Phototoxic Drug Research Articles

MAGNETIC FIELD EFFECTS ON THE PHOTOHEMOLYSIS OF HUMAN ERYTHROCYTES BY KETOPROFEN AND PROTOPORPHYRIN IX

Application of a static magnetic field (3350 G) during UV-irradiation (> 300 nm) reduced the time for 50% photohemolysis of human erythrocytes by the phototoxic drug ketoprofen (3-benzoyl-alpha-methylbenzoacetic acid) from 96 min to 78 min. This observation can be attributed to a magnetic field induced decrease in the rate of intersystem crossing (kISC) of the geminate triplet radical pair generated by the reduction of ketoprofen in its triplet excited state by erythrocyte membrane constituents, probably lipids. The decrease in kISC results in an increase in the concentration and/or lifetime of free radicals that escape from the triplet radical pair. Thus the critical radical concentration needed to cause membrane damage cell lysis is reached sooner in the presence of the magnetic field. In contrast, the photohemolysis induced by the photodynamic agent protoporphyrin IX was not affected by the magnetic field. Protoporphyrin IX photohemolysis, which is initiated by singlet oxygen, does not involve the initial generation of a triplet radical pair and so is not influenced by the magnetic field. The example of a magnetic field effect on a toxicological process involving free radicals.

Thiols as potential UV radiation protectors: An in vitro study

The following thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetylcysteine, and penicillamine. As a measure for protection, the inhibition of in vitro irreversible photobinding of the labeled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to protein and DNA was used. Besides photobinding to biomacromolecules, the photodegradation of CPZ and the formation of promazine (PZH) and hydroxypromazine (PZOH) were measured as well. Because of the H-atom and electron donating capacity of the thiols, the ratio [PZOH]/[PZH] was expected to be decreased and the photodegradation of CPZ was expected to be higher in the presence of thiols. Maximum inhibition of CPZ photobinding ranged for the different thiols between 21–100% (DNA) and 17–87% (human serum albumin). All thiols enhanced the photodegradation of CPZ (19–84%) and inhibited the ratio [PZOH]/[PZH] (90–97%). 8-MOP photobinding to human serum albumin was also clearly inhibited (75–96%), but remarkably less to DNA (2–41%). This study indicates that thiols are able to cope with a variety of reactive species. Scavenging of radicals, quenching of singlet molecular oxygen species and reaction with excited states seem to be essential mechanisms involved with this process.

Skin concentration of 8-methoxypsoralen, 5-methoxypsoralen and 4,5,8-trimethylpsoralen in guinea pigs

The skin concentrations of 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) and 4,5,8-trimethylpsoralen (TMP) were studied in the albino guinea pig following oral administration and intraperitoneal injection. The skin concentration of phototoxic drugs after oral administration peaked at 1.5 h, and the concentration of 8-MOP was 3.5 times greater than that of 5-MOP. The skin concentration of TMP was not detected in our study (limit of sensitivity 5 ng/ml). The highest skin concentrations of 8-MOP and 5-MOP after intraperitoneal injection were achieved for both drugs at 0.5 h, with the level of 8-MOP approximately 1.3 times higher than that of 5-MOP. The level of TMP could not be measured even in the case of intraperitoneal injection.

UV-radiation protecting efficacy of thiols, studied with UVA-induced binding of 8-MOP and CPZ to rat epidermal biomacromolecules in vivo.

The following topically-applied thiols were investigated with regard to their possible UV-radiation protective properties: captopril, cysteamine, ergothioneine, mesna, mercaptopropionylglycine, N-acetyl-cysteine and penicillamine. As a measure for protection the inhibition of in vivo irreversible photobinding of the labelled phototoxic drugs chlorpromazine (CPZ) and 8-methoxypsoralen (8-MOP) to rat epidermal biomacromolecules was used. Ergothioneine, mesna and penicillamine did not show any effect; probably, as a result of their charge they are not able to enter the stratum corneum. Captopril, cysteamine, mercaptopropionylglycine and N-acetylcysteine showed a considerable inhibition of CPZ and 8-MOP photobinding. Captopril and N-acetylcysteine were clearly the most potent whereas cysteamine was the least effective. Captopril, mercaptopropionylglycine and N-acetylcysteine appeared to have a wider action range and to be a more effective protector than dl-alpha-tocopherol and di-butyl-hydroxytoluene. Cysteamine and mercaptopropionylglycine were only capable of protecting the stratum corneum. Captopril and N-acetylcysteine on the other hand showed an additional dose-dependent inhibition of photobinding to the viable epidermis. Gradually with increasing time after application, the protecting efficacy with regard to the viable layer of the epidermis decreased; the duration of protection depending on the dose.

