Comparative analysis of the phototoxicity induced by BRAF inhibitors and alleviation through antioxidants.

BACKGROUND: Small molecules tackling mutated BRAF (BRAFi) are an important mainstay of targeted therapy in a variety of cancers including melanoma. Albeit commonly reported as side effect, the phototoxic potential of many BRAFi is poorly characterized. In this study, we evaluated the phototoxicity of 17 distinct agents and investigated whether BRAFi-induced phototoxicity can be alleviated by antioxidants. METHODS: The ultraviolet (UV) light absorbance of 17 BRAFi was determined. Their phototoxic potential was investigated independently with a reactive oxygen species (ROS) and the 3T3 neutral red uptake (NRU) assay in vitro. To test for a possible phototoxicity alleviation by antioxidants, vitamin C, vitamin E phosphate, trolox, and glutathione (GSH) were added to the 3T3 assay of selected inhibitors. RESULTS: The highest cumulative absorbance for both UVA and UVB was detected for vemurafenib. The formation of ROS was more pronounced for all compounds after irradiation with UVA than with UVB. In the 3T3 NRU assay, 8 agents were classified as phototoxic, including vemurafenib, dabrafenib, and encorafenib. There was a significant correlation between the formation of singlet oxygen (P = .026) and superoxide anion (P < .001) and the phototoxicity observed in the 3T3 NRU assay. The phototoxicity of vemurafenib was fully rescued in the 3T3 NRU assay after GSH was added at different concentrations. CONCLUSION: Our study confirms that most of the BRAF inhibitors exhibited a considerable phototoxic potential, predominantly after exposure to UVA. GSH may help treat and prevent the phototoxicity induced by vemurafenib.

Insect stings: clinical features and management.

BACKGROUND: In human beings, local and systemic reactions can be caused both by blood-sucking insects and by venomous insect stings. In Central Europe, the insects that most commonly cause such reactions are honeybees, certain social wasps, mosquitoes, and flies. METHODS: This article is based on a selective literature review, including guidelines from Germany and abroad. RESULTS: Insect venom induces a toxic reaction at the site of the sting. Large local reactions are due to allergy and occur in up to 25% of the population; as many as 3.5% develop IgE-mediated, potentially life-threatening anaphylaxis, of which about 20 people die in Germany each year. Mastocytosis is found in 3% to 5% of patients with sting anaphylaxis, rendering these patients prone to very severe reactions. Blood-sucking by hematophagous insects can elicit a local allergic reaction, presenting as a wheal or papule, in at least 75% of the population. Large local reactions may ensue, but other diseases are rare. The acute symptoms of an insect sting are treated symptomatically. Patients who have had a systemic reaction or a large local reaction due to insect allergy must take permanent measures to avoid further allergen contact, and to make sure they can treat themselves adequately if stung again. Most patients with systemic anaphylactic reactions to bee or wasp stings need specific immunotherapy. CONCLUSION: Insect stings can cause severe disease. Anaphylaxis due to bee or wasp stings is not a rare event; specific immunotherapy protects susceptible persons from further, potentially life-threatening reactions.

Hymenoptera venom allergy.

Allergic reactions to Hymenoptera stings usually present as large local reactions or systemic reactions with symptoms of immediate type allergy (anaphylaxis). In Central Europe they are predominantly elicited by stings of the honeybee or Vespula spp. Acute reactions are managed by symptomatic treatment. Long-term care includes patient education (allergen avoidance, course of action at re-sting) and prescription of an emergency kit for self-treatment. Venom immunotherapy is established as specific treatment for Hymenoptera venom allergic patients. Diagnosis of Hymenoptera venom anaphylaxis is based on history, skin tests and measurement of venom-specific serum IgE antibodies. "False negative" or "false positive" results are possible with all test methods. If standard tests are negative, additional tests using the patient's peripheral blood leucocytes can be useful. Venom immunotherapy is usually well tolerated. After reaching the maintenance dose, therapeutic efficacy should be assessed by a sting challenge test. If the patient again develops a systemic reaction, an increase of the maintenance dose (usually 200 microg are sufficient) nearly always induces protection. In most patients venom immunotherapy can be stopped after (3 to) 5 years. However, if there is an increased risk of sting anaphylaxis due to intense allergen exposure (e.g. in beekeepers) or if there are individual risk factors for particularly severe reactions (especially mastocytosis and/or elevated baseline serum tryptase concentration, severe cardiovascular disease), modifications of the standard venom immunotherapy are necessary.

