Biomedical subjects
Publications and source records attributed to H Hönigsmann.
In 15 patients with polymorphic light eruption, we tested the protective action of a therapeutic sunscreen agent containing both UVB and UVA filters. The photoprovocation test showed that the preparation successfully suppressed the development of skin lesions in both wavelengths.
Photosensitizers were first used to treat psoriasis 15 years ago when the phototoxic reaction of psoralens and UVA was found to induce remissions of the disease. The effect of this reaction on DNA, particularly the formation of cross-links, was thought to be the decisive event. Strong cross-linking agents such as 8-MOP, TMP and 5-MOP are clinically effective whereas most compounds which produce only monofunctional adducts are virtually ineffective. Orally administered 8-methoxypsoralen (8-MOP) is the most widely used compound. 4,5',8-Trimethylpsoralen (TMP) is poorly absorbed from the intestine but has marked efficacy when applied topically. 5-MOP may be a useful alternative to 8-MOP because it is less erythemogenic and does not cause nausea. These three furocoumarins appear to be similar photochemically and may introduce similar risks. However, the photobiological properties of furocoumarins can be modified by altering one or more parts of the molecule. Such modifications might yield effective analogues with reduced cytogenetic hazards. Several psoralens and angular furocoumarins are being tested for effectiveness combined with fewest long-term side-effects, especially carcinogenesis. Encouraging preliminary results have been obtained with 7-methyl-pyridopsoralen and 4,6,4'-trimethylangelicin. Other important approaches to increasing the safety of photochemotherapy may be the use of different photoactivating wavelengths or the introduction of new classes of photosensitizers.
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Amiodarone (AD) induces photosensitivity in 75% of the patients treated with this drug. Phototoxic reactions can be experimentally elicited with UVA but not with UVB. The UVA-MED is significantly reduced after 12 months of treatment. The development of photosensitivity depends on the total dose of AD; 40 g is the minimal cumulative dose requirement. Under the regimens commonly used, photosensitivity can be expected after 4 months of continuous AD treatment and appears to be unrelated to the skin type. Photosensitivity gradually decreases and returns to normal between 4 and 12 months after the withdrawal of AD. AD-related hyperpigmentation develops after an average of 20 months of continuous AD treatment and a minimal total dose of 160 g AD in about 8% of the patients (mainly of skin type I). Electron microscopic examination of the sun-exposed skin of patients without AD discoloration shows pigment deposits similar to those already described in patients with AD hyperpigmentation in exposed and non-exposed skin. Light and electronmicroscopic examination of sun-exposed skin of both clinically photosensitive and non-photosensitive patients reveals perivascular inflammation even in the absence of a clinical rash. Reduplications of vascular basal laminae occur in sun-exposed skin of both patients with and without UVA photosensitivity but are absent from non-exposed skin. In one patient, followed for 33 months after drug withdrawal, massive AD-induced hyperpigmentation was found to be reversible.
A 12-year-old boy developed a phototoxic rash with subsequent progression to Stevens-Johnson syndrome due to prophylactic ingestion of antimalarials (chloroquine and sulfadoxine-pyrimethamine; Fansidar). The patient recovered from his skin symptoms after 4 weeks during which he received systemic corticosteroids and antibiotics. This unusual combination of two different patterns of adverse cutaneous drug reactions was most probably caused by the sulfonamide component of Fansidar.
Necrobiotic xanthogranuloma is a rare generalized dermatosis occurring exclusively in association with paraproteinemia. Clinically it is characterized by large, ulcerating, nodular and plaque-like tumors of the dermis and subcutis. Histologically the lesions are composed of a nonspecific, lymphocytic and plasmacellular infiltrate and highly characteristic granulomas with giant cells of the Touton and foreign body type. Ultrastructurally, tubular cystic organelles with a central lamella and a few ribosomes at their outer membranes are found. By means of histochemical studies we excluded the skin infiltrates as the site of the paraprotein release. The pathogenesis of the disease remains unclear; it is suggested that the paraprotein has functional features of a lipoprotein, which may bind to lipoprotein receptors of the histiocytes, thereby inducing xanthoma formation.
