HISTORY

Khellin has been used as an herbal folk medicine, with use in the Mediterranean dating back to ancient Egypt, to treat a variety of maladies including: renal colic, kidney stones, coronary disease, bronchial asthma, vitiligo and psoriasis.

COMPOSITION

It is a major constituent of the plant Ammi Visnaga, also known as Bishop’s weed. Once purified, khellin exists as colorless, odorless, bitter-tasting needle-shaped crystals and is classified as a gamma-pyrone, a furanochromone derivative.

Chemical Structure

Khellin as a photosensitizer, a furanochromone extracted of the plant Amnivisnaga (5, 8 dimetoxi.2 methyl-4, 5 furo-6,7 chromone), and UVA irradiation (KUVA). The main advantage is its lack of phototoxicity, making it safe for use either as a home treatment or a treatment involving natural sunlight, even on a daily regimen.1 It is also less mutagenic than psoralens, and lessens the darkening of normal skin.

Topical Khellin

Khellin can also be formulated for topical applications, incorporated into a moisturizing cream or Carbopol gel, at a concentration of 3 to 5%. Sunlight irradiation in the form of topical ‘KUVA-sun’ could also be very useful in sunny countries where it is possible to receive low doses of natural sunlight over several months, with very nice results.

Systemic Khellin- Mode of Action:

Although still in some dispute, current theory holds that in vitiligo, interfollicular melanocytes die, ultimately resulting in a depigmented epidermis. Perifollicular melanocytes are thought to survive, and in successful treatment modalities, it is postulated that it is this reservoir of melanocytes that is stimulated to proliferate and migrate back into the epidermis.2 Also, at some stage, the melanocytes must reactive their melanogenic pathway, synthesize melanin and transfer this to the surrounding keratinocytes, resulting in the repigmentation of the skin. For a vitiligo treatment to be effective, it must enhance or activate one or more of these processes, either by acting on the melanocyte itself or on the surrounding melanocyte environment (or both).

Khellin has a direct effect on proliferation of pigment cells in vitro.9

A recent ground-breaking study has definitively demonstrated that in mice, melanocyte stem cells are resident within a niche area in the hair follicle and that on appropriate stimulation. These melanocytes proliferate and can migrate into the epidermis or hair follicle, become differentiated and melanogenic.10 Our results suggest the possibility that in vitiligo treatments, khellin/KUVA stimulates the proliferation of melanocyte stem cells and that these cells migrate out of the follicle and begin to repigment the skin in the typical, well-described, perifollicular pattern.

Review of literature

Twenty-eight patients with vitiligo were treated with a new photochemotherapeutic regimen using khellin, a furanochromone, as photosensitizer, together with ultraviolet A (UVA) irradiation. Twenty-five patients received khellin orally and three patients were treated with topical khellin.12 Treatments were given three times weekly. As opposed to psoralens, khellin did not induce skin phototoxicity with UVA but it induced repigmentation like psoralens. The treatment success strongly depended on the number of treatments14. More than 70% repigmentation was achieved in 41% of the patients who had received 100 to 200 treatments. This success rate is comparable to the rate obtained with psoralens. Seven patients experienced a mild elevation of liver transaminases within the initial treatment phase and their treatments were discontinued. No long-term internal organ or skin toxicity was observed.3,7,9

Adverse Effects & Monitering

Few patients under systemic khellin treatment, a mild elevation of liver transaminases (aspartate aminotransferase, AST, SGOT, alanine aminotransferase, AST, SGPT, and gamma glutamyl transferase, GGT), with values of up to three times the normal limit, was observed within the first 2 months of treatment.11 These laboratory changes occurred unrelated   to systematic symptoms such as nausea, and it has to be mentioned that these patients had normal values at the beginning and showed negative hepatitis antibody screening findings.14 After discontinuation of khellin administration the values returned to normal within 5 to 12 weeks.2 A second course of khellin in two of these patients again resulted in a similar increase of transaminases after 4 and 8 weeks, respectively.

