Protective effects of ß-carotene and melanin against protoporphyrine IX-induced phototoxicity in the photo hen's egg test.

PURPOSE: The aim of our study was to evaluate the photoprotective potential of melanin and ß-carotene against protoporphyrine IX-induced phototoxicity via photo hen's egg test. METHODS: In three independent test groups, the yolk sac blood vessel system of hen's eggs was exposed to protoporphyrine IX and irradiated with ultraviolet A (UVA). One of the test groups also received melanin to investigate its photoprotective capacity; another test group received ß-carotene for the same purpose. Morphological changes and embryo lethality were recorded in these three test groups for a period of 24 h. The same parameters were obtained in five different control groups. RESULTS: The control groups exhibited only minimal morphological changes and no fatalities. In contrast, severe phototoxic damage and a high lethality rate (75%) were observed in the test group exposed to protoporphyrine IX and UVA. Lethality was somewhat lower in the ß-carotene test group (58%) and was considerably lower in the melanin test group (17%). CONCLUSIONS: The photoprotective potential against protoporphyrine IX-induced phototoxic damage was moderate for ß-carotene and was remarkable for melanin. Given that synthetic melanocyte stimulating hormone (MSH) analogues induce a de novo synthesis of melanin without any previous ultraviolet irradiation in human skin, the application of MSH analogues might be conceived of as 'light hardening' without light. Synthetic MSH analogues thus may represent a new promising therapeutic option for photodermatoses especially for erythropoietic protoporphyria.

Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study.

BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment for actinic keratoses (AK); however, it is time consuming and often painful for the patient. Daylight-PDT would make the treatment independent of the clinic and less painful due to the continuous activation of small amounts of porphyrins during its formation. OBJECTIVES: The objective of this randomized controlled study was to compare response rates and adverse effects after methyl aminolevulinate (MAL)-PDT using conventional red light-emitting diode (LED) light vs. daylight. PATIENTS/METHODS: Twenty-nine patients with AK of the face and scalp were treated with MAL-PDT in two symmetrical areas. One area was illuminated by red LED light (37 J cm(-2)) after 3-h incubation with MAL under occlusive dressing. The other area was treated with daylight for 2.5 h after the MAL cream had been under occlusion for half an hour. RESULTS: We found no significant difference in the treatment effect between the two treatments (P = 0.13), with a reduction of AK lesions of 79% in the daylight area compared with 71% in the LED area. Treatment response in the daylight area did not depend on the intensity of the daylight. Illumination with LED was more painful than daylight (P < 0.0001). Erythema and crusting occurred after both treatments and were similar in the two areas. CONCLUSIONS: PDT of AK by continuous activation of porphyrins by daylight proved to be as effective as conventional PDT. PDT using daylight activation will make the treatment of these extremely common premalignant tumours more time and cost effective, and more convenient for the patient.

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial.

BACKGROUND: Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS: We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS: The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION: Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Detection of female lower genital tract dysplasia using orally administered 5-aminolevulinic acid induced protoporphyrin IX: a preliminary study.

OBJECTIVE: Previous studies have suggested that 5-aminolevulinic acid (ALA) may be used topically on the cervix to allow optical detection of cervical dysplasia, based on the fluorescence of protoporphyrin IX (PpIX) synthesized in situ from ALA. However, the uniformity of distribution of topically applied PpIX and the sensitivity and specificity of detection are not optimal. The current study was undertaken to demonstrate the feasibility of administering ALA by mouth (po) with the hypothesis that systemic administration might provide a more reliable diagnostic tool. METHODS: Oral ALA was administered to 14 patients with abnormal Pap smears in a dose- and time-intensity design. Institutional review board approval was obtained. A starting dose of 10 mg/kg of po ALA was administered and colposcopy was performed in 3 patients at 1 h, 3 patients at 2 h, 6 patients at 3 h, and 2 patients at 4 h. The study was written with the intent to increase the dose in 10 mg/kg increments if fluorescence was not detected; however, fluorescence was detected at the first dose level. Liver function tests were checked pre and post ALA and follow-up telephone calls were made regarding possible side effects. Both white and blue light colposcopy examinations were performed by two blinded clinicians and biopsies of all abnormal areas were performed. RESULTS: All patients tolerated po ALA well, with no systemic side effects. At the 10 mg/kg dose there was no reported nausea or photosensitivity. Optimal fluorescence was achieved at the 3-h time point, with quenching noted at the 4-h time point. Excellent absorption was documented with fluorescence of the lip demonstrated with Wood's lamp. In some cases fluorescence correlated with dysplasia on biopsy. CONCLUSION: 5-ALA given via the po route and at the dose and time period studied is well tolerated and affords fluorescence of the cervix. Future study is needed to demonstrate the successful identification of dysplastic lesions, with the ultimate goal of treating dysplasia of the lower genital tract with 5-ALA and light therapy.

