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PubMed1977

Photochemotherapy of psoriasis using methoxsalen and sunlight. A controlled study.

Fifty-one patients with psoriasis were treated with oral methoxsalen and sunlight exposure. Twelve of these patients received either methoxsalen or placebo prior to whole-body exposure. The remainder were treated with methoxsalen and sunlight to one side of the body and sunlight alone to the other. The conventional dose of methoxsalen (0.6 mg/kg) was compared with a low dose (0.3 mg/kg). Oral methoxsalen when used in the higher dose followed by sun exposure is an effective treatment for psoriasis. Accurate ultraviolet dosimetry is essential to avoid phototoxic burns. The advantages and disadvantages of solar photochemotherapy are discussed.

Clinical Trials as Topic↗
PubMed1986

Quantification of methoxsalen-DNA adducts with specific antibodies.

Methods are now available for the quantification of carcinogen-DNA adducts in human tissues and can be used to screen populations for exposure to environmental carcinogens. One approach utilizes highly specific antibodies in sensitive immunoassays for quantifying adduct levels in DNA from various tissues. We have recently developed a panel of monoclonal antibodies that specifically recognize DNA modified by methoxsalen and ultraviolet A light (320-400 nm) (UVA). These antibodies have been characterized as to sensitivity and specificity by an enzyme-linked immunosorbent assay (ELISA). In a competitive ELISA, 50% inhibition of antibody binding occurred with 17 fmol methoxsalen-DNA photo adducts. There was also some antibody cross-reactivity with DNA modified by 4'-aminomethyl-4,5,8-trimethylpsoralen and 4',5-dimethylangelicin but not with free methoxsalen. A more sensitive ELISA has also been developed using fluorescence detection of enzyme activity. With this assay, one adduct per 10(8) bases can now be detected reliably. Adduct levels have been quantified in myeloma cells and lymphocytes treated in vitro with methoxsalen and UVA. In addition, in preliminary studies, adducts have been measured in lymphocytes isolated from patients undergoing extracorporeal photophoresis for cutaneous T-cell lymphoma. Quantification of methoxsalen adducts in patients should provide a basis for estimating risk resulting from psoralen plus UVA (PUVA) treatment.

Antibodies, Monoclonal↗
PubMed1982

Topical methoxsalen followed immediately by long-wave UV irradiation. A preliminary report on the treatment of psoriasis.

In the treatment of psoriasis with topically applied methoxsalen, the patient is exposed to long-wave UV (UV-A) energy two hours after the application of methoxsalen. Using the guinea pig as an experimental model, we found that UV-A irradiation given immediately after the topical application of methoxsalen resulted in the notable suppression of tritiated thymidine incorporation into epidermal basal cells. This finding suggests that the rate of suppression of epidermal DNA synthesis by PUVA (methoxsalen plus UV-A light) may not correlate with the interval between methoxsalen application and UV-A irradiation. This modified method of PUVA therapy (immediate irradiation) was successfully used in the treatment of psoriasis.

Administration, Topical↗
PubMed1987

Inactivation of human liver cytochrome P-450 by the drug methoxsalen and other psoralen derivatives.

The effects of psoralen derivatives on cytochrome P-450 have been studied in human liver microsomes. CO-binding cytochrome P-450 was decreased by 33% after 10 min of incubation with 1.5 mM EDTA, an NADPH-regenerating system and 20 microM methoxsalen (8-methoxypsoralen). No destruction of cytochrome P-450 was observed when either NADPH or methoxsalen was omitted. A similar (27%) decrease in CO-binding required a 100-times higher concentration of allylisopropylacetamide (2 mM). The activities of 7-ethoxycoumarin deethylase and benzo(a)pyrene hydroxylase were decreased by about 50% in the presence of 12.5 microM methoxsalen. At this low concentration, neither cimetidine nor SKF 525-A or piperonyl butoxide had any significant inhibitory effect. Monooxygenase activities were also decreased in the presence of 12.5 microM bergapten (5-methoxypsoralen) or 12.5 microM psoralen, but not with 12.5 microM trioxsalen (trimethylpsoralen). CO-binding cytochrome P-450 was not decreased after 10 min of incubation with 1.5 mM EDTA, an NADPH-regenerating system and 20 microM trioxsalen. We conclude that methoxsalen is an extremely potent suicide inhibitor of cytochrome P-450 in human liver microsomes. Bergapten and psoralen are also inhibitory whereas trioxsalen has little effects. In the latter derivative, a methyl group is attached on the furan ring and may hinder its metabolic activation and the inactivation of cytochrome P-450.

