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PubMed1988

Incidence of skin cancer in Japanese psoriatic patients treated with either methoxsalen phototherapy, Goeckerman regimen, or both therapies. A 10-year follow-up study.

To determine the long-term cutaneous side effects of methoxsalen phototherapy (PUVA) and Goeckerman regimen, a total of 151 Japanese psoriatic patients treated with PUVA, Goeckerman regimen, or both therapies in our department from 1976 to 1986 were evaluated for skin cancers. Sixty-seven patients had been treated with PUVA, 43 with Goeckerman regimen, and 41 with both therapies. One patient alone (62-year-old man) developed squamous cell carcinoma on the leg with cumulative ultraviolet A (UVA) dose of only 51 joules/cm2, he had a history of treatment with superficial x-ray therapy to this area 30 years prior to PUVA. The cancer was detected after 1.4 years of PUVA treatment. However, other patients at follow-up, even those who had received a cumulative dose of UVA of more than 1000 joules/cm2, had no skin cancer after more than 2 years. This report in Japanese patients confirms that only previous exposure to other risk factors such as ionizing radiation appears to be a most important factor for skin cancer formation in PUVA-treated Japanese patients.

Adolescent↗

PubMed1996

Rectal suppositories of 8-methoxsalen produce fewer gastrointestinal side effects than the oral formulation.

BACKGROUND: Gastrointestinal side effects are associated with the oral ingestion of 8-methoxsalen (8-MOP), including the liquid and crystalline formulations. OBJECTIVE: The objective of this study was to determine whether the gastrointestinal symptoms associated with 8-MOP could be decreased by altering the route of administration. METHODS: In an open pilot study, 8-MOP rectal suppositories were given to six patients with psoriasis vulgaris who had significant nausea or abdominal pain with the oral liquid form of the drug. RESULTS: On a scale of 0 to 5, this group of patients reported a mean score of 4.4 for nausea, 0.3 for vomiting, 2.1 for abdominal pain, and 1.3 for headaches with oral 8-MOP. With the suppository form, the mean scores were 0 for nausea, 0 for vomiting, 0 for abdominal pain, and 0 for headaches. These latter values represent scores for the entire treatment period. Clinical severity scores of psoriasis improved from a mean of 6.5 (maximum possible score = 9) at the start of the trial to a mean of 1 at its conclusion. Plasma 8-MOP levels of more than 100 ng/ml were observed in all patients who received the suppositories; in only one patient were the 8-MOP plasma levels significantly higher with the oral form than with the rectal form. CONCLUSION: Rectal suppositories of 8-MOP were associated with significantly fewer gastrointestinal side effects than the oral form of the drug; this was accomplished without compromising clinical efficacy.

Abdominal Pain↗

PubMed2000

The effect of PUVA on langerhans cells in rat oral epithelium photosensitized with systemic methoxsalen or topical trioxsalen.

BACKGROUND/PURPOSE: Ultraviolet-A radiation (UVA) of the oral mucosa after photosensitization with either systemic methoxsalen (8-MOP) or topical trioxsalen (TMP), i.e. mouth-PUVA, has been reported to be successful in the treatment of oral lichenoid lesions. In the case of PUVA treatment of skin disorders, local immune suppressive effects have been demonstrated, and the antigen presenting epithelial Langerhans cells (LCs) have been shown to be especially sensitive to ultraviolet treatments. Our aim was to compare the photobiological effects of PUVA in oral mucous membrane (OMM) using topical TMP or systemic 8-MOP photosensitization. METHODS: Rat OMM photosensitized with topical TMP or systemic 8-MOP was treated with PUVA using UVA doses of 1-8 J/cm2. The LCs were demonstrated in epithelial sheets of the treated OMM with ATPase staining. RESULTS: Both treatments caused a sim ilar, dose-dependent depletion of ATPase-positive LCs, with a maximal depletion of 80% or 73% with 8 J/cm2 at 2 days after irradiation as photosensitized with TMP or 8-MOP, respectively. This contrasts with earlier published findings in human skin, where topical TMP is an order of magnitude greater a sensitizer than 8-MOP, and PUVA-induced depletion of LCs occurs maximally 5 days after irradiation. CONCLUSION: The depletion of LCs of rat OMM after PUVA treatment is greater using topical TMP compared to systemic 8-MOP, but the difference is significantly smaller than reported earlier in human skin.

