|CONTINUING MEDICAL EDUCATION
|Year : 1997 | Volume
| Issue : 5 | Page : 276-287
CR Srinivas, Satish Pai
C R Srinivas
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Srinivas C R, Pai S. Psoralens. Indian J Dermatol Venereol Leprol 1997;63:276-87
Psoralens are chemical compounds derived from certain plants such as ammimajus found in Egypt and Indian plant babachee which is also called as Psoralea corylifolia. Psoralen has been found in more than 30 plants such as lime, lemon, bergamot, parsley, celery, fig and cloves. The medical use of these plants in the treatment of vitiligo by the ancient Egyptians dates back to as early as 1500 B.C. and by the Indians to 1400 B.C.
| Chemistry|| |
Psoralen and many of its derivatives are naturally occurring tricyclic furocoumarins. The derivative most widely used in photochemotherapy is 8 - methoxypsoralen (8MOP, methoxsalen, xanthotoxin) which is principally of plant origin but it is available as a synthetic drug. 4, 5, 8-trimethyl psoralen (TMP, trioxsalen) is a synthetic compound which is less phototoxic after oral administration and is primarily used for the treatment of vitiligo. Newer psoralens under research are 5-methoxypsoralen (bergapten, 3-carbethoxypsoralen and angelicin. [3,4] The photobiological activity of angelicin is low. The introduction of one or more methyl groups results in the increased photobinding capacity of angelicin towards DNA. These various methyl derivatives of angelicin are called the new angelicins. 4, 4, 6-methyl angelicin is the most promising of the new angelicins.
| Pharmacology|| |
When taken by mouth, methoxsalen (8-MOP) is absorbed from the gastrointestinal tract. Increased photosensitivity is present 1 hour after the dose, reaches a peak at about 2 hours and disappears after about 8 hours. The absorption of methoxsalen and hence clinical response may be increased by concomitant food ingestion as well as by differences in drug formulations. A liquid preparation in soft gelatin capsules or a microenema gave higher serum concentration more rapidly than did crystalline methoxsalen in tablets or capsules. Methoxsalen has high but variable intrinsic metabolic clearance and is almost completely metabolised. Individuals with a high clearance and low maximum serum concentration usually show reduced sensitivity to PUVA. These patients i.e. those not responding to usual dose may respond to higher dose of psoralens or to the administration of the drug by other routes such as bath water delivery. After oral administration the drugs are metabolised in the liver by hydroxylation and glucuronide formation and over 90% is excreted in the urine within 12 hours. Methoxsalen has a serum half-life of approximately 1 hour and is rapidly eliminated which prevents photosensitivity.
Psoralen appears to be distributed to all tissues after oral administration and there is no risk of accumulation in any organ in patients with normal liver and kidney function.
When applied locally 8-MOP rapidly penetrates the skin and can be detected in the urine after 4 hours. The plasma levels of 8-MOP in patients receiving total body topical 8-MOP are comparable to those found during oral 8-MOP ingestion. The plasma concentration of TMP after bath treatment is only approximately 1% of the plasma after oral ingestion.
| Mechanism of action|| |
The exact mechanism by which psoralens produce cutaneous photosensitivity reactions is not precisely known. Mode of action of psoralens does not occur at one level, but at several levels simultaneously including cellular DNA, RNA proteins, mitochondria, cell membrane lipids etc. In the normal skin or in the skin of psoriatic patients, psoralen induced skin photosensitization involves two distinct types of reactions occurring independently of each other and concurrently when psoralen treated skin is exposed to 320 - 400nm radiation.
- 1. Type I is an anoxic reaction not requiring oxygen and the site of cellular damage is primarily in DNA of cell nuclei.
- 2. Type II is a sensitized reaction dependent on oxygen and involves the formation of oxygen reactive species such as 02, 0-2 and free radicals.
In these 2 modes of reactions, the reactive form of psoralen is in its triplet state. The sites of reaction are
- a) Cell nuclei (DNA and chromatin)
- b) Cell membrane of the epidermal, dermal and endothelial cells
- c) Cytoplasmic constituents (enzymes, RNA, lysosomes etc.).
