Extracorporeal Photopheresis in the Treatment of Mycosis Fungoides and Sézary Syndrome.

Extracorporeal photopheresis (ECP) is an immunomodulating procedure that leads to an expansion of peripheral blood dendritic cell populations and an enhanced TH1 immune response in cutaneous T-cell lymphoma (CTCL). Because of its excellent side effect profile and moderate efficacy, ECP is considered first-line therapy for erythrodermic mycosis fungoides (MF) and Sézary syndrome. Patients with a measurable but low blood tumor burden are most likely to respond to ECP, and the addition of adjunctive immunostimulatory agents may also increase response rates. There may be a role for ECP in the treatment of refractory early stage MF, but data are limited.

Drug metabolism within the brain changes drug response: selective manipulation of brain CYP2B alters propofol effects.

Drug-metabolizing cytochrome P450 (CYPs) enzymes are expressed in the liver, as well as in extrahepatic tissues such as the brain. Here we show for the first time that drug metabolism by a CYP within the brain, illustrated using CYP2B and the anesthetic propofol (2, 6-diisopropylphenol, Diprivan), can meaningfully alter the pharmacological response to a CNS acting drug. CYP2B is expressed in the brains of animals and humans, and this CYP isoform is able to metabolize centrally acting substrates such as propofol, ecstasy, and serotonin. Rats were given intracerebroventricularly (i.c.v.) injections of vehicle, C8-xanthate, or 8-methoxypsoralen (CYP2B mechanism-based inhibitors) and then tested for sleep time following propofol (80 mg/kg intraperitoneally). Both inhibitors significantly increased sleep-time (1.8- to 2-fold) and brain propofol levels, while having no effect on plasma propofol levels. Seven days of nicotine treatment can induce the expression of brain, but not hepatic, CYP2B, and this induction reduced propofol sleep times by 2.5-fold. This reduction was reversed in a dose-dependent manner by i.c.v. injections of inhibitor. Sleep times correlated with brain (r=0.76, P=0.0009), but not plasma (r=0.24, P=0.39) propofol concentrations. Inhibitor treatments increased brain, but not plasma, propofol levels, and had no effect on hepatic enzyme activity. These data indicate that brain CYP2B can metabolize neuroactive substrates (eg, propofol) and can alter their pharmacological response. This has wider implications for localized CYP-mediated metabolism of drugs, neurotransmitters, and neurotoxins within the brain by this highly variable enzyme family and other CYP subfamilies expressed in the brain.

Retinal toxic reactions following photopheresis.

BACKGROUND: Extracorporeal photochemotherapy (ECP), also known as photopheresis, is a generally well-tolerated therapeutic, immunomodulatory approach successfully used in cutaneous T-cell lymphoma and other diseases produced by T-lymphocytes such as graft vs host disease. OBSERVATIONS: On 2 separate occasions, a 54-year-old white man with Sézary syndrome developed cutaneous phototoxic reactions and chorioretinitis after being treated with ECP. A pharmacokinetic study showed therapeutic blood levels of 8-methoxypsoralen as long as 18 weeks after therapy had been terminated. However, the analysis of mutations in genes involved in the drug's disposition could not explain these abnormal levels. CONCLUSIONS: To our knowledge, there has been no previous description of ECP-related retinal toxic effects. This adverse effect was probably linked to impaired drug elimination. Further studies would be needed to determine the underlying mechanism.

Skin permeation of 5-methoxypsoralen from topical dosage forms.

The topical photochemotherapy of dermatoses with psoralens (PUVA therapy) requires an adequate drug level at the target site (basal epidermis) at the time of UVA radiation. The aim of this work was to enhance 5-methoxypsoralen transport to the basal epidermis, with the goal to shorten the delay between drug application and UVA irradiation. 5-Methoxypsoralen transport through rabbit skin was studied in vitro from topical formulations (water solution, gel. and emulsion). The results obtained show that the use of the emulsion increased the flux through rabbit ear skin, even if partitioning was not favorable. Additionally, the time lag was sensibly reduced, compared with the gel and solution. Furthermore, drug accumulation in human skin in vitro was determined using the thin slicing technique. Human skin accumulation profile was significantly higher for the emulsion, compared with the gel, indicating that the delay between psoralen application and UVA irradiation can be shortened.