Patients who did not develop an elevation of transaminases within the initial treatment period retained normal values throughout the entire treatment.15

So, during the consumption of Khellin, hepatic monitoring is essential.5

Furthermore, it has been reported that khellin treatment (KUVA) does not induce hyperpigmentation of the adjacent nonvitiliginous skin, as is often the case with PUVA treatment.

Effectiveness in vitiligo

Khellin can be given orally at 100 mg, 2 hours before treatment.

Khellin-UVA photochemotherapy is effective in restoring normal skin color in more than 70% of the originally involved vitiliginous areas.

With regard to short term side effect, khellin has the advantage of being nonphototoxic even after exposure doses of up to 100 joules/cm2. Therefore, severe erythema reactions as may occur in PUVA therapy, particularly in fair-skinned whites, can be avoided. Khellin photochemotherapy can be considered safe with natural sunlight, as a UVA source or also as home treatment with artificial UVA, provided the patients are instructed.13

Stantial number of patients with vitiligo after 1 to 2 years of continuous therapy. However, as with psoralen photochemotherapy (PUVA), complete repigmentation is never achieved since certain skin areas, such as the distal dorsal surfaces of the hands and feet, tips of the fingers and toes, areas of bony prominences, palms, soles, and nipples, do not respond at all.4-8

Conclusion:

Khellin photochemotherapy can be recommended as a valuable alternative option to conventional PUVA for the treatment of vitiligo in patients who do not develop an elevation of liver transaminases.

Both oral & topical khellin photochemotherapy may be less hazardous with respect to long term side effects and can be performed easily with sunlight or as home treatment with commercially available UVA sources.

References:

  1. Schwartz RA. Janniger CK. Vitiligo. Cutis 1997:60: 239-44
  2. Kovacs SO. Vitiligo (review). J Am Acad Dermatol’ 1998: 38: 647-66.
  3. Morliere P. Honigsmamm, H. Averback D Et al. Phototherapeutic, photobiological, and photosensitizing, properties of khellin. J Invest Dermatol 1988; 90: 720-4
  4. Abdel-Fattah A. Abdoul-Enein MN. Wassel GM, EI-Menshawi BS. An approach to the treatment of vitiligo by khellin. Dermatological 1982; 165; 136-40
  5. Ortel B. Tanew A. Honigsmann H. Khellin UVA phototherapy of vitiligo, Photochem photobiol 1984; 39: 528
  6. Honigsmann H. Ortel B. Khellin photochemotherapy of vitiligo. Photodermatology 1985; 2: 193-4
  7. Ortel B. Tanew, A. Honigsmann H. Treatment of vitiligo with khellin and ultraviolet A. J Am Acad Dermatol 1988: 18: 693-701.
  8. Hofer A. Kerl H. Wolf P. Long term results in the treatment of vitiligo with oral khellin plus UVA. Eur J Dermatol 2001: 11: 225-9.
  9. Marconi B. Mancini F. Colombo P Et al. Distribution of khellin in excised human skin following iontophoresis and passive dermal transport. J Control Releases 1999: 60: 261-8.
  10. Nishimura EK. Jordan SA. Oshima H et al. Dominant role of the niehe in melanocyte stem-cell fate determination. Nature 2002: 416: 854-60.
  11. Vedaldi D. Cafferi S. Dall’Acqua F et. al. Khellin, a naturally occurring furochromone, used for the photochemotherapy of skin diseases: mechanisms in action. Farmaco [Set] 1988: 43: 333-46.
  12. Riccio ML, Coratza G. Bovalini L. Martelli P. Investigation of the mutagenic activity in Salmonella typhimarian of the furochromone khellin, proposed as a therapeutic agent for skin diseases. Mutat Res 1992: 279: 103-8.
  13. Nordlund JJ. Halder RM, Grimes P. Management of vitiligo, Dermatol Ther 1993: 11: 27-33.
  14. Orecchia G. Perfetti L. Photochemotherapy with topical khellin and sunlight in vitiligo, Dermatology 1992: 184: 120-3.
  15. Orecchia G. Sangalli ME. Gazzaniga A. Giordano F. Topical photochemotherapy of vitiligo with new khellin formulation: preliminary clinical results. J. Dermatol Treat 1998: 9: 65-9.