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.     

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.     

Assessment of minimal phototoxic dose following 8-methoxypsoralen bath: maximal reaction on average after 5 days

An essential procedure before starting bath psoralen ultraviolet (UV) A (PUVA) photochemotherapy is the evaluation of the minimal phototoxic dose (MPD), which is traditionally assessed 3 days after irradiation. However, there are no controlled studies supporting the 72 h peak of bath-PUVA erythema. The aim of this study was therefore to determine the exact time course of the erythematous reaction in human skin following bath-PUVA. For this purpose, the skin of 10 volunteers was exposed to 0.5-3.0 J/cm2 UVA directly after a 20-min 8-methoxypsoralen bath (0.5 mg/L, 37 degrees C). At 24, 48, 72, 96, 120 and 144 h (1-6 days) after irradiation, the MPD and the erythema sum score (ESS) were determined in each subject. The results showed a maximal erythematous reaction on average 5 days after irradiation. The mean MPD gradually decreased from day 2 (> 3.0 J/cm2) to day 5 (mean +/- SD 1.15 +/- 0.63 J/cm2) and started to increase at day 6 (mean +/- SD 1.6 +/- 0.52 J/cm2). The mean +/- SD ESS correspondingly increased from day 2 (0 +/- 0) to day 5 (10.5 +/- 3. 7) with a decrease at day 6 (7.5 +/- 3.1) (difference between day 3 and beyond statistically significant at P < 0.05). As our study indicates a maximal erythematous reaction to the bath-PUVA up to 5 days after irradiation, the traditional MPD assessment at 3 days generates a risk of phototoxic side-effects within the phototherapy course by underestimating the phototoxic effect in some patients. These findings contribute towards a more defined understanding of the kinetics of the phototoxic reaction in bath-PUVA therapy.     

Contact allergy to 8-methoxypsoralen

A 36-year-old female patient was treated with PUVA for dyshidrotic eczema that had not shown sufficient response to topical therapy over the previous months. PUVA therapy caused acute aggravation of the eczema. Patch testing demonstrated Type IV sensitization to 8-methoxypsoralen in Meladinine solution.     

Microenema of 8-methoxypsoralen in photochemotherapy of psoriasis

Summary Reasonably high plasma levels were obtained 1/2 h after 8-methoxypsoralen (8-MOP) administration by microenema. This method was used in photochemotherapy of psoriasis and reasonably good clinical results with no serious side effects were obtained. The advantages of this modality include noninvolvement of the upper gastrointestinal tract, high bioavailability of psoralen, peak levels at a predictable time, and rapid elimination of the drug.     

甲氧沙林脂质体对小鼠黑素瘤细胞黑素生成影响的研究

目的:探讨甲氧沙林脂质体(8-MOPL)对小鼠B16F黑素瘤细胞增殖、黑素含量、酪氨酸酶活性的影响。方法:采用体外培养的小鼠B16F黑素瘤细胞株,以等浓度的甲氧沙林(8-MOP)为对照,用四甲基偶氮唑蓝(MTT)法测定细胞增殖情况;NaOH裂解法测定黑素合成;多巴氧化法测定酪氨酸酶活性。结果:与等浓度8-MOP相比,低浓度8-MOPL(10-25μmol/L)能显著提高酪氨酸酶活性和黑素含量(P<0.05)。高浓度8-MOPL(100-200μmol/L)对细胞的抑制作用更显著(P<0.05)。结论:用脂质体作为8-MOP的载体可以显著提高8-MOP对靶细胞的作用,为8-MOPL制剂治疗白癜风的临床应用提供了实验依据。     

0.05%地奈德软膏联合8-甲氧补骨脂素治疗面部白癜风疗效观察

目的：评价0.05%地奈德软膏联合8-MOP（8-甲氧补骨脂素）治疗颜面部白癜风的临床疗效及安全性。方法：60例颜面部的白癜风患者分3组,第一组患者（18例）单用8-MOP,第二组（19例）单用0.05%地奈德软膏,第三组患者（即联合用药组,23例）采用8-MOP和0.05%地奈德软膏联合治疗,治疗后12周评价疗效。结果：3组有效率分别为53.84%,57.89%和73.91%,实验组的临床疗效明显优于两对照组,差异有统计学意义（P均〈0.05）。3组不良反应发生率分别为50.00%,21.05%和4.34%,其中实验组与两对照组相比,不良反应发生率明显减少。结论：0.05%地奈德软膏联合8-MOP治疗颜面部白癜风疗效好,不良反应发生率低。     

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.     

