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Photodynamic therapy (PDT) and fluorescence diagnosis (FD) are being developed for a number of clinical applications. Since fluorophores and photosensitising drugs are usually given systemically their effect on blood elements are of significant importance. Photodynamic effects on erythrocytes occur naturally in patients with erythropoietic protoporphyria (EPP). Exposure to small fluences, as obtained by the erythrocytes when they pass capillaries in the skin, leads to transfer of the photosensitiser protoporphyrin IX (PP IX), from EPP erythrocytes to endothelial cells. Thus, the erythrocytes are partly protected while the endothelial cells suffer photodamage. During photodynamic therapy in vivo erythrocytes are regularly photosensitised. This side effect is partly intended but mostly unwanted, and a summary of this topic is given. Furthermore, the effect of UV-A on erythrocytes that is accompanied with the formation of bilirubin is reviewed. Erythrocytes serve as convenient model cells for experimental research. Such use of erythrocytes to screen new photosensitisers may be of limited value. A combination of photohaemolysis and haemoglobin oxygenation may become the basis for an assay for in vitro phototoxicity. Erythrocytes from birds are good model cells for exploration of physiological and molecular mechanisms involved in PDT. A potential mechanism of PDT induced behaviour resembling apoptosis in erythrocytes is provided.PDT for sterilisation of erythrocyte concentrates has a potential for medical use. Photodynamic effects on the erythrocytes themselves should be avoided. This is realised by choosing a virus-selective photosensitiser, low fluences and treatment of the concentrates with agents like dipyridamole and antioxidants. Future aspects of applications of photosensitisation of red blood cells are discussed.

Although oxygen radicals are thought to play a key role in the skin injury that is caused by protoporphyria, there is no direct evidence of generation of these radicals in vivo. This study measured the generation of oxygen radicals caused by visible light non-invasively in the skin of griseofulvin-induced protoporphyria model mice, using an in vivo electron spin resonance spectrometer equipped with a surface-coil-type resonator that could detect radicals within about 0.5 mm of the skin surface. A durable nitroxyl radical was administered intravenously as a probe. Light irradiation enhanced the decay of the nitroxyl signal in griseofulvin-treated mice, whereas light irradiation did not enhance the signal decay in control mice. The enhanced signal decay was completely suppressed by intravenous administration of hydroxyl radical scavengers, superoxide dismutase or catalase, or the intraperitoneal administration of desferrioxamine. The enhanced signal decay with illumination was reversible, and quickly responded to turning the light on and off. These observations suggest that the hydroxyl radical is generated via an iron-catalyzed reaction in the skin. This paper demonstrates, for the first time, the specific generation of oxygen radicals in response to light irradiation of the skin of protoporphyria model mice.

A Phase III 3 year placebo-controlled trial, in which patients were blinded as to when placebo was given, was conducted to determine if the administration of L-cysteine-HCl was effective in preventing or ameliorating the photosensitivity associated with erythropoietic protoporphyria. Forty-seven patients participated in the trial. Placebo was administered in the first month of the trial and then 500 mg of cysteine was given in two divided doses per day for the duration of the study. To measure efficacy, baseline and follow-up visit history forms and light-exposure diaries were filled in by the patients, and those seen in Boston were phototested. Analysis of the data from the questionnaires, the minutes of symptom-free light exposure recorded in diaries and history forms and the results of the phototests showed that cysteine increased the time of symptom-free light exposure to a statistically significant degree.

