allopurinol and Dermatitis--Contact

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

This study evaluated the effects of crude drugs obtained from the silkworm in mice with oxonic acid-induced hyperuricemia using xanthine oxidase inhibitory activity and plasma uric acid levels. The plasma uric acid level was analyzed using an improved HPLC with UV detection (HPLC-UV) method, which enabled high-sensitivity analysis of a microliter of plasma. Using this method, we evaluated natural products administered orally to the hypouricemic mice. The plasma uric acid level of mice administered a water-soluble extract from silkworm larvae with botrytis (used in traditional Chinese medicine to reduce wind, lower blood pressure, and change platelet coagulation) was significantly lower than in the control group 1, 2, and 3 h after treatment. In addition, water soluble extracts from a fungus (NBRC 31161) metabolite and silkworm pupae and larvae reduced the plasma uric acid levels in mice compared with the control group.

Topics: Administration, Oral; Animals; Biological Products; Biomarkers; Blood Pressure; Bombyx; Chromatography, High Pressure Liquid; Complex Mixtures; Dermatitis, Contact; Disease Models, Animal; Enzyme Inhibitors; Hyperuricemia; Mice; Oxonic Acid; Platelet Aggregation; Uric Acid; Xanthine Oxidase

Exposure to solar ultraviolet (UV) radiation suppresses adaptive immune responses. This contributes to skin carcinogenesis but may protect from some autoimmune diseases. However, the molecular changes occurring within UV-exposed skin that precipitate the downstream events leading to immune suppression are not fully understood. Using a combination of in vitro and in vivo mouse models, we have discovered that UV induces significant cutaneous production of immune suppressive uric acid. The ability of UV-induced uric acid to inhibit a contact hypersensitivity response was successfully blocked by the gout-treating drug Allopurinol. Up-regulation of NLRP3 mRNA by UV was also found to be dependent on UV-induced uric acid. This suggested that the target of UV-induced uric acid included proteins involved in the formation and activation of the NLRP3-inflammasome. However, in contrast to NLRP3, the adaptor protein ASC, which is required for formation of the NLRP3-inflammasome, was significantly down-regulated. Furthermore, this down-regulation was not dependent on UV-induced uric acid production because Allopurinol treatment failed to prevent the reduction in ASC. Hence, our results identify uric acid as an important molecule involved in sterile UV-induced inflammation and immune suppression. UV-induced uric acid may therefore offer a unique therapeutic target for preventing and treating skin cancer.

Topics: Allopurinol; Animals; Apoptosis Regulatory Proteins; CARD Signaling Adaptor Proteins; Carrier Proteins; Cells, Cultured; Cytoskeletal Proteins; Dermatitis, Contact; Disease Models, Animal; Down-Regulation; Female; Gout Suppressants; Immunosuppression Therapy; In Vitro Techniques; Keratinocytes; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein; Skin; Ultraviolet Rays; Up-Regulation; Uric Acid

The immunomodulatory effects of allopurinol were investigated in a mouse contact hypersensitivity model. Allopurinol caused a time- and dose-dependent lethal effect in dinitrofluorobenzene (DNFB)-sensitized mice. Furthermore, allopurinol markedly increased ear swelling in the remaining mice. In contrast, TMX-67, a newly synthesized xanthine oxidase/xanthine dehydrogenase (XOD/XDH) inhibitor, had almost no effect on DNFB-sensitized mice. Allopurinol reduced both the spleen weight and white blood cell count in DNFB-sensitized mice without affecting the T cell subset of splenocytes. The production of interferon (IFN)-gamma, in the splenocytes of DNFB-sensitized mice was reduced by allopurinol administration. Death due to allopurinol was much lower in the non-sensitized mice than in the DNFB-sensitized mice. These findings indicate that allopurinol may interact with DNFB to enhance its toxicity and allopurinol might also modulate or enhance the inflammatory effect of DNFB. Also, DNFB may cause metabolic alterations via inflammation, leading to enhanced allopurinol toxicity.