5-Methoxypsoralen↗
PubMed2006

Drug-drug interaction after single oral doses of the furanocoumarin methoxsalen and cyclosporine.

Furanocoumarins increase the bioavailability of drugs that are CYP3A4 substrates. A possible interaction of methoxsalen with cyclosporine was evaluated in 12 healthy volunteers following oral administration of 40 mg methoxsalen, 200 mg cyclosporine, or a combination of both in a randomized crossover study. Methoxsalen increased area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) of cyclosporine by 29% (range, -20% to 172%; P < .05) and 8% (range, -10% to 26%; P < .05), respectively, compared to cyclosporine alone. The AUC geometric means ratio (95% confidence interval) for cyclosporine plus methoxsalen/cyclosporine alone was 1.14 (1.02, 1.27), and treatments were therefore not bioequivalent. Methoxsalen causes a clinically significant interaction with cyclosporine in some susceptible individuals. The reasons for susceptibility and the clinical implications for chronic cyclosporine administration have not been established. Caution is recommended in combination therapy, and more frequent monitoring of cyclosporine plasma levels and clinical monitoring is advised.

Administration, Oral↗
PubMed1992

Hypocholesterolemic effect of khellin and methoxsalen in male albino rats.

Khellin (CAS 82-02-0) and methoxsalen (CAS 298-81-7) were examined in male albino rats to evaluate their ability to modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. The drugs were evaluated in four-week double dose studies. After four weeks at 0.45 mg/100 mg b.wt. for khellin and 0.27 mg/100 g b.wt. for methoxsalen, per day, both drugs significantly lowered low density lipoprotein cholesterol, high density lipoprotein cholesterol and total cholesterol. Very low density lipoprotein cholesterol and triglycerides were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with a lower dose of khellin (0.23 mg/100 g b.wt./d). A dose of 0.13 mg/100 g b.wt./d of methoxsalen had no observable effect in this study. Confirmation of the hypocholesterolemic activity of khellin and methoxsalen in this study enhances the therapeutic potential of these compounds against atherosclerosis.

Animals↗
PubMed1979

Comparison of crude coal tar and topical methoxsalen in treatment of psoriasis.

Fluorescent sunlamp bulbs have been an effective light source for treatment of psoriasis when they are used in combination with crude coal tar. In addition to their ultraviolet B (UVB) emission, the spectral output of these bulbs contains a substantial amount of ultraviolet A (UVA). Prior testing with this light source and topically applied methoxsalen achieved excellent results in psoriasis. This study compared topically applied methoxsalen to crude coal tar in 16 patients who had plaque-type psoriasis, using the same fluorescent sunlamp source of irradiation. Fourteen of 16 patients had complete clearing of plaques when they were treated with methoxsalen, compared with six patients who had complete clearing with the tar treatment. These results indicate that the use of methoxsalen and ultraviolet light may be more effective than tar, when used as they were in this study. The advantages of a clean, white, nonstaining topical agent also makes outpatient therapy more cosmetically acceptable.

Coal Tar↗
PubMed1984

Quantitative determination of methoxsalen in human serum, suction blister fluid and epidermis by gas chromatography mass spectrometry.

A selected ion-monitoring gas chromatographic mass spectrometric method is described for the determination of methoxsalen employing trioxsalen as internal standard. Methoxsalen in the serum and skin of 5 psoriatic patients after PUVA bath therapy was determined. Quantitative gas chromatographic mass spectrometric analysis was performed in the election impact mode by monitoring the ratio of ions m/z 216/228. The methoxsalen level in human serum varied between 3-15 ng/ml, in suction blister fluid between 2-9 ng/ml and in suction blister roof (epidermis) between 6-242 ng/g during the first 30 min after the methoxsalen bath.

Blister↗
PubMed1981

Photochemotherapy of psoriasis with methoxsalen and longwave ultraviolet light (PUVA).

The effectiveness of methoxsalen and ultraviolet light (PUVA) in treating is reviewed. The use of this therapy, its mechanism of action, pharmacology, pharmacokinetics, adverse reactions, dosage, and comparison with other forms of therapy, are discussed. Administered orally, methoxsalen in combination with long-range ultraviolet light (UVA) is effective in treating patients with moderate to severe forms of psoriasis. Although the short-term risks associated with PUVA therapy are minimal, the long-term risks of oncogenicity have not been evaluated thoroughly. Common adverse reactions to methoxsalen and UVA are nausea, pruritus, and erythema, but usually they can be managed by minor modifications in the treatment regimen. Methoxsalen and UVA therapy should be reserved for patients with moderate to severe forms of psoriasis that do not respond to other forms of therapy until the long-term risks of oncogenicity are evaluated.

