Susceptibility to serious skin and subcutaneous tissue disorders and skin tissue distribution of sodium-dependent glucose co-transporter type 2 (SGLT2) inhibitors.

Objectives: In Japan, sodium-glucose co-transporter type 2 (SGLT2) inhibitors have been reported to be associated with serious skin and subcutaneous tissue disorders. A post-marketing surveillance (PMS) study suggested that the association was specific for ipragliflozin and, to a lesser extent for dapagliflozin. These studies were performed to confirm the association of 6 SGLT2 inhibitors with serious skin disorders in a clinical setting, to elucidate the role of melanin in serious skin disorders and to understand the underlying mechanisms. Methods: The latest PMS records were retrieved from the Japanese Adverse Drug Event Report (JADER) database, and the associations were analyzed by data mining techniques. In silico 3-D docking simulation of SGLT2 inhibitors with melanin was performed using the MOE software. The skin tissue distribution of SGLT2 inhibitors was evaluated using albino rats after oral administration at clinical doses. Results: The adjusted reporting odds ratio (95% confidential limit) was 1.667 (1.415, 1.963) for ipragliflozin, 0.514 (0.317, 0.835) for dapagliflozin, 0.149 (0.048, 0.465) for tofogliflozin, 0.624 (0.331, 1.177) for luseogliflozin, 0.590 (0.277, 1.257) for canagliflozin and 0.293 (0.073, 1.187) for empagliflozin, when drugs other than the SGLT2 inhibitors were referred, and the association was detected only for ipragliflozin in clinical use. In silico 3-D docking simulation suggested the influence of melanin in ipragliflozin-specific serious skin disorders. The skin tissue-to-plasma concentration ratio of ipragliflozin was 0.45 ± 0.20 (±SD) at 1 hr after administration and increased in a time-dependent manner to 5.82 ± 3.66 at 24 hr (p<0.05), but not in case of other SGLT2 inhibitors. Conclusions: Serious skin disorders were suggested to be specific for ipragliflozin. Interaction with melanin might be implicated in ipragliflozin-specific serious skin disorders. Ipragliflozin was retained in the skin tissue, which suggested its interaction with the skin tissue in serious skin disorders.

English version of the interim report published in 1998 by the members of the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to set up severity scoring systems for atopic dermatitis (AD). Its interim report was published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998) by Chairman Hikotaro Yoshida. Because of the strong demand for an English version, we have decided to publish the report in English. This prospective study was designed to evaluate the status of 259 AD patients using Method 1, which involves a simple global evaluation of disease severity; Method 2, which involves global evaluation by summing severity scores obtained from five body regions (i.e. the head and neck, anterior and posterior trunks, and upper and lower limbs); Method 3, which consists of both assessment of the extent of involved areas at each of the five body regions and that of the severity scores of each eruption component observed in the most severely affected body region; and Method 4, which consists of the evaluation of only subjective components (daytime pruritus and sleep disturbance). Employing the results obtained with Method 1 as a tentative benchmark, we analyzed its correlation with those of Methods 2, 3 and 4 to statistically assess the validity and reliability of these methods. Method 2, Method 3 and the portion of Method 4 involving evaluation of only the subjective symptom of daytime pruritus but not the sleep disturbance were considered useful in evaluating AD severity.

English version of the concluding report published in 2001 by the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to develop a severity scoring system for atopic dermatitis (AD). Its interim and concluding reports were published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998 and 111: 2023-2033, 2001). Because of the strong demand for an English version, we have decided to publish the reports in English. This manuscript is the English version of the concluding report. The interim report suggested that eruption components such as erythema, papule, erosion, crust, excoriation and lichenification with extent of involved areas in five body regions, including the head and neck, anterior and posterior trunks, and upper and lower limbs, were important items for assessing AD severity. Additionally, it was recommended that streamlining of eruption components was mandatory for improving the statistical validity and reliability. The committee members subsequently concentrated their efforts on this task, and finally proposed an Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

Induction of allergic contact dermatitis by astigmatid mite-derived monoterpene, alpha-acaridial.

alpha-Acaridial [2(E)-(4-methyl-3-pentenyl)butenedial] is a novel monoterpene secreted from the house dust mites. Because of its molecular nature of a highly reactive, small lipidic compound, we addressed whether alpha-acaridial might function as a haptenic allergen that induced allergic contact dermatitis. Mice sensitized with alpha-acaridial were challenged by the same antigen on the ear skin. After 2 days, significant ear swelling with a prominent infiltration of CD4(+) T lymphocytes was observed. In vitro, alpha-acaridial exhibited an outstanding ability to quickly interact with and chemically modify a reference protein. Virtually all cysteine residues and a sizable fraction of lysine residues were found to be selectively modified, suggesting that alpha-acaridial could potentially interact with any proteins. Previously, numerous mite-derived proteinaceous allergens have been associated with contact dermatitis. Our study now emphasizes that small lipidic compounds released from mites comprise a new class of mite allergens, and therefore, is of significant medical implications.

Fragrance contact dermatitis - a worldwide multicenter investigation (Part III).

The purpose of this study was to determine the frequency of responses to selected fragrance materials in patients who were fragrance sensitive. 218 fragrance sensitive subjects were evaluated in eight centres worldwide with a fragrance mixture (FM) and 17 less well-studied fragrance materials. Reaction to the fragrance mixture (FM) occurred in 76% of the subjects. The (FM) detected all reactions to nerol and hydroxycitronellol and 93% of the reactions to clove bud oil. Ten fragrance materials were not detected by the FM and deserve further study: benzenepropanol, beta, beta, 3-trimethyl, hexyl-salicylate, dl-citronellol, synthetic ylang ylang oil, benzyl mixture, cyclohexyl-acetate, eugenyl methyl ether, isoeugenyl methyl ether, 3-phenyl-1-propanol, and 3, 7-dimethyl-7-methoxyoctan-2-ol.

New aspects of metal allergy.

A common clinical manifestation of metal allergy is allergic contact dermatitis, however, there are some other exceptional manifestations such as lichen planus, pustulosis palmaris et plantaris including dyshidrotic eczema and severe form of alopecia areata. Evidence for such exceptional cases are: reproducible positive patch test reactions to various metal ions; analytical results of dental metal testing demonstrating the presence of metals to which the patients are undoubtedly hypersensitive; and dramatic curative effects of allergenic metal elimination. These dental metals are presumed to elute thus leading to the disease when they electrochemically turn to be a cathode. Cases which could not have been cured by antisymptomatic treatment but by allergen elimination are reported.

Cloning and characterization of the thiD/J gene of Escherichia coli encoding a thiamin-synthesizing bifunctional enzyme, hydroxymethylpyrimidine kinase/phosphomethylpyrimidine kinase.

A 1.7 kb DNA fragment isolated from an E. coli genomic library was able to complement the thiamin requirement of strains carrying the thiM, thiJ and thiD mutations. The three genes encode hydroxyethylthiazole kinase, hydroxymethylpyrimidine (HMP) kinase and phosphomethylpyrimidine (HMP-p) kinase, respectively. Sequence analysis revealed that the 1.7 kb fragment contained two ORFs of 708 bp and 801 bp. The former ORF complemented the thiM mutation and the latter ORF both the thiJ and thiD mutations. The latter ORF was cloned into the expression vector pET3a, and the encoded protein was purified through three successive column chromatographies. The purified protein was able to convert HMP to its monophosphate and the monophosphate to its pyrophosphate. These results suggest that the two distinct enzyme activities, HMP kinase and HMP-P kinase, are indeed a bifunctional enzyme encoded by a single gene, designated thiDIJ.