Red meat and colon cancer: the cytotoxic and hyperproliferative effects of dietary heme.

The intake of a Western diet with a high amount of red meat is associated with a high risk for colon cancer. We hypothesize that heme, the iron carrier of red meat, is involved in diet-induced colonic epithelial damage, resulting in increased epithelial proliferation. Rats were fed purified control diets, or purified diets supplemented with 1.3 micromol/g of hemin (ferriheme), protoporphyrin IX, ferric citrate, or bilirubin (n = 8/group) for 14 days. Feces were collected for biochemical analyses. Fecal cytotoxicity was determined from the degree of lysis of erythrocytes by fecal water. Colonic epithelial proliferation was measured in vivo using [3H]thymidine incorporation into colonic mucosa. The colonic epithelial proliferation in heme-fed rats was significantly increased compared to control rats [55.2 +/- 5.8 versus 32.6 +/- 6.3 dpm/microg DNA (mean +/- SE); P < 0.05]. The fecal water of the heme group was highly cytotoxic compared to the controls (90 +/- 2% versus 2 +/- 1%; P < 0.001), although the concentrations of cytotoxic bile acids and fatty acids were significantly lower. Organic iron was significantly increased compared to the controls (257 +/- 26 versus 80 +/- 21, microM; P < 0.001). Spectrophotometric analyses suggest that this organic iron is heme-associated. Thiobarbituric acid-reactive substances were greatly increased in the fecal water of heme-fed rats compared to the controls (177 +/- 12 versus 59 +/- 7 microM; P < 0.05). Heme itself could not account for the increased cytotoxicity because the addition of heme to the fecal water of the control group, which was equimolar to the organic iron content of the fecal water of the heme group, did not influence the cytotoxicity. Hence, an additional heme-induced cytotoxic factor is involved, which may be modulated by the generation of luminal-reactive oxygen species. Protoporphyrin IX, ferric citrate, and bilirubin did not increase proliferation and cytotoxicity. In conclusion, dietary heme leads to the formation of an unknown, highly cytotoxic factor in the colonic lumen. This suggests that, in heme-fed rats, colonic mucosa is damaged by the intestinal contents. This results in a compensatory hyperproliferation of the epithelium, which supposedly increases the risk for colon cancer.

Sn-protoporphyrin use in the management of hyperbilirubinemia in term newborns with direct Coombs-positive ABO incompatibility.

In two separate studies, in which two different treatment regimens of Sn-protoporphyrin were used, a total of 69 control and 53 treated infants were studied to determine whether this potent inhibitor of the enzyme, heme oxygenase, could ameliorate the severity of the hyperbilirubinemia which develops in term babies with direct Coombs-positive ABO incompatibility. The results indicate that Sn-protoporphyrin can, in appropriate doses, moderate the postnatal rate of increase of plasma bilirubin levels and diminish the intensity of hyperbilirubinemia in treated babies. In addition, a decreased use of phototherapy in Sn-protoporphyrin-treated infants was observed. No rebound hyperbilirubinemia was detected during the six- to eight-day period after Sn-protoporphyrin administration. The plasma clearance (t1/2) of Sn-protoporphyrin was much faster in newborns than in adults (approximately 1.6 hours v 3.5 hours, respectively). The incidence of clinical side effects in the 53 Sn-protoporphyrin-treated infants was limited to the development of transient erythema during the use of concurrent phototherapy in two babies. In both infants this reaction subsided completely without sequelae. The use of Sn-protoporphyrin or related synthetic heme analogues to diminish the severity of hyperbilirubinemia in newborn infants merits further study because inhibition of the rate-limiting enzyme in the catabolism of heme to bilirubin may prove to be a useful therapeutic approach in the clinical management of neonatal hyperbilirubinemia, especially in settings in which, for social or economic reasons, other treatment modalities are not available.