Of 8-methoxypsoralen 8-MOP

Martens-Lobenhoffer et al. (1999) have studied the stability of 8-methoxypsoralen (8-MOP) in various ointments. They found that after 12 weeks storage, the drug was stable in Unguentum Cordes and Cold Cream Naturel however, the Unguentum Cordes emulsion began to crack after 8 weeks. When formulated in a Carbopol gel, 8-MOP was unstable. 

An important apphcation of psoralens and UV-A light (PUVA therapy) was introduced into clinical practice by Parrish et al. A treatment consisting of the oral administration of 8-methoxypsoralen (8-MOP), followed by artificial ultraviolet illumination (UV-A) of patients skin was used for the first time to cure psoriasis, a disease characterized by hyperproliferation of skin cells. It is now recognized that psoriasis is an autoimmune disorder, and hyperproliferation is only one aspect of its manifestation. 

Beijersbergen van Henegouwen, G.M.J., Wijn, E.T., Schoonderwoerd, S.A., and Dall Acqua, R, Method for the determination of the in vivo irreversible binding of 8-methoxypsoralen (8-MOP) to epidermal Hpids, proteins and DNA/RNA of rats after PUVA treatment, /. Photochem. PhotobioL, B Biol., 3, 631,1989. 

In the oxygen-independent Type III reactions the excited/sensi-tized psoralen donates its excitation energy directly to, or reacts with, the target compound. This occurs if the substrate and the target compound (e.g., DNA) are already in close proximity or intercalated. The reactions will proceed very rapidly via the excited singlet state, and are, typically, cyclization reactions or electron-transfer between the sensitizer and the target. In addition, the psoralen can be ionized, either directly or via the excited state, and react with the target compound in the form of a radical cation. Furocoumarins are also employed in treatment of cutaneous T-cell lymphoma and some infections connected with AIDS, by so-called photopheresis processes [71, 74-76]. In this case, peripheral blood is exposed to, e.g., photoactivated (sensitized) 8-methoxypsoralen (8-MOP) in an extracorporeal flow system. This... 

Several modifications of the basic parent compounds have also been suggested, primarily by methyl or methoxy substituents (cf. Fig. 4.13). Two of the most active and widely used psoralens are 8-methoxypsoralen (8-MOP) and trimethylpsoralen (TMP). With the exception of 3-CP, the substituents reduce the ionization energies by 5-10 kcal mol-1 compared with the unsubstituted parent compounds (Tab. 4.4). In bulk water the effects are somewhat smaller. The largest effects are observed for TMP and AMT. The IP of flavin are very similar to those of the unsubstituted psoralen. 

A set of N1-unsubstituted furo[2,3- ]quinolin-2(l/f)-ones including 81a-c, 83, and 84a and 84b were prepared by the route shown in Scheme 11, and their photobiological activities were compared with those of the photoche-motherapeutic drugs 4,6,8,9-tetramethylfuro[2,3-, ]quinolin-2(l//)-one (HFQ) and 8-methoxypsoralen 8-MOP <2002BMC2835>. The anti-proliferative activity of these furoquinolinones was tested upon UVA irradiation in mammalian cells, and almost all were found more active than 8-MOP, and free of any mutagenic activity and skin phototoxicity. 

Data from animals and humans indicate that at least some photoirritants enhance UV-associated skin carcinogenesis. 8-Methoxypsoralen (8-MOP), used in psoralen plus UVA treatment therapy,12 is considered to be a photococarcinogen in humans, whereas several fluoroquinolones have been demonstrated to be photoirritants and photochemical carcinogens in hairless mice.11 However, data for many other classes of pharmaceuticals are unavailable. 

Figure 7.11. 8-Methoxypsoralen (8-MOP) is oxidized to an epoxide, and either the epoxide or a ring-opened product derived from it is responsible for inactivation of P450. The structures of two drugs, tamoxifen and carbamazepine (CBZ), that inactivate P450 by unknown mechanisms are also shown.

Furanocoumarin 8-methoxypsoralen (8-MOP) (1-100 pg/ml) in the dark showed a protective affect against hypotonic hemolysis of the erythrocyte membrane. However, the effect against heat-induced hemolysis was dependent on the concentration of 8-MOP lower concentrations of 8-MOP showed an inhibiting effect, whereas higher concentrations caused acceleration of hemolysis. The erythrocytes reacted with 8-MOP in the dark were shrunk and had altered shapes. It can be deduced that modification of erythrocyte membrane by 8-MOP is via the reaction with membrane lipids and proteins [295]. From these results, it could be concluded that the effect on the cell membrane by coumarins could have an important role in their bioactivity. 

