Photoreaction potential of orally administered levofloxacin in healthy subjects.

OBJECTIVE: To evaluate the photoreaction potential of levofloxacin on exposure to solar-simulating radiation. Solar-simulating is ultraviolet (UV) light, defined as UVA in the 320-400 nm range and UVB in the 290-320 nm range. DESIGN: In a single-center, double-blind, randomized study, 30 adults (20 men, 10 women) received oral levofloxacin (500 mg qd x 5 d) or placebo. At baseline photoexposure prior to drug administration, each subject was exposed to UVB light at 0.75, 1.0, and 2.0 times the minimal erythema dose and to UVA light (25 J/cm2). Photoexposure was repeated on day 5, two hours following final drug administration, and response was determined using both a photoreaction rating scale and investigator assessment. RESULTS: Using the photoreaction rating scale, following UVB exposure on day 5, no abnormal photoreactions were observed among levofloxacin recipients. UVA exposure was associated with mild reactions in 20 of 24 levofloxacin-treated and three of six placebo-treated subjects, with no associated symptoms. By investigator assessment, all subjects had a negative reaction to UVB photoexposure, and 10 of 24 levofloxacin-treated and three of six placebo-treated subjects had a photoreaction following UVA photoexposure. Dermal reactions were mild and similar for both treatment groups. No subject experienced an immediate wheal-and-flare reaction. There were no statistically significant differences between treatment groups for any of the comparisons. CONCLUSIONS: Levofloxacin has a low photosensitizing potential when administered to healthy subjects.

Quantitative assessment of cumulative damage from repetitive exposures to suberythemogenic doses of UVA in human skin.

Daily exposures to relatively small suberythemogenic fluences of UVA (50-200 kJ/m2) for 8 days resulted in cumulative morphological skin alterations indicative of early tissue injury. Histologically, irradiated skin revealed epidermal hyperplasia, inflammation and deposition of lysozyme along the dermal elastic fiber network. Sunburn cells were also present within the epidermis. These changes were quantified by image analysis and were found to be related to the cumulative UVA fluence. A long UVA waveband (UVAI, 340-400 nm) was as effective as a broad UVA band (320-400 nm), suggesting that these changes are induced by longer UVA wavelengths.

Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin.

BACKGROUND: The skin is repeatedly exposed to solar UV radiation. Long-term photodamage is a consequence of cumulative UV radiation injury. Hence an examination of the repetitive effects of UV exposure is more likely to yield clues to the early alterations that lead to photoaged skin than a single exposure. OBJECTIVE: We examined the effects of repetitive low-dose UV irradiation on human skin with the aim of identifying UVA-induced effects that may have a different wavelength dependence than acute erythema. METHODS: Areas on the lower part of the back were each exposed to a suberythemal dose (0.5 minimal erythema dose [MED]) of solar simulated radiation (290 to 400 nm) and of UVA (320 to 400 nm) once daily, 5 days a week, for 28 doses. One site was also treated daily with a sunscreen having a sun protection factor of 22 and then exposed to 11 MEDs of solar simulated radiation for the same duration. Epidermal and dermal changes were analyzed and quantified by histochemical stains in combination with computer-assisted image analysis of tissue sections. RESULTS: At equal 0.5 MED doses, UVA induced greater cumulative changes than solar simulated radiation, as assessed by development of a greater cumulative erythema response in the first week of treatment, the presence of epidermal hyperplasia and stratum corneum thickening, depletion of Langerhans cells, dermal inflammatory infiltrates, and deposition of lysozyme on elastin fibers. These changes were not prevented by the sunscreen. A single short-term dose of UVA did not elicit these changes. CONCLUSION: These findings suggest that UVA may contribute significantly to long-term actinic damage and that the spectral dependence for cumulative damage does not parallel the action spectrum for acute injury (erythema) in human beings.

Determination of UVA protection factors by means of immediate pigment darkening in normal skin.

A method is described for screening potentially useful photoprotective agents against UVA radiation by the use of immediate pigment darkening as an end point. Threshold doses of immediate pigment darkening showed a log normal distribution and the response was found to obey dose-reciprocity at irradiance levels below 50 mW/cm2. With this procedure, several marketed sunscreens containing benzophenone-3 as the only UVA absorber were found to have poor UVA protection factors, whereas those containing combinations of benzophenone-3 and butyl methoxydibenzoyl methane or melanin were more effective. There was no correlation between the sun protection factor cited on the label and the calculated immediate pigment darkening-protection factor.

