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5-Aminolevulinic Acid

5-Aminolevulinic Acid
 
Synonyms: 5-ALA; 5-Aminolaevulinic Acid; 5-Aminolevulínico, ácido; δ-Aminolaevulinic Acid; ALA
Chemical name: 5-Amino-4-oxopentanoic acid
Molecular formula: C5H9NO3 =131.1
CAS: 106-60-5
ATC code: L01XD04

Aminolevulinic Acid Hydrochloride

(US Adopted Name)

Drug Nomenclature

Synonyms: Aminolaevulinic Acid Hydrochloride; Aminolevulínico, hidrocloruro ácido
USAN: Aminolevulinic Acid Hydrochloride
Chemical name: 5-Aminolevulinic acid hydrochloride
Molecular formula: C5H9NO3, HCl =167.6
CAS: 5451-09-2
ATC code: L01XD04

Hexaminolevulinate Hydrochloride

(US Adopted Name)

Drug Nomenclature

Synonyms: P-1026
USAN: Hexaminolevulinate Hydrochloride
Chemical name: Hexyl 5-amino-4-oxopentanoate hydrochloride
Molecular formula: C11H21NO3,HCl =251.8
CAS: 140898-91-5

Methyl Aminolevulinate Hydrochloride

(US Adopted Name)

Drug Nomenclature

Synonyms: Methyl Aminolaevulinate Hydrochloride; Metilaminolevulinato, hidrocloruro de; P-1202
USAN: Methyl Aminolevulinate Hydrochloride
Chemical name: Methyl 5-amino-4-oxopentanoate hydrochloride
Molecular formula: C6H11NO3,HCl =181.6
CAS: 79416-27-6
ATC code: L01XD03

Adverse Effects and Precautions

The mechanism of action of topical 5-aminolevulinic acid or its derivatives generally results in local phototoxicity, manifest as a localised burning or stinging sensation, erythema, oedema, pruritus, scabbing, or pain. Symptoms are usually mild to moderate, and transient. During treatment, patients should be advised to avoid sunlight or prolonged exposure to bright light.

Other common adverse effects on the skin include scaling or crusting, ulceration, suppuration, blistering, bleeding, sensation of heat, erosion or exfoliation, and skin infection. Urticaria, rash, and changes in skin pigmentation may also occur. Application site discharge, eczema, and allergic contact dermatitis have been reported. Other common adverse effects include paraes-thesia and headache. Nausea, fatigue, eye swelling or eye pain, and wound haemorrhage have been reported.

Handling

US licensed product information warns that nitrile gloves should be worn during application and removal of methyl aminolevulinate hydrochloride cream; vinyl or latex gloves do not provide adequate protection.

Hypersensitivity

Allergic reactions to aminolevulinic acid and methyl aminolevulinate have been reported.

Porphyria

5-Aminolevulinic acid and its derivatives are considered to be unsafe in patients with porphyria.

Interactions

Use with other known photosensitisers such as griseofulvin, thiazide diuretics, sulfonylureas, phenothiazines, sulfonamides, and tetracyclines might increase the photosensitivity reaction commonly seen with 5-aminolevulinic acid or its derivatives.

St John’s wort

A patient taking St John’s wort had a pronounced phototoxic reaction consisting of an erythematous rash and swelling of the face, neck, and hands, 6 hours after receiving oral aminolevulinic acid. Although both drugs have been associated with photosensitivity, the authors suggested a synergistic effect had occurred. Tests in vitro appeared to confirm this.

Pharmacokinetics

After intravenous and oral doses of aminolevulinic acid hydrochloride equivalent to 100 mg of aminolevulinic acid, the mean half-life of aminolevulinic acid is stated to be about 0.83 hours and 0.7 hours, respectively; oral bioavailability is about 50 to 60%. In-vitro studies of dermal absorption found that the mean cumulative absorption of methyl aminolevulinate through healthy human skin after 24 hours was 0.26% of a dose and a skin depot containing 4.9% of the dose was formed.

Uses and Administration

5-Aminolevulinic acid is a naturally occurring haem precursor that is metabolised in the body to protoporphyrin IX, a photo sen sitiser, and then to haem. It has been formulated for topical use in photodynamic therapy (see under Porfimer Sodium). It is used to treat actinic keratoses and basal cell carcinoma (see below). Aminolevulinic acid hydrochloride is applied topically as a 20% solution in the treatment of non-hyperkeratotic actinic keratoses of the face or scalp. This is followed, 14 to 18 hours later, by illumination with blue wavelength light sufficient to supply a dose of 10 J/cm. Treatment may be repeated once after 8 weeks if necessary.

