TOPICAL MINOXIDIL AND AMINEXIL SOLUTION

HAIR4U 10%
Dr. C Sakthivel

Hair Growth Cycle

Hair Growth Cycle

Stages
Anagen = growth; Catagen = involution; Telogen = rest

Hair Growth Cycle

Normal scalp activity
Anagen = 90-95% Catagen = <1% Telogen = 5-10%

At the end of telogen, hair is released and the next cycle is initiated Up to 100 hairs in telogen are shed each day and about the same number of follicles enter anagen

Alopecia
Definition:
Origin: Gr. Alepekia = a disease in which the hair falls out Loss of hair. Absence of hair from skin areas where it is normally present

Androgenetic Alopecia (AGA) Definition

Hereditary thinning of the hair induced by androgens in genetically susceptible men and women

Also known as
Male-pattern hair loss or common baldness in men Female-pattern hair loss in women

30% of white men by age of 30. 50% of white men by age of 50

Androgenetic alopecia
Miniaturization of follicles Decreased anagen/Increased telogen Increased latency to go into anagen phase

Patterned hair loss from the scalp.

Whites 4x than black men

Average rate of hair loss of about 5% per year

Some men go completely bald in less than 5 years but most take 15-25 years

Male-pattern baldness
Hair loss occurs on the temples and crown of the head with sparing of the sides and back. hair thinning in an "M"-shaped pattern pattern reflects the distribution of androgen-sensitive follicles androgens shorten the anagen phase and promote follicular miniaturization, leading to gradual hair thinning

Progression of male pattern baldness

Progression of male pattern baldness

Role of DHT
Testosterone converted to DHT with the help of 5 reductase. Persons with an inherited deficiency of type II 5 -reductase & castrated prepubertal boys or eunuchs do not develop androgenic alopecia Under the influence of DHT, the terminal follicle is converted to a vellus follicle High concentrations of DHT seen in the scalp of patients with androgenic alopecia.

Androgenetic Alopecia
Women also may experience AGA, often with thinning in the central and frontal scalp area but usually without frontal temporal recession conditions of hyperandrogenism, such as hirsutism, ovarian abnormalities, menstrual irregularities, acne, and infertility are responsible. Concomitant decrease in estrogens may also contribute to AGA.

Pathophysiology
Normally; On the top: Androgen-sensitive follicles On the sides and back of the scalp: androgen-independent follicles In genetically predisposed individuals;(Under Influence of Androgens) Terminal hair follicles are transformed into vellus. (terminal and intermidiate hairs) Shortened anagen and an increased telogen. Decreased growth of hair on the scalp as well as axilla

PATHOGENESIS
1. Increased telogen hair count:
During successive passages through the hair cycle the anagen phase becomes shorter and the telogen phase elongates. Anagen to telogen ratio : 12:1 to 5:1

Telogen hairs are more loosely anchored to the follicle The new anagen hair is shorter than its predecessor

Increased telogen count - increased hair shedding

latency period between telogen and anagen becomes longer

2. Follicular miniaturization
Progressive diminution of hair shaft diameter and length in response to androgens stepwise in size of the follicle with each successive cycle

Diagnosis & Evaluation

Androgenetic alopecia diagnosis
Characteristic pattern of hair loss
Miniaturization in thinning areas Family history is supportive but not necessary

Evaluation
Trichoscan
Normal scalp
Thick terminal hair Fine vellus hair

Miniaturization
Thick terminal hair Fine vellus hair Intermediate diameter hair

Evaluation
Regions of the scalp

Patient Evaluation
Studies reveal negative psychosocial impact with hair loss
Body image dissatisfaction Negative stereotype:
Older Weaker Less attractive

Counselling patients on expectations with treatment

Minoxidil
Therapeutic class: Orally: Antihypertensive, Peripheral Vasodilator Topically: For alopecia

Indication and dose : ALOPECIA ANDROGENETICA

Dose is 1 ml of the high strength (10%) solution applied to the affected areas of the scalp twice daily. (maximum total daily dose is 2 ml). Hair and scalp should be dry prior to application. Duration: till adequate clinical response.

Mechanism of minoxidil
1. increase the linear growth rate of hair

2. increase the diameter of the hair fibre

3. alter the hair cycle, either shortening telogen or prolonging anagen, 4. or act through a combination of these effects. Present evidence suggests that minoxidil acts mainly on the hair cycle; it may also increase hair diameter.

Mechanisms of action
Minoxidil may affect the androgen metabolism in the scalp by inhibiting the capacity of androgens to affect the hair follicles. Acts at the level of the hair follicle, as a potassium-channel agonist or a direct stimulant Minoxidil sulfate is active metabolite responsible for stimulating hair follicles reverse the miniaturization process of androgenetic alopecia by normalizing the hair follicle cycle.