Polymorphous light eruption is an acquired photodermatosis, whose causal factors have not yet been identified. The diagnosis is based on the clinical picture and on histology. During the symptomless periods, photo-testing is the most important technique to confirm the diagnosis, since there are no specific laboratory parameters. Regarding our own patients, typical lesions could be provoked by UVA in 50%, by UVB in 20% and by both in 30%. The majority of the patients can be protected during the summer season by intermittent preventive photo(chemo)therapy.
Twenty-eight patients with vitiligo were treated with a new photochemotherapeutic regimen using khellin, a furanochromone, as photosensitizer, together with ultraviolet A (UVA) irradiation. Twenty-five patients received khellin orally and three patients were treated with topical khellin. Treatments were given three times weekly. As opposed to psoralens, khellin did not induce skin phototoxicity with UVA but it induced repigmentation similar to psoralens. The treatment success strongly depended on the number of treatments. More than 70% repigmentation was achieved in 41% of the patients who had received 100 to 200 treatments. This success rate is comparable to the rate obtained with psoralens. Seven patients experienced a mild elevation of liver transaminases within the early treatment phase and their treatments were discontinued. No long-term internal organ or skin toxicity was observed. The major advantage of khellin is that it does not lead to phototoxic skin erythema and thus can be considered safe for home treatment. Because of its photochemistry it may be considered less hazardous than psoralens regarding mutagenicity and carcinogenicity.
This study was performed in order to (1) assess the magnitude of a possible protective effect of oral carotenoids on ultraviolet B (UVB)-, ultraviolet A (UVA)-, and psoralen ultraviolet A (PUVA)-induced erythema in human skin and (2) to evaluate whether the postulated prevention of skin cancer by prophylactic administration of carotenoids is based on a decrease in UVB-induced DNA damage. Twenty-three healthy volunteers received oral carotenoids (150 mg/day) for 4 weeks. Serum levels were quantitated, and ranged from 390 to 1710 micrograms/dl. Before and after carotenoid administration, the UVA- and UVB-MEDs and the PUVA-MPD were determined by standard phototesting. DNA damage was assessed by autoradiographical measurement of unscheduled DNA synthesis (UDS) following UVB exposure before and after treatment. No statistically significant carotenoid-dependent protection was found against UVA, UVB, and PUVA erythema by comparing the pre- and postcarotenoid erythema doses. Also at the DNA level there was no indication of a protective effect that could be detected with the methods employed: the amount of UVB-induced UDS was not decreased after carotenoid treatment. We conclude that (1) carotenoids do not reduce UVB-, UVA-, or PUVA-induced erythema in human skin; that (2) reactive oxygen species may not be involved in PUVA-erythema production or, alternatively, carotenoids may not quench these radicals sufficiently in vivo; and that (3) carotenoid protection against UVB-induced carcinogenesis does not operate by reducing the number of mutagenic lesions in DNA.
Khellin, whose chemical structure closely resembles that of psoralen, is reported to be an efficient drug for treating vitiligo when combined with ultraviolet A irradiation. Photobiological activity on yeast is found to be much lower than that of bifunctional psoralens such as 5-methoxypsoralen. In vitro experiments reveal that khellin is a poor photosensitizer. It behaves as a monofunctional agent with respect to DNA photoaddition. It does not photoinduce cross-links in DNA in vitro or in Chinese hamster cells in vivo. This behavior may explain the low photogenotoxicity in yeast and the lack of phototoxic erythemal response when treating vitiligo with khellin.
The effect of nicotinamide on the phototest response was investigated in 14 patients suffering from polymorphous light eruption (PMLE). In contrast to the favourable effect in the prevention of PMLE reported by other groups, oral nicotinamide did not affect the phototesting results in our patients.
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The clinical, histological and photobiological features of persistent light reaction and actinic reticuloid are discussed with reference to the literature. Both conditions are characterized by extreme light sensitivity, have been reported exclusively in elderly men, and are interpreted as a consequence of a photoallergic reaction. In our view, persistent light reaction and actinic reticuloid do not represent separate entities, but rather the two extremes of a single spectrum of disease; in common with other workers, we prefer to call it chronic actinic dermatitis. This opinion is supported by a detailed analysis of three of our patients, who illustrate all variations of this photodermatosis.