- d) Membrane lipids involving a photodynamic reaction and the production of reactive oxygen species.
The major photochemical reaction of psoralen contributing to the cellular damage is undoubtedly the formation of monofunctional and bifunctional adducts of psoralen with pyrimidine bases in DNA and is a type I reaction.
The formation of monofunctional and bifunctional photo adducts in DNA results in immediate inhibition of DNA synthesis. Subsequently, cell proliferation is also inhibited in patients with psoriasis who receive repeated PUVA treatment.
PUVA causes photoconjugation of psoralens to DNA and subsequent suppression in mitosis, DNA synthesis and cell proliferation. It is also possible that PUVA may affect specific cells such as lymphocytes or polymorphonuclear leucocytes which are believed to be involved in the pathophysiology of psoriasis.
It is quite possible that immunological alterations are an essential component of the therapy. A decrease in the percentage of circulating T-lymphocytes following PUVA treatment has been reported.
The mechanism by which PUVA induces repigmentation in vitiligo remains unclear although the following ways have been speculated.
- 1. By increasing the number of functional melanocytes as a result of mitosis or by activation of dormant melanocytes in the epidermis and appendages.
- 2. By inducing hypertrophy of melanocytes and an increased arborization of their dendrites.
- 3. By augmenting the development and melanization of melanosomes and increasing the transfer of melanosomes to keratinocytes.
- 4. By stimulation of tyrosinase activity
- 5. By enhancing the migration of activated melanocytes from skin appendages
- 6. By generating a suppressor cell population which suppresses the stimulus for melanocyte destruction during therapy.
| Fundamentals of psoralen therapy (psoralen + UVA)|| |
The rationale of PUVA is to bring about repeated, controlled phototoxic reactions. Drug or UVA aone is not effective.
For photochemotherapy, mainly broad band, high intensity UVA sources are used. The action spectrum is reported to be between 320 and 380nm. Most UVA treatment units currently available are equipped with fluorescent bulbs. Because accurate dosing is necessary for safe therapy, the spectral power distribution of the UVA system has to be known and UVA dosing must be adjusted accordingly. UVA doses are given in J/cm2, usually measured with a photometer with a maximum sensitivity at 360nm.
| Solar irradiation|| |
Although 8-methoxypsoralen in conjunction with sunlight exposure (PUVASOL) is effective, the controlled irradiance of an artificial light source is preferable. A major disadvantage of solar irradiation as a light source in PUVASOL therapy is the difficulty in quantifying UV light. The total amount of UVA reaching the skin at any one time varies widely depending on the season, time of the day, latitude, and conditions of the atmosphere.
| Exposure time to sunlight for ultraviolet light therapy|| |
It is important to take both UVA and UVB into consideration as both photoaugmentation and photoaddition has been reported. The known erythemogenic property of high dose UVA may be additive to subclinical or visible erythema induced by UVB. Exposure time to sunlight for 1 J/cm2 of UVA at 11 a.m. and 3 p.m. was determined at our hospital.
| Indications of PUVA|| |
The indications are: (1) Psoriasis (2) vitiligo (3) cutaneous T-cell lymphoma (4) atopic dermatitis (5) lichen planus (6) urticaria pigmentosa (7) preventive treatment for photodermatoses like (a) polymorphic light eruption (b) solar urticaria (c) chronic actinic dermatosis (d) persistent light reaction (e) hydroa vacciniforme and (8) miscellaneous conditions such as acute and chronic pityriasis lichenoides, lymphomatoid papulosis, pityriasis rubra pilaris and alopecia areata.
| Methods of treatment|| |
The general principle is to hold the dose of the drug and interval between drug intake constant and to vary the UVA dose according to the sensitivity of the patient. 8-MOP in the dose of 0.6 to 0.8 mg/kg body weight is administered orally followed by whole body irradiation after 1-3 hours. The initial dose of UVA is predetermined by either skin typing or phototoxicity testing. Repeated exposures are necessary to clear PUVA responsive diseases, and as pigmentation develops UVA doses have to be increased. In Indian skin erythema cannot usually be seen. The frequency of treatment is reduced after a satisfactory clearing of the disease is achieved and the last UVA dose is used as a maintenance dose. The duration of this maintenance phase and the frequency of treatment depend on the disease being treated and its propensity to relapse.