Other mechanisms of action

Minoxidil is a potent activator of the cytoprotective isoform of prostaglandin endoperoxide synthase-1, which is the main isoform present in the dermal papilla Incorporation of cysteine into the follicle is measurably increased. There is no apparent antiandrogen effect on hair follicle epithelium. Increased scalp blood flow Prolongation of the anagen phase may result in follicular hypertrophy. Minoxidil appears to work only on suboptimal follicles, with no further stimulation of normal hair follicles

Minoxidil-induced hair growth mediated by adenosine

Adenosine
Ecto-ATPase Adenosine Receptors ABC transporter PIP3 , cAMP

ATP
K+

Minoxidil Sulfate

SUR

Kir

Dermal Papilla Cells

KATP channel

Ca2+ c-fos VEGF

Release to extra-cellar

Hair growth
Li et al., J Invest Dermatol, 117, 1594-, 2001

Place in therapy
Topical minoxidil appears to be effective in producing moderate hair regrowth in 30% of men and 45% to 60% of women with alopecia androgenica
(Price, 1987a; DeVillez et al, 1994; Jacobs et al, 1993).

Response is best in patients less than 35- to 40-years-old, vertex balding of less than 10 cm diameter, and more than 100 intermediate hairs within the balding area at baseline
(DeVillez, 1990; Karam, 1993).

The American Academy of Dermatology guidelines for androgenetic alopecia list topical minoxidil solution as first-line medical treatment for both men and women (Drake et al, 1996).

J Dermatol. 2009 Aug;36(8):437-46.

Randomized clinical trial comparing 5% and 1% topical minoxidil for the treatment of androgenetic alopecia in Japanese men.
Tsuboi R, Arano O, Nishikawa T, Yamada H, Katsuoka K. Department of Dermatology, Tokyo Medical University, Tokyo, Japan.

The objective of this double blind trial was to verify the superiority in clinical efficacy of 5% topical minoxidil to 1% topical minoxidil The trial included 300 Japanese male patients aged 20 years or older with androgenetic alopecia Conclusion: Findings confirmed the superiority of 5% topical minoxidil to 1% topical minoxidil in treating Japanese men with androgenetic alopecia

British Journal of Dermatology Volume 138 Issue 3, Pages 407 - 411

Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells
Lachgar, Charveron, Gall & Bonafe 0 Laboratoire de Biologie Cellulaire Cutane, Institut de Recherche Pierre Fabre, Facult de Mdecine Rangueil, 133, route de Narbonne, 31064 Toulouse, France

The hair follicle dermal papilla which controls hair growth, is characterized in the anagen phase by a highly developed vascular network. VEGF mRNA is strongly expressed in dermal papilla cells (DPC) in the anagen phase,

Increasing minoxidil concentrations induced a dose-dependent expression of VEGF mRNA

Review: Topically Applied Minoxidil in Baldness

ERVIN NOVAK, M.D., THOMAS ). FRANZ, M.D., IOHN T. HEADINCTON, M.D.,AND RONALD C. WESTER, PH.D. From the Upjohn Company. Kalamazoo. Michigan. School of Medicine. University of Washington. Seattle. Washington, Medical School. University of Michigan, Ann Arbor, Michigati, and School of Medicine and School of Pharmacy. University of California, San Francisco, California

Blood Flow of the Scalp

Cumulative penetration increases with increased concentration minoxidil solutions High strength minoxidil solution increased blood flow when compared with the other treatments.

 High concentration of minoxidil suppressed activity of the enzyme lysyl hydroxylase thereby collagen synthesis Higher concentration of minoxidil produces higher scalp blood flow

Comparison of mean percentage change in interval hair weight per square centimetre for three treatment groups: 5% minoxidil, 2% minoxidil and placebo. Vertical line at 96 weeks indicates cessation of treatment.

 Mean change from baseline in nonvellus hair counts (per square centimetre) in men treated with 5% minoxidil solution (TMS), 2% minoxidil and placebo.

Why 10 % Minoxidil
Hair re-growth in response to minoxidil is dose dependent Minoxidil 5% is proven to grow 45% more than the 2% formula.

High strength minoxidil gives rapid response - as quick as 2 months

Minoxidil 10% faster results than the 2% or 5% minoxidil Minoxidil 10% is for those who have failed to regrow hair from 2% or 5% Minoxidil.

Place in therapy
Minoxidil has been tested in hundreds of clinical studies on thousands of volunteers and has been shown to be effective in the treatment of hair loss particularly on the vertex of the head. Minoxidil has been approved for use in treating male-pattern hair loss for more than 15 years.

