Interleukin (IL) 31 induces in cynomolgus monkeys a rapid and intense itch response that can be inhibited by an IL-31 neutralizing antibody.

BACKGROUND: Overexpression or administration of interleukin 31 (IL-31) has been shown to induce a profound itch response in mice and dogs. The chronic pruritus observed in mouse IL-31 transgenic mice results in the development of skin lesions and alopecia through excoriation from excessive scratching, a condition similar to that observed in patients with atopic dermatitis (AD). OBJECTIVE: To test whether IL-31 induces pruritus in non-human primates and, if so, whether treatment with an anti-IL-31 neutralizing monoclonal antibody (mAb) can block the response. METHODS: A series of studies was conducted in cynomolgus monkeys to evaluate the itch response to recombinant cynomolgus IL-31 (cIL-31) administration. Three routes of cIL-31 administration (intravenous, intradermal, and subcutaneous) were evaluated. Subcutaneous treatment with a humanized anti-human IL-31 mAb cross-reactive to cIL-31 was subsequently tested for its ability to block the response to intradermal cIL-31 administration. RESULTS: Each route of cIL-31 delivery elicited a scratching response immediately after cIL-31 administration and lasted at least 3 h. Treatment with the IL-31 mAb inhibited the cIL-31-mediated scratching response in a dose-dependent manner. CONCLUSION: These results demonstrate that an IL-31 mAb can inhibit IL-31-mediated pruritus in vivo, and could be an effective therapy for pruritic skin conditions like AD where IL-31 upregulation may play a role.

Bioavailability and relative tissue distribution of [125I]-recombinant human thrombin following intravenous or subcutaneous administration to non-human primates.

BACKGROUND: Recombinant human thrombin (rhThrombin) is being developed as a general adjunct to hemostasis. Endogenous thrombin is rapidly inactivated by complex formation with antithrombin III and other inhibitors. It follows that these inhibitors will also inactivate any rhThrombin that reaches the systemic circulation. OBJECTIVES: Study goals were to determine the pharmacokinetic characteristics of [(125)I]-rhThrombin and [(125)I]-rhThrombin complexed to endogenous inhibitors, and the tissue distribution of rhThrombin-associated radioactivity in non-human primates. Hematology, serum chemistry and coagulation status were also monitored. METHODS: [(125)I]-rhThrombin was administered intravenously (i.v.; 3.5 U kg(-1)) or subcutaneously (s.c.; 350 U kg(-1)) to male cynomolgus monkeys. Plasma was analyzed for rhThrombin-associated radioactivity and non-compartmental analysis was used to determine the corresponding pharmacokinetic parameters. A size exclusion-high pressure liquid chromatography (SE-HPLC) method was used to quantitate rhThrombin complexes, non-complexed rhThrombin, and free [(125)I]. Whole-body gamma scintigraphy was used to follow radioactivity localization up to 72 h postdose. RESULTS: No adverse events were observed following [(125)I]-rhThrombin administration. The pharmacokinetic profile of rhThrombin-associated radioactivity following i.v. injection was multi-exponential with an initial half-life of approximately 10 min. Following both i.v. and s.c. dosing, the terminal half-life was approximately 15 h. SE-HPLC analysis revealed that rhThrombin was rapidly complexed to antithrombin III and other inhibitors in the systemic circulation following i.v. administration. Thus, rhThrombin-associated radioactivity in the blood was complexed and presumed inactive. [(125)I]-rhThrombin inhibitor complexes accumulated and were eliminated in the liver following both routes of administration. CONCLUSIONS: These data suggest that rhThrombin rapidly binds to endogenous inhibitors following either i.v. or s.c. administration.

Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats.

The goal of these studies was to determine if chronic (+)methamphetamine ((+)METH) administration affects the production of anti-(+)METH antibodies during active immunization of rats. Active immunization for the treatment of chronic drug abuse has been proposed for drugs such as cocaine and nicotine. However, studies have not adequately addressed whether continual drug use during treatment would affect the development of an immune response. For the current studies, male Sprague-Dawley rats were immunized with either keyhole limpet hemocyanin (KLH; control group) or a (+)METH hapten ((+)METH with a six carbon spacer group at the para position of the ring structure)-KLH conjugate. The (+)METH-KLH animals were further divided into two groups. One group was immunized with no subsequent administration of (+)METH, while the other group was immunized and repeatedly challenged (twice a week throughout the study) with an i.p. dose of 3 mg/kg (+)METH. The results showed that the two groups of (+)METH-KLH immunized rats developed and maintained anti-(+)METH antibody titers. The anti-(+)METH immune responses of the two groups were not statistically different (P < 0.05) as measured by serum titers and the relative antibody affinities. These data suggest that repeated administration of (+)METH does not affect the generation of an anti-(+)METH antibody response in actively immunized rats.