Rumex Japonicus Houtt (RJH), a plant indigenous to Okinawa, Japan, has been used traditionally by the local people for treatment of acute and chronic cutaneous diseases; however, its pharmacological effect is not clearly understood. To investigate its active function, we examined the antioxidative effect of RJH on the hematoporphyrin-induced photooxidative reaction. We measured intracellular reactive oxygen species (ROS) in cultured transformed human vascular endothelial cells (ECV-304) by flow cytometry, lipid peroxide (LPO) in erythrocyte ghosts by spectrofluorometry, and hemolysis by spectrophotometry. Results showed the generation of intracellular ROS in ECV-304, LPO production in erythrocyte ghosts, and hemolysis after visible light irradiation in the presence of hematoporphyrin. In the RJH root extract treated group, generation of intracellular ROS, LPO production, and hemolysis were inhibited significantly. It has been reported that the RJH root contains emodin and chrysophanic acid. In our study, three fractions were separated from the RJH root extract by thin layer chromatography (TLC). We found that fraction 1 (near the origin) showed a strong inhibitory effect on LPO levels; however, fraction 2 (equal to emodin) and fraction 3 (equal to chrysophanic acid) showed no inhibitory effect on LPO levels. Our experiments verified that RJH has an antioxidative effect against photohemolysis and supports our hypothesis that RJH may have potential as a protective agent against oxidative stress associated with some diseases such as porphyrias.

The authors report a case of aplastic anemia in which refractory anemia, a subtype of myelodysplastic syndrome (MDS), developed 15 years after the onset and was subsequently followed by erythropoietic protoporphyria (EPP). Defects of stem cells in MDS are thought to be responsible for the disturbance of the heme biosynthetic pathway, leading to the development of EPP.

We report the case of a 4-year-old girl, who had been suffering for 2 years from a recurrent, painful crisis affecting both hands, following sun exposure. There were no obvious cutaneous lesions, which initially caused us to consider a diagnosis of a psychiatric disorder. However, the diagnosis of erythropoietic protoporphyria was then established by the demonstration of elevated levels of free protoporphyrin in erythrocytes. The present case illustrates the effectiveness of beta-carotene associated with canthaxanthin in erythropoietic protoporphyria.

Erythropoietic protoporphyria is a rare photodermatosis for which treatment options are limited. The present report describes the clinical features of a patient with erythropoietic protoporphyria and liver function test abnormalities associated with treatment with beta-carotene. Subsequent treatment with narrow-band UVB phototherapy resulted in marked subjective improvement in photosensitivity, which was confirmed by abolition of demonstrated abnormalities on monochromator phototesting. The therapeutic options for photosensitivity in erythropoietic protoporphyria are reviewed and discussed.

The all-trans-beta-carotene serum level of patients suffering from erythropoietic protoporphyria increases substantially during continuous treatment with beta-carotene (either with the synthetic all-trans compound or with beta-carotene from a natural source consisting of a cis-trans isomeric mixture). On continuous daily ingestion, the beta-carotene serum level rose from day 0 to day 30, and no further increase was observed between day 30 and day 150. Slightly lower beta-carotene steady state serum levels were observed with the natural isomeric mixture than with synthetic beta-carotene. Higher levels of 13-cis-beta-carotene, in some cases up to 10% of the total beta-carotene, were detected after ingestion of the synthetic compound. The level of 9-cis-beta-carotene was below or close to the limit of quantification in all samples, even when the isomeric mixture containing high amounts of 9-cis-beta-carotene was applied.

There is evidence that reactive oxygen species and free radicals may be involved in the pathogenesis of photosensitivity in erythropoietic protoporphyria (EPP). Considering the well-known antioxidant properties of vitamin C, we investigated whether oral supplementation with this vitamin was photoprotective in patients with EPP. Twelve patients with EPP received either oral vitamin C 1 g daily or placebo, for 4 weeks, followed by a crossover period of another 4 weeks. Nine patients were already receiving beta carotene at entry and continued this at the same dose throughout the study. Patients compared their sunlight tolerance throughout each of the treatment periods with sunlight tolerance at entry on a 10 cm visual analogue scale; at the end of the study, they were asked to choose which treatment period they felt had been associated with least photosensitivity. Eight patients stated that they were able to tolerate sunshine better during the vitamin C period, 2 during the placebo period and 2 noticed no difference between the two periods. This distribution of preferences approached but did not reach statistical significance in favour of vitamin C. Visual analogue scores improved by a median of 1.2 cm in the vitamin C period. This change too approached but did not reach statistical significance. Although these results do not reach statistical significance, it appears possible that oral vitamin C may reduce photosensitivity in some patients with EPP. A larger study is necessary to confirm this impression.

