubMed1987

Topical minoxidil in early androgenetic alopecia.

A randomized, double-blind trial was conducted to determine the relative efficacy and safety of topical minoxidil solution for progressive male pattern baldness. One hundred fifty men with a discernible vertex balding spot were randomly assigned to treatment with either 2% topical minoxidil, 3% topical minoxidil, or placebo. After 4 months, patients receiving placebo were crossed over to 3% minoxidil. The study was concluded after 12 months of treatment, at which time 100 subjects were evaluable. Efficacy was determined primarily by objective hair counts at monthly intervals and by subjective patient evaluations at 4 and 12 months. Patients applying active medication had significantly greater growth of nonvellus hairs at 4 months than did their placebo counterparts (p = 0.0018 for 2% minoxidil vs placebo; p = 0.0167 for 3% minoxidil vs placebo). In patients crossed over from placebo to 3% minoxidil, the rate of growth of nonvellus hairs increased to fifteen hairs a month during the next 4 months and slowed to ten hairs a month during the last 4 months. Within-group analyses for month 12 evaluable patients demonstrated significant increases in total hair counts for all three groups (p less than or equal to 0.0001). According to investigator evaluations at month 12, 82% of the 2% minoxidil group, 78% of the 3% minoxidil group, and 83% of the placebo to 3% minoxidil group had new hair growth. Clinically insignificant minoxidil blood levels resulted from scalp absorption. Thirty-six medical events in twenty-six patients were deemed related to the study drug; twenty-seven of these events were dermatologic in nature, and all were mild and self-limiting.

Administration, Topical↗
PubMed1989

Minoxidil stimulates mouse vibrissae follicles in organ culture.

Minoxidil, a potent vasodilator, stimulates the growth of terminal hair from vellus or miniaturized follicles in balding scalp. To study minoxidil's action on isolated follicles we developed and validated an organ culture system using mouse whisker follicles. Control follicles cultured without minoxidil showed macroscopic changes including kinking of the hair shafts and bending of the follicles. Necrosis was evident in the differentiating epithelial elements forming the cuticle, cortex, and inner root sheath. These abnormalities were eliminated or greatly reduced in minoxidil-treated follicles. The morphology of these follicles was consistent with the production of new hair during culture. Direct measurement demonstrated that minoxidil-treated follicles grew significantly longer than control follicles during the 3-d culture. Minoxidil increased the incorporation of radiolabeled cysteine and glycine in follicles compared with control treatment. Doses of minoxidil up to 1 mM caused increased cysteine incorporation, while higher doses were inhibitory. Experiments with labeled thymidine indicated that minoxidil induced proliferation of hair epithelial cells near the base of the follicle. Autoradiography also showed that cysteine accumulated in the keratogenous zone above the dermal papilla. These studies demonstrate that organ cultured follicles are suitable for determining minoxidil's mechanism of action and may be useful for studying other aspects of hair biology. The results also show that minoxidil's effect on hair follicles is direct. This suggests that minoxidil's action in vivo includes more than just increasing blood flow to hair follicles.

Animals↗
PubMed1987

Suppression of fibroblast proliferation and lysyl hydroxylase activity by minoxidil.

The effect of minoxidil on lysyl hydroxylase activity and proliferation of human skin fibroblasts in culture was examined. Exposure of cells to minoxidil resulted in a specific loss of lysyl hydroxylase activity, the extent of which was dependent on the concentration of minoxidil from 25 to 500 microM and the duration of the treatment from 6 to 48 h. This phenomenon was unaffected by culture conditions, i.e. ascorbic acid status, serum concentration, and cell density. Minoxidil added directly to cell extracts had no effect on lysyl hydroxylase activity, showing a requirement for intact cells. Mixing experiments with extracts of minoxidil-treated cells and controls gave additive results which rule out the possibility that a metabolite derived from minoxidil could be inhibiting the enzyme activity. The effect of minoxidil on fibroblast lysyl hydroxylase activity disappeared in the presence of cycloheximide, an inhibitor of protein synthesis. Moreover, the recovery of the enzyme activity that occurred after removal of minoxidil from the culture medium could be prevented by actinomycin D, an inhibitor of RNA synthesis. These results indicate that minoxidil may inhibit the synthesis of lysyl hydroxylase in the cell. In addition to suppressing fibroblast lysyl hydroxylase activity, minoxidil caused inhibition of cell growth within 48 h in a manner dependent on the concentration from 10 to 1000 microM, the latter resulting in almost complete cessation of cell proliferation. This effect was not accompanied by cytotoxicity as judged by the criteria of dye exclusion, plating efficiency, growth recovery, and protein synthesis. The inhibition of fibroblast proliferation by minoxidil appeared to be related to its ability to inhibit DNA synthesis measured by incorporation of tritiated thymidine into acid-precipitable material.

Antihypertensive Agents↗
PubMed1980

Rebound hypertension following minoxidil withdrawal.