Quantitative In Vitro Assessment of Phototoxicity by a Fibroblast-Neutral Red Assay

We have adapted the neutral red uptake assay for quantitative assessment of injury to fibroblast cultures by potential phototoxins. Tetracycline derivatives, quinolone derivatives, and chlorpromazine were used as model compounds for development of the assay. Human fibroblasts were incubated with potential phototoxins, the cell cultures irradiated with UV, and the capacity for neutral red uptake determined. Demeclocycline and doxycycline, two known photosensitizers, showed a 94% and 95% decrease of neutral red uptake, respectively, indicating photo-induced cytotoxicity. Minocycline, a non-photosensitizing tetracycline derivative, showed no decrease in uptake. Tetracycline, a weak phototoxin, showed minor (10%) decrease at equivalent concentrations (20 micrograms/ml). Microscopic observation of neutral red uptake and cell damage paralleled the spectrophotometric findings. Chlorpromazine, a non-tetracycline phototoxin, showed 91% decrease. An additional group of phototoxic drugs, quinolone antibacterials, were studied. Nalidixic acid, ofloxacin, ciprofloxacin, and norfloxacin all demonstrated phototoxicity, with nalidixic acid showing the greatest decrease in neutral red uptake. This methodology may provide a useful rapid method to quantify phototoxic potential of new drugs or suspected phototoxins.

The effect on liver transaminases of phototoxic drugs used in systemic photochemotherapy

1. Christensen 0, Moller H. Nickel allergy and hand eczema. Contact Dermatitis 1975;1:129-35. 2. Christensen0. Nickel dermatitis. Dermatol Clin 1990;8:3740. 3. Gawkrodger D, Cook S, Fell G, et al. Nickel dermatitis: the reaction to oral nickel challenge. Br J Dermatol 1986; 115:33-8. 4. WestB, Sunderman F. Nickel poisoning. Am J Med Sci 1958;236:15-21. 5. Sunderman F. Nickel and copper mobilization by sodium diethyldithiocarbamate. J New Drugs 1964;4:154-61. 6. Kaaber K, Menne T, Veien N, et al. Treatment of nickel dermatitis with Antabuses; a double-blind study. Contact Dermatitis 1983;9:297-300. 7. Kaaber K, MenneT, TjellJ, etal. Antabuse®treatmentof nickel dermatitis: chelation-a new principle in the treatmentofnickeldermatitis.ContactDermatitis 1979;5:221-8. 8. Menne T, Kaaber K.Treatment ofpompholyxdue to nickel allergy with chelating agents. Contact Dermatitis 1978; 4:289-90. 9. Christensen 0, Moller H. External and internal exposureto the antigen in hand eczema of nickel allergy. Contact Dermatitis 1975;1:136·41. 10. Nielsen G, Jepsen L, Jorgensen P, et al, Nickel-sensitive patients with vesicular hand eczema: oral challenge with a diet naturally high in nickeL Br J Dermatol1990;122:299308. 1L Santucci B, Manna F, Cristaudo A, et al. Serum concentrations in nickel-sensitivepatients after prolongedoral administration. Contact Dermatitis 1990;22:253-6. 12. Menne T. Flare up of cobalt dermatitis from Antabuse® treatment. Contact Dermatitis 1985;12:53.

Study of the skin concentrations after administration of the various phototoxic drugs

The skin concentrations of 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP), and 4, 5', 8-trimethylpsoralen (TMP) were studied in the guinea pig following oral administration and bathing. The skin concentration of phototoxic drugs after oral administration peaked at 1.5 hours, and the concentration of 8-MOP was 3.5 times greater than that of 5-MOP. The skin concentration of TMP was not detected in our study (limit of sensitivity 5ng/ml). The skin concentrations of phototoxic drug after bathing decreased in the order of 5-MOP, TMP, and 8-MOP.