Stinging Hymenoptera and mastocytosis.

PURPOSE OF REVIEW: Patients suffering from mastocytosis are at risk for a particularly severe Hymenoptera sting anaphylaxis. The purpose of this review is to evaluate the current knowledge on pathophysiologic events, which might explain the specific risk of patients with mastocytosis. RECENT FINDINGS: Mast cell products can neutralize major toxins of snake or bee venoms. beta-tryptase from mast cells is able to degrade allergens and IgE antibodies. Thus, mast cells and their mediators should protect patients from venom toxicity and should also lead to a decreased allergenicity. However, these theoretically beneficial effects of mast cells on downregulating allergic immediate type reactions are insufficient to protect patients with mastocytosis from severe anaphylaxis. In contrast, these patients are at an even higher risk. Many compounds of Hymenoptera venom can induce Fcepsilon receptor-independent mast cell degranulation. In the context of mast cell activation induced by Hymenoptera venom, FcepsilonRI-dependent stimulation of mast cells via bridging of specific IgE-antibodies may be of particular importance. Abundance and dysfunction of mast cells in patients with mastocytosis may explain a significant portion of the particularly high anaphylactic risk in patients with mastocytosis. SUMMARY: The particular anaphylactic risk of patients with mastocytosis results from a variety of mechanisms. However, their individual contribution still needs further clarification.

Changes in intracellular cyclic adenosine monophosphate levels in peripheral blood leukocytes during immunotherapy with vespid venom.

BACKGROUND: The allergen-induced release of mediators from basophils is known to be decreased after rush venom immunotherapy (VIT) compared with pretreatment values. A rise in the intracellular cyclic adenosine monophosphate (cAMP) level is known to inhibit mediator release. OBJECTIVES: To determine changes in cAMP levels in peripheral blood leukocytes (PBLs) during rush VIT and to evaluate their relation to allergen-specific reactivity of basophils. METHODS: Ten patients allergic to vespid venom (VV) were investigated before rush VIT and after reaching the maintenance dose. Five VV-allergic patients not undergoing VIT served as controls. Patients' PBLs were incubated with VV, and allergen-induced histamine and leukotriene release from basophils was measured. Levels of cAMP were determined in PBLs and in plasma. RESULTS: Immediately after rush VIT, VV-induced histamine release (P = .04) and VV-induced leukotriene release (P = .01) were significantly reduced. Intracellular cAMP levels increased significantly (P = .047). However, 6 months after VIT, mediator responses in basophils were comparable with pre-VIT values. No significant changes were found in the control group. CONCLUSIONS: An increase in intracellular cAMP levels might account for the decreased reactivity of basophils to allergen after 1 week of VIT. However, similar to the decreased mediator release after 1 week of VIT, this is not a long-term effect as values returned to baseline after 6 months.

[Expert opinion on occupational skin diseases: a Munich statement regarding the Bamberg medical bulletin (Bamberger Merkblatt)]. / Begutachtung von Berufskrankheiten der Haut: Eine Münchner Stellungnahme zum Bamberger Merkblatt.