Administration, Oral↗

PubMed2005

Structures of human microsomal cytochrome P450 2A6 complexed with coumarin and methoxsalen.

Human microsomal cytochrome P450 2A6 (CYP2A6) contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. The CYP2A6 structure shows a compact, hydrophobic active site with one hydrogen bond donor, Asn297, that orients coumarin for regioselective oxidation. The inhibitor methoxsalen effectively fills the active site cavity without substantially perturbing the structure. The structure should aid the design of inhibitors to reduce smoking and tobacco-related cancers.

Aryl Hydrocarbon Hydroxylases↗

PubMed2001

The effect of methoxsalen dose on ultraviolet-A-induced erythema.

There is considerable interindividual variation in bioavailability of Methoxsalen (8-methoxypsoralen) after ingestion of the standard dose used in photochemotherapy (psoralen plus ultraviolet A). A dose change may be used to alter the degree of photosensitivity, although there is limited information on the effect of 8-methoxypsoralen dose alterations on phototoxicity within individuals. We studied the effect of changes of 8-methoxypsoralen dose over a narrow range in 15 subjects with psoriasis. Two hours after ingestion, serum 8-methoxypsoralen concentration was determined and phototesting was performed at 350 +/- 30 nm (0.45-14 J per cm2). The minimal phototoxic dose at 72 h was recorded, erythema was measured using a reflectance instrument, and dose-response curves were constructed. Each subject was tested on three occasions using doses of 25 mg per m2 (conventional dose) or conventional dose +/- 10 mg. Median serum 8-methoxypsoralen concentration increased from 96 to 143 to 229 ng per ml with dose increases from conventional dose - 10 mg to conventional dose and conventional dose + 10 mg, respectively (p < 0.001). The median minimal phototoxic dose and D0.025 (the objective equivalent of the minimal phototoxic dose derived from the dose-response curve) were significantly reduced with increasing 8-methoxypsoralen dose from conventional dose minus 10 mg (minimal phototoxic dose 1.7 J per cm2; D(0.025) 2.8 J per cm2) to conventional dose (1.2; 1.4 J per cm2) and conventional dose plus 10 mg (0.9; 1.0 J per cm2) (p < 0.001). Change in 8-methoxypsoralen dose had no detectable effect on the maximum slope of the psoralen plus ultraviolet A erythema dose-response curve. Thus, 8-methoxypsoralen dose changes within individuals, over a narrow but clinically relevant range, significantly altered the threshold response to psoralen plus ultraviolet A erythema but not the rate of increase in erythema with increasing ultraviolet A dose.

Adult↗

PubMed1997

Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study.

BACKGROUND: Photochemotherapy with oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is an effective treatment for psoriasis. However, PUVA is mutagenic, increases the risk of squamous-cell skin cancer, and can cause irregular, pigmented skin lesions. We studied the occurrence of melanoma among patients treated with PUVA. METHODS: We prospectively identified cases of melanoma and documented the extent of exposure to PUVA among 1380 patients with psoriasis who were first treated with PUVA in 1975 or 1976. Using incidence data, we calculated the expected incidence of melanoma in this cohort and compared it with the observed incidence. Using regression models, we assessed the risks of melanoma associated with a long time (> or = 15 years) since the first treatment and with a large number of PUVA treatments (> or = 250). RESULTS: From 1975 through 1990, we detected four malignant melanomas, about the number expected in the overall population (relative risk, 1.1). From 1991 through 1996, we detected seven malignant melanomas (relative risk, 5.4; 95 percent confidence interval, 2.2 to 11.1). The risk of melanoma was higher in the later period than in the earlier one (incidence-rate ratio, 3.8) and higher among patients who received at least 250 PUVA treatments than among those who received fewer treatments (incidence-rate ratio, 3.1). CONCLUSIONS: About 15 years after the first treatment with PUVA, the risk of malignant melanoma increases, especially among patients who receive 250 treatments or more.

Adult↗

PubMed2002

Methoxsalen stimulates electrogenic Cl- secretion in the mouse jejunum.