Topics: Allopurinol; Animals; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Ear; Flow Cytometry; Male; Mice; Mice, Inbred BALB C; Survival Rate

Allopurinol is widely used and generally well-tolerated. However, when used in patients with renal insufficiency it may have life-threatening toxic effects known as allopurinol hypersensitivity syndrome (AHS). We previously found that allopurinol increased ear swelling and mortality in a DNFB-induced contact hypersensitivity mouse model. In the present study, we investigated the toxic effect of allopurinol on DNFB-sensitized mice in order to clarify the mechanism responsible for the lethal effect of allopurinol. Allopurinol increased plasma GPT and GOT in DNFB-sensitized mice and markedly increased plasma creatinine and BUN. The increase in plasma GPT and GOT was moderate and declined time-dependently. In contrast, the increase in plasma creatinine and BUN was striking and continued until 18 hr after administration of allopurinol at 100 mg/kg/day. Although allopurinol increased GOT and GPT in DNFB-sensitized mice, no effect was observed in non-sensitized mice even at 100 mg/kg/day, indicating that allopurinol essentially has no toxic effect on the liver. A high dose of allopurinol induced renal impairment even in non-sensitized mice. These observations indicate that there is some biological interaction between allopurinol and DNFB, and suggest that allopurinol may modulate or enhance the inflammatory reactions induced by DNFB, and/or that DNFB may cause metabolic changes via inflammation, leading to the enhanced toxicity of allopurinol. In contrast, TEI-6720, a newly synthesized XOD/XDH inhibitor, had almost no effect on DNFB-sensitized mice. TEI-6720 at 1 mg/kg, in terms of hypouricemic effect, appeared to be more potent than allopurinol at 3 mg/kg. Therefore, the nephrotoxic effect of allopurinol observed in the present study may not be related to XOD/XDH inhibitory activity.

Topics: Acute Kidney Injury; Allopurinol; Animals; Blood Urea Nitrogen; Creatinine; Dermatitis, Contact; Dinitrofluorobenzene; Enzyme Inhibitors; Febuxostat; Liver; Male; Mice; Mice, Inbred BALB C; Thiazoles; Xanthine Oxidase

Allopurinol is widely prescribed for primary and secondary hyperuricaemia, and cutaneous adverse reactions are seen in 0.8-2.1% of recipients. The majority of these are mild and include pruritus, diffuse or maculo-papular erythema, urticaria and ichthyosis. More severe reactions are well recognized and include exfoliative dermatitis, toxic epidermal necrolysis and a generalized hypersensitivity syndrome. The latter typically comprises fever, rash, hepatic and renal dysfunction and eosinophil leucocytosis. The occurrence of toxic pustuloderma due to allopurinol, confirmed by re-challenge, is reported.

Topics: Allopurinol; Dermatitis, Contact; Humans; Male; Middle Aged

The effect of apigenin-7-glucoside on skin inflammation induced by different generators of reactive oxygen species and free radicals was studied. Skin inflammation in rats was induced by intradermal injection of glucose-oxidase (hydrogen peroxide), xanthine-oxidase/hypoxanthine (superoxide anion radical), and cumene hydroperoxide (peroxyl radical). Subsequent intradermal application of liposomal apigenin-7-glucoside inhibited in a dose dependent manner skin inflammation caused by xanthine-oxidase and cumene hydroperoxide. Glucose-oxidase induced dermatitis was not significantly inhibited. The results are in good agreement with the in-vitro superoxide anion radical and peroxyl radical scavenging properties of apigenin and indicate that its antioxidant properties contribute to the anti-inflammatory effect in this model system.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Apigenin; Benzene Derivatives; Dermatitis, Contact; Flavonoids; Glucose Oxidase; Histamine Release; Liposomes; Male; Prostaglandins; Rats; Rats, Wistar; Xanthine Oxidase

Topics: Allopurinol; Ampicillin; Aspirin; Cell Migration Inhibition; Colistin; Dermatitis, Contact; Drug Eruptions; Hemagglutination Tests; Humans; Immunity, Cellular; Immunoglobulin E; Leukocytes; Lymphocyte Activation; Penicillins; Phenobarbital; Quinine; Skin Tests; Sulfonamides; Tetracycline

Topics: Adult; Allopurinol; Clioquinol; Dermatitis, Contact; Enteritis; Enzyme Therapy; Humans; Male; Psoriasis; Xanthine Oxidase