This application is a continuation-in-part of U.S. patent application Ser. 10/291,795, filed Nov. 8, 2002, now U.S. Pat. No. 7,090,691, which claims priority to U.S. Provisional Application 60/338,295, filed Nov. 9, 2001, which are both hereby incorporated in their entireties as if fully set forth.
FIELD OF THE INVENTION
This invention relates to the use of photodynamic therapy (PDT) and the use of PDT with appropriate photosensitizers to stimulate hair growth.
In particular, the use of photosensitizers and PDT for treating conditions relating to hair loss, such as androgenetic alopecia and alopecia areata, is described.
The present invention further relates to increases in proinflammatory cytokines induced by PDT, which stimulates hair growth, as well as to methods of determining the level of hair growth stimulation mediated by PDT.
BACKGROUND OF THE INVENTION
Alopecia is the general term referring to any disease or condition involving hair loss. There are several different types of hair loss, the most common being androgenetic alopecia (AGA; see Sawaya, M. E. Seminars in Cutaneous Medicine and Surgery 17(4):276-283, 1998), alopecia areata (AA; see Fiedler & Alaiti, Dermatologic Clinics 14(4): 733-738, 1996, as well as chemotherapy and drug-induced alopecia. Androgenetic alopecia (AGA) is by far the most common type of alopecia. AGA is a patterned, progressive loss of an excessive amount of hair from the scalp.
Significant AGA occurs in 50% of men by the age of fifty and 50% of women by the age of sixty. AGA is believed to be a result of both genetic predisposition and the presence of a sufficient level of circulating androgens. It is thought that the enzyme 5 alpha-reductase present in dermal papilla cells converts testosterone to dihydrotestosterone (DHT). DHT binds to androgen receptors, also localized in the dermal papilla cells, triggering changes in the hair follicle that result in (1) shortening of the anagen or growth phase of the hair cycle, (2) development of a latent phase in the hair cycle following shedding of the telogen hair, and (3) follicular miniaturization process that reduces the caliber of the anagen hairs produced. It is thought that the differential expression of 5-alpha-reductase and/or androgen receptors in various types of hair follicles accounts for patterned hair growth and loss.
Currently approved treatments for AGA include minoxidil (Rogaine™), an anti-hypertensive drug for which the mechanism of action in promoting hair growth is unknown. Minoxidil must be applied topically on a twice-daily basis and is therefore somewhat inconvenient to use.
Studies have shown that 2% Minoxidil can provide an increase in the numbers of terminal hairs after 4-12 months (De Villez et al, Journal of the American Academy of Dermatology, Vol. 16, No. 3, Part 2 (Mar. 1987) 669-672). However, this benefit disappears over time or once the treatment is stopped. Another drug used in the treatment of AGA is finasteride (Propecia™), a selective inhibitor of the type 2 isoenzyme 5-alpha reductase. This treatment has marginal efficacy, requires daily oral administration and can have some anti-androgenic side effects such as alteration of libido. Hair transplants and scalp reduction are also performed on patients with hair loss associated with AGA. These procedures are too expensive or time consuming for many people. In addition, many people are put off by the surgical nature of the treatment.
Alopecia areata (AA) has been reported to account for 2% of new outpatients in dermatology clinics (Fiedler & Alaiti supra). AA is a nonscarring form of hair loss which occurs in humans and other species and is thought to be due to an inflammatory reaction caused by autoimmune response directed against the anagen stage hair follicle structure (McElwee et al. Pathobiology 66(2): 90-107, 1998).
A number of therapeutic modalities have been tested for the treatment of AA, with variable results ranging from no effect to partial or full hair regrowth. In some cases, chronic maintenance treatment is required. Major drawbacks of these treatments are side effects, which can be local or systemic in nature. Fiedler & Alaiti (supra) and Shapiro (Dermatological Clinics 11(1): 35-46, 1993) have reviewed the various treatments available for AA, including steroids (topical, intralesional and systemic), minoxidil, anthralin, photochemotherapy, cyclosporin A and other agents, as well as combination treatments.
