Psoralens

Definition and Overview
Psoralens are a class of naturally occurring or synthetic furocoumarins that become pharmacologically active upon exposure to ultraviolet A (UVA) radiation (320–400 nm). These agents are primarily used in photochemotherapy (PUVA therapy) for several hyperproliferative, pigmentary, and autoimmune skin disorders. Psoralens exhibit photosensitizing properties, meaning they intercalate with DNA, and upon activation by UVA, form monoadducts and cross-links with pyrimidine bases, thereby disrupting DNA synthesis and inducing apoptosis or growth arrest in hyperactive cells.

This class of drugs has both topical and systemic formulations and requires carefully timed administration with UVA exposure to minimize adverse effects and maximize therapeutic benefit.

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1. Classification of Psoralens

Psoralens may be classified based on origin and use:

A. Naturally Occurring Psoralens

• Methoxsalen (8-MOP; 8-methoxypsoralen)

• Trioxsalen (TMP; 4,5′,8-trimethylpsoralen)

• Bergapten (5-methoxypsoralen)

• Found in plants such as Ammi majus, Citrus, Ficus carica, and Psoralea corylifolia

B. Synthetic Psoralens

• Oxsoralen-Ultra (methoxsalen capsules)

• Uvadex (methoxsalen solution for extracorporeal use in photopheresis)

C. Based on Route of Administration

• Oral: Methoxsalen capsules

• Topical: Methoxsalen lotion or gel

• Bath water delivery: Psoralen solutions in immersion PUVA

• Extracorporeal: Methoxsalen in photopheresis (ECP)

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2. Mechanism of Action

Psoralens are photosensitizing agents that require activation by UVA light to exert their biological effect.

Step-by-step pharmacodynamics:

1. Absorption and Distribution: Psoralens are ingested or applied topically and accumulate in epidermal cells.

2. UVA Activation: Upon UVA exposure, psoralens absorb light and become excited.

3. DNA Binding: The excited psoralen intercalates into DNA between pyrimidine bases (primarily thymine).

4. Covalent Bond Formation: A single UVA photon induces monoadducts; a second photon results in interstrand DNA cross-links.

5. Cellular Response:

   • Inhibits DNA replication and RNA synthesis

   • Promotes apoptosis of hyperproliferative or immune-reactive cells

   • Leads to therapeutic depigmentation, immunomodulation, and cell cycle arrest

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3. Therapeutic Indications

PUVA therapy (psoralen + UVA) is FDA-approved or clinically established in treating:

A. Psoriasis vulgaris

• Moderate-to-severe chronic plaque psoriasis unresponsive to topical agents

B. Vitiligo

• Especially generalized or segmental vitiligo; promotes repigmentation by stimulating melanocyte proliferation and migration

C. Cutaneous T-cell lymphoma (CTCL)

• Including mycosis fungoides in early stages

D. Alopecia areata

• PUVA may induce remission in patchy disease, though not first-line

E. Atopic dermatitis (refractory)

F. Lichen planus, pityriasis lichenoides, prurigo nodularis

G. Graft-versus-host disease (GVHD)

• Extracorporeal photopheresis (ECP) with psoralens is used in steroid-refractory GVHD

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4. Formulations and Dosage

Route	Formulation	Example	Dosage & UVA Timing
Oral	Capsules (10 mg, 20 mg)	Methoxsalen (Oxsoralen-Ultra)	0.6 mg/kg (max 30 mg) 2 hours before UVA exposure
Topical	Lotion or gel	1% methoxsalen topical solution	Apply 30 mins before UVA
Bath PUVA	1 mg/L psoralen in water	Full-body soak	15–20 min soak followed by UVA
Extracorporeal	Injectable solution (Uvadex)	Used in photopheresis machines	Dose: 0.01–0.02 mg/kg added to buffy coat

UVA exposure is titrated based on minimal phototoxic dose (MPD), Fitzpatrick skin type, and cumulative dose limits.

