Possible Association of Interleukin-31/-31RA Signalling and Basophils with Itch in Porokeratosis.

is missing (Short communication).

Therapeutic approach to mite-induced intractable dermatitis using novel immunomodulator FTY720 ointment (fingolimod) in NC/Nga mice.

BACKGROUND: The increasing incidence and prevalence of atopic dermatitis (AD) demands new therapeutic approaches for treating the disease. We investigated the therapeutic efficacy of immunomodulator FTY720 ointment (fingolimod) for mite-induced intractable AD using an NC/Nga mouse model. METHODS: Female NC/Nga mice that developed severe AD were divided into four groups: (1) FTY720 (0.001% FTY720 ointment), (2) tacrolimus (tacrolimus hydrate ointment) (3) betamethasone (betamethasone ointment), and (4) ointment base (hydrophilic petrolatum), all of which received treatment six times per week. Therapeutic efficacy after two weeks was evaluated in terms of AD severity, histochemical observations (epidermal hypertrophy, mast cell accumulation, and CD3(+) T cell infiltration), transepidermal water loss (TEWL), and epidermal barrier function (filaggrin expression). RESULTS: Betamethasone treatment showed little effect, confirming that the AD was intractable. In the FTY720 group, AD improved significantly compared with the ointment base group, as did epidermal hypertrophy, mast cell accumulation, and CD3(+) T cell infiltration. In contrast, AD in the tacrolimus and betamethasone groups did not improve significantly, nor did epidermal hypertrophy or mast cell accumulation. Furthermore, in the FTY720 group, TEWL decreased significantly compared with the ointment base group, and filaggrin expression significantly increased compared with the betamethasone and ointment base groups. CONCLUSIONS: FTY720 ointment is a promising candidate for treatment of intractable AD. These findings also provide the first evidence that FTY720 ointment ameliorates epidermal barrier function.

Increased touch-evoked itch (punctate hyperknesis) in postherpetic itch: Implications of reduced intraepidermal nerve fibers representing small fiber neuropathy.

Chronic itch conditions are often accompanied by neural itch sensitization, known as hyperknesis (excessive itch induced by stimuli that would normally induce only mild itching or pain) and alloknesis (considerable itch evoked by light tactile stimuli). Herpes zoster (shingles) can cause neuropathic itch (postherpetic itch), although it is unknown whether hyperknesis accompanies postherpetic itch. The authors report five patients with postherpetic itch who showed increased touch-evoked itch (punctate hyperknesis) in the affected skin areas compared with the contralateral site. Collected skin biopsy specimens from two patients showed histopathologically detected reduced intraepidermal nerve fibers in the affected skin areas, reflective of small C/Aδ fiber neuropathy. In one case, improvement in itching and comparable levels of touch-evoked itch on the affected and contralateral sites were noted after 6 months without any medication, accompanied by restored intraepidermal nerve fibers proven through rebiopsy of the affected site. Reduced intraepidermal nerve fibers could be one of the precipitating factors for postherpetic itch and its associated punctate hyperknesis.

IL-31 and IL-31 receptor alpha in pemphigus: Contributors to more than just itch?

Pemphigus is an autoimmune blistering disorder with four major subtypes: pemphigus vulgaris (PV), pemphigus vegetans (PVe), pemphigus foliaceus (PF), and pemphigus herpetiformis (PH). Among them, PF and PH present itching as a clinical feature; however, the mechanisms behind the pruritus are still unclear. In this report, we sought to investigate the expression of a type 2 inflammation-related pruritogenic cytokine IL-31 and its receptor subunit IL-31RA through immunofluorescence staining analysis. The number of eosinophils, basophils, and mast cells, and the expression levels of thymic stromal lymphopoietin (TSLP) and periostin were also investigated. Evaluation showed an increase in the number of dermal IL-31+ cells and IL-31RA+ cells in PH and PVe. Epidermal expression of IL-31RA increased in PV, PF, and PVe, but not in PH, compared to healthy individuals. The number of dermal eosinophils and basophils was also increased in PVe and PH. The number of dermal mast cells and expression levels of TSLP and periostin did not change among pemphigus subtypes and healthy controls. Collectively, enhanced IL-31/IL-31RA signaling and the increased numbers of dermal eosinophils and basophils may participate in itching in PH. On the other hand, IL-31/IL-31RA signaling seemed unable to provoke itching in PVe, a non-pruritic subtype of pemphigus, although it might contribute to epidermal thickening and dermal fibrosis.

High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate.

The antimetastatic activity of a novel camptothecan conjugate, MEN4901/T-0128, in which 7-ethyl-10-aminopropyloxy-camptothecin (T-2513) is bound to a biodegradable carboxymethyldextran via a Gly-Gly-Gly linker, was observed in this study. High antimetastatic activity of MEN4901/T-0128 was demonstrated in a clinically-relevant orthotopic mouse model of human colon cancer. MEN4901/T-0128 and irinotecan were compared for anti-metastatic activity as well as efficacy against the primary tumor. An imageable, metastatic model was made by surgical orthotopic implantation (SOI) of the green fluorescent protein (GFP)-expressing HT-29 tumor in nude mice. MEN4901/T-0128 and irinotecan were administered intravenously at various doses and schedules. MEN4901/T-0128, with treatment beginning on d 49 after SOI, was highly effective on lymph node metastasis as well as against the primary tumor. Both GFP imaging and histology demonstrated a markedly lower metastatic incidence of lymph nodes in all MEN4901/T-0128 treated mice compared with irinotecan-treated and untreated mice. At the most efficacious dose of MEN4901/T-0128, only 1 of 12 animals had lymph node metastasis compared with 19 of 20 in the control group. The present study demonstrates the principle that when a camptothecan is conjugated to an appropriate polymer, the drug can become extremely effective with important clinical potential for antimetastatic therapy, a most urgent need.

MEN4901/T-0128, a new camptothecin derivative-carboxymethyldextran conjugate, has potent antitumor activities in a panel of human tumor xenografts in nude mice.

PURPOSE: The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. EXPERIMENTAL DESIGN: We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. RESULTS: MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. CONCLUSIONS: Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.