Photochemotherapy therapy for AA using psoralen and high energy UVA (PUVA) treatment has met with very limited success and its effectiveness for AA is in doubt (Lebwohl, M. Lancet 349:222-223, 1997). Side effects of PUVA treatment such as nausea, pigmentary changes, the risk of skin cancer formation, and cataracts have been reported (Fiedler & Alaiti, supra). Antioxidants have been used to ameliorate the side-effects of PUVA therapy (Ptapenko & Kyagova, Membr. Cell Biol. 12(2): 269-278, 1998). The use of 2% khellin, a compound with a chemical structure that resembles psoralen, and UVA for alopecia areata was found to be successful in 5 of the 10 patients tested (Orasa et al. Int. J. Dermatol. 32(9): 690, 1993). Since khellin did not cause phototoxicity, the authors have suggested its use as an alternative to psoralen.
Hematoporphyrin and high energy UVA has been used in a very limited study by Monfrcola et al. (Photodermatology 4:305-306, 1987). Two patients were treated with topical hematoporphyrin (0.5%, HP) and UVA irradiation with three times a week for eight weeks. In the first week of treatment, there was significant erythema and mild scaling followed by hyperpigmentation in the HP-treated sites. Side effects included unpleasant reddish skin coloration for several hours and sometimes burning sensations during the irradiation phase. The authors point out that severe phototoxic reactions could occur with the use of HP concentrations greater than 1%. They also state that more work is needed before this approach can be subject to routine clinical use.
Photodynamic therapy (PDT) has been utilized for the removal of unwanted hair in human subjects. Briefly, the treatment involves a topical application of a photosensitizer on a selected area of the skin, a period for absorption of the photosensitizer, followed by a pulse or continuous irradiation or vibration of the area. The process involves inactivating or destroying the hair follicles or destroying the tissue feeding the hair follicles (see U.S. Pat. Nos. 5,669,916; 5,871,480; WO 97/32046).
Photodynamic therapy is a minimally invasive two-step medical procedure that uses photoactivatable drugs called photosensitizers to treat a range of diseases. First, a photosensitizer is administered and, once it has permeated the target tissue, the photosensitizer is then activated by exposure to a dose of electromagnetic (usually light) radiation at a particular wavelength. Photodynamic therapies have been approved for a number of indications including the treatment of non-small cell lung cancer (Photofrin™), age-related macular degeneration (Visudyne™), actinic keratosis (Metvix™, Levulan™), and basal cell carcinoma (Metvix™).
There continues to be a need for an effective, non-surgical procedure that results in a rapid increase in the number of terminal hairs but has minimal side effects.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates or contents of these documents.
SUMMARY OF THE INVENTIONIt has been discovered that photodynamic therapy (PDT) can stimulate hair growth and restore hair growth in areas of hair loss. The discovery includes the ability to use a variety of photosensitizers in PDT to treat hair growth reduction or hair loss. In light of the use of PDT to remove unwanted hair by inactivating or destroying hair follicles or destroying the tissue feeding the hair follicles, as discussed above, the instant invention relates to a surprising and unexpected discovery.
The instant invention provides methods and compositions for treating lack of hair growth or a reduction or loss of existing hair by stimulating and/or restoring hair growth with PDT. Thus one aspect of the invention relates to methods for stimulating, inducing, restoring, reviving, renewing, replacing or otherwise activating hair growth in animals characterized by a lack of hair growth or a reduction in the amount of, or loss of, hair. In particular, the treatment methods of the invention comprise i) administering an effective and/or sufficient amount of photosensitizer resulting in an effective or desired degree of biodistribution; ii) irradiating at least a portion of the external surface of the animal with light including one or more wavelengths capable of activating said photosensitizer for a time period sufficient to activate the photosensitizer. The administrating and irradiating acts of (i) and (ii) may be repeated as necessary or desired to result in the desired level of hair growth.
The desired therapeutic response of hair growth can also be accomplished by the irradiation of skin, which has been treated with an effective amount of a photosensitizer, with light including one or more wavelengths capable of activating said photosensitizer for a time period sufficient to activate the photosensitizer and result in the desired level of hair growth. Moreover, the methods of the invention may be practiced with any photosensitizer, which may be delivered systemically or locally.
Thus in one application of the invention, the invention provides for the use of photodynamic therapy (PDT) to stimulate an increase in hair count numbers and restore hair growth in areas of hair loss. One embodiment of this application comprises:
- (a) administering an effective and/or sufficient amount of a photosensitizer to an area of a subject’s skin where hair growth is desired; and
- (b) irradiating the area with electromagnetic energy containing a wavelength capable of activating, or appropriate to activate, said photosensitizer for a time period sufficient to activate the photosensitizer; and optionally
- (c) repeating (a) and (b)
wherein there is an increase in hair count numbers in the treated area.
