Flutagel ist eine innovative Weltneuheit. Es ist ein Gel, welches 1% Flutamide enthält. Flutamide (3`-trifluoromethyl-4`-nitromethyl propionylanilide) ist ein nichtsteroides Antiandrogen.

Es inhibiert die Bindung von Dihydrotestosteron (DHT) an den Androgenreceptor [1]. Diese Substanz, produziert von Schering-Plough, wurde als eine neue potente Substanz gegen Prostata Karzinome eingeführt (Martindale, 1993). Flutamide wird gut absorbiert und extensiv metabolisiert;

Sein aktiver Metabolit, 2-hydroxyflutamide, bildet sich schnell und wird nahezu vollständig von den Nieren ausgeschieden. Die systemische (orale) Verabreichung von Flutamide verursacht einige unerwünschte Nebenwirkungen, wie z.B. leichter Durchfall, Gynecomastia, reduzierte Libido und beeinträchtigte Spermienbildung in Männern und Feminisierung von männlichen Föten in schwangeren Frauen.

Topische Anwendung ist daher ein wichtiges Ziel für solch eine Substanz, insbesondere wenn manbeabsichtigt, sie bei Problemen der Haut anzuwenden. An dieser Stelle wollen wir betonen, dass unser Produkt nur für Männer gedacht ist. Frauen dürfen unser Produkt nicht verwenden. Die Motivation für uns, dieses Gel herzustellen, kommt hauptsächlich von einem Artikel von Sintov et al. [2] und wir haben nahezu die gleiche Formulierung für unser Gel gewählt, wie die Autoren in ihrer Arbeit.

Sintov et al. transplantierten menschliche Kopfhaut-Transplantate von Spendern mit Haarausfall auf sogenannte SCID-Mäuse (SCID = Severe combined immune deficient). Sie bestrichen die haarausfallanfälligen Haarfollikel mit einem 1% Flutamide-Gel, um zu versuchen, die miniaturisierten Haarfollikel wieder zu vergrössern. 

Hier sind einige Zitate aus dem Artikel von Sintov et al. [2] :

“Testosterone metabolites exert a significant hormonal influence on hair growth by interacting with receptors at the follicular papilla. It has long been known that an increased susceptibility of scalp follicles to these androgens is the main cause of androgenetic alopecia (or male-pattern baldness) in genetically predisposed individuals (Imperato-McGinley et al., 1974; Ebling et al., 1991).

In this type of alopecia, scalp follicles exhibit increased levels and activity of scalp 5a-reductase isoenzyme, which converts testosterone (T) to dihydrotestosterone (DHT) (Bingham and Shaw, 1973; Schweikert and Wilson, 1974). Taken together, increased conversion of T to DHT and increased DHT binding capacity in bald scalp as compared to hairy scalp (Sawaya et al., 1989) provide a mechanistic explanation for androgenetic alopecia. DHT shortens the hair cycle and progressively miniaturizes scalp follicles. The miniaturized follicles all remain present and thus the possibility of reversal by re-enlargement exists.

It is reasonable, therefore, to suppose that by administration of 5a-reductase inhibitors and:or non-steroidal antiandrogens, this reversal should occur.”


“Chen et al. (1995) showed that topical administration of finasteride (in ethanol:propylene glycol vehicle) caused local inhibition of androgen-controlled sebaceous gland growth in hamster flank organ and that had a similar action to that of the same doses of flutamide.
To date, clinical studies have not been performed for testing the efficacy of topical flutamide in male-pattern baldness.

It is likely thatthe success (i.e. effective with minimal systemic exposure) of this drug would be dependent on a well-designed vehicle that would increase skin accumulation and decrease percutaneous absorption.”

Ihre Ergebnisse waren beeindruckend :

“The two topical formulations, finasteride and flutamide gels, showed significantly greater efficacy (PB0.05) than the vehicle formulation in enlarging hair length and diameter as well as in increasing the number of hairs per graft. Fig. 1 presents the results after 60 days of graft treatment with the two antiandrogenic formulations and with the vehicle. For the grafts treated with flutamide and finasteride gels, the number of hairs were 1.22+-0.47 and 0.88+-0.95 hairs/0.5 mm² graft, respectively, versus 0.35+-0.6 hairs/graft for the vehicle-treated graft. Hair lengths were 5.82+- 0.50 and 4.50+-0.32 mm for the flutamide and finasteride groups, respectively, compared to 2.83+-0.18 mm for the vehicle-treated grafts.

The diameter of the hair shafts for the two drug-treatment groups was approximately twice that for grafts treated with the vehicle alone. It should be noted that hair growth in the two treatment groups started as early as after 36 days post transplantation. It can been seen in Fig. 1 that the topical application of flutamide, representing the anti-androgenic mechanism of action, resulted in more hairs per graft and longer hair shafts than the topical finasteride (5a-reductase inhibition). The difference was statistically significant (P< 0.05).

Histological examination of the grafts treated with finasteride and flutamide (Table 1) demonstrated relatively more hairs in the growth (anagen) phase than in regression (catagen) and rest (telogen) phases (see also photographs a–c of Fig. 4), with some superiority of the topical flutamide over finasteride. In the two drug groups, before the treatment and in the vehicle group most if not all the hairs were in the catagen and the telogen phases (100 and 85.5%, respectively) (Fig. 4, photograph d). These findings, as shown in Table 1, support the above-described clinical results for hair growth, as presented in Fig. 1. Table 2 presents the plasma monitoring of T and DHT. The measurements show that there was no systemic effect that might change the androgenic balance as a consequence of the topical applications of either flutamide or finasteride.”

“According to the present study, the effective topical delivery of flutamide and finasteride for alopecia is thus feasible, giving similar (if not better)results to those obtained with oral finasteride, i.e. with no systemic side effects, as demonstrated by T/DHT monitoring. It should be noted that, although the reversal of the vellus to terminal hair can occur in both the human scalp-grafted mouse and in man, it is still difficult to predict the degree of efficacy of this treatment in clinical studies or to compare it with oral finasteride trials.” 

References

 [1]  Goldspiel, B.R.; Kholer, D.R.
       Flutamide: An Antiandrogen for Advanced Prostate Cancer.
       Drug Intelligence and Clinical Pharmacy, 1990, 24, 616–623.
 

[2]  Amnon Sintov, Sima Serafimovich, Amos Gilhar
      New topical antiandrogenic formulations can stimulate hair
      growth in human bald scalp grafted onto mice.
      International Journal of Pharmaceutics, 194 (2000), 125–134.