Kinetics and dose-response of photosensitivity in cream psoralen plus ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three standard preparations.

BACKGROUND: Topical photochemotherapy with bath psoralen plus ultraviolet (UV) A irradiation (PUVA) has been developed to reduce possible side-effects of oral PUVA therapy. Although the efficacy of bath PUVA therapy appears to be similar to oral PUVA therapy, provision of bathing facilities has obvious economic, logistic and sanitary implications. Cream PUVA therapy has recently been developed as a variation of topical PUVA. OBJECTIVES: To understand the photobiological effects and to increase the safety and effectiveness of this novel topical PUVA therapy, we assessed the kinetics and dose-response of phototoxicity of 8-methoxypsoralen (8-MOP) cream in order to develop a treatment schedule for this treatment option. METHODS: Ninety-eight patients (63 men and 35 women) undergoing cream PUVA therapy were studied. The phototoxic properties of topically applied 8-MOP in three different water-in-oil creams as vehicles were assessed. In a dose-response study, four concentrations of 8-MOP cream (0.0006-0.005%) were used for determination of the minimal phototoxic dose (MPD). The kinetics of photosensitization were tested by determination of MPDs after different application times of 8-MOP cream (10, 20, 30 and 60 min). The persistence of phototoxicity was assessed by UVA exposure at defined time intervals after application of 8-MOP cream (0, 30, 60 and 120 min). RESULTS: The concentration required to produce sufficient but not undue photosensitization of the skin was 0.001% 8-MOP. The duration of application leading to the lowest MPD was 30 min. Greatest photosensitization was achieved when UVA irradiation was performed between 0 and 30 min after 8-MOP removal. These findings showed no significant difference between the three vehicles used. CONCLUSIONS: Based on our data we recommend application of 0.001% 8-MOP in a water-in-oil cream for 30 min. Irradiation with UVA should be performed within 30 min after removal of 8-MOP cream, as there is a rapid decrease in photosensitivity thereafter.

Psoralen-ultraviolet A-induced erythema: sensitivity correlates with the concentrations of psoralen in suction blister fluid.

Since the advent of psoralen-ultraviolet A (PUVA) therapy, the value of plasma 8-methoxypsoralen (8-MOP) concentrations to predict PUVA-induced erythema has been widely investigated. Plasma 8-MOP concentrations have not been proportional to, and cannot alone predict, the degree of PUVA-induced erythema. We assumed that PUVA-induced erythema was related more closely to psoralen concentrations in the skin tissue rather than those within blood vessels. This study was designed to investigate the correlations between the 8-MOP concentrations in suction blister fluid (SBF) and in plasma, with the degree of PUVA-induced erythema. 8-MOP concentrations in plasma and SBF were measured in 15 vitiligo patients and 11 volunteers. Blood and SBF samples were collected 2 h after taking 8-MOP, and 8-MOP concentrations in plasma and SBF were quantified using reverse-phase high-performance liquid chromatography. Eleven volunteers were phototested using a series of doses of ultraviolet A at the time of sampling. The erythema responses were estimated visually to determine the minimal phototoxic dose (MPD). SBF 8-MOP concentrations showed a weak positive correlation with plasma 8-MOP concentrations, which means that we could not predict the exact SBF 8-MOP concentrations using the plasma 8-MOP concentrations. The MPD showed a better correlation with the log of the SBF 8-MOP concentration than with that of the plasma 8-MOP concentration. These results show that plasma 8-MOP concentration cannot represent the exact SBF 8-MOP concentration, and that SBF 8-MOP concentrations, which are representative of the skin tissue 8-MOP level, are more closely related to the erythemal sensitivity during PUVA therapy.