| PUVA for psoriasis|| |
Two major treatment protocols of oral PUVA have evolved in the United States and in Europe respectively.
| US protocol|| |
The first treatment exposure dose is based on the skin typing and the patients are treated either twice or thrice a week. Dose increments range from 0.5 - 1.5 J/cm2 depending on erythema production and therapeutic response.
| European protocol|| |
The first treatment is administered after determination of the individual's minimum phototoxic dose (MPD) and the initial UVA dose is the patient's MPD. Four treatments are given per week.
Two treatments are given on consecutive days followed by a rest on day 3 after which treatment is resumed for 2 days. Increments of dose are performed only after the first four treatments if no more than a pink erythema has developed and range from 0.5 to 2 J/cm2 depending on the patient's MPD ability to develop pigmentation. The MPD is defined as the minimal dose of UVA delivered to the skin after ingestion of 8-MOP that produces a barely perceptible, well-defined erythema when small template test areas are exposed to increasing doses of UVA ranging from 0.5 - 5 J/cm2. The erythema readings are performed 72 hours after testing when the phototoxicity has reached a peak. Lesions of the lower limbs tend to respond slower, so extra treatment may be needed. These areas are irradiated with an additional 0.5 - 5J/cm2, the dose being gradually increased.
| Manipal protocol|| |
The usual starting dose is 4 - 6J/cm2. Dosage increments of 0.5 J/cm2 are done each time till a maximum of 18 J/cm2 is reached. Treatment is given thrice or four times a week. We have consistently failed to demonstrate MPD on Indian skin.
PUVA therapy is an extremely effective way of clearing psoriasis. The efficacy of PUVA treatment has been confirmed by many studies. Complete clearing is defined as eradication of 95% or more of the amount of psoriasis before treatment. Improvement of skin lesions is usually seen by the fifth or sixth treatment. In patients responding more slowly, an accelerated schedule of increments of UVA dosage should be considered. Failure to achieve improvement by the 20th treatment is usually regarded as treatment failure.
The average number of exposures required for clearing is about 20, but varies from 15-25. The final clearance dose of UVA radiation is about 5-20 J/cm2 depending upon the skin type.
The mean total cumulative UVA dose needed for all skin types to clear was 103, and 79 J/cm2 in two European trials. The mean cumulative UVA dose was considerably higher (245 J/cm2) for the US trial. Psoriasis of nails, palms and soles does not respond well to oral PUVA.
Most patients relapse during the first months after clearance if no maintenance therapy is given. An average remission time of 6 months without maintenance has been reported.
If maintenance PUVA treatment is given for 2-3 months and then stopped in patients who are still clear, it has been shown that majority of patients remain free of disease for atleast 6 - 12 months.
| Topical psoralens|| |
Topical application of psoralens followed by UVA irradiation has been used in the treatment of psoriasis. The treatment schedule for topical PUVA has not yet been standardized. A lotion containing 0.1 to 1% 8-MOP is used. Many clinicians allow 1 - 2 hours to elapse between the topical application of the psoralen and UVA exposure, but reports have shown that topical 8-MOP followed immediately by UVA irradiation can also clear psoriatic lesions. This treatment is given 3-5 times weekly with UVA dose being gradually increased. Maintenance dose may be needed.
Alternatively a vanishing cream consisting of 0.01 or 0.1% TMP or a lipophilic ointment of 0.01% TMP is painted with a cotton tipped applicator on each lesion 10-20 minutes prior to UVA exposure. Among the psoralens TMP is most convenient for topical application because of its weak penetrability. It has been shown that psoralen compounds penetrate into the epidermis rapidly (within 10 minutes after the painting) in normal human skin and presumably more rapidly in psoriatic lesions. The penetrated drug would make photo adducts with DNA molecules even if UVA light is given as soon as the drug is painted resulting in significant inhibition of epidermal DNA synthesis. Even with suberythemogenic doses of UVA light, DNA synthesis was notably suppressed.