Effects of 10% Minoxidil in treating male-pattern hair loss report that a majority of patients found Very effective to effective results in promoting new hair growth over the period of treatment

Pharmacokinetics
Elimination half-life of minoxidil is 22 hours; due to the rate of percutaneous absorption. Topical absorption of minoxidil is increased by increasing the dose applied, increasing the frequency of dosing and decreasing the barrier function of stratum corneum. Minoxidil is metabolized mainly in the liver and its metabolites are excreted in the urine.

Adverse effects
Itching and skin irritation of the treated area of scalp Dryness, irritation and pruritis was noted in less than 5% of patients. Contact dermatitis, scaling of the scalp, and inflammation or erythema of the scalp could also occur.

Changes in hair pigments (reddish tint in dark hair; salt-and-pepper appearance in dark hair; yellowish color in white hair.
unwanted hair growth on other parts of the body, including facial hair growth in women , local erythema, scalp flaking and rarely exacerbation of hair loss. LEUKODERMA of the scalp, darkening of skin.

Rarely changes in BP, Hypotension and M.I have occured

Perifollicular Fibrosis
Condition that accompanies all alopecia Research shows - abnormal build-up of thick, rigid, collagen often hindered new hair growth. Collagen around the hair root becomes rigid and tightens, pushing the root to the surface and causing premature hair loss. This causes the roots to become rigid and compresses the blood vessels that nourish and stimulate them leads to accelerated aging of hair roots. In men, stiffening of roots spreads; the roots produce hair that is increasingly fine and has an ever shorter life span.

AMINEXIL
Aminexil, patented research product of L'Oral's laboratories, came on the international market on June 20, 1996. Aminexil has been shown to increase hair density and hair growth by preventing perifollicular fibrosis. Hair thickness increased by 6% Many people suffer from hair loss after the summer or wintertime. Aminexil showed that such persons are no longer troubled by seasonal hair loss.

Clinical trials
In one world-wide placebo controlled study (1994 -1995) Aminexil was used for 42 consecutive days. 130 test participants; aged between 18 and 55 years, with Alopecia type II to V;

Increase in number of hair.

Hair thickness
The hair growth thickness investigation showed that by using Aminexil hair thickness increased by 6%.

Hair preservation

Thus aminexil controls seasonal hair loss

Clinical studies
Study was done to evaluate whether topical Aminexil lotion prevents or reduces hair loss which occurs after stoppage of oral finasteride treatment. 18 male patients aged from 20 to 43 years
Evaluation from global photographs showed a moderate decrease in 3 patients, a slight decrease in 6 patients and no changes in the remaining 9 patients. Conclusion : may be helpful in preventing hair loss after stopping finasteride treatment.

HAIR4 U
Minoxidil: 10 % Aminexil: 1.5% Formulation : solution. Bioadhesive polymer technology: Hydroxypropyl cellulose (0.15% and 0.3%)
A study in 22 healthy male volunteers proved that the extent of minoxidil absorption increases with an increase in contact time of drug on the scalp. (J Pharm Sciences Vol 79, Issue 6, pp 483-486, 1989)

Bioadhesive polymer
Minoxidil must remain in contact for at least four hours for sufficient absorption (75%). Addition of the bioadhesive polymer would prolong the contact time of the drug with the scalp. Keep minoxidil in solution form and prolong the time of absorption

Bioadhesive polymer
Marketed preparation contains alcohol and propylene glycol that evaporates resulting in a supersaturated solution. This leads to precipitation of minoxidil and thus abrupt absorption pattern addition of the polymer would not allow the thermodynamic activity of the formulation to change as quickly as the plain solution. It would keep minoxidil and aminexil in a solution form. In a study with excised mouse skin it was found that in a formulation (gel) containing the polymer, minoxidil was released over a prolonged period of 24 h.

Hydroxypropyl cellulose
derivative of cellulose soluble in both water and organic solvents. Trap water and produces a film that serves as a barrier to water loss. Hydroxypropyl cellulose possesses good surface activity but does not gel as it forms open helical coils In general Hydroxypropyl cellulose is a water-soluble thickener, emulsifier and film-former.

Contraindications
individuals with a history of sensitivity reactions to any of its components Pregnancy and breast feeding.

WARNINGS
Low blood pressure or are taking blood pressure lowering medications. People with heart failure or significant coronary heart disease Not be used in patients using occlusive dressings or other medicines on the scalp, a red, inflamed, infected, irritated or painful scalp (including psoriasis and sun burn) DISCONTINUE : RAPID HEART BEAT, DIZZINESS OR SHORTNESS OF BREATH

To prevent growth in unwanted areas: application only to the scalp, wash hands with soap and water immediately after use.

Dosage & administration

Applied directly to the scalp twice a day, every day, without skipping applications. 1 ml of the high strength (10%) solution applied to the affected areas The hair and scalp should be dry prior to topical application of minoxidil. Shake the solution well before use. care should be taken to apply the medicine on the scalp along with application on hair. Not to apply on other areas Wash hands after use.

Thanks