Single-dose methoxsalen effects on human cytochrome P-450 2A6 activity.

Methoxsalen (8-methoxypsoralen) is an effective and selective mechanism-based inhibitor of human hepatic cytochrome P-450 (CYP)2A6 in vitro, and may have utility as a clinical probe for CYP2A6-catalyzed xenobiotic metabolism in humans in vivo. This investigation explored single-dose oral methoxsalen effects on human CYP2A6 activity in vivo, assessed by coumarin 7-hydroxylation. Eleven volunteers received 50 mg of oral coumarin on two occasions in a randomized crossover, 90 min after oral methoxsalen or nothing (controls). Plasma and urine 7-hydroxycoumarin and plasma methoxsalen concentrations were determined by HPLC. Methoxsalen pretreatment diminished area under the curve of plasma 7-hydroxycoumarin versus time by 24% (2.40 +/- 0.48 versus 3.20 +/- 0.55 microg. h. ml(-1); P <.001), and also decreased plasma 7-hydroxycoumarin C(max) (0.80 +/- 0.26 versus 1.4 +/- 0.5 microg/ml; P <.05); however, 7-hydroxycoumarin concentrations were only diminished 0.75 to 2 h after coumarin administration, but not thereafter. Methoxsalen diminished urine 7-hydroxycoumarin excretion in 0- to 1- and 1- to 2-h samples, but not thereafter, and total excretion was unchanged. Considerable individual variability in methoxsalen plasma concentrations was observed. There were significant correlations between the decrease in plasma 7-hydroxycoumarin C(max) and plasma methoxsalen C(max), but not between the decrease in plasma 7-hydroxycoumarin area under the curve and methoxsalen disposition. These results show that single-dose oral methoxsalen, in conventional doses, was a moderately effective inhibitor of human CYP2A6 activity in vivo, however, the duration of inhibition was limited. Interindividual variability in the extent of CYP2A6 inhibition appeared attributable to variability in the absorption and first-pass clearance of methoxsalen. Alternative doses, timing, and/or routes of methoxsalen administration are required for greater, longer, and more reproducible CYP2A6 inhibition than that provided by single-dose methoxsalen.

Carcinogenic risk of bath PUVA in comparison to oral PUVA therapy.

The potential carcinogenic risk of bath PUVA therapy was compared to that of systemic (oral) PUVA. An analysis of the epidemiological data on cancer risk following bath PUVA with trimethylpsoralen does not support the conclusion that bath PUVA per se is less carcinogenic than systemic PUVA with 8-methoxypsoralen (8-MOP). Pharmacokinetic studies indicate that both the concentration of 8-MOP in the target organ for PUVA carcinogenicity (skin) at the relevant time point (time point of UVA irradiation) and the extents of biological effects in the skin are comparable following bathwater or systemic 8-MOP administration. Furthermore, the therapeutic effects of PUVA arise from the same photochemical reaction mechanisms as do the carcinogenic effects. Theoretically, the ratio of (desired) cytotoxic versus (undesired) mutagenic effects could increase with increasing efficiency of the PUVA therapy itself. On the basis of the available evidence, it is concluded that all forms of PUVA therapy, independently of the route of 8-MOP administration, contribute to a small but dose-dependent increase in nonmelanoma skin cancer risk.

Measurement of 5-methoxypsoralen and 8-methoxypsoralen in saliva of PUVA patients as a noninvasive, clinically relevant alternative to monitoring in blood.