Kinetics of [14C-5] 8-methoxypsoralen distribution in rabbits

Summary Distribution, kinetics and localization of 8-methoxypsoralen (8-MOP) was determined in rabbits over 24 h following i.v. administration of [¹⁴C-5] labeled and carrier 8-MOP at respective concentration of 50 Ci and 5 mg/kg. Peak levels were reched by kidneys at 1 h (18,500 ng/g) at 2 h by liver (2,470 ng/g) and at 8 h by bile (64,000 ng/g). Muscles, lymphatic tissues and brain showed low drug uptake (800 ng/g). Endocrine organs also had low drug concentration. In gastrointestinal tract the maximum level of 8-MOP was 1,500 mg/g at 1 h in jejunum. Plasma 8-MOP concentration was 3,700 ng/ml at 5 min post injection with 100 ng/ml still detectable at 24 h. Urine label concentration peaked at 1 h (4×10⁵ cpm/ml) and was 2×10² cpm/ml at 24 h. The intact skin concentration was at the maximum during the first 30 min (1,958 ng/g) declining progessively thereafter to 155 ng/g at 24 h. The UVA irradiated skin (320–380 nm at the rate of 14.2 mW/cm²×s^-1 for 1 h) had a higher 8-MOP concentration (2,834 ng/g at 1 h and 280 ng/g at 24 h).Supported by the Research Foundation of the Washington Hospital Center and by Ophthalmic Research Foundation, Washington, DC     

Pharmacokinetics of 8-methoxypsoralen in serum and suction blister fluid

Summary Micronized 8-methoxypsoralen (8-MOP), with a smaller crystal size, produced significantly higher serum level profiles than nonmicronized 8-MOP. Furthermore, the absorption of the micronized drug was more rapid, resulting in peak serum levels within 1 h in 75% of the patients. Our blister fluid studies suggest, however, that reduction of the photosensitizer concentration is slower in skin than in serum. This implies that despite markedly reduced 8-MOP serum level after 2 h the skin remains sufficiently sensitized up to that point of time.     

Action spectra for 8-methoxypsoralen and 3-carbethoxypsoralen in skin fibroblasts in vitro

Summary 8-methoxypsoralen (8-MOP) and 3-Carbethoxypsoralen (3-CPs) are known photoreagents which have been employed in the treatment of psoriasis. Using skin fibroblasts grown in vitro we have determined the action spectra of both compounds in the long ultraviolet range. Narrow-band interference filters were applied to a Xenon lamp. Reduction in methyl-³H-thymidine (³H-TdR) uptake served as a parameter for photoinhibited cells. The results show a linear increate of 8-MOP-mediated photoinhibition with increasing wavelengths; 3-CPs showed comperatively weak inhibitory rates at the lower wavelength range (349–365 nm). Possibly this is due to the formation of 3-CPs photoproducts which are unreactive with DNA. Compared to 8-MOP, the monofunctional photoreagent 3-CPs is a weak photoinhibitor.This work was supported by Stiftung Volkswagenwerk     

Comparison of the relative therapeutic efficacy of 7-methyl pyridopsoralen and 8-methoxypsoralen in photochemotherapy in psoriasis treatment

