Review Topically Applied Minoxidil in Baldness ERVIN NOVAK,M.D., THOMASJ. FRANZ, M.D., JOHN T. HEADINGTON,M.D., AND RONALD C. WESTER,PH.D. From the Upjohn Company, Kalamazoo, Michigan, School idil and its metabolites can be removed by hemodi- of Medicine, University of Washington, Seattle, alysis. Washington, Medical School, University of Michigan, Ann Fluid retention and hypertrichosis are the most Arbor, Michigan, and School of Medicine and School of Pharmacy, University of California, San Francisco, California commonly occurring side effects of minoxidil. Hair regrowth in a patient with male pattern baldness was described in a case report of a hypertensive patient treated twice daily with 20 mg oral minoxidil.6 The Minoxidil, an orally administered, peripheral va- extensive hair regrowth continued after 10 months sodilator used to treat hypertension, causes hypertri- of therapy. New and increased hair growth as a side chosis in more than 80% of users. The drug reduces effect was also detected in an early clinical study elevated blood pressure by decreasing peripheral involving five of eight patients on oral minoxidil vascular resistance. Chemically, minoxidil is 2,4-di- therapy for 2 month^.^ Zappacosta' reported reversal amino-6-piperidinopyrimidine-3-oxide; it is soluble in of baldness in a patient on minoxidil for the treatment water to the extent of approximately 2 mg/ml, is of hypertension. more readily soluble in propylene glycol or ethanol, After the third week of therapy with oral minoxidil, and is nearly insoluble in acetone, chloroform, or hypertrichosis usually appears between the eyebrows ethyl acetate. Following oral administration of minox- and the hair line, in the malar and temporal areas, idil and in association with the reduction in peripheral on the backs of the arms, on the shoulders, and on vascular resistance, cardiac output is augmented, salt the legs. Hair growth has been noted at all dose and water are retained, and plasma renin activity levels, although it appears later and is less marked rises.',2 after the smaller doses of 10 mg or less per day. New When taken orally, minoxidil is at least 90% ab- hair growth ceases abruptly when minoxidil therapy sorbed from the human gastrointestinal tract. After is discontinued, but the patient's appearance does one 5-mg tablet of minoxidil, blood levels of the not return to normal for several months. Normal parent drug reach a maximum of 156.6 ng/ml within hormonal assays were recorded in 50 patients who the first hour and decline rapidly thereafter to 1.5 received minoxidil for 1 year or longer,'~~and we do ng/ml within 24 hours (Table 1). The average plasma not believe that excessive hair growth is a result of half-life in humans is 4.2 hours for the combination an endocrine abnormality. of parent drug and its metabolites. About 90% of administered drug is metabolized, predominantly by Overview of Efficacy and Safety conjugation with glucuronic and parent drug Dermal acute toxicity studies in rats have shown and metabolites are principally excreted in the urine. that minoxidil is not toxic when applied 10 mg/rat/ Minoxidil does not bind to plasma proteins, and its day and is slightly toxic at 30 mg/rat/day and 60 renal clearance corresponds to the glomerular filtration mg/rat/day. While no gross or microscopic lesions rate. In the absence of functional renal tissue, minox- were found in the rat skin, the pharmacologic effects included dose-related decreases in hemoglobin, de- creased erythrocyte counts, decreases in serum so- Address for correspondence: E. Novak, M.D., The Upjohn dium and chloride levels, and increases in serum Company, 7254-24-2. 301 Henrietta Street, Kalamazoo, MI 49001. cholesterol and heart and liver weight. 82 No. 2 MlNOXlDlL IN BALDNESS Novak eta/. 83 TABLE1. Mean Minoxidil Blood Levels from 20 Patients After Ingestion of One 5-rng Tablet Hours 0.0 1.o 2.5 4.0 7.0 11.0 16.0 24.0 Mean concentration of minoxidil (ng/rnl) 6.65 156.5 71.0 54.4 23.3 7.8 5.7 1.5 We are conducting the clinical research program treated 21 healthy men with pattern baldness with for topical minoxidil slowly and with caution because twice-daily topical applications of 1Yo or Soh minoxidil of the potent action of the systemic formulation of or the vehicle for minoxidil (water-propylene glycol- minoxidil on the cardiovascular system in hypertensive alcohol). The shortest and longest hairs measured patients. Initially, three 14-week studies involved were recorded for each treatment site through study daily bilateral applications