In a previous study we evaluated a microcrystalline preparation of 5-methoxypsoralen (5-MOP; Bergapten) for its photochemotherapeutic properties. Preliminary data indicated that the clinical efficacy of 5-MOP is comparable to that of 8-methoxypsoralen. 5-MOP appeared as a promising alternative photosensitizer for the management of psoriasis because of the almost complete lack of phototoxic and drug intolerance reactions that are frequently encountered in patients undergoing 8-MOP photochemotherapy. With a new liquid preparation of 5-MOP we have now extended our earlier investigation on a larger clinical scale and have correlated the clinical response with the bioavailability of the drug. Serum level determinations showed an absorption rate of only approximately 25% that of 8-MOP. When administered in the same dosage as 8-MOP, 5-MOP turned out to be significantly less effective; however, by doubling the oral dosage, comparable results in terms of clearing of psoriasis were obtained. Also with this high-dose 5-MOP regimen, no drug intolerance was noted and other side effects, such as severe erythema, pruritus, and nausea, occurred only rarely. We propose 5-MOP as a valuable alternative for photochemotherapy (PUVA) of PUVA-responsive diseases.
Unscheduled DNA synthesis (UDS) has been shown to be saturated above a threshold dose of UV-C in human fibroblasts in vitro. We have investigated by autoradiography whether a similar saturation occurs in human skin in vivo with UV-B and whether this phenomenon correlates with the erythemal response. In addition, we determined the time course of UDS at 24 h after exposure and the effect of dual exposures separated by 24 h. The dose-response curve was established by exposure to 1/16, 1/8, 1/4, 1/2, 1, 2, 3, 4 and 6 MEDs UV-B. For the time-course study, areas exposed to 1/2 and 2 MEDs were biopsied after 1, 3, 6, 12 and 24 h. Autoradiography was performed in vitro. The dose-response curve showed a significant increase in UDS from 1/16 to 1 minimal erythema dose (MED), whereas no significant difference was observed between 1 MED and the higher UV-B doses tested. The 24 h time sequence revealed a gradual decrease in UDS activity. The 1/2 MED curve declined more rapidly and reached the zero-level between 12 h and 24 h, whereas about 50% of the initial UDS value was still retained 24 h after 2 MEDs. The dual-dose study revealed that a second hit of fractions of the MED resulted in lower levels of UDS than induced by these fractions alone in previously untreated areas. UDS increases with the erythemal dose between 1/16 and 1 MED. It reaches a plateau after 1 MED and cannot be increased by doses up to 6 MEDs, suggesting a saturation of excision repair in vivo. Time course studies support such a saturation phenomenon. The failure to increase significantly UDS by a second irradiation 24 h after the first exposure needs further clarification. Since persistence of DNA lesions may lead to an accumulation after repeated exposures, additional mechanisms other than excision repair may protect human skin by error-free removal of possibly mutagenic sites. Photoreactivation may be important in this respect.
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In the continuation of the European PUVA Study, 1,643 patients of the original cohort of 3,175 patients enrolled in this prospective study were reevaluated for skin tumors after an average observation period of 96 months. Thirty-six patients with a total of seventy-one tumors (forty squamous cell carcinomas, twenty-three basal cell carcinomas) were observed. In contrast to the U.S. sixteen-center study, we were unable to demonstrate a clinically relevant increase in the risk of tumors induced by psoralens with ultraviolet A (PUVA), and we also failed to show a clear relationship between PUVA exposure and tumor development. Almost all patients with tumors had been exposed to various carcinogens before the initiation of PUVA. No tumors were detected in patients without such prior treatment, although 10% of the patients had received more than 3,000 joules/cm2 total cumulative phototoxic PUVA dose during the observation period. The discrepancy between the results of the U.S. study and our findings may partly be explained by a variety of factors such as a different treatment approach, a different attitude toward sun exposure, and the overall lower incidence of skin cancer in the European population.
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