A newly-synthesized, monofunctional psoralen derivative, 7-methyl pyrido (3,4-C) psoralen (MPP) was compared with 8-methoxypsoralen (8MOP) with respect to their therapeutic efficacy in photochemotherapy of psoriasis. Psoriatic lesions of six patients were treated with topical application of MPP plus UVA (MPP PUVA) or with 8MOP plus UVA (8MOP PUVA). The UVA doses used in each treatment were 7.5 or 10 J/cm² with MPP and from 1.2 to 3.6 J/cm² with 8MOP. In every patient, marked improvement was observed after 2 to 6 treatments with MPP PUVA or 8MOP PUVA. Three patients showed clearance of each psoriatic lesion treated 9 to 17 times with MPP or 8MOP PUVA. Althought MPP required much higher UVA doses than 8MOP, MPP PUVA was as effective as 8MOP PUVA in treating psoriasis. When irradiating with identical doses of UVA, MPP PUVA appeared to be less active than 8MOP PUVA. None of the patients developed any severe dermatitis reactions during 20 exposures to MPP PUVA, indicating that the probability of inducing allergic contact and photocontact dermatitis may be extremely low. Erythemogenic and pigmentogenic activities of MPP and 8MOP were also compared. The data demonstrated that 8MOP is more than 8 times as effective as MPP for both activities. With the UV doses used in this study, however, every patient produced marked pigmentation after MPP PUVA therapy. Finally, the UVA dose-dependency of MPP PUVA was studied with an additional patient. Both therapeutic and pigmentogenic effects increased as a function of the UVA dose; it appeared impossible to clear psoriasis without producing pigmentation.     

Extended extracorporeal photochemotherapy with extracorporeal administration of 8-methoxypsoralen in systemic sclerosis. An Austrian single-center study

BACKGROUND: Extracorporeal photochemotherapy (EXP) is an immunomodulating therapy that has been used in a limited number of patients with systemic sclerosis (SSC) with controversial results. The present study was performed to evaluate the efficacy and safety of extended EXP with extracorporeal application of liquid 8-methoxypsoralen (8-MOP) in the treatment of SSC. METHODS: Eleven women with progressive SSC of recent onset were treated for a period of 16-57 months. Skin changes, physical performance, extracutaneous manifestations, and quality of life were evaluated before initiation of EXP and at regular intervals thereafter. RESULTS: From the start to the last set of EXP, we observed an overall improvement and/or stabilization of skin changes and physical performance in 5 of 11 patients (45%). Extracutaneous manifestations deteriorated in 10 of 11 patients (91%) (P<0.05), and quality of life deteriorated in 9 of 11 patients (82%) from a mean score of 10 before, to 17 at the last set of EXP (P<0.05). No major side effects were noted. CONCLUSION: Extended EXP with extracorporeal administration of 8-MOP is a safe and well tolerated treatment modality. However, it provides only (minor) improvement of skin changes of a subset of SSC patients and does not beneficially influence extracutaneous manifestations and quality of life.     

Pharmacokinetics and metabolite-pattern of 8-methoxypsoralen in man following oral administration as compared to the pharmacokinetics in rat and dog

Summary Following oral administration of ¹⁴C labelled 8-methoxypsoralen (8-MOP) in man the plasma level course, the metabolite-patterns and the elimination of the parent compound and its metabolites have been investigated. Additionally the results discovered have been compared with the data of pharmacokinetics on dog and rat. In man and rat the plasma protein binding of 8-MOP has been determined.Maximal levels of the total radioactivity in the plasma were achieved 2 h after dosing. At this time 8-MOP represents 50% of the radioactivity in the plasma.The plasma protein binding in vitro of ¹⁴C 8-MOP valued from 88% to 91% in man, and between 75% and 83% in the rat.Urinary elimination of the total radioactivity as a measure of the extent of absorption varies greatly and depends on the therapeutic formulation being employed. Following the administration of the solution 74% is recovered within 48 h. Faecal elimination of the total radioactivity reached 14% within 3 days.The metabolite-pattern does not show the unchanged ¹⁴C 8-MOP. Several polar metabolites occur in the urine among which biochemical conjugates have been recognized. Only polar metabolites are observable in the faeces from which the radioactivity is incompletely extractable. From a comparison of the metabolite profiles, the rat as well as the dog seem to be a useful animal species for experimental investigations with 8-MOP.     