We used the short-circuit current (I(sc)) and patch-clamp techniques to investigate the effects of methoxsalen (MTX) on the electrogenic Cl- secretion of the mouse jejunum. MTX stimulated a sustained increase in Isc that was dose dependent. Bumetanide inhibited MTX-stimulated Isc in a dose-dependent manner consistent with activation of Cl- secretion. MTX failed to stimulate I(sc) following maximal activation of the cAMP pathway by forskolin, but did increase Isc after a submaximal dose of forskolin. Glibenclamide, a blocker of the cystic fibrosis transmembrane conductance regulator (CFTR), reduced the MTX-stimulated increase of Isc by 59 +/- 6%. The cAMP-dependent K+ channel blocker 293B did not alter the MTX-activated I(sc); however, clotrimazole, an intermediate Ca2(+)-activated K+ channel (IK(Ca)) blocker, reduced the MTX-stimulated I(sc). MTX did not alter Na(+)-glucose cotransport across the mouse jejunum. In cell-attached membrane patches, MTX increased the open probability of the basolateral IK(Ca) channel of isolated crypts. These data suggest that the CFTR and IK(Ca) channels participate in the MTX-activated, sustained Cl- secretory response of the mouse jejunum.

Animals↗

PubMed2003

An intraindividual study of the characteristics of erythema induced by bath and oral methoxsalen photochemotherapy and narrowband ultraviolet B.

We compared the characteristics of psoralen and ultraviolet A (PUVA) erythema in skin photosensitized by bath or oral methoxsalen in 20 subjects. Erythema was assessed visually and with a reflectance instrument at 24 h intervals for 7 days. In addition, narrowband ultraviolet B (TL-01 UVB) erythema was examined in 19 of these subjects at 4, 8, 12, 24, 48 and 72 h and in another nine subjects at 12, 15, 18, 21 and 24 h. Both bath and oral PUVA exhibited broad erythemal peaks beyond 72 h. For topical PUVA the lowest minimal phototoxic dose (MPD) occurred at 120 and 144 h (P = 0.01 and 0.03 compared with 72 h). Oral PUVA erythema peaked earlier at 96 h: the MPD was significantly lower at 96, 120 and 144 h compared with 72 h (P = 0.001, 0.01 and 0.02, respectively). At 120 h, bath PUVA had a significantly steeper slope compared with oral PUVA. The TL-01 UVB minimal erythema dose was significantly lower at 12 h compared with 24 h (P = 0.019). The majority of subjects were at maximal erythema at 12 h (22 of 28) and 15 h (eight of nine). Our results suggest that peak erythema for bath PUVA, oral PUVA and TL-01 UVB occurs at 120, 96 and 12-15 h, respectively.

Administration, Oral↗

PubMed1991

Outcomes of pregnancies among women and partners of men with a history of exposure to methoxsalen photochemotherapy (PUVA) for the treatment of psoriasis.

Because oral methoxsalen and UV-A radiation (PUVA) therapy is mutagenic, concern exists about the potential for teratogenic effects resulting from the use of this therapy at the time of conception and during pregnancy. After 12.8 years of prospective study, we documented the pregnancy outcomes among 1380 patients (892 men and 488 women) who received PUVA treatments. Ninety-four men reported 167 pregnancies in their partners, and 93 women reported 159 pregnancies. For 34% of pregnancies among partners of male patients, the man received PUVA therapy near the time of conception. Nineteen percent of female patients reported exposure to PUVA at the time of conception or during pregnancy. Induced and spontaneous abortions were reported as the outcome of pregnancy more often by female than by male patients (12% vs 30%). Two congenital malformations and two stillbirths occurred, an incidence not significantly different from that expected for the general population. Although the power of our study to detect an increase in the risk of specific defects is limited, our data show no evidence to suggest that PUVA is a potent teratogen. Still, because PUVA is mutagenic, we believe it prudent for patients to avoid PUVA treatment during pregnancy whenever practical.

Abortion, Induced↗

PubMed1979

Topical methoxsalen photochemotherapy in the treatment of palmoplantar pustulosis and psoriasis.