Background: Assuming that flavonoids have anti-oxidative properties and may protect against abnormal skin reactions in erythropoietic protoporphyria (EPP), we investigated whether systemic treatment with hydroxyethylrutosides (2.7 g/day) could decrease skin sensitivity to blue light in a 37-year-old female patient who suffered from EPP., Design and Results: Before treatment, skin exposure during 5 min to a xenon high-pressure gas discharge lamp with filter was sufficient to produce intense erythema, irritation and later swelling. After 1, 2 and 3 months of treatment, the exposure times, necessary to produce similar effects, gradually increased. This improvement coincided with an increased tolerability to sunlight. No adverse effects were observed., Conclusion: These results encourage the set-up of a more systematic, placebo-controlled study of the protective effects of hydroxyethylrutosides in EPP.

Erythropoietic protoporphyria is an autosomal dominant or autosomal recessive photodermatosis characterized by a deficiency of the enzyme ferrochelatase. The diagnosis is based on the very typical complaints of burning and pain on sun exposure and on increased protoporphyrin concentration in the red blood cells, the plasma and the feces. Different treatment modalities have been proposed. The treatment of choice has always been beta-carotene. For severe cases, PUVA treatment can be given three times a week until a total UVA dose of 120-200 J/cm2. In younger children, UVB phototherapy can be used if beta-carotene gives unsatisfactory therapeutic results. The irradiations are given four times a week until a total dose of 1-1.5 J/cm2 is reached.

Chenodeoxycholate (3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid) is a primary bile acid directly synthesized from cholesterol. It is an amphipathic molecule, possessing both a hydrophobic side and a polar hydrophilic side, giving it the ability to solubilize lipids in a water environment. Bile acids are necessary for the absorption of fats and fat soluble vitamins. Chenodeoxycholate inhibits the rate-limiting step of cholesterol synthesis, the formation of hydroxymethyl-glutaryl-coenzyme A. It was first reported to be useful in the dissolution of cholesterol gallstones in 1972. Today, chenodeoxycholate has other medicinal uses and is used for the management of cerebrotendinous xanthomatosis, hypertriglyceremia, congenital liver diseases, rheumatoid arthritis, and constipation. This article details some finer points of chenodeoxycholate biochemistry and physiology and discusses in some detail the current and past clinical uses of chenodeoxycholate. This is not an exhaustive discussion on gallstone dissolution therapies, but an overview of some of the lesser-known uses for this drug.

The photodermatosis in erythropoietic protoporphyria (EPP) is caused by the accumulation of photosensitizing protoporphyrin (PP) in the skin, due to a defect in ferrochelatase, the enzyme that inserts ferrous iron into PP to form heme. Hydroxyl radical (.OH) and singlet oxygen generation with subsequent lipid peroxidation are thought to play a major role in the pathogenesis of the photodermatosis in EPP. Hydrogen peroxide (H2O2) can generate .OH in the Haber-Weiss as well as the Fenton reaction, and is thus a potentially harmful intermediate in the photoreduction of O2. The use of oxyradical scavengers, such as beta-carotene, has been reported to be beneficial in the treatment of EPP photodermatosis. In this study, N-acetylcysteine (NAC) 1800 mg/day was used for 3 reasons: (i) its -SH groups directly scavenge H2O2; (ii) ferrochelatase can be activated by sulfhydryl groups; (iii) NAC was reported to upregulate the glutathione redox system, which is a major endogenous anti-oxidant system. However, in a double-blind crossover placebo controlled study on 6 EPP patients, we could neither demonstrate an effect through photosensitivity tests, nor on light hypersensitivity as reported by the patients. This dosage of NAC could not increase reduced glutathione and did not affect the red blood cell PP content nor the excretion of PP in the feces. Neither were adverse effects observed. We conclude that the oral administration of NAC, in the relatively low dose used here, is not effective in the treatment of photodermatosis in EPP.