Methoxypsoralen (8-MOP) was selected for the present study because of its favorable physicochemical properties and because it forms a large proportion of divalent adducts with DNA [2]. These properties allow one to cross-link efficiently free DNA which makes these chromatin domains selectively amenable to isolation (vide infra). 

The fiuanocoumarins are another class of compounds that have been shown to inactivate rat and human liver P450s via modification of the apoprotein [424-426]. Furanocoumarins such as beigamottin (BG), 8-methoxypsoralen (8-MOP) and 8-geranyloxypsoralen (Fig. 5.24) are found as components in many foods and have... 

Photosensitizers are agents that sensitize cells to radiation in the visible and near ultraviolet region of the radiation spectrum. Therapeutic use has been made of naturally occurring psoralens to treat vitiligo and psoriasis, in so-called photodynamic therapy. With newly developed UV irradiation systems that emit high-intensity UVA radiation, the principle has been extended to the treatment of severe psoriasis, mycosis fungoides and many other skin diseases. Agents used in psoralen photochemistry (PUVA) medicine include methoxypsoralen (8-MOP), trioxysalen and other synthetic psoralens. 

PUVA is the acronym originally introduced to describe the combined administration of psoralen and subsequent exposure to high-intensity ultraviolet radiation from an artificial source (UVA). In the United States, orally administered 8-methoxypsor-alen (8-MOP) is the psoralen most frequently used in combination with UVA light therapy and will be the focus of this discussion. However, the term PUVA also refers to therapy with other oral and topical psoralens, most commonly 4,5, 8-trimethylpsoralen (TMP), a synthetic psoralen, and 5-methoxypsoralen (5-MOP), not available in the United States. 

Excipients—Ingredients that are intentionally added to therapeutic products but that do not directly exert pharmacologic effects at the intended dosage Indirect Photoeffects—Effects of an agent, vehicle, or product on the optical, structural, molecular, or physiologic properties of the skin, such that the interaction of light and skin or effects of drug in skin are altered IR—Infrared radiation 0.76-1000 pm MED—Minimal erythema dose 8-MOP—8-methoxypsoralen... 

In psoriasis, PUVA therapy (psoralen and UVA) leads to an inhibition of abnormally high rates of epidermal cell growth associated with the disease [297]. It has been shown that photoactivated psoralens are also potent inhibitors of epidermal cell growth in vitro. There are several lines of evidence that indicate the psoralen receptor is not associated with the DNA [298]. Studies on the distribution of compounds in cells based on their fluorescence properties demonstrated that psoralen (2) was present in the cytoplasm and cell surface membranes [299]. When cell membrane Auction of HeLa cells were prepared, psoralen receptor binding could be detected [297]. Using [3H]-8-MOP (methoxypsoralen), the cellular distribution of covalently bound psoralen in HeLa cells was also examined [300]. In these experiments, cells were treated with [3H]-8-MOP, then pulsed with UV light. It was indicated that labeled 8-MOP was distributed in cytoplasm and membrane finctions. These results have been repeated in several laboratories and all of them implicate targets outside of the nucleus... 

PUVA therapy consists of the patient receiving total body irradiation with ultraviolet A (UVA) light several times a week after taking a psoralen. Most commonly available psoralens for photochemotherapy include 8-methoxypsoralen or 8-MOP (also called methoxsalen or xanthotoxin), 5-methoxypsoralen or 5-MOP (or bergapten), angelicin, 4,5 -dimethylangelicin, and 4,5, 8-trimethoxypsoralen or 4,5, 8-trimethoxypsoralen (TMP) [104]. Psoralen is taken 2 h before irradiation and can be administered orally (5-MOP or 8-MOP) or topically, either painted onto the skin surface or, more frequently, using a bath delivery system... 

A completely different and unusual appHcation of psoralens, without Hght activation, is to exploit the ability of some derivatives to interact with ionic channels. It was recently shown that 5-methoxypsoralen (5-MOP) and 5,8-disubstituted psoralens, can block voltage-dependent channels (K ). In addition,... 

Oxidative processes were studied by Rodighiero et al. and Musajo et al. that showed that photolysis of psoralen and 5-methoxypsoralen (5-MOP), in water-methanol solution in the presence of flavin-mono nucleotide, leads to the formation of 6-formyl-7-hydroxycoumarin (from psoralen) and 6-formyl-7-hydroxy-5-methoxycoumarin, derived from 5-MOP. The corresponding aldehyde deriving from 8-methoxypsoralen (8-MOP) was isolated by Rodighiero et al. ... 

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