Advantages of topical psoralen therapy are that systemic side effects such as nausea and hazards such as carcinogenic effects can be avoided. But there are certain disadvantages also: (1) Topical PUVA is laborious and time consuming, if every lesion has to be treated individually. (2) The formation of erythema and blisters is more common with topical psoralen application. (3) Intense irregular pigmentation may be seen at the site of treated plaques.
These side effects are reduced by psoralen bath technique. If extensive areas of the skin are treated, then blood levels are comparable with those achieved during oral treatment and precautions like protection to the eyes need to be taken.
| Bath water delivery of 8-MOP and trioxsalen|| |
Another route of psoralen delivery is bath water. Topical trioxsalen used in baths was found to be effective in the treatment of psoriasis by Fisher and Alsins in 1976. Studies of therapeutic effectiveness of psoralen baths suggest that the results are as good as with oral administration of psoralen.
In a single blind placebo controlled study at our hospital bath water delivery of 8 - MOP was compared with oral delivery of 8-MOP in the treatment of psoriasis. In this study patients on bath water 8 - MOP showed earlier and better response than the oral group. The mean EST score between the two modes of treatment was found to be statistically significant after 5 treatments and at the end of 15 treatments. Bath water psoralen delivery plus UVA has also been found to be equal to or better than local application of psoralen with ointments, creams or lotions.
There are several factors that make psoralen bath delivery easier for the patient than other topical treatments. Psoralen can be administered as a short 15 minute bath. The bath eliminates the laborious application required with other topical modalities. Furthermore the even skin distribution delivered by bath water leads to even pigmentation. Penetration of bath delivered psoralen into the blood stream is markedly less than for oral psoralens. Trioxsalen is more effective than methoxsalen. Bath water delivery of 8 - MOP was found to be as effective as oral administration of 8 - MOP and required smaller amounts of UVA radiation and yielded fewer side effects.
| Methodology|| |
Bath solutions are prepared by diluting 50ml of 8-MOP in 100 litres of bath water resulting in a final concentration of 3.75 mg/L. Patients soak for 15 minutes in this solution and then quickly wipe dry. Immediately patients are given whole body irradiation with UVA, the initial dose depending upon the skin type.
| Bath-suit delivery of psoralen|| |
In India use of bath tub is not in vogue. Water problem is perenial and most of the attending patients are poor. Hence bath suit therapy is another alternative. In a randomized double-blind placebo controlled study at our hospital bath-suit therapy was found to be an effective therapy for psoriasis. The improvement in 8-MOP bath suit group was statistically significant when compared to the placebo group.
Advantages of bath-suit delivery of 8-MOP are: (1) It requires only 2 litres of water and 0.8 ml of 8-MOP solution when compared to bath water therapy which needs 100 litres of water and 50 ml of 8-MOP (2) This treatment can be carried out at home with sunlight as the UVA source (PUVASOL) (3) The cost of the drug is less when compared to bath water delivery and oral psoralens. (4) Systemic side effects such as nausea and cataracts seen with oral PUVA, are not seen (5) Easy and less time consuming when compared to topical psoralen therapy (6) Irregular pigmentation seen with topical PUVA is overcome.
Disadvantage of bath-suit delivery are: (1) The entire body surface especially head does not come in contact with the drug (2) The concentration of the drug may not be uniform in the bath suit.
| PUVA for vitiligo|| |
The most common recommended treatment of vitiligo involves the ingestion of either 8-MOP or TMP followed by exposure to solar irradiation (PUVASOL) or to UVA radiation from artificial light sources. The criteria for patient selection are age 12 or over, ability to follow the protocol, availability for 12-24 months of continuous therapy, opthalmological examination and vitiligo other than lip-tip variant.