of 1%, 3%, or 5% minoxidil week 25 (Table 2). Medications were applied only to circular areas 2 cm in diameter on the scalps of for 15.7 weeks (110 successive days), and no medi- patients with male pattern baldness. As expected, no cation was applied during weeks 16-25. Results were systemic side effects were observed. There was some expressed as the difference between an individual’s evidence of hair growth stimulation, appreciably de- minimum and maximum lengths of hair at baseline layed and variable in occurrence among patients. and at each evaluation period. A minimal increase in Long-term clinical studies of 6-12 months were mean hair length was seen in all treatment groups, started in 1980 and 1981. Since then, several clinical including the placebo group, between weeks 3-9 studies have been completed and new ones started. and at week 25. There were no statistically significant For example, in one open-label study, we evaluated differences among the groups in the hair growth the effectiveness of twice-daily unoccluded applica- during the 12-week medication period. tions of 5% minoxidil in men and women with After 15.7 weeks of treatment in this study, clinical alopecia areata and alopecia androgenetica. Therapy and statistical evaluations of the blood chemistries, was scheduled for 6 months in alopecia areata and CBC, urinalysis, and EKC were similar for subjects for 1 year in pattern baldness. Stimulation of hair receiving the 1% or 5% solutions of minoxidil and growth ranged from minimal early evidence to appre- those receiving the placebo vehicle, nor was there a ciable restoration toward typical terminal scalp hair. difference between mean pre- and postmedication It took 3-8 months to obtain the more definitive values in blood pressure, pulse rate, and body weights evidence of stimulated hair growth. Other investiga- in these subjects. Mild stinging, burning, itching, and tors who used a topically applied solution of 1% erythema were noted only after the evaluation at minoxidil in three patients with alopecia areata un- week 2 in 11 of 21 subjects (2 receiving 1% minoxidil, responsive to conventional treatments found local 4 receiving 5% minoxidil, and 5 receiving the vehicle). hair regrowth in the area of application within 4-6 These effects were thought to be due to the vehicle. weeks in two of the patients.” Fenton and Wilkinson” induced hair growth in 22 Absorption and Excretion After Topical Minoxidil of 30 (80.8%) patients with alopecia areata after 6 months of twice-daily topical applications of 1Yo In animal and human topical absorption studies, minoxidil lotion or ointment. Sixteen of these patients we have used I%,3%, and 5% minoxidil in a grew acceptable terminal hair. propylene glycol-ethanol-water vehicle. When ve- In a double-blind study, Headington and Novak’* hicles containing propylene glycol-alcohol-water TABLE2. Mean Hair Length (mm) in Topically Treated Area of Scalp in 21 Men with Pattern Baldness 1% Minoxidil 5% Minoxidil Placebo Week N Min Max N Min Max N Min Max 0 7 1.o 1.1 7 1.o 1.1 7 1.1 1.9 3 7 1.o 2.4 7 1.4 2.6 7 1.3 2.6 4 7 1.4 2.0 7 1.1 1.9 7 1.7 2.4 5 7 1 .o 1.1 7 1.o 1.1 7 1.o 1.9 9 5 1.4 2.8 6 2.2 3.3 6 1.3 2.0 13 5 2.4 2.4 7 2.7 2.7 5 1.4 2.0 25’ 3 20.0 49.7 6 43.3 48.3 4 22.5 26.3 * p = 0.0625 84 INTERNATIONAL JOURNAL OF DERMATOLOGY March 1985 Vol. 24 TABLE3. Percutaneous Absorption of Topical "C-Minoxidil in the Rat and Monkev __~~~~ Drug % of Applied Animal N Concentration Regimen Dose Absorbed' Rat 5 1% Single application 18.1% Single application after 9 daily applications 35.6% Rat 5 4% Single application 17.9% Single application after 9 daily applications 26.0% Monkey 3 1% Single application 17.2% Monkev 4 4% Single application 5.6% ~ ~ ~~~~ * Derived from the percentage of applied dose of labeled drug excreted in urine and stool were used, the in vitro transport data over 72 hours so tested at 2, 4, and 8 weeks tended to range from showed a cumulative penetration of 3.0 mg, 3.7 mg, nondetectable levels (radioimmunoassay sensitivity and 4.0 mg of drug from the 1%, 3%, and 5% of 1.4 ng/ml) to a maximum of 6.2 ng/ml. In a minoxidil solutions, respectively. The extent of per- double-blind study of 21 men with pattern baldness,'* cutaneous absorption in the rat and monkey, based a radioimmunoassay with a sensitivity of 1.4 ng/ml upon the percentage of the applied dose of 14C- showed no consistency or trend in minoxidil serum minoxidil excreted in the urine and stool, is shown levels (Table 4). The highest levels of minoxidil (6.2 in Table 3.