Topical 8-methoxypsoralen enhances the therapeutic results of targeted narrowband ultraviolet B phototherapy for plaque-type psoriasis

Targeted broadband ultraviolet B (UVB) phototherapy as well as 308‐nm excimer laser have been reported to significantly improve or clear localized psoriatic plaques within 5 to 10 treatments when medium fluences [i.e. 4–6 multiples of minimal erythema doses (MED)] were used. Our study was conducted to determine the effects of different concentrations of topical 8‐methoxypsoralen (8‐MOP) cream when used in combination with targeted UV phototherapy with regard to number of treatments and cumulative UV doses to clear localized psoriasis. Ten evaluable patients with stable plaque‐type psoriasis completed the study. Three different concentrations of 8‐MOP creams (0.001%, 0.01% and 0.1%) were applied prior to irradiation with 4 MEDs of targeted narrowband UVB (NB‐UVB), whereas 0.001% 8‐MOP cream was used in conjunction with 5 J/cm² UVA. All irradiations took place once weekly for 12 weeks. Psoriasis severity index (PSI) score was used to evaluate the efficacy of the treatment. With area‐under‐the‐curve analysis, 0.1% 8‐MOP/NB‐UVB was superior to other modalities in reducing the PSI scores. The number of treatments and cumulative NB‐UVB doses necessary to achieve PSI‐95, a 95% reduction in the scores, was also lower in the 0.1% 8‐MOP/NB‐UVB group, although the differences were not statistically significant. We conclude that topical 8‐MOP cream enhances the therapeutic effects of targeted NB‐UVB phototherapy without significantly increasing the short‐term adverse effects.     

Localization of radioactivity in rat organs after oral administration of tritiated 8-methoxypsoralen in therapeutic doses

Summary Tritiated 8-methoxypsoralen was given perorally to rats in amounts corresponding to therapeutic human doses. The rats were exposed to UVA light or kept in darkness. None of the fractions (apart from ³H₂O from the lens) examined changed their level of radioactivity under the influence of UVA light.Time-radioactivity curves were recorded for the skin, lens, residual eye, and the liver. Four fractions were measured: ³H₂O, soluble pool, DNA-RNA, and protein. Tritiated water appeared already 1 h after ingestion, and attained maximum value 9–24 h after ingestion, indicating the efficiency with which the liver degrades 8-MOP. ³H-8-MOP and metabolites could be detected in the soluble pool in maximum amounts 2–3 h after the administration. Pretreatment with trypsin increased the concentration of ³H-8-MOP and metabolites; the origin of this extra radioactivity was the protein fraction.The ³H-8-MOP binding to DNA or RNA was studied by pretreatments of the homogenates with DNase or RNase followed by measurement of radioactivity in the TCA extracts. This indicated that no measurable amount of ³H-8-MOP had been bound to DNA or RNA.We conclude that 8-MOP administered to rats in amounts corresponding to human therapeutic doses does not bind to DNA or RNA in measurable amounts either after UV-light or in darkness. The experiments have shown proteins to be the main binding site in rat organs.Supported by the Danish Medical Research Council, grant no. 512-3287     

Hand and foot PUVA soaks: An audit of the Massachusetts General Hospital''s experience from 1994 to 1998

Palmoplantar psoriasis and eczema can be chronic recalcitrant dermatoses. Oral psoralen plus ultraviolet A (PUVA) has proven effective for these, but has a number of unwanted side effects. Previous studies have shown that regional PUVA therapy using the 8-methoxypsoralen (8-MOP) soak method followed by immediate UVA irradiation is also beneficial and well tolerated. The purpose of this audit was to determine the efficacy of hand and foot PUVA soaks by reviewing the experience of the Massachusetts General Hospital's Phototherapy Unit with this treatment modality. Phototherapy records of all patients who underwent hand and foot PUVA soaks from 1994 to 1998 were reviewed. Details regarding the treatment procedure, patient compliance, patient response and incidence of side effects were noted and summarized. Of the 56 patients who underwent at least 20 treatments, 29% had excellent response, 42% had minimal to moderate response, and 29% had poor response. The average number of treatments to induce clearing was 41. The average maximum treatment dose at clearing was 5.85 J/cm2, while the average cumulative dose to achieve clearing was 267.17 J/cm2. 8-MOP PUVA soak therapy is quite useful for chronic hand and foot dermatoses. Patient compliance must be emphasized to obtain favorable results.