BACKGROUND: Monitoring of psoralen concentration and time-course in PUVA patients is vital for efficient PUVA therapy. Blood sampling is invasive and labour-intensive and thus unsuited for routine use and repeat measurements over the course of therapy. OBJECTIVE: Psoralen pharmacokinetics in saliva were investigated and validated as a noninvasive, simple and biologically relevant alternative to measurements in blood. METHODS: The time-course of psoralen concentration was measured in saliva and serum of volunteers and patients receiving PUVA or extracorporeal photopheresis therapy. The samples were analysed by high-performance liquid chromatography. Three commonly used oral psoralen preparations were tested: Psoraderm5 (5-methoxypsoralen; 5-MOP), Meladinine and Oxsoralen (both 8-methoxypsoralen; 8-MOP). RESULTS: The pharmacokinetic parameter Cmax in saliva averaged 10% (range 6-20%) of the serum values for 8-MOP, and < or = 4% for 5-MOP. These concentrations correspond to the therapeutically relevant, non-albumin-bound fraction of psoralen in serum that is available to diffuse into the tissues. The parameter tmax in saliva and serum coincided, indicating that psoralens diffuse rapidly between the two compartments. CONCLUSION: Monitoring of psoralens in saliva is a valuable, noninvasive alternative to measurements in serum, suitable for routine use. A series of five or six saliva samples is sufficient to determine tmax in a patient beginning photochemotherapy. To determine Cmax, three independent saliva measurements at t = tmax are recommended.

Pharmacokinetics of 8-methoxypsoralen during extracorporeal photopheresis.

BACKGROUND/PURPOSE: Extracorporeal photopheresis (ECP) is a widely used therapy for the treatment of diverse diseases such as cutaneous lymphomas and graft-vs-host disease. Knowledge of the effective concentration of 8-methoxypsoralen (8-MOP) in the photopheresis apparatus and the photodegradation time-course of 8-MOP during ECP is a prerequisite for a successful therapy. METHODS: The time course of 8-MOP concentration was measured in patients' serum and in the photoactivation chamber (so-called buffy coat fraction) during ECP. Samples were analyzed by high-performance liquid chromatography. Half-lives of 8-MOP in both fractions were calculated assuming first-order kinetics (exponential decay). Losses due to adsorption and photodegradation were investigated and the recovery of bioavailable 8-MOP calculated. RESULTS: In female patients (average age 61+/-9 years) given 0.4-0.6 mg 8-MOP/kg body weight in the form of Oxsoralen capsules, peak serum concentrations averaged 420+/-80 ng/ml (n=8). In contrast, peak concentrations in the photoactivation chamber averaged only 134 ng/ml, or 32% of serum values. In serum, peak 8-MOP concentrations were reached < or =40 min following ingestion; the half-life of 8-MOP in the serum was 50+/-14 min (n=7). The effective half-life of 8-MOP in the photoactivation chamber was considerably longer (about 4 h). The recovery of free, bioavailable 8-MOP in the photoactivation chamber at the end of ECP averaged 42% of the applied dose; losses stemmed mainly from photodegradation of 8-MOP and from adsorption of 8-MOP to the surfaces of the apparatus. CONCLUSION: We conclude that interpretation of investigations on clinical success and dose-response aspects of ECP must take into account the complex pharmacokinetic behaviour of 8-MOP during the ECP procedure.

5-Methoxypsoralen. A review of its effects in psoriasis and vitiligo.