Reciprocity for solar simulators used in sunscreen testing.

Reciprocity for sunscreen solar protection factors (SPFs) and for delayed erythema was examined using a solar simulator equipped with neutral density filters to vary the beam intensity. Similar SPFs were obtained over a 15-fold intensity difference, using a sunscreen with a low (SPF-4) and a high (SPF-15) protection factor. Reciprocity was also observed for delayed erythema in unprotected skin.

The photoprotective potential of the new superpotent sunscreens.

A sun protection factor (SPF)-15 and an SPF-30 sunscreen were compared with regard to their ability to prevent sunburn cell formation after the exposure of human skin to a standardized dose of solar-simulated radiation. The SPF-30 sunscreen provided a significantly superior degree of photoprotection and almost prevented sunburn cell induction. Because sunburn cells may be markers of ultraviolet radiation-induced damage to DNA, the new superpotent sunscreens should offer an advantage in the prevention of skin cancer and long-term actinic damage to skin.

Photosensitizing potential of certain nonsteroidal anti-inflammatory agents.

The nonsteroidal anti-inflammatory drugs (NSAIDs) have been repeatedly associated with photosensitivity reactions. The underlying mechanism however is not known, and the clinical features are not always consistent with either a phototoxic or a photoallergic mechanism. In this study, four NSAIDs were investigated for their phototoxicity potential in human volunteers using an oral dosing protocol. Phototoxicity, consisting of wheal-and-flare reactions following exposure to ultraviolet radiation, was demonstrated following the administration of naproxen and nabumetone, but was not seen in volunteers who received piroxicam, a drug reported to cause photosensitivity. Thus, although certain NSAIDs are potentially capable of producing phototoxicity reactions, others can presumably provoke clinical photosensitivity through other mechanisms.

Quantification of visible light-induced melanogenesis in human skin.

Exposure of normal skin to visible light (400-700 nm) resulted in the induction of immediate pigment darkening (IPD), immediate erythema and a persistent (delayed) tanning reaction. The intensity of pigmentation and time course of the reaction were monitored by measuring chromaticity coordinates. Both IPD and immediate erythema faded over a 24-h period but, unlike erythema, the pigmentation did not totally disappear and the residual tanning response remained unchanged for the rest of the 10-day observation period. The threshold dose for IPD with visible light was between 40 and 80 J/cm2, while the threshold dose for "persistent" pigmentation was greater than or equal to 80 J/cm2.

Comparison of sun protection factors obtained with a xenon solar simulator and an Ultravitalux lamp.

The influence of the type of UV source on the sun protection factor (SPF) was investigated in healthy volunteers with skin Types I to III. In an open-paired comparison, sunscreens with low, medium and high SPF were examined under identical test conditions using either a 150-watt xenon-arc solar simulator or a set of four 300-watt Osram Ultravitalux bulbs as the UV source. Despite wide differences in the spectral output of the two sources, both yielded similar mean SPF for each of the three test sunscreens. The only significant difference observed was with the FRG standard, for which a lower mean SPF (3.1) was obtained with the Ultravitalux lamps compared to the solar simulator (mean SPF 4.0). There were no differences between the calculated arithmetic and geometric means.

An action spectrum for 8-methoxypsoralen-sensitized inhibition of DNA synthesis in vivo.

The wavelength dependence for 8-methoxypsoralen (8-MOP)-sensitized inhibition of scheduled DNA synthesis was investigated in the epidermis of albino hairless mice. Topical (0.1%) applications of 8-MOP followed by exposure to narrow bands from a monochromator in the range of 300-380 nm produced a dose-dependent inhibition of DNA synthesis. Prior treatment with 8-MOP did not alter the dose-dependent inhibition of DNA synthesis following exposure to 300 nm and to 310 nm. By contrast, DNA synthesis inhibition following exposure to UVA wavelengths was seen only after treatment with 8-MOP. An action spectrum, constructed from the dose-response regression lines, showed peak effectiveness at 335 nm. Since the therapeutic usefulness of psoralen photochemotherapy may be related to inhibition of cell proliferation, it is suggested that light sources with peak emission in the 335-nm region would be more efficient than the commonly employed UVA blacklights.

The clinical spectrum of the persistent light reactor.