Humans↗
PubMed1994

Skin pigmentation as a predictor of minimal phototoxic dose after oral methoxsalen.

BACKGROUND AND DESIGN: Twenty-eight subjects were phototested to determine their erythemal responses to oral methoxsalen with UV-A and UV-B irradiation. Skin pigmentation was measured by skin reflectance at 550 and 660 nm before irradiation. The smallest UV radiation dose to produce erythema (minimal phototoxic dose and minimal erythema dose, respectively) was determined. The serum concentration of methoxsalen was measured at the time of UV-A irradiation. RESULTS: There was a positive correlation between skin pigmentation and both 72-hour minimal phototoxic dose and 24-hour minimal erythema dose. No correlation was demonstrated between methoxsalen serum concentration and minimal phototoxic dose. The combination of skin pigmentation and methoxsalen level did not give a better prediction of minimal phototoxic dose than skin pigmentation alone. CONCLUSIONS: Skin pigmentation measurements can be used to predict the minimal phototoxic and erythema doses. Skin pigmentation measurements are easy to perform and should be included in both phototherapy and photochemotherapy to improve the efficiency and reliability of the treatment.

Administration, Oral↗
PubMed1992

Comparison of the carcinogenic potential of trioxsalen bath PUVA and oral methoxsalen PUVA. A preliminary report.

BACKGROUND AND DESIGN: There is an increasing concern about the long-term carcinogenic effect of oral psoralen with long-wave UV radiation in the A range (PUVA). Most follow-up investigations indicate a definite risk of squamous cell carcinoma of the skin with long-term PUVA treatment. In a recently published study of 4799 Swedish patients who had received PUVA, it was noted that 833 patients who had received trioxsalen bath or oral trioxsalen did not show any increased risk of skin cancer in contrast to oral methoxsalen. This finding has been further investigated in this study. We compared four dermatologic university clinics in Sweden with regard to the carcinogenic potential of the PUVA regimen used. One clinic used trioxsalen bath PUVA exclusively and the other three used oral methoxsalen. Information on their PUVA-treated patients was collected and linked with information from the Swedish Cancer Registry to identify individuals with squamous cell carcinoma of the skin. RESULTS: A total of 18 squamous cell carcinomas of the skin were reported in 2975 PUVA-treated patients until 1987. The expected number was 3.1. The center using bath PUVA only had no increased risk of squamous cell carcinoma of the skin in contrast to the three centers using oral methoxsalen-PUVA. The increased risk for male subjects from those centers varied from six to 13 times that in the general population, but for female subjects a significant increased relative risk was found only at one center. CONCLUSION: In this preliminary report, PUVA treatment with trioxsalen bath seems to be less carcinogenic than the oral dosage. However, differences in the patient populations might also have affected the outcome of the study. More information on this field is needed.

Administration, Oral↗
PubMed1995

Combination of methoxsalen and ultraviolet B (UVB) versus UVB radiation alone in treatment of psoriasis: a bilateral comparison study.

A bilateral comparison study of the therapeutic effects of broad-band ultraviolet (UBV) (FS-40 Sunlamp bulbs) radiation versus UVB radiation plus methoxsalen was conducted in patients with psoriasis. Ten patients were given up to 30 exposures to the two treatments on paired, similarly affected limbs. There was no detectable difference in the response of limbs treated with UVB plus methoxsalen versus UVB phototherapy alone although all patients did show a therapeutic response. Other areas of the body treated with methoxsalen and broad-band UVA radiation (PUVA bulbs) responded more rapidly and to a greater extent than areas exposed to UVB radiation.

Adult↗
PubMed1981

In vitro availability profiles of oral methoxsalen commercial products.

The in vitro release rate of methoxsalen from three commercially available tablets and an experimental tablet were evaluated at pH 2 and 7, using the USP dissolution test. The experimental tablet and one commercial product showed that 74% of the labeled amount is released in 1 h and almost completely released after 3 h at pH 2 and 7. Two products showed that only 12 and 10% of the labeled amount was released in 1 h and a maximum of 25 and 23% after 3 h at pH 2. At pH 7, the percent released from these two products were slightly higher. These results correlate with the reported clinical effectiveness of one of the products showing fast methoxsalen release. Since exposure to long-wave UV radiation is carried out 1-3 h following methoxsalen oral administration, delayed release might explain the failure of some products to give satisfactory clinical results.

Hydrogen-Ion Concentration↗
PubMed1987

Long-term efficacy of PUVA treatment in lichen planus: comparison of oral and external methoxsalen regimens.