The Bamberg medical bulletin (Bamberger Merkblatt) is intended to assure as an anticipated expert opinion an objective as possible assessment of the sequels of an occupational disease. However, the Bamberg medical bulletin is not suitable for this task in form and content. In case of an allergic contact dermatitis recognized under No. 51 01 in appendix 1 of the German ordinance on occupational diseases the disadvantage for the insured person consists mainly in the live-long existing change of the immune system and not as much in the intensity of the skin condition triggered by a new exposure to the allergen. The prerequisite for compensation imposed by the regulator, i.e. that the skin condition must be so severe as to have forced the affected individual to refrain from all activities which led or could lead to the development, aggravation or recurrence of the condition, is in its function as a typing sign widely unnecessary in the case of an allergic occupational dermatosis. The omission of all activities which led or could lead to the development, aggravation or recurrence of the condition imposed on the affected individual by the regulator has to be taken in account for the calculation of the reduction in earning capacity in the Bamberg medical bulletin. The Bamberg medical bulletin is by no means an anticipated expert opinion. Even as a qualified experience it urgently needs a revision which might be done with, but not governed by, the statutory occupational accident insurance. Our critical scientific comments do not absolve the medical evaluator from the responsibility to consider existing recommendations as the Bamberg medical bulletin. Our aim is to initiate a process leading to an appropriate judgement of the sequels of an occupational skin disease in each individual case.

[Work-related diseases of the skin]. / Berufsbedingte Erkrankungen der Haut. Schnelles Handeln erhält den Arbeitsplatz.

Work-related diseases of the skin are aetiologically completely different diseases. The common denominator is that they are all triggered by occupational activity. Allergic and cumulative irritant contact eczema occur the most frequently. Early reporting of occupational dermatosis to the accident insurance carrier should first and foremost lead to adequate preventive measures at the workplace. Early recognition, systematic therapy and rapidly implemented prevention should enable the affected person to continue to work in his or her occupation. To implement appropriate preventive measures, the collaboration of the family physician, dermatologists, company doctor and accident insurance carrier is desired.

Mastocytosis and Hymenoptera venom allergy.

PURPOSE OF REVIEW: Mastocytosis is a rare disease characterized by increased mast cells in skin and/or internal organs. We evaluate the impact of mastocytosis on diagnosis and treatment of Hymenoptera venom allergy. RECENT FINDINGS: Patients with Hymenoptera venom allergy who suffer from mastocytosis develop life-threatening sting reactions more often than those who do not. When patients with Hymenoptera venom allergy were systematically examined for mastocytosis, it was found to be represented to an abnormally high extent. Most patients with mastocytosis tolerate venom immunotherapy with no or only minor systemic symptoms. Venom immunotherapy was found to be marginally less effective in patients with mastocytosis than in those without evidence of mast cell disease (defined as absent cutaneous mastocytosis combined with a serum tryptase concentration of <11.4 microg/l). Several deaths from sting reactions were reported in patients with mastocytosis after venom immunotherapy was stopped. These patients should have venom immunotherapy for the rest of their lives. SUMMARY: Patients suffering from mastocytosis and Hymenoptera venom allergy are at risk from a particularly severe sting anaphylaxis. They need optimal diagnosis and treatment. In patients presenting with Hymenoptera venom allergy, screening tests by measurement of serum tryptase concentration, and a careful skin examination, are highly recommended.

Anaphylaxis to viscotoxins of mistletoe (Viscum album) extracts.

BACKGROUND: Extracts of mistletoe (Viscum album) are used in many countries for adjuvant cancer therapy. These extracts contain mistletoe lectins and viscotoxins that are supposed to have immunostimulating and cytotoxic effects, respectively. The treatment is usually well tolerated. OBJECTIVE: To report a case of severe anaphylaxis secondary to mistletoe extract administration with demonstrable anti-IgE antibodies to mistletoe. METHODS: Skin prick tests, basophil histamine release, basophil activation test, and immunoblotting were performed to characterize the pathophysiology of this reaction. RESULTS: The patient had immediate-type skin prick test reactions to the whole commercial preparation and to its mistletoe extract component. A histamine release test and a flow cytometric basophil activation test performed with the patient's peripheral blood leukocytes by incubation with the mistletoe extract yielded a concentration-dependent histamine release and expression of the activation marker gp53 in up to 98% of anti-IgE-positive cells. Immunoblotting revealed IgE binding to 5-kDa proteins of mistletoe in the patient's serum, which corresponds to the molecular weight of viscotoxins. The results of all these tests were negative in controls. CONCLUSIONS: Until now, anaphylaxis to mistletoe extracts has been only rarely reported. In our patient, viscotoxin specific IgE evidently had induced an anaphylactic reaction.

