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Abstract:In this work we have studied the influences of nicotinic agents on the antinociception of morphine in formalin test. Nicotine (0.001-0.1 mg/kg) induced antinociception in mice in a dose-dependent manner in the early phase of formalin test, and also potentiated the morphine effect. The nicotinic receptor antagonist, mecamylamine (0.5 mg/kg), but not hexamethonium decreased the antinociception induced by nicotine (0.1 mg/kg) in both phases. The muscarinic receptor antagonist atropine ( 5 and 10 mg/kg) also decreased the response of nicotine. Mecamylamine, hexamethonium or atropine did not alter morphine antinociceptive response, while naloxone decreased responses induced by nicotine or morphine. The antagonists by themselves did not elicit any response in formalin test, however, high doses of mecamylamine tend to increase pain response. It is concluded that central cholinergic and opioid receptor mechanisms may be involved in nicotine-induced antinociception.Nicotine has many effects on the central nervous system as alters spontaneous activity, brain excitability, heart rate and blood pressure and causes convulsions, antidiuresis and antinociception (Martin et al. 1983). Nicotine is also known to release a number of neurotransmitters (Balfour 1982). In the central nervous system, nicotinic receptor stimulation enhances release of norepinephrine from the hippocampus (Hall & Turner 1972;Goodman 1974) and dopamine from the limbic system (Imperato et a/. 1986) and striatal slices (Goodman 1974; Giorguieff et al. 1979). It also increases the release of acetylcholine from the cortex (Chiou et a/. 1970; Nordberg ef al. 1989). Muscarinic receptors have been suggested to be involved in analgesia (Chen 1958;Herz 1962;Harris et al. 1968). Nicotine-induced antinociception has been suggested to have different mechanisms than cholinergic-induced antinociception, even different mechanisms for the antinociceptive action of nicotine have been indicated (Tripathi et a/. 1982). There is also good evidence that nicotine is involved in activating opioid system(s) (Balfour 1982;Davenport et al. 1990 However, some investigators (Sahley & Berntson 1979) suggested that nicotine antinociception is mediated through the release of acetylcholine, others (Phan et a/. 1973) did not find evidence for antagonism by atropine in mice. The mechanisms of nicotine-induced antinociception are not fully understood. Our previous study showed that nicotine could attenuate naloxone-induced jumping in morphine-dependent mice (Zarrindast & Farzin 1996). In the present investigation, the possible role of cholinergic and opioid receptor mechanisms in nicotine-or morphine-induced antinociception have been studied. Materials and MethodsAnimals. Male Swiss albino mice weighing 20-25 g were used in groups of 10 in a light-controlled room (lights on 7 a m -7 p.m.) constant temperature (21 k2"C) . Animals had free access to food and water except during the experiments. Groups of 7-14 mice were used. The experimental protocol was approved by the Research a...

Using the methyl nicotinate induced vasodilation and histamine ionotophoresis in vivo models for screening anti-inflammatory activity F Liebel, A Wagner, J Idkowiak-Baldys and J Lyga Avon Products, Inc., Suffern, NY Skin erythema can be induced by multiple pathways. To screen actives for broad anti-inflammatory benefits, we used two different induced-inflammation models for evaluation: topical application of methyl nicotinate (MN) and iontophoretic application of histamine. Topical MN induces a rapid vasodilatation of the peripheral blood capillaries of the skin and is mediated by prostaglandin release. While topical histamine penetration is generally poor, iontophoretic application of histamine enhances skin permeability and releases neuropeptides to induce erythema (flare). After a 3 day pretreatment application of the known antiinflammatory Tetrahydrocurcumin (THC), a metabolite of curcumin, both the MN induced erythema and the histamine induced erythema were reduced significantly. These results demonstrate the broad anti-inflammatory activity of THC. 1060JAK inhibitor CTP-543: Modeled exposure-response profile suggests improved therapeutic window K Hogan, V Uttamsingh, C Hamilton, A Aslanian, C Brummel, V Braman, J Cassella and D Wong Concert Pharmaceuticals, Lexington, MA CTP-543, a deuterated analog of ruxolitinib, is a JAK inhibitor (JAKi) that preferentially targets JAK1 and JAK2. The deuterium modification has the potential to improve its PK profile without affecting the intrinsic pharmacology. JAK inhibitors target proinflammatory cytokine pathways (e.g., JAK1/2-coupled IFNg and JAK1/2/TYK2-coupled-IL6) and have shown efficacy in autoimmune disorders (e.g., alopecia areata [AA], RA and atopic dermatitis). JAKs also mediate essential pathways such as lymphocyte development (JAK1/3) and hematopoiesis (JAK2/2). For JAKi, differences in JAK subtype specificity, drug exposure and dosing regimens may be important determinants of clinical benefits and risks. Pharmacology assays, human PK and pharmacodynamic (PD) analyses and PK/PD modeling were used to explore the impact of deuterium substitution on the exposure-response relationship of CTP-543 relative to ruxolitinib. CTP-543 most potently inhibited JAK1/2-coupled cytokine pathways and was 2-10x and 6-30x more selective relative to JAK1/3-and JAK2/2-coupled pathways, respectively. PD analysis confirmed potent inhibition of IFNg and IL6 pathways in humans and correlated with in vitro assays. In humans, CTP-543 had a significantly longer T 1/2 (p< 0.05) relative to ruxolitinib, without a significant increase in C max . PK/PD modeling suggests that CTP-543 is differentiated from ruxolitinib in prolonging the time above IC 50 for JAK1/2 proinflammatory pathways (e.g., IFNg and IL6) without increased inhibition of essential JAK2/ 2 pathways associated with side effects (e.g., GM-CSF, IL3 and EPO). CTP-543 is a JAK1/2 inhibitor with a selective cytokine inhibition profile biased towards proinflammatory cytokines. PK/PD modeling suggests that CTP-543 may provide the...

Papulopustular rash occurs in 80% of patients receiving Epidermal Growth Factor Receptor Inhibitor therapy for cancer. Topical vitamin K1, a phosphatase inhibitor, could reduce epidermal growth factor receptor inhibitor-induced rash. This preliminary safety study evaluated a novel topical 0.1% vitamin K1product for potential use