Minoxidil, a potent peripheral vasodilator, was used concomitantly with other antihypertensive drugs for severe hypertension in three children for 47 to 158 weeks at the dosage of 40 to 50 mg/day. Two patients had three and two courses of minoxidil, respectively. Attempts were made to withdraw minoxidil in all children because of severe hypertrichosis. Minoxidil was withdrawn over periods varying from four to 12 weeks. Rebound hypertension manifesting as hypertensive encephalopathy occurred in all when minoxidil was withdrawn rapidly. The occurrence of rebound hypertension correlated with the total cumulative dose of minoxidil in mg/kg/week given prior to the withdrawal (P less than 0.05) and the rapidity (four to eight weeks) with which minoxidil was withdrawn (P less than 0.05), but not with the total duration of therapy, duration at maximal dosage, or the amount of minoxidil in mg/kg on the day prior to withdrawal. Rebound hypertension also did not occur when minoxidil was withdrawn gradually (12 weeks) or if the patient was receiving a small dose (2.5 to 5 mg/day). Pretreatment with an alpha-blocking agent (prazosin) or the discontinuation of the concomitantly administered beta-blocker (propranolol) prior to the withdrawal seemed to prevent rebound hypertension. We suggest that the dosage of minoxidil should be decreased very gradually.

Adolescent↗
PubMed1986

Dose-response study of topical minoxidil in male pattern baldness.

Eighty-nine healthy men with male pattern baldness completed a 6-month double-blind, placebo-controlled study of 0.01%, 0.1%, 1%, and 2% topical minoxidil. Subjects on 2% topical minoxidil had a statistically significant increase in mean total target area hair count over baseline compared to the placebo, 0.01%, and 0.1% topical minoxidil groups (p = 0.04). Changes from baseline were more impressive with the 2% topical minoxidil group but not significantly different from the 1% topical minoxidil group in all parameters of objective response to treatment. The investigator, however, rated more subjects as having at least a moderate cosmetic response to treatment in the 2% versus 1% topical minoxidil treatment group. These results indicate that 1% topical minoxidil is the lowest effective concentration of topical minoxidil for male pattern baldness of those tested. Because of the more impressive changes in hair counts and the cosmetic preference for the 2% versus 1% topical minoxidil, 2% topical minoxidil may be the standard preferred treatment for male pattern baldness.

Adult↗
PubMed1990

The action of diazoxide and minoxidil sulphate on rat blood vessels: a comparison with cromakalim.

1. The actions of diazoxide and minoxidil sulphate have been compared with those of cromakalim in rat aorta and portal vein. 2. Diazoxide and minoxidil sulphate hyperpolarized the rat portal vein in a similar manner to cromakalim. 3. Cromakalim, diazoxide and minoxidil sulphate increased 42K and 86Rb efflux from rat portal vein, although minoxidil sulphate had only a small effect on 86Rb efflux. 4. Cromakalim, diazoxide and minoxidil sulphate increased 42K efflux from rat aorta but only cromakalim and diazoxide increased 86Rb efflux from this tissue. 5. Glibenclamide inhibited the relaxant actions of cromakalim, diazoxide and minoxidil sulphate on rat aorta and the increase in 42K efflux produced by these agents in this tissue. 6. Diazoxide relaxed an 80 mM KCl-induced contraction of rat aorta, whilst cromakalim and minoxidil sulphate were without effect. 7. Cromakalim, diazoxide and minoxidil sulphate had no effect on cyclic AMP or cyclic GMP concentrations in rat aorta. 8. It is concluded that diazoxide and minoxidil sulphate like cromakalim exhibit K+ channel opening properties in vascular smooth muscle. Diazoxide exerts an additional inhibitory action not related to the production of cyclic AMP or cyclic GMP. The action of minoxidil sulphate may be primarily located at a K+ channel which is relatively impermeable to 86Rb.

Animals↗
PubMed1992

The importance of proper vehicle selection in the detection of minoxidil sensitivity.

BACKGROUND: The correct selection of vehicles for patch testing specific substances is essential in the evaluation of suspected allergic contact dermatitis. A reaction to a chemical may be dependent not only on the concentration tested but also on the vehicle in which it is tested. In cases of suspected allergic contact dermatitis to minoxidil, propylene glycol, and alcohol formulations, patch testing is usually done with the formulation of minoxidil in alcohol and/or minoxidil in petrolatum. OBSERVATIONS: An acute contact dermatitis of the scalp developed in a 34-year-old white man while he was using minoxidil (Rogaine [2% minoxidil in a solution of alcohol 60% vol/vol, propylene glycol, and water]) solution. Patch testing with 2% minoxidil in alcohol and 2% minoxidil in petrolatum showed no reaction, while both Rogaine solution and 2% minoxidil in propylene glycol produced papulovesicular plaques. CONCLUSIONS: Patch testing in cases of suspected minoxidil allergic contact dermatitis should include testing with minoxidil in propylene glycol. Omitting this testing may cause diagnoses and therapeutic formulation alternatives to go unrecognized.

Adult↗