Hypothalamic melanin-concentrating hormone and estrogen-induced weight loss.

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced by neurons of the lateral hypothalamic area (LHA). Because genetic MCH deficiency induces hypophagia and loss of body fat, we hypothesized that MCH neurons may represent a specific LHA pathway that, when inhibited, contributes to the pathogenesis of certain anorexia syndromes. To test this hypothesis, we measured behavioral, hormonal, and hypothalamic neuropeptide responses in two models of hyperestrogenemia in male rats, a highly reproducible anorexia paradigm. Whereas estrogen-induced weight loss engaged multiple systems that normally favor recovery of lost weight, the expected increase of MCH mRNA expression induced by energy restriction was selectively and completely abolished. These findings identify MCH neurons as specific targets of estrogen action and suggest that inhibition of these neurons may contribute to the hypophagic effect of estrogen.

Comparison of central administration of corticotropin-releasing hormone and urocortin on food intake, conditioned taste aversion, and c-Fos expression.

Corticotropin-releasing hormone (CRH) is a potent regulator of the hypothalamic-pituitary-adrenal axis, and reduces food intake when administered into the third cerebral ventricle (i3vt). However, CRH also promotes conditioned taste aversion (CTA) learning which indicates that its anorectic effects are accompanied by aversive consequences that would reduce food intake independently of energy regulation. Urocortin (Ucn) is a closely related mammalian peptide that binds to both identified CRH receptor subtypes and also reduces food intake when administered i3vt. The present experiments compared the aversive consequences of i3vt administration of CRH and Ucn at doses that produced comparable decrements in food intake. Experiment 1 found that 1.0 microg Ucn and 2.0 microg CRH produced similar reductions in food intake. Experiment 2 demonstrated that, at these doses, CRH but not Ucn promoted robust and reliable CTA learning. A third experiment showed comparable increased c-Fos-like immunoreactivity after Ucn and CRH in forebrain and hindbrain structures associated with food intake. It is concluded that Ucn, at doses that reduce food intake to levels like that observed after administration of CRH, do not produce similarly aversive consequences.

A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences.

Studies using nonselective agonists and antagonists of melanocortin-3 receptor (MC3R) and MC4R point to the importance of the CNS melanocortin system in the control of food intake. We describe here a novel compound that is highly selective as an agonist at the MC4 receptor but has minimal activity at the MC3 receptor. When administered centrally to rats, this selective agonist increased Fos-like immunoreactivity in the paraventricular nucleus, central nucleus of the amygdala, nucleus of the solitary tract, and area postrema, a pattern of neuronal activation that is similar to that induced by a nonselective MC3/4R agonist. Additionally, it suppresses food intake when administered centrally to rats or peripherally to db/db mice that lack functional leptin receptors via a mechanism that is not accompanied by illness or other nonspecific effects. Conversely, a related compound that is a selective MC4R antagonist potently increased food intake when administered centrally in rats. These results support the hypothesis that the brain MC4R is intimately involved in the control of food intake and body weight and provide evidence that selective activation of MC4R causes anorexia that is not secondary to aversive effects.

Orbital Wegener granulomatosis without systemic findings.

PURPOSE: To describe a case of orbital Wegener granulomatosis without systemic disease. METHOD: Case report. RESULTS: A 69-year-old patient with bilateral inflammatory lacrimal gland masses underwent multiple biopsies that showed a nonspecific lymphoplasmacytic infiltrate consistent with orbital pseudotumor. After unsuccessful treatment with systemic corticosteroids and radiation, severe orbital disease rapidly progressed and the patient underwent unilateral enucleation. The enucleated specimen showed multifocal vasculitis, tissue necrosis, and granulomas consistent with Wegener granulomatosis (WG). Elevated antineutrophil cytoplasmic antibody titers supported the diagnosis of WG. The patient did not have any extraocular signs of WG and continues to be disease-free systemically. CONCLUSION: The authors believe this is the first report of bilateral lacrimal gland masses presenting as a localized form of WG in the total absence of systemic disease.