Topical methoxsalen photochemotherapy has been assessed in 22 patients suffering from recalcitrant palmoplantar pustulosis or psoriasis predominantly involving the hands and feet. Although 20 out of 22 patients improved and good results were obtained in exactly half of those treated, only 4 patients were classified as being "clear" or "minimally involved" at the end of 12 weeks. Two patients have shown no improvement at all. Minor local side effects were relatively common and included symptomatic erythema, blistering and local pigmentation. The histological findings in post PUVA treated skin are discussed and the pros and cons of topical photochemotherapy in this group of diseases is reviewed.

Administration, Topical↗

PubMed1982

PUVA therapy for polymorphous light eruptions: comparison of systemic methoxsalen and topical trioxsalen regimens and evaluation of local protective mechanisms.

Twenty-six patients with long-standing, recurrent polymorphous light eruptions were treated with psoralen photochemotherapy. Thirteen patients received oral methoxsalen, while 13 were photosensitized by trioxsalen baths. After an average of 20 PUVA exposures, a good or excellent therapeutic result was achieved in 12 of the orally treated and 10 of the topically treated patients. In most of the cases, clinical desensitization lasted throughout the summer season, without further PUVA exposures. When the polymorphic phototest reaction (PPR) was registered 72 h after skin testing with a medium pressure mercury lamp, a remarkable reduction or total abolition of the reaction was seen in tests made on PUVA-exposed skin, as compared with tests made on a comparable skin site, shielded from UVA exposure during the treatments. A concomitant decrease in the erythemal reactivity (MED) of the skin was usually--though not invariably--seen. It is concluded that in addition to including an increase in the shielding properties of stratum corneum, PUVA treatment may induce non-responsiveness in PMLE skin by other, possibly anti-inflammatory or immunological mechanisms.

Administration, Oral↗

PubMed1984

Skin typing for assessment of skin cancer risk and acute response to UV-B and oral methoxsalen photochemotherapy.

Skin typing is a clinical classification system based on a patient's historical reporting of the acute skin response to sunlight. It is advocated as a means of determining an individual's relative risk of skin tumors and has been used to determine the initial therapeutic dose of UV radiation for UV-B phototherapy or oral methoxsalen photochemotherapy (PUVA) for psoriasis. Among PUVA-treated patients, the relative risk of cutaneous carcinoma was significantly higher among patients with skin types I and II compared with patients with skin type IV (3.2 and 2.3, respectively). Skin type was a better predictor of this risk than eye or hair color. The minimal erythemal dose ( MErD ) and minimal phototoxic dose (MPD) increased with increasing skin type number, but within a given skin type each varied as much as sixfold. Skin type was a good clinical predictor of skin cancer risk, but lacked specificity as a predictor of an individual's MErD or MPD.

Administration, Oral↗

PubMed1984

Lens opacities appearing during therapy with methoxsalen and long-wavelength ultraviolet radiation.

Therapy with methoxsalen and type A (long-wavelength) ultraviolet radiation (PUVA) has recently become a common method of treating psoriasis and other dermatologic conditions. This treatment could induce cataractous changes in the human lens through a reaction between the psoralen in the lens and either UVA or ambient light. In a 28-month-long prospective study of 78 patients treated with PUVA, small lens opacities appeared in 3 patients, aged 67, 48 and 32 years. The two younger patients had not worn their protective glasses for 24 hours after each treatment, as recommended. Therefore, although it cannot be concluded that PUVA therapy caused these opacities, eye protection during treatment and for 24 hours thereafter should be emphasized to the patients.

Adult↗

PubMed1981

Effect of methoxsalen photochemotherapy on cost of treatment for psoriasis. An example of technological assessment.

In 1974 a new therapy that employs methoxsalen and ultraviolet A irradiation (PUVA) was introduced as an outpatient treatment for severe psoriasis. To study the effect of this therapy on the cost of treatment, we documented for 1,320 patients two major components of cost--hospitalization and PUVA treatments. When the one-year period before initiation of PUVA therapy was compared with a one-year period after initiation of PUVA therapy, average hospital days per person per year declined 77% (5.1 vs 1.2). This decrease in hospitalization was most notable among patients who continued to use PUVA therapy. Largely offsetting the reduction in cost from reduced hospitalization was the cost of PUVA treatments. Our data confirm the previously known effectiveness of PUVA therapy, and they provide no support for the hypothesis that PUVA substantially increases the cost of treating patients with severe psoriasis.

Ambulatory Care↗

PubMed1980

Treatment of palmoplantar psoriasis with topical methoxsalen plus long-wave ultraviolet light.

Fourteen patients with chronic plaque-type psoriasis involving the palms and soles and 14 patients with palmoplantar vesiculopustular dermatosis, including three cases of localized pustular psoriasis, were treated with topical application of methoxsalen, followed by exposure to long-wave ultraviolet energy (topical PUVA). Approximately two thirds of the patients with palmoplantar plaque-type psoriasis and half of those with vesiculopustular dermatosis responded with considerable improvement, as evidenced by flattening of plaques, decreased scaling and erythema, and decreased vesicle and pustule formation after 15 to 40 treatments. Complete clearing of the treated areas was achieved in five patients with palmoplantar psoriasis, three of whom had the pustular variety. Most patients required continued maintenance therapy with topical PUVA. The condition of the patients with palmoplantar vesiculopustular dermatosis, especially those with severe involvement, was more labile and more difficult to control with PUVA therapy than in those with chronic scaling plaques.

Adolescent↗

PubMed1985

Methoxsalen and ultraviolet A radiation in treatment of chronic cutaneous graft-versus-host reaction.

Chronic cutaneous graft-versus-host reaction following bone marrow transplantation has been difficult to manage in some patients because of poor response to immunosuppressive agents or because of toxicity to these drugs. We recently used methoxsalen and ultraviolet A therapy and found it to be successful in controlling chronic cutaneous lichenoid graft-versus-host reaction in a bone marrow transplant patient. Although there was an initial flare of an eruption resembling acute cutaneous graft-versus-host reaction, both this acute eruption and the lichenoid lesions subsided and cleared with continued treatment. The skin lesions recurred when treatment was discontinued but responded promptly when it was initiated for the second time. Other than mild phototoxicity, there were no other significant side effects.

Adolescent↗

PubMed1986

Status of ultraviolet A dosimetry in methoxsalen plus ultraviolet A therapy.

The carcinogenic risk of methoxsalen plus ultraviolet A treatment (PUVA) is almost certainly related to the cumulative UVA exposure dose. A reliable estimate of UVA dose is a major component, therefore, in determining the long-term safety of this treatment modality. Thirty-one UVA meters from twenty-nine different PUVA treatment centers were compared with a calibrated UVA meter. The results inferred that 95% of UVA meters used in PUVA centers are reading between 57% and 159% of the true UVA irradiance, a factor of 2.8 in relative sensitivity. This wide variation in accuracy between the UVA meters gives cause for concern. These variations were attributed to differences in calibration procedure, optical properties of the sensors, and, most importantly, poor quality control by the manufacturers. The situation that appears to have existed since the introduction of PUVA therapy can be improved only if dermatologists agree that the present inaccurate and uncertain approach to UVA measurements is unsatisfactory. Manufacturers of UVA meters should be encouraged to provide instruments as reliable as the dosimeters used in radiotherapy, in which the prescribed dose is probably within 5% of the true value. Ideally, a standard type of UVA meter with appropriate physical properties and an agreed calibration procedure should be used by all centers engaged in PUVA treatment.

Humans↗

PubMed1985

Comparison of trioxsalen bath and oral methoxsalen PUVA in psoriasis.

Fifty patients with chronic plaque psoriasis were treated with trioxsalen bath PUVA and 43 patients with oral methoxsalen PUVA. The two treatment regimens gave similar results; 75% and 77% of the patients had excellent or good clearing and a follow-up of one year revealed relapses in 61% and 58% of the patients, respectively. The cumulative UVA dose remained significantly lower in bath PUVA (mean 23.5 J/cm2) than in oral PUVA (mean 131 J/cm2). Nausea and headache occurred in 21% of the patients receiving oral PUVA but in none in the bath PUVA group. Local side-effects were found in 30% of the patients receiving bath PUVA and in 17% of the patients in the oral PUVA group.

Adult↗