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5. Pharmacokinetics

• Absorption: Oral psoralens reach peak plasma concentrations in ~1.5–2 hours

• Distribution: Distribute to skin, especially stratum corneum and basal layer

• Metabolism: Primarily hepatic (CYP450); inactive metabolites

• Elimination half-life: ~1–2 hours

• Excretion: Urinary, as glucuronide/sulfate conjugates

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6. Adverse Effects

Acute (Short-Term):

• Photosensitivity: Sunburn-like erythema, pruritus, blisters

• Nausea, vomiting, headache

• Dizziness, malaise

• Conjunctivitis, photophobia (hence eye protection is essential)

Chronic (Long-Term):

• Photoaging: Premature skin wrinkling and leathering

• Lentigines: Freckling, pigmentation

• Cataracts: From UVA eye exposure; UV-protective glasses are mandatory

• Skin cancer:

  • Increased risk of squamous cell carcinoma (SCC)

  • Possible increased melanoma risk at high cumulative doses (>250 treatments)

Contraindications:

• Lupus erythematosus

• Xeroderma pigmentosum

• Porphyrias

• Hepatic impairment

• History of melanoma or actinic keratoses

• Pregnancy and breastfeeding

• Children under 12 years (except in vitiligo)

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7. Drug Interactions

Psoralens can interact with other agents in ways that increase phototoxicity or alter metabolic clearance.

Interacting Drug	Interaction Type	Clinical Concern
Tetracyclines, sulfonamides, thiazides	Additive photosensitization	Severe phototoxic reactions
CYP3A4 inhibitors (e.g., ketoconazole, grapefruit)	Reduced metabolism	Psoralen accumulation, prolonged photosensitivity
CYP inducers (e.g., rifampin)	Accelerated clearance	Reduced efficacy
Retinoids (e.g., acitretin)	Increased phototoxic risk	Avoid combination PUVA/retinoids
Alcohol	Increased nausea	Caution due to GI irritation

8. Precautions and Monitoring

• Eye protection: UVA-protective wrap-around glasses for 24 hours after oral methoxsalen

• Skin examination: Regular dermatologic exams for signs of photoaging or malignancy

• Pregnancy status: Verify non-pregnancy before initiation

• Liver function: Periodic monitoring in long-term therapy

• Cumulative UVA dose tracking: Especially in PUVA for psoriasis

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9. Comparative Effectiveness

Psoralen	Potency	Side Effect Profile	Use Preference
Methoxsalen (8-MOP)	High	More nausea	Widely used, both systemic and topical
Trioxsalen (TMP)	Moderate	Fewer systemic effects	Better tolerated topically
Bergapten	Lower	Fewer phototoxic effects	Preferred in vitiligo (less sunburn)

10. Therapeutic Alternatives

PUVA is gradually being replaced or complemented by:

• Narrowband UVB (NB-UVB): Lacks need for psoralens; safer long-term

• Excimer laser/light: Targeted UVB, useful in vitiligo/psoriasis

• Biologics: e.g., TNF-α inhibitors, IL-17/IL-23 blockers in psoriasis

• JAK inhibitors: Oral or topical in vitiligo (e.g., ruxolitinib)

• Topical calcineurin inhibitors

However, PUVA remains effective in recalcitrant, widespread, or early-stage CTCL where other modalities fail.

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11. Psoralens in Herbal/Traditional Medicine

Some natural remedies used traditionally contain high concentrations of psoralens:

• Babchi oil (Psoralea corylifolia): Used in Ayurvedic and Unani medicine for vitiligo

• Fig extracts, celery seed oils: Photosensitizing

• Unregulated use may lead to burns, hyperpigmentation, or carcinogenic exposure

Hence, herbal psoralens should be avoided unless under medical supervision.

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12. Regulatory and Brand Names

Drug	Brand	Regulatory Status
Methoxsalen	Oxsoralen-Ultra	FDA-approved for PUVA
Methoxsalen (solution)	Uvadex	FDA-approved for extracorporeal photopheresis
Trioxsalen	Vitilinex	Approved in some countries for vitiligo
Methoxsalen (topical)	Meladinine, PUVA lotion	Used in bath or localized PUVA

In many jurisdictions, psoralens are restricted-use medications due to the risk of carcinogenesis, and require specialized UV equipment and trained supervision.