Preferably, the increase in hair count is an increase in terminal hairs, which are long, pigmented hairs that are produced by follicles with sebaceous (oil) glands. They are found on the scalp, beard, armpits, and pubic areas and are in contrast to vellus hairs, which are short hairs, often only a centimeter or two long, that contain little or no pigment. The follicles that produce vellus hairs do not have sebaceous and never produce any other kind of hairs. Terminal hairs also differ from Lanugo hair, which develops on an unborn baby. In people who have inherited a tendency to baldness terminal hairs may gradually become thinner and shorter until they look like vellus hairs. This may be due to the growth of terminal hairs being influenced by hormones (e.g. androgens) while vellus hairs are not so influenced.
The progression of conditions such as AGA is for a gradual decrease in the number of terminal hairs over time. The terminal hairs may also gradually become thinner and shorter until they look like vellus hairs. It is surprising, therefore, that the current method can actually increase the number of hairs after 3 months. In addition to treatment of hair loss, the method of the present invention may be used for the stimulation of hair growth in areas not recognized as experiencing hair loss. As used herein, the term “hair growth” refers to an increase in the number of terminal hairs present. Terminal hair counts can be conducted in a number of ways as known in the art. A non-limiting example is where the terminal hair is counted by trained and validated technicians who perform a computer-assisted count on macro photographs. In brief, a target area on the scalp is chosen, the hair clipped and the scalp permanently marked with a single dot tattoo in the center in order to facilitate the exact positioning at each subsequent photo session. The macrophotography is performed using a preset camera with a macro lens and a stand that provides a constant reproduction ratio and electronic flashes that reproducibly illuminate the area to photograph. The images are taken in triplicate, centering the camera using the tattoo and the color slide films are processed at a central facility. The quality of the images is assessed and large transparencies are made of the best images. The terminal hairs on the target circle of the transparencies are then counted by the trained technicians.
In all embodiments of the invention, the disclosed PDT mediated methods may be repeated over time and preferably result in a 2% or more increase in the number of terminal hairs within 3 months.
In another aspect, the invention is directed to formulations or compositions comprising photosensitizers for treating lack of hair growth or a reduction or loss of existing hair with the methods of the invention. These compositions comprise an effective amount of photosensitizer, optionally with a pharmaceutically acceptable carrier or excipient, and may also be used to prevent or inhibit the development of hair growth reduction or hair loss. The invention includes pharmaceutical compositions targeted to hair follicles, the surrounding tissue, or tissues which feed hair follicles. In particular, formulations comprising photosensitizers conjugated to agents, which specifically target or bind appropriate scalp or skin tissues, hair follicles, or tissues and cells surrounding said hair follicles, are preferred for use in the methods of the invention. Compositions comprising conjugated or unconjugated photosensitizers are optionally formulated with agents suitable or preferred for application to the scalp, or other skin where hair growth is desired. Examples of such agents include pharmaceutically acceptable carriers or excipients.
The invention also provides for methods of using photosensitizer formulations and compositions in preparing an area of skin for PDT to increase the number of terminal hairs in said area, or to treat AGA, said methods comprising administering, preferably by topical administration, such formulations, and compositions to said area.
In one set of preferred embodiments, the invention is practiced with a photosensitizer that is photoactivated by the light of a wavelength from about 400 to about 900 nm. In another set of preferred embodiments of the invention, the treatment methods and compositions comprise the use of a particularly potent group of photosensitizers known as green porphyrins, which are described in detail in Levy et al., U.S. Pat. No. 5,171,749 issued Dec. 15, 1992, which is incorporated herein by reference. The term “green porphyrins” refers to porphyrin derivatives obtained by reacting a porphyrin nucleus with an alkyne in a Diels-Alder type reaction to obtain a mono-hydrobenzoporphyrin. In particular, green porphyrin compounds such as benzoporphyrin derivative mono-acid (BPD-MA), EA6, and B3 may be used in the invention. Two preferred members of the green porphyrin family are verteporfin (comprising the 4 enantiomers shown below) and QLT 0074.