UNLABELLED: 5-Methoxypsoralen, a naturally occurring linear furocoumarin, has been successfully used in combination with ultraviolet (UV) A irradiation [psoralen plus UV (PUVA)] to manage psoriasis and vitiligo. In patients and volunteers, PUVA 5-methoxypsoralen causes a dose-related increase in cutaneous photosensitivity. However, mean minimum phototoxic doses (MPD) were 30 to 50% greater with 5-methoxypsoralen than with 8-methoxypsoralen within individuals; this suggests lower photoactivity with 5-methoxypsoralen. In comparative clinical trials of parallel design, psoriasis clearance rates of > 90% or > 97% were observed in similar numbers of patients (60 to 77%) receiving oral PUVA 5-methoxypsoralen (typically 1.2 mg/kg) or oral PUVA 8-methoxypsoralen (0.6 mg/kg) treatment. Generally, 5-methoxypsoralen recipients required a greater total UVA exposure than 8-methoxypsoralen recipients to achieve end-point. However, study end-point was achieved sooner with oral or topical PUVA 5-methoxypsoralen in a small number of patients with psoriasis who received both treatments simultaneously and contralaterally. Up to 56% of patients with vitiligo achieved > 75% repigmentation with 5-methoxypsoralen (oral or topical) combined with UV irradiation (lamp or sun); the face and trunk were the most responsive areas. Lack of response to PUVA 5-methoxypsoralen treatment was observed in up to 16% of patients with psoriasis and, in 1 trial, in 22% of those with vitiligo. Lesion spreading during treatment of vitiligo was also observed in 7 (19%) patients in 1 study. The incidence and severity of adverse events was generally lower in PUVA 5-methoxypsoralen 1.2 mg/kg than in PUVA 8-methoxypsoralen 0.6 mg/kg recipients. Nausea and/or vomiting, pruritus and erythema were the most commonly reported adverse events in the short term; they occurred about 2 to 11 times more frequently in 8-methoxypsoralen than 5-methoxypsoralen recipients within clinical trials. Adverse hepatic events after oral administration of the drug were uncommon. Long term tolerability data for PUVA 5-methoxypsoralen are scarce; however, carcinogenicity was not reported during a 14-year observation period of 413 patients with psoriasis. CONCLUSION: Similar lesion clearance rates were observed with oral 5- or 8-methoxypsoralen plus UVA exposure in patients with vitiligo or psoriasis, although patients given 5-methoxypsoralen often required a greater total UV exposure than 8-methoxypsoralen recipients. The incidence of short term cutaneous and gastrointestinal adverse effects is markedly less with 5-methoxypsoralen than with 8-methoxypsoralen, which is an advantage, although the long term tolerability of 5-methoxypsoralen has yet to be fully established. Nevertheless, in appropriately selected patients, PUVA 5-methoxypsoralen therapy may be recommended as an alternative first-line systemic treatment option for the management of vitiligo or psoriasis.

Plasma and buffy coat concentration of 8-methoxypsoralen in patients treated with extracorporeal photopheresis.

Recently, a new therapy involving an extracorporal activation of orally administered 8-methoxypsoralen (8-MOP), photosensitizing furocoumarin, is established for the treatment of different skin diseases, extracorporeal photopheresis (ECP). The pharmacokinetic profile of 8-MOP has been pursued as part of a clinical study which should assess the efficacy of ECP in patients with progressive systemic sclerosis and cutaneous T-cell lymphoma. The enormous intra-individual variations proofed for plasma as well as buffy coat concentration are unfavourable for oral 8-MOP therapy. Therefore, the introduction of liquid 8-MOP formulation that allows the direct administration of the drug in to the treatment bag of the ECP device is challenging.

Drug monitoring of orally administered 8-methoxypsoralen in patients treated with extracorporeal photopheresis.

Recently extracorporeal photopheresis (ECP), a new therapy involving extracorporeal activation of orally administered 8-methoxypsoralen (8-MOP), has been established for the treatment of different skin diseases. The pharmacokinetic profile of 8-MOP has been pursued in a clinical study which aimed to assess the efficacy of ECP in patients with progressive systemic sclerosis and cutaneous T-cell lymphoma. However, the enormous intraindividual variations in plasma as well as buffy coat concentrations affect the efficacy of oral 8-MOP therapy. Therefore, the introduction of a liquid 8-MOP formulation enabling the direct administration of the drug into the treatment bag of the ECP device is challenging.

Treatment of psoriasis with a new micronized 5-methoxypsoralen tablet and UVA radiation.