Effective results may occur with either TMP or 8-MOP, TMP is the preferred drug of treatment, with sunlight as the UVA source. On an average, a course of treatment consists of atleast 150 exposures of PUVA, and many patients improve significantly after about 50 exposures. However total repigmentation is only rarely achieved and some 30% of patients do not respond at all. In these cases punch grafting can be done followed by PUVA or PUVASOL, with good response after 3 - 6 months. Topical psoralen (8-MOP 0.1% or TMP 0.01%) therapy may also be tried in cases with isolated lesions.
| PUVA for cutaneous T-cell lymphoma (CTCL)|| |
There are several reports on the efficacy of PUVA in CTCL. PUVA is dramatically effective in early stage disease (IA, IB) when it induces complete and long lasting remissions. The mode of action is the direct phototoxic destruction of the atypical cells in the epidermis and dermis. The protocol for PUVA treatment in CTCL is essentially the same as in psoriasis. In late stages of the disease PUVA improves quality of life and may prolong survival when used in combination with more aggressive treatment modalities.
| PUVA for atopic dermatitis|| |
Most cases of atopic dermatitis improve with PUVA therapy. However, the number of treatments needed to bring about remission may be more than that for psoriasis. Also there is a high and early recurrence rate necessitating maintenance exposures. A combination of PUVA and topical steroids may be more beneficial than PUVA alone.
| PUVA for lichen planus|| |
PUVA is an effective alternative for systemic steroids in generalized lichen planus. However, lichen planus may be more resistant to treatment with PUVA than psoriasis. More exposures with higher cumulative doses are needed for clearance. We feel that relapse rate following PUVA is less than following systemic steroids (unpublished observation).
| PUVA for urticaria pigmentosa|| |
In cutaneous mastocytosis, PUVA treatment results in temporary involution of skin lesions with loss in Darier's sign, relief of itching, flattening and disappearance of cutaneous lesions with improvement in the systemic symptoms. However the exact mechanism of action is unknown.
[TAG:2]PUVA as prevention treatment for photodermatoses[/TAG:2]
Treatment with UV radiation (PUVA) is used in photosensitivity diseases to achieve long lasting tolerance to light.
Several studies have shown that PUVA therapy represents the most effective preventive treatment for P.L.E. Patient needs about 5 - 10 exposures during early spring to induce hardening. This schedule can be repeated each year. In solar urticaria, PUVA is the most effective prophylactic treatment and is better than indomethacin and antihistamines.
| Contraindications for PUVA|| |
The relative contraindications of PUVA are: (1) a personal or family history of melanoma (2) immunosuppressed patients (3) previous exposure to carcinogens such as x-rays, arsenic (4) outdoor workers in relatively sunny areas (5) children and youths and (6) minimal disease.
Absolute contraindications are: (1) pregnancy or when patient is trying to conceive (2) xeroderma pigmentosum (3) lupus erythematosus and (4) severe hepatic and renal failure.
| Side - effects of PUVA|| |
Acute side effects include:
Erythema, pruritus, nausea, headache, Koebner reaction, dizziness, drug eruption,, contact allergy, bronchial reaction, and severe skin pain.
Chronic side-effects are: Xerosis, hyper-pigmentation, ageing / wrinkling, chronic phototoxicity, hypopigmentation, legoedema, hypertrichosis, nail changes like pigmentation, subungual hemorrhage, and photoonycholysis, dyskeratotic or precancerous skin conditions such as actinic keratoses, keratoacanthoma, Bowen's disease, cutaneous malignacy - squamous cell carcinoma, lack of concentration, malaise, depression, insomnia, and cataract. PUVA is known to aggravate certain skin diseases such as seborrheic dermatitis, acne, bullous pemphigoid and lupus erythematosus. There are isolated reports of linking of certain conditions with PUVA therapy.
Melanoma, hypotension, hepatotoxicity, nephrotic syndrome, exacerbation of gouty arthritis, leukaemia, and lichenoid eruption.
| Recent advance in psoralens|| |
Furocoumarins in combination with UVA light has an antiretroviral activity against HIV - 1.
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