Eight patients had a chronic photodermatitis of five to 19 years' duration. The clinical and photobiological features were consistent with the pattern observed in persistent light reactors. Severity and clinical presentation, however, were quite variable, ranging from a few isolated papules to extensive lichenification involving the entire exposed skin. Three had positive photopatch tests to halogenated salicylanilides, while the remaining five reacted to musk ambrette. Exposure of the uninvolved skin to UV-B or solar-simulated radiation provoked abnormal delayed papular or infiltrated reactions. Histological evaluation of these reactions in three cases disclosed moderate to dense perivascular lymphocytic infiltrates with occasional eosinophils, focal exocytosis, and epidermal spongiosis. We conclude that persistent light reactivity associated with photoallergic contact dermatitis shows a spectrum of disease activity and photosensitivity. Recognition of the subtle forms of this disease is important.

Photoprotective adaptation. Some quantitative aspects.

The magnitude and time course of UV radiation-induced photoprotection was investigated in fair-skinned volunteers. Resistance to sunburn was evident three days following single exposures to UV-B, reached a maximum by seven days, and declined gradually over a period of 30 to 40 days. Both the magnitude and time course of UV radiation-induced photoprotection were dose related. The maximal mean protection factor following an exposure to 2 minimal erythemal doses was 4.2. The present findings, along with earlier studies, suggest that there are pronounced spectral differences with regard to the induction of photoprotective adaptation and that UV-B wavelengths are the most effective.

Studies on the mechanism of clinical tolerance in solar urticaria.

Tolerance to artificial ultraviolet radiation (UVR) was induced in three patients with solar urticaria by administering graded whole body exposures to long-wave ultraviolet radiation (UV-A, 320-400 nm) in a phototherapy cabinet. Plasma histamine levels, mast cell ultrastructure and cutaneous responses to intradermally injected codeine and histamine were examined before and after the induction of tolerance. No evidence of serum complement activation could be demonstrated following exposure of serum samples to UVR in vitro. These studies suggest that the state of tolerance is due neither to mediator (histamine) depletion nor to a systemic effect induced by UV-A but may be due to an increase in the mast cell degranulation threshold.

The influence of UVA and visible radiation on acute damage by short-wave UVR (lambda less than 320 nm).

The influence of UVA and visible radiation on the acute damage by short-wave ultraviolet radiation (UVR) (lambda less than 320 nm) was investigated in human volunteers, using delayed erythema and sunburn cell production as markers of injury. It was found that subsequent exposure to UVA + visible radiation produced a significant reduction of the threshold erythema dose by short-wave UVR, in a dose-dependent manner. Subsequent exposures to varying doses of UVA + visible radiation, as well as to visible light alone failed to influence sunburn cell production. It is concluded that there is a positive interaction between short-wave UVR and UVA in the induction of delayed erythema, but this may not apply to epidermal cell injury. Photorecovery was not observed.

Human models for identification of photosensitizing chemicals.

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.

The influence of infrared radiation on short-term ultraviolet-radiation-induced injuries.

Because heat has been reported to influence adversely short- and long-term ultraviolet (UV)-radiation-induced skin damage in animals, we investigated the short-term effects of infrared radiation on sunburn and on phototoxic reactions to topical methoxsalen and anthracene in human volunteers. Prior heating of the skin caused suppression of the phototoxic response to methoxsalen as evidenced by an increase in the threshold erythema dose. Heat administered either before or after exposure to UV radiation had no detectable influence on sunburn erythema or on phototoxic reactions provoked by anthracene.

Phototoxicity to benoxaprofen.

Photosensitization to benoxaprofen has been studied in human volunteers. The wavelengths that mediate the reaction lie mainly just outside the sunburn range in the near ultraviolet, UVA region including, however the terminal portion of the UVB region. The photosensitivity reaction begins with sharp burning during exposure, sometimes accompanied by itching. This may be followed by erythema and a flare, which generally fade in about one hour or less. High doses of ultraviolet light can elicit whealing. Photosensitivity to benoxaprofen is typically an immediate-type, short-lived reaction, dominated by subjective sensations of burning-smarting and redness. With large UVA doses, a sunburn-type reaction may also be present at 24 hours. The photosensitivity is of the phototoxic type. It may appear within 48 hours of starting the drug and usually disappears with 48 hours after stopping. The population most at risk are type 1 and type 2 light-skinned persons who burn easily and tan poorly. Pigmented races are quite resistant, viz, blacks and orientals. Dark-skinned type 4 Caucasoids, such as Mexicans, Indians, etc., have high innate protection. Deep tanning and SPF 15 sunscreens provide adequate protection.