Since 1974, phototherapy with psoralen and ultraviolet A (UVA) has been used successfully for the treatment of psoriasis. However, undesirable side effects, including phototoxicity, nausea, stomach pain and headaches, have led investigators to develop new psoralen compounds. 5-Methoxypsoralen (5-MOP) has thus been introduced as an alternative to 8-MOP because of its less pronounced side effects. Since the absorption kinetics and bioactivity of 5-MOP are known to be variable, a new micronized tablet form (5-MOPm) has been developed. In an open randomized study, oral treatments with 5-MOP or 5-MOPm plus UVA radiation were compared in 22 psoriatic patients. Skin type and initial psoriasis area severity index did not differ significantly between treatment groups. Serum concentrations were significantly higher (320 vs 85.82 ng/ml) and occurred earlier (51.8 vs 229.09 min) with 5-MOPm. In addition, a reduction in PASI of more than 90% was achieved sooner (10.63 vs 17.27 treatments) and with a lower cumulative UVA dose (145.89 vs 232.11 J/cm2), in the group treated with 5-MOPm. No side effects were observed with 5-MOPm. Our data indicate that 5-MOPm has a higher bioavailability, clinical efficacy and tolerability than the commonly used 5-MOP.

Parenteral administration of 8-methoxypsoralen in photopheresis.

BACKGROUND: Extracorporeal photochemotherapy (EP) is used for the treatment of cutaneous T-cell lymphoma (CTCL), progressive systemic sclerosis (PSS), pemphigus vulgaris, and rheumatoid arthritis. During this procedure, the oral administration of the photoactive drug 8-methoxypsoralen (8-MOP) results in an unpredictable range of serum levels and in side effects limiting its efficacy. OBJECTIVE: To circumvent this limitation, extracorporeally administrable 8-MOP (EX-8-MOP) was developed. It is administered directly to the leukocyte/plasma concentrate in the treatment bag of the EP apparatus before irradiation with UVA light. METHODS: Efficacy, tolerance, and side effects of EX-8-MOP were evaluated in 108 consecutive treatments of 16 patients who had previously been treated with oral 8-MOP (91 treatments). RESULTS: With EX-8-MOP constant drug levels for UV light exposure were obtained; for equivalent levels only a small fraction of the oral dose (1/250 to 1/500) was required with none of the side effects associated with oral 8-MOP. Effective and reproducible inhibition of lymphocyte proliferation and cell viability was attained. No difference in clinical efficacy could be observed. CONCLUSION: EX-8-MOP eliminates the need for premedication and drug level monitoring of 8-MOP and should improve the effectiveness of EP.

A new micronized 5-methoxypsoralen preparation. Higher bioavailability and lower UVA dose requirement.

A new tablet of micronized 5-methoxypsoralen (5-MOP) and a commonly used tablet in therapy (Psoraderm 5) were compared in 12 healthy subjects. Each subject ingested 1.2 mg/kg body weight of each formulation on different days. Bioavailability and phototoxicity of 5-MOP were compared. The results showed that serum and suction blister concentrations were significantly higher and occurred earlier after the oral intake of the micronized preparation. A series of graduated UVA doses were administered, one dose each time the concentration serum peaked, in order to determine the minimum phototoxic dose for each formulation. The micronized preparation induced greater photosensitivity than the unmicronized one. The micronized 5-MOP tablet may thus allow lower doses of UVA to achieve therapeutic results in photochemotherapy and a shortened waiting period following ingestion of drug.

[The pharmacokinetic and toxicologic profile of 8-methoxypsoralen. The basis for safe and effective PUVA therapy]. / Das pharmakokinetische und toxikologische Profil von 8-Methoxypsoralen. Die Basis für eine sichere und effektive PUVA-Therapie.

On the basis of approximately 60 publications and in view of our own results we present a comprehensive review as to the mode of action, the pharmacokinetics, the metabolism and the toxicology of 8-methoxypsoralen (8-MOP) and its consequences in the PUVA therapy of psoriasis. The interaction of 8-MOP with DNA is presently considered to be the most likely mode of action. 8-MOP is subject to strong first-pass effects with considerable individual variations in plasma levels. An exact timing of drug dose and light dose is essential for a successful therapy, simultaneously minimizing the potential short-term and long-term risks of PUVA therapy.