Methyl aminolevulinate hydrochloride is a derivative of 5-aminolevulinic acid that is applied topically for the treatment of non-hyperkeratotic, non-pigmented actinic keratoses of the face or scalp when other therapies are considered inappropriate. It is also used for the treatment of superficial and/or nodular basal cell carcinoma unsuitable for other therapies. In some countries, methyl aminolevulinate is licensed for the treatment of Bowen’s disease (squamous cell carcinoma in situ) when surgical excision is inappropriate.

A cream containing the equivalent of 16% methyl aminolevulinate is applied to the lesions and covered with an occlusive dressing. After 3 hours the cream is removed and the lesions are exposed to red wavelength light in a dose of 75 J/cm; exposure to the cream for more than 4 hours should be avoided. For actinic keratoses, one session of photodynamic therapy is given, and again after 3 months if necessary. For basal cell carcinoma or Bowen’s disease two sessions are given a week apart.

Patients should avoid sunlight or bright light sources for about 2 days after application.

Hexaminolevulinate hydrochloride is used as a diagnostic agent for the detection of bladder cancer, and is under investigation for the photodynamic therapy of bladder cancer.

Malignant neoplasms

The use of topical aminolevulinic acid or methyl aminolevulinate in the photodynamic therapy (PDT) of actinic keratosis and basal cell carcinoma has been reviewed. Both aminolevulinic acid and methyl aminolevulinate are considered to be effective in clearing non-hyperkeratotic actinic keratoses of the face and scalp, with response rates comparable to topical 5-fluorouracil and cryotherapy; cosmetic response is superior to that with cryotherapy. More than 80% of lesions cleared completely after 2 treatments with aminolevulinic acid PDT; a recurrence rate of 19% was reported over 12 months. Single treatment with methyl aminolevulinate is effective for thin lesions but thicker, non-responsive lesions may benefit from repeated treatment.

No significant differences in efficacy were seen between PDT with aminolevulinic acid or methyl aminolevulinate in the treatment of scalp actinic keratosis. Aminolevulinic acid is considered as effective as cryotherapy but with superior healing and cosmetic results for superficial basal cell carcinoma; it is less effective for nodular disease. Intrale-sional use has been investigated to improve penetration of the photosensitiser, with good preliminary results. Methyl aminolevulinate topical PDT may be preferable for difficult-to-treat basal cell carcinoma. Aminolevulinic acid is as effective in Bowen’s disease (squamous cell carcinoma in situ) as cryotherapy or 5-fluorouracil, but with fewer adverse effects. Topical methyl aminolevulinate PDT was more effective and cosmetically acceptable compared with topical 5-fluorouracil for pre-malignant skin disease in a small study in organ transplant recipients.

PDT using oral 5-aminolevulinic acid as the photosensitiser, at doses of 30 or 60 mg/kg, has been used to treat Barretts oesophagus, which is a major risk factor for oesophageal adenocarcinoma. A small study found similar clinical responses with low-dose (30 mg/kg) and high-dose (60 mg/kg) aminolevulinic acid protocols. Good long-term results have been reported with aminolevulinic acid PDT in patients with early neoplasia or high-grade intraepithelial neoplasia.

Aminolevulinic acid is also under investigation for the photodynamic detection and treatment of brain tumours. It has also been used for the fluorescence detection of pleural malignancies

An intravesical solution of aminolevulinic acid has been instilled for the detection and management of superficial bladder cancer. Hexaminolevulinate is used for the diagnosis of bladder cancer, and it appears to be more effective than standard white light cystoscopy.

A topical application of 5-aminolevulinic acid 3% has been tried in the treatment of cervical intraepithelial neoplasia, with poor response.

5-Aminolevulinic AcidSkin disorders

5-Aminolevulinic acid has been used topically in the photodynamic therapy (PDT) of skin conditions such as psoriasis, recalcitrant viral warts, acne vulgaris, and cutaneous T-cell lymphoma. Variable results have been reported with this therapy in patients with plaque psoriasis; in one study therapy was generally well-tolerated, but in the other all patients reported stinging or burning during irradiation.

A study comparing 5-aminolevulinic acid and methyl aminolevulinate for PDT of acne found both to be equally effective, although methyl aminolevulinate seemed to be better tolerated Topical methyl aminolevulinate-based PDT has been found to be effective in the treatment of facial acne vulgaris. PDT with 5-aminolevulinic acid has been reported to significantly improve an infected leg ulcer resistant to conventional therapies. A topical 10% solution has been used with intraurethral PDT to treat condylomata acuminata.

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.

Austria: Metvix;
Germany: Metvix;
Italy: Metvix;
Norway: Metvix;
New Zealand: Metvix;
Spain: Metvix;
Sweden: Hexvix; Metvix;
Switzerland: Metvix;
United Kingdom: Metvix; Porphin;
United States: Levulan Kerastick

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