Ultraviolet B-induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-alpha-tocopherol.

DNA damage caused by ultraviolet (UV) irradiation is considered the main etiologic factor contributing to the development of skin cancer. Systemic or topical application of antioxidants has been suggested as a protective measure against UV-induced skin damage. We investigated the effect of long-term oral administration of a combination of the antioxidants ascorbic acid (vitamin C) and D-alpha-tocopherol (vitamin E) in human volunteers on UVB-induced epidermal damage. The intake of vitamins C and E for a period of 3 mo significantly reduced the sunburn reaction to UVB irradiation. Detection of thymine dimers in the skin using a specific antibody revealed a significant increase of this type of DNA damage following UVB exposure. After 3 mo of antioxidant administration, significantly less thymine dimers were induced by the UVB challenge, suggesting that antioxidant treatment protected against DNA damage.

[Systemic contact eczema against Balsam of Peru]. / Hämatogen-allergisches Kontaktekzem auf Perubalsam.

Balsam of Peru (PB; Myroxylon pereirae) is a natural product derived from resin of a tropical tree (MyroxyIon balsamum (L.) Harms var. pereirae (Royle) Baillon). Because of its antiseptic and aromatic properties PB or PB-components can be found worldwide not only in many health care and cosmetic products, but also in food items and semiluxury food. PB contains a wide variety of potent contact allergens leading to hypersensitivity reactions not only after topical application but also oral uptake. We report a 51-year-old brewer with chronic eczema of the hands who showed delayed-type patch test reactions against PB and fragrance-mix. Oral PB-challenge led to exacerbation of the eczema 5 and in a repeated test 2 days later. We here review this probably quite often overlooked disease and the therapeutic consequences which require profound knowledge about the wide distribution of PB when advising the patient about a PB-restricted diet. In addition, this unusual case report demonstrates that one has to consider marked delayed hypersensitivity reaction when investigating a systemic contact allergy.

Impairment of the ß-Adrenergic System of Peripheral Blood Leukocytes in Atopic Patients with Seasonal Allergic Rhinoconjunctivitis.

Compared to 7 healthy women, an altered ß2-adrenoceptor/cyclic adenosine monophosphate (cAMP) system has been observed in a combined study on both expression and function of ß2-adrenoceptors on peripheral blood leukocytes (PBL) of 7 atopic women suffering from acute seasonal rhinoconjunctivitis. A reduced affinity of the ß-adrenergic radioligand 125Icyanopindolol to its binding site (equilibrium dissociation constant Kd 6.4 ± 1.0 vs. 3.4 ± 0.6 pmol/l in controls; p <0.05) a reduced sensitivity of the intracellular cAMP formation to isoprenaline (concentration necessary to achieve half-maximal effectiveness EC501,088.6 ± 669.0 vs. 71.0 ± 51.0 nmol/l in controls; p <0.01), and a reduced intracellular cAMP increase in response to isoprenaline (Emax as a percentage of the basal cAMP content E0 117 ± 3 vs. 145 ± 8% E0 in controls; p <0.01) point to a subsensitivity of ß2-adrenoceptors. A reduced E0 (4.9 ± 0.8 vs. 8.4 ± 1.3 pmol/l06 cells in controls; p <0.05) suggests an increased activity of the cAMP-degrading enzyme phosphodiesterase. A reduced sympathetic tone in atopy was further confirmed by lower cAMP plasma concentrations (25.7 ± 1.2 vs. 31.3 ± 1.6 nmol/l in controls; p <0.05). The results indicate that more than just one mechanism are involved in the impairment of the PBL ß2-adrenoceptor/ cAMP system in atopy.