Forty-three patients with lichen planus (LP) were treated with either oral methoxsalen PUVA (10 cases), bath methoxsalen PUVA (13 cases) or no PUVA (20 cases). In the bath treatment series, a good or excellent clearing of the lesions was registered in 10 out of 13 cases after courses of 8-46 irradiations, while in the orally medicated group only 5 out of 10 had a similar response after 8-30 irradiations. In addition, 11 of the 23 PUVA-treated patients showed progressive improvement of their condition during the first few months after PUVA therapy. A clinical follow-up study was made 15 and 10 months later in the oral and bath PUVA groups, respectively, and at 10 months in the no-PUVA group. Six of the 23 PUVA-treated patients (23%) were found to be totally clear, but the remaining 17 patients (74%) had clinical signs of LP. Eleven of the 20 no-PUVA-treated patients (55%) showed total clearing. It is concluded that while both oral and bath methoxsalen PUVA regimens have a distinct immediate (1-2 months) clearing effect on LP, the late outcome of the rash is not better than with no UV treatment; PUVA treatment may possibly even prolong the ultimate course of LP.

Administration, Oral↗
PubMed1986

Bioavailability of a new oral methoxsalen formulation. A serum concentration and photosensitivity response study.

A new encapsulated liquid preparation of methoxsalen (soft gelatin capsule) was compared with the currently marketed hard gelatin capsule form and with an oral solution of methoxsalen in a random crossover design. Serial serum samples were collected from 25 healthy adult subjects and assayed by a high-performance liquid chromatography technique. Additionally, photosensitivity was determined by serial testing in 12 subjects. The soft-capsule formulation resulted in a 59% increase in extent of absorption and in a greater rate of absorption of methoxsalen than from the hard capsule. This was demonstrated by consistently higher peak serum concentrations (225 vs 199 ng/mL), which occurred at earlier times (1.8 vs 3.0 hours) following administration of the soft capsule. Photosensitivity testing confirmed these results, as photosensitivity was greater (9.53 vs 12.68 J/cm2) and reached a maximum earlier (1.5 vs 4.25 hours) following administration of the soft capsule. The soft capsule can be considered equivalent to the oral solution in both serum concentrations (peak concentration, 231 vs 225 ng/mL, and time of peak, 1.6 vs 1.8 hours) and photosensitivity response (maximum photosensitivity, 9.24 vs 9.53 J/cm2, and time of maximum photosensitivity, 1.32 vs 1.50 hours).

Administration, Oral↗
PubMed1979

Serum concentration and phototoxic effect of methoxsalen in patients with psoriasis.

The correlation between serum concentration of methoxsalen (8-methoxypsoralen; 8-MOP) and phototoxic effect using long-wave ultraviolet light has been studied in 5 psoriatic patients. The maximum serum concentration occurred between 0.5 and 2 hr after oral administration of 0.6 mg/kg of methoxsalen. The lowest value for the minimum phototoxic dose (MPD), i.e., highest photosensitivity, was obtained between 1 and 2 hr. There was a significant negative correlation between the logarithm of the serum concentration and minimum phototoxic dose (MPD) (r = 0.780). Hence, the degree of photosensitivity appears to be related to the serum level of methoxsalen.

Adult↗
PubMed1976

Oral methoxsalen photochemotherapy of mycosis fungoides.

The cutaneous manifestations of mycosis fungoides have been successfully treated in nine patients for 16 to 28 months with oral methoxsalen and subsequent irradiation with longwave ultraviolet light. The efficacy of this therapy was confirmed in one patient, who showed complete clearing of generalized plaques after 1 month (12 treatments) except for a shielded control area which worsened during this period. Methoxsalen photochemotherapy may prove a valuable addition to therapies currently available for mycosis fungoides and may obviate some of the problems associated with conventional management of this disorder.

Administration, Oral↗
PubMed1980

Toxic hepatitis from oral methoxsalen photochemotherapy (PUVA).

A 59-year-old white woman with long-standing psoriasis, who had a damaged liver from methotrexate, developed a toxic hepatitis while on oral methoxsalen photochemotherapy (PUVA). Fever and marked elevation of liver enzymes occurred after the fifteenth PUVA treatment and spontaneously returned to normal within 5 days. One week later, following the next PUVA treatment, the same toxic hepatitis developed and again spontaneously resolved. Topical methoxsalen photochemotherapy with ultraviolet A (UVA) did not produce the toxic hepatitis and provided a suppression of the psoriasis on a maintenance basis.

Administration, Oral↗