Studies on the Effects of Various Topical Phototoxic Drugs and UVA on Melanocytes of C57 BL Mice

Studies on the Effects of Various Topical Phototoxic Drugs and UVA on Melanocytes of C57 BL Mice

The effect of UVA irradiation on the epidermal melanocyte after 8-MOP and TMP administration

Morphotogical and numerical changes in the epidermal melanocytes of black C57BL mice after phototoxic drug administration followed by ultraviolet A irradiation were studied to compare the effects of photochemotherapy on the epidermal melanocytes using 8-methoxypsoralen and trimethylpsoralen. One hour after intraperitoneal injection of the phototoxic drugs, 1.5 mg/kg in the small dose group and 6.0 mg/kg in the large dose group, the mice were exposed to UVA irradiation. This procedure was performed twice a week for 8 weeks at the small dose group and for 5 weeks in the large dose group. Skin biopsies were taken before irradiation in both groups, and follow up biopsies were done at each week. The number and size of the melanocytes were observed in a split-DOPA preparation. In the drug treated groups, there was an increase in the size of the perikaryon, and the number, length, width, and arborization of dendrites. Such changes were more clearly seen in the group treated with trimethylpsoralen compared with the 8-methoxypsoralen treated group. Therefore, trimethylpsoralen is more effective than 8-methoxypsoralen in the increase of the perikaryon size, and the number, length, width, and arborization of dendrites of melanocytes in the intraperitoneal injection.

Optical Radiation and Visual Health

This book provides a focus on the parameters of ultraviolet light, visible, and infrared radiation s which could cause long-term visual health problems in humans. It reviews early research on radiation effects on the eye, and gives detailed attention to the hazardous effects of optical radiation on the retinal pigment epithelium and the photoreceptors. These data are further analyzed with regard to five potential long-term visual health problems; retinal degeneration, visual aging, disorder of visual development, ocular drug phototoxicity, and cataracts. Finally, epidemiologic principles for studying the relationships between optical radiation and long-term visual health problems are reviewed, concluding with the implications for future research and radiation protection. The contents include: historical perspectives; optical radiation and cataracts; the involvement of the retinal pigment epithelium (RPE); optical radiation damage to the ocular photoreceptors; possible role of optical radiation in retinal degenerations; optical radiation and the aged eye; optical radiation effects on aging and visual perception; optical radiation effects on visual development; and index.

Benign cutaneous lesions potentially misdiagnosed as malignant neoplasms.

Presented are five benign skin lesions that have features simulating malignant skin lesions. Although not a comprehensive review of all such potentially troublesome lesions, those reviewed here include (1) keratoacanthoma, (2) desmoplastic trichoepithelioma, (3) sclerosing hemangioma, (4) phototoxic drug eruption, and (5) pigmented spindle cell nevus. Those features, allowing their separation from malignant lesions, are presented.

Selective killing of T lymphocytes by phototoxic liposomes.

Two-fold specificity in drug delivery obtained through the localized activation of drugs by physical means and the attachment of drugs to proteins that bind to target cells might be used for highly selective cancer chemotherapy or for immunosuppression. Toward this end, a monoclonal antibody against an antigen on the surface of T lymphocytes was covalently attached to liposomes containing a phototoxic drug, pyrene, bound to the lipid bilayer. When unfractionated peripheral blood lymphocytes, or B- and T-cell lines, were irradiated after treatment with these liposomes, T cells were killed while B cells were spared, demonstrating the validity of the approach in a simple in vitro assay.

Receptor-mediated photo-cytotoxicity: Synthesis of a photoactivatable psoralen derivative conjugated to insulin

4'-Aminomethyl-4,5',8-trimethylpsoralen has been chemically conjugated to insulin using a carbodiimide derivative. The psoralen moiety retains its photochemical reactivity as evidenced by its ability to crosslink DNA after exposure to long wavelength ultraviolet light (UVA, 320-400 nm). This chimeric molecule has been used to selectively kill a population of lymphocytes whose expression of insulin receptors has been stimulated with phytohemagglutinin. Insulin carries the psoralen into the cell via receptor-mediated endocytosis, where it is subsequently activated by exposure to UVA light. The UVA induced activity of AMT-insulin can be blocked by the presence of native insulin. The viability of unstimulated lymphocytes was not affected by AMT-insulin and UVA light. The hybrid insulin-psoralen molecule may be a prototype for a family of phototoxic drugs which can be selectively delivered to subsets of lymphocytes.

The effect of phototoxic drugs on the epidermal melanocytes in photochemotherapy

The effect of phototoxic drugs on the epidermal melanocytes in photochemotherapy

The delivery of phototoxic drugs to selected cells.

The delivery of phototoxic drugs to selected cells.

