Correlation between bathing time and photosensitivity in 8-methoxypsoralen (8-MOP) bath PUVA

Bath PUVA (psoralen plus ultraviolet A) using 8-methoxypsoralen has become increasingly popular in recent years as an effective treatment option for a continuously expanding range of skin disorders. Among the various variables of bath PUVA treatment, the impact of bathing time on photosensitivity has never been investigated in detail. We therefore determined the threshold UVA dose for erythema induction after different bathing periods. A marked influence of bathing time on photosensitivity was found. Increasing the soaking period from 5 min to 30 min resulted in a greater than 60% reduction of the minimal phototoxic and minimal perceptible phototoxic dose. Our results demonstrate that the duration of the psoralen bath is a critical parameter in bath PUVA treatment and has a major influence on UVA dose requirements.     

Plasma levels of 8-methoxypsoralen following oral or bath-water treatment

The plasma levels of 8-methoxypsoralen (8-MOP) were determined in 18 patients on PUVA treatment for their psoriasis and in two control volunteers. Seven of the patients were on oral therapy and 13 having bath treatment. The plasma levels of 8-MOP were determined up to 6 h after treatment and varied between less than 10 ng/ml and 360 ng/ml for the orally treated group, and in the bath-treatment group were all less than 10 ng/ml.     

Effects of water temperature on photosensitization in bath-PUVA therapy with 8-methoxypsoralen

The pharmacokinetic aspects of bath-PUVA are not completely clarified. Therefore, we determined the phototoxic response of human skin following psoralen baths at temperatures ranging from 32°C to 42°C (71.6–107.6°F) and UVA doses ranging from 0.5 to 5.5 J/cm². The highest therapeutical photosensitization (i.e., lowest minimal phototoxic dose) was assessed at temperatures of 37°C (98.6°F) and above. Photosensitization was significantly decreased at lower temperatures. These data indicate that a bath temperature of 37°C (98.6°F) should be used to gain optimal therapeutic efficiency in a clinical setting. Furthermore, in order to minimize the risk of adverse phototoxic effects in bath-PUVA, it is important to use a constant temperature during the psoralen bath.     

Plasma levels of 8-methoxypsoralen after bath-PUVA for psoriasis: relationship to disease severity

Plasma levels of 8-methoxypsoralen (8-MOP) were determined by high-pressure liquid chromato-graphy in 19 patients with psoriasis who were receiving bath-PUVA treatment, at different time points after the psoralen bath. The levels of 8-MOP varied between < 5 ng/ml (lower limit of detection) and 34 ng/ml, and we found a relationship between the plasma psoralen levels and the severity of the disease.     

Phototesting in bath-PUVA: marked reduction of 8-methoxypsoralen (8-MOP) activity within one hour after an 8-MOP bath

It is not known how long after 8-MOP bath-PUVA administration erythema can be induced. Therefore, after determination of dose-dependence and kinetics of bath-PUVA erythema, we investigated the development of erythema using an erythematogenic UVA-dose (3 J/cm²) in time course experiments. Our results show that there is a loss of biological 8-MOP activity already 1 h after 8-MOP bath. This has important consequences for clinical practice with bath-PUVA, concerning the optimum time interval between the 8-MOP bath and irradiation as well as the persistence of photosensitivity in normal skin after bath-PUVA.     

A polychromatic action spectrum for photosensitivity to orally administered 8-methoxypsoralen in humans

The action spectrum for producing minimal phototoxic erythema after oral administration of 8-methoxypsoralen (8-MOP) was determined in the range of 312-368 nm in 12 human volunteers using six different UV radiation sources. The peak sensitivity was found to be at 343 nm. The 8-MOP photosensitivity was at a high level (1.75 of maximum) between 336 and 355 nm. Conventional UVA radiation sources, like the Philips TL/09R tube, have a high energy output within 335 and 355 nm, and are therefore highly recommended in oral psoralen plus UVA radiation treatment.     

Half-side comparison study on the efficacy of 8-methoxypsoralen bath-PUVA versus narrow-band ultraviolet B phototherapy in patients with severe chronic atopic dermatitis

In patients with severe chronic atopic dermatitis (AD), both photochemotherapy [psoralen ultraviolet A (PUVA)] and narrow-band (TL-01) UV B phototherapy have been reported to be very effective. As no data exist on the relative therapeutic efficacy of these two regimens, we performed a randomized investigator-blinded half-side comparison study on 12 patients with severe chronic AD. Half-side irradiation with threshold erythemogenic doses of 8-methoxypsoralen bath-PUVA and narrow-band UVB was performed three times weekly over a period of 6 weeks. The severity of the disease was assessed separately for the paired halves of the patients' bodies by a modified SCORAD score at baseline and after 2, 4 and 6 weeks of treatment. Ten of the 12 patients completed the trial. All but one showed marked improvement or complete remission with both treatments. The mean baseline SCORAD score decreased by 65.7% by the bath-PUVA treatment and by 64.1% by the narrow-band UVB treatment (P = 0.48). No serious adverse reactions to either of the two regimens were observed. Our data confirm the high efficacy of bath-PUVA and narrow-band UVB phototherapy in the treatment of patients with chronic severe AD. Both regimens appear to be equally effective when administered in equi-erythemogenic doses.     

The relationship between 8-methoxypsoralen skin and blood levels

A method is described to determine the 8-methoxypsoralen (8-MOP) concentration in vivo in the skin by means of high-performance liquid chromatography (HPLC). Skin and blood samples were taken from 80 rats at specific intervals after oral administration of [3H]8-MOP. The pharmacokinetic results obtained for the skin levels were compared to the blood levels. In addition, liquid scintillation counting (LSC) was done on all the samples to compare the concentrations of 8-MOP plus metabolites to the concentrations of 8-MOP alone. There was a good correlation between the 8-MOP skin and blood levels. The values obtained with LSC were higher in function of time than the corresponding values obtained by HPLC, which indicates the presence of metabolites in both the skin and the blood. No statistically significant difference in the time of peaking was noted for the skin and blood levels. The blood levels seem to be a good parameter for the 8-MOP skin concentration.     

Plasma levels of 8-methoxypsoralen in psoriatic patients receiving topical 8-methoxypsoralen

Using a high-pressure liquid chromatographic technique, plasma psoralen levels have been measured in patients receiving total-body topical photochcmothcrapy (PUVA). Levels comparable with those found during oral 8-methoxypsoralen (8-MOP) treatment were observed, suggesting that topical therapy has no advantage over the oral route as far as the hazards of systemic therapy are concerned.     

The influence of food on 8-methoxypsoralen serum concentration and minimal phototoxic dose

Ten adult volunteers were given three oral doses of 0.46-0.56 mg/kg body weight of 8-methoxypsoralen (8-MOP) in a liquid formulation under fasting conditions, and after ingestion of a low-fat or fat-rich breakfast. 8-MOP serum levels and photosensitivity were measured 0.5-4 h after drug ingestion. The 1-h 8-MOP serum levels and photosensitivity were significantly higher in fasting conditions than after ingestion of a low-fat or fat-rich meal (intra-individual median difference in photosensitivity 7.5 J/cm2). On 12 of 20 occasions when the drug was taken after food ingestion, the 1-h 8-MOP serum concentration was below 30 ng/ml. A survey of 43 out-patients undergoing regular PUVA treatment showed that the frequency of erythemal reactions was significantly higher when 8-MOP was ingested with a > 50% smaller quantity of food than usual (P < 0.005). This study demonstrated food-induced variations in 8-MOP photosensitivity both in an experimental situation and in an out-patient survey. In order to optimize the therapeutic effect of PUVA, the quantity of food taken before 8-MOP should remain constant, and the timing of UVA irradiation should be adjusted according to the preceding food intake.     

Variation in 8-methoxypsoralen profiles during long-term psoralen plus ultraviolet A therapy and correlations between serum 8-methoxypsoralen levels and chromametric parameters.

Three serum 8-methoxypsoralen (8-MOP) kinetics tests were performed on 15 patients undergoing PUVA therapy. The first test was carried out before beginning PUVA treatment, the 2nd one at the 10th session and the 3rd test at the 20th PUVA session. Blood samples were taken every 30 min after the drug was taken and a standard meal ingestion during 3 h to determine the serum 8-MOP peak level and corresponding time. For 14 patients, UVA-induced erythema was measured with a Minolta CR 200 chromameter, 3 (before beginning PUVA treatment, just before 10th session and 48 h later) or 5 times (before beginning PUVA treatment, just before 10th session and 48 h later, just before 20th session and 48 h later). There was a wider distribution of serum 8-MOP peak levels in the 3rd test than in 2nd one and in the 2nd one than in the first one. These facts suggest a heterogeneity in 8-MOP metabolism in the 15 patients: 11 patients showed an earlier serum 8-MOP peak and an earlier appearance of the drug in blood in the 3rd and 2nd test than in the first one. For 9 of these 11 patients, serum 8-MOP peak levels were higher and higher from the first profile to the 3rd one, suggesting an inhibition of 8-MOP metabolism in time. In the remaining 4 patients, the 8-MOP peak time and the appearance of the drug in blood were delayed in the 3rd test compared with the first profile.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between plasma levels of 8-methoxypsoralen and the phototoxic effect

Plasma concentrations of 8-MOP were studied in 6 subjects at three dose levels and the minimal phototoxic dose determined after 60, 120 and 180 min. Although there is an inverse correlation between these two values, none of the eight mathematical expressions examined gave a perfect fit in all cases.     

Interaction between 8-methoxypsoralen and phenytoin. Consequence for PUVA therapy

A patient with epilepsy and psoriasis in phenytoin therapy was treated with PUVA with no effect at all. The PUVA treatment failure was demonstrated as being due to abnormally low serum levels of 8-methoxypsoralen (8-MOP) during phenytoin therapy, while normal serum levels of 8-MOP were observed after phenytoin was discontinued. The effect is probably due to an induction of the hepatic enzyme system by phenytoin, leading to an increased metabolism of 8-MOP. Other drugs with hepatic enzyme inducing properties might possibly also interfere with psoralen metabolism with further consequences for PUVA therapy.     

5-S-cysteinyldopa excretion after treatment with 8-methoxypsoralen and UVA light

The excretion of the specific melanocytic metabolite 5-S-cysteinyldopa was studied in patients with psoriasis treated by 8-methoxypsoralen and UVA light. A pronounced increase was found after only 2 days treatment, although no increase in pigmentation could yet be observed. Peak values for urinary 5-S-cysteinyldopa were noted after 1 or 2 weeks treatment. Increase in pigmentation persisted after the excretion maxima for 5-S-cysteinyldopa.     

Absence of cataract ten years after treatment with 8-methoxypsoralen

Thirteen patients treated with 4-41 g of 8-methoxypsoralen (8-MOP) for vitiligo were examined with regard to ocular damage 2-12 years after start of the treatment. No signs of eye damage were registered. This result indicates the need for more comprehensive retrospective examinations of 8-MOP-treated patients in order to gain information on the practical risk of cataract formation.     

New studies on the interaction between 8-methoxypsoralen and DNA in vitro.

Some aspects of the interactions between DNA and 8-methoxypsoralen (8-MOP) in its ground state (complex formation) or in its excited state (photobinding) have been investigated. 8-MOP shows a low affinity towards DNA in the complex formation; this fact minimizes the possible biological consequences deriving from this interaction, when it occurs in vivo. In covalent photobinding to DNA, 8-MOP forms mainly monofunctional adducts, and to a lesser extent bifunctional adducts, showing a behavior similar to that of other linearly condensed furocoumarins (psoralens); the ratio between mono- and bifunctional adducts was found to be 9:1. The covalent photobinding to DNA does not occur at random along the macromolecule, but preferentially at the level of specific receptor sites. The regions having an alternate sequence of A-T seem to be the best receptor sites for the formation of monoadducts while the regions containing an alternate sequence of A-T and C-G appeared to be the preferential sites for the cross-linkage formation.     

Penetration kinetics of 8-methoxypsoralen after 8-methoxypsoralen bath procedure with and without UVA irradiation.

Administration of 8-methoxypsoralen (8-MOP) in a dilute bath water solution is an effective therapeutic alternative for systemic application of 8-MOP, avoiding systemic side effects such as nausea and cataractogenesis. The aim of our study was to determine the epicutaneous penetration of 8-MOP in a dilute bath water solution with and without additional UVA irradiation in human skin under in vitro conditions. To simulate the PUVA bath procedure, 8 skin samples were exposed to radioactively labeled 8-MOP in a water solution. After 20 min, the test solution was removed and the skin surface was dried. Immediately after the bath procedure, 4 of the skin samples were irradiated with 0.5 J/cm2 UVA. During a test period of 15 h, the 8-MOP penetration was observed. In both test groups (with and without UVA irradiation) 8-MOP permeated through all skin layers between 30 min and 1 h after application. Compared to the unirradiated skin samples, the UVA-irradiated skin samples showed a significantly slower increase and a lower maximum of 8-MOP permeation. Following our results, UVA irradiation of 8-MOP-exposed skin samples led to a significantly decreased permeation rate. This might be due to UVA-induced links between 8-MOP molecules and human DNA. In addition, we investigated the levels of radioactivity emitted by tritium-labeled 8-MOP in stratum corneum, epidermis and dermis up to 30 min after 8-MOP bath in two further test groups with and without additional UVA irradiation. The statistical analysis revealed no significant differences between these two test groups. Thus, the levels of radioactivity remained constant in the epidermis and dermis during the test period of 30 min. Since the levels of radioactivity were constant up to 30 min after UVA irradiation, a previously supposed marked loss of 8-MOP concentration might not be responsible for the rapid extinction of observed in vivo photosensitivity within 1 h after PUVA bath observed in vivo in human skin.     

5-S-Cysteinyldopa and dopa in serum during treatment with 8-methoxypsoralen and UVA light

5-S-Cysteinyldopa and dopa concentrations in serum were studied by high-performance liquid chromatography (HPLC) in patients with psoriasis treated by 8-methoxypsoralen and UVA light. A marked increase in 5-S-Cysteinyldopa was found after 3 days' treatment, although no increase in pigmentation could yet be observed. The highest concentrations of 5-S-Cysteinyldopa in serum were noted after 1 or 2 weeks' treatment. In one patient who showed no increase in serum 5-S-Cysteinyldopa treatment was unsuccessful. During PUVA treatment of 3 patients with psoriasis confined to the palms and/or soles a delayed increase in serum 5-S-Cysteinyldopa was noted after 5 weeks. This delayed response after treatment of a small area of the body is remarkable, and may indicate the formation of a systemic melanocyte stimulation factor. There was no increase in the serum dopa concentrations during PUVA treatment, and dopa analysis was of no value in assessing the activity of the melanocytes. Some unexpectedly high dopa values recorded before and during PUVA treatment may be explained by the fact that dopa originates in the nervous system or the adrenals.