德國欣髮源 Thymuskin

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Action of Thymuskin in Experimental Models and Probable Modes of Action
Thymuskin在實驗模式中的作用以及可能的作用方式

Biological activity

Thymuskin (development code GLK 02) is a synthetic peptide library identical to the former hydrolyzed extract of bovine thymus. Since Thymuskin GKL 02 consists of several components (various tetra peptides) it is difficult to clarify the mode of action and to attribute it to single components. Most likely several components contribute to the action. Though the clarification of the mode of action is desirable from a scientific point of view it is secondary for the successful treatment of hair loss. However it has been shown that Thymuskin exerts biological effects in various human cells, cultures and on biological substrates such as enzymes. These effects could explain the clinical efficacy of Thymuskin in the various forms of alopecia.

 
 
生理活動

Thymuskin(產品碼 GLK 02)是一種合成胜肽庫與之前牛胸腺的水解萃取物相似。因為GLK 02由許多物質組成(各種四胜肽)，所以要釐清作用方式以及是那個單一物質造成的是非常困難的一件事。最有可能的是多種物質造成這種作用。雖然從科學的角度來說，可以釐清作用方式會比較令人滿意，不過成功的治療禿頭還是首要的。然而，Thymuskin已被證實對多種人類細胞、培養和對生物基質像是酵素，產生作用。這些影響可以解釋為什麼Thymuskin對各種掉髮有效。

Stimulation of Proliferation

Investigation in human blood cells show that Thymuskin stimulates the proliferation of lymphocytes (6). The effect is dose dependent up to 100 μg/ml and reaches statistical significance (p=0.03) versus controls (figure4). The mechanism of proliferation stimulation is independent of interleukin, as was shown in these investigations. A stimulatory effect also on the cells of the hair follicle could explain the positive effect of Thymuskin on hair growth.

刺激增生

根據人類血液細胞的調查指出，Thymuskin刺激淋巴細胞的增生(6)。這樣的效果與劑量有關，當劑量到達100μg/ml時與對照組相比，會達到統計學上的顯著意義(p=0.03)。刺激增生的機制獨立於介白素( 細胞介素的一類,對於免疫反應及宿主的防禦力具有多重作用)，對毛囊細胞的刺激作用也可以解釋為什麼Thymuskin對頭髮生長有正面的效果。

Enhancement of Cell Vitality  

Thymuskin was tested in the EpiDerm®-model (7). The test tissue in this model consists of a multilayer culture of human keratinocytes and mimics structure and function of human skin extremely well. In this model a 10% solution of Thymuskin tended to increase the vitality of the test tissue. The viability or vitality increases dependent on the concentration and on the duration of action of Thymuskin as shown in figure 5. Keratinocytes are skin cells which form keratin, the ground-substance of hair. It may be expected that Thymuskin exerts corresponding effects on the viability and vitality of keratinocytes in hair follicles. Thus these findings point to an important basic action which may be fundamental for the clinical efficacy. This fundamental biological effect could explain why Thymuskin is effective in hair loss of various etiologies.

加強細胞生命力

Thymuskiny在EpiDerm®模式下被測試(7)。這個模式的測試組織有人類表皮細胞的多層培養，並且把人類細胞的結構與功用模仿得唯妙唯肖。在這個模式下，10%Thymuskin的溶液被用來增加測試組織生命力。在Thymuskin作用期間，測試組織的生存力與生命力隨著濃度增加，如圖5。角質細胞是形成角質的皮膚細胞，但也是頭髮的基礎物質。我們或許可以預期Thymuskin對毛囊裡的角質細胞的生存力與生命力會發揮相同的效果。因此，這些發現指向有可能是臨床有效性根本的重要基本作用。這項根本的生理作用可解釋為什麼Thymuskin對於各種病原的落髮有幫助。

 
Inhibition of Mast Cell Effects on Hair Follicles

In a mouse model of alopecia it was observed under the microscope that during the catagen phase which precedes the telogen end phase of the growth cycle, the number of mast cells and their degranulation increases greatly (8). After the hairs have fallen out, the number of mast cells normalizes again. The authors conclude that mast cells play an essential role in hair loss. Mast cells of course contain the serine proteases tryptase and trypsin. The keratinocytes of human skin dispose of receptors (PAR) which are activated by serine proteases. Activation of these receptors lead to changes in cell function with not yet fully recognized consequence 。It has been shown (9) that Thymuskin inhibits tryptase and trypsin (figure 6). By the way, this inhibitory action of Thymuskin on those enzymes is also utilized in an assay in quality control. From the role of mast cells in hair loss and the inhibition of the serine proteases from mast cells it can be postulated that Thymuskin would be capable to reduce or even prevent the death of hair forming follicle cells.

抑制肥大細胞對毛囊的影響

在老鼠禿頭症模式中由顯微鏡可觀察到毛囊由退化期至休止期，肥大細胞(Mast Cell，可釋放組織胺histamine或其他參與發炎的化學物質的組織細胞)的數量以及它們的脫粒作用會大大增加(8)。在頭髮掉落之後，肥大細胞再次正常化。此研究人員因此認為肥大細胞對落髮扮演重要的角色。肥大細胞當然包括了絲氨酸蛋白酶類胰蛋白和蛋白酶。人類皮膚的角質細胞會處理掉絲胺酸蛋白酶活化的接受器(PAR)。活化這些接受器導致不明結果的細胞功能改變。Thymuskin已被證實會抑制胰蛋白和蛋白酶(圖6)。還有，Thymuskin在這些酵素的抑制作用也做為品質管理的分析。從肥大細胞在落髮中的角色以及肥大細胞中絲胺酸蛋白酶的抑制作用來看，我們可以假設Thymuskin有可能降低甚或預防形成頭髮的毛囊細胞的死亡。

 
Good Skin Preparation 

The biological effects reported above only become relevant if Thymuskin reaches the hair root in a sufficient concentration. Investigations on the penetration in vitro through human scalp and abdominal skin have documented that about 45% of a 1% solution of Thymuskin penetrates deeply enough into the skin (10). Thus it is provne that considerable amounts of topically applied Thymuskin reaches the relevant depth of the skin to exert its efficacy on the hair roots.

好的皮膚滲透性

上述的生理效果只有在Thymuskin在一定的濃度下達到髮根才會成立。透過試管試驗的來調查Thymuskin滲透頭皮以及腹部皮膚的有效劑量，約45%的濃度1%Thymuskin溶液可以穿透皮膚的非常深層(10)。因此證實，相當數量的局部塗抹Thymuskin可以達到深層皮膚來發揮對髮根的功效。

Executive Summary

Thymuskin has shown甚 clinical efficacy in the three most frequent forms of hair loss in men and equally well or even better in women. In several experimental models, Thymuskin has exhibited biological activity. Thymuskin stimulates the proliferation of human blood lymphocytes and might also stimulate as well the cells in the hair follicle. Thymuskin increases the viability and vitality of human kerationocytes which are greatly involved in producing the ground substance of hair. Thymuskin impairs the main enzymes of human mast cells which have been shown to play a mayor role in the transition of the anagen to the katagen and telogen phases of the hair growth cycle. These three actions can easily explain why Thymuskin is effective in different types of hair loss.

施行摘要

Thymuskin在三種最常在男性中發生的掉髮在臨床上是有效的，且對女性一樣，甚至更有效。在多個實驗模式中，Thymuskin展現生理活性。Thymuskin刺激人類血液細胞的增生，且可能也一樣刺激了毛囊的細胞。Thymuskin增加角質細胞的生存力與生命力，且與頭髮基礎物質的製造有關。Thymuskin損害人類的肥大細胞的主要酵素，這些酵素在頭髮生長周期中，於成長期轉換為退化期與休止期中扮演重要角色。這三個作用可以很容易的解釋為什麼Thymuskin對不同型態的落髮有效。

編譯By iwanthair's blog & Jinny

 References:

1. Mössler, K.: Thymu-Skin: Neuer Therapieansatz bei der Behandlung der Alopecia androgenetica und der Alopecia areata. Der Deutsche Dermatologe 39, 945-956, 1991

2. Local Therapy of Androgenetic Alopecia with a New Synthetic Peptide Library - A Pilot Trial with Thymuskin GKL 02. Internal Study Report on File

3. Lüpke, N.-P.: Zusammenfassender Bericht zur adjuvanten lokalen Anwendung von Thymu-Skin-Präparationen bei Patienten mit zytostatischer Chemotherapie. Deutsche Zeitschrift für Onkologie 22, 13-22, 1990 

4. Klobusch, J.; Mössler, K.; Rabe, T.; Runnebaum, B.: Neue Ansätze in Diagnostik und Therapie der Alopezie in der Gynäkologie. Therapeutische Rundschau 47 (12) 985-990, 1990

5. Mössler, K.; Hagedorn, M.: Lokaltherapie mit Thymusextrakt bei Alopecia areata totalis sive universalis. Der Deutsche Dermatologe 11, 1175-1182, 1993

6. Maurer, H. R.: Preclinical Investigation of Thymic Preparations GKL 01 and GKL 02.

Internal Investigational Report 2005

7. NeuroBiotec: Investigations of skin irritation of GKL 02 as aqueous solutions (10%) using the EpiDerm® model MatTek Corporation, Ashland, USA), Internal Investigational Report 2005

8. Maurer, M. et al.: Activated skin mast cells are involved in murine hair follicle regression (catagen). Lab. Invest. 77 (4), 319-332, 1997

9. Birr, C.: Development of a Bioassay for the Quality Control of the Drug

Substance GKL02 by Biological Means. 2005

10. PhaCos: Pharmakokinetische Untersuchungen von GKL02. Internal Report 1999

Compiled in July 2006 by Klaus J. Hahn, MD, PhD
Rahnfelsstr. 9a D-68163 Mannheim
Germany