Human Models for Identification of Photosensitizing Chemicals<xref ref-type="fn" rid="FN1">1</xref>

The human is an appropriate and sensitive animal for identifying photosensitizing drugs administered either topically or systemically. Topically effective phototoxic agents are quite easily revealed when they are applied to normal or scarified skin which is subsequently exposed to 2 X 10(5) J.m-2 of near UV light (UVA, 320-400 nm). Systemically effective phototoxic drugs can be identified by exposing intradermally injected sites to either solar-simulating or UVA radiation. Drugs that cause photocontact allergy can usually be recognized by irradiating pretreated sites six times over a 3-week period with a solar simulator and then challenging the sites with UVA. Existing models, the human model especially, should make it possible to recognize important photosensitizing drugs before they are marketed.

Benoxaprofen: side-effect profile in 300 patients.

Out of 300 patients who had taken benoxaprofen for a mean of 6.4 months, 196 (65.3%) reported side effects, resulting in 104 patients (34.6%) having the drug withdrawn. Out of 42 patients aged over 70, 35 (83.3%) had side effects and 29 (69.0%) had the drug withdrawn because of them. cutaneous side effects accounted for 180 (69.5%) of all 259 side effects reported. The commonest cutaneous side effect was photosensitivity, which occurred in 86 patients (28.6%). Photosensitivity, which occurred in half of the patients treated in the summer, resulted in withdrawal of benoxaprofen in 26 (30.2%) of the patients who experienced it. Onycholysis was observed in 38 patients (12.6%) and was frequently unnoticed by patients. The overall incidence of gastric side effects was 12.6% (38 patients), and the figure rose to 40.5% (17 cases) in patients over 70. During treatment with benoxaprofen one patient developed an active duodenal ulcer but no cases of major gastrointestinal haemorrhage occurred. Multiple subepidermal cysts (milia) were observed in 16 patients, who had been treated for a mean of 10.8 months. These findings show that benoxaprofen is a potent phototoxic drug and that the manufacturers' recommended dosage of 600 mg daily is associated with an unacceptable incidence of side effects in the elderly.

Evaluation of drug phototoxicity by photosensitization of Trichophyton mentagrophytes.

Long wave ultraviolet radiation to suspensions of T. mentagrophytes, in the presence of photosensitizing chemicals, resulted in death of the fungus as measured by loss in colony-forming ability. Photosensitization could be demonstrated, with appropriate exposures and concentrations, with chlorpromazine, promethazine, perphenazine, anthracene, sulphanilamide, trimethylpsoralen, tolbutamide, tetrachlorosalicylanilide, and tribromosalicylanilide. No phototoxicity was detected with demethylchlortetracycline and thiazides. The present system seems to be simple, reproducible, and sensitive as an in vitro screening test for the photosensitizing potential of chemicals.

Ultraviolet Light and Epidermal Polyamines

Numerous studies have indicated that the activities of the polyamine biosynthetic enzymes, ornithine decarboxylase (ODC) and S-adenosyl methionine decarboxylase (SAM.D) are increased in hyperplastic and neoplastic growth. The levels of the polyamines themselves, putrescine, spermidine, and spermine are also often altered in these situations. Epidermal ODC activity is greatly elevated in response to tumor promoting chemicals and also in response to irradiation with short-wave length and mid-wave length ultraviolet. In addition, the levels of the epidermal polyamines change after mid-wavelength ultraviolet irradiation, leading to elevation of putrescine and spermidine, but depression of the spermine level. The spermidine to spermine ratio was significantly elevated after chronic ultraviolet irradiation. Preliminary studies on human skin also shows that mid-wavelength ultraviolet light is capable of inducing ODC. Different pharmacological agents have been found to significantly inhibit the ultraviolet induction of epidermal ODC. Topical corticosteroids and indomethacin significantly inhibit ultraviolet induced opidermal ODC. In addition, retinoic acid inhibited the ultraviolet induction of this enzyme in some experimental situations. Long-wave length ultraviolet alone produced no significant induction of ODC, however, certain phototoxic drugs (8-methoxypsoralen and anthracene) in combination with long-wave length ultraviolet did induce epidermal ODC. It is possible that further studies of changing epidermal polyamine metabolism in response to ultraviolet and tumor promoting agents, may lead to a greater understanding of cutaneous carcinogenesis.

Photoaugmentation in Drug Phototoxicity

The phototoxic reaction to chlorpromazine and other drugs is provoked by long-wave ultraviolet light (UVA). It was shown by the in vivo mouse tail technique that the reaction is enhanced by medium-wave ultraviolet light (UVB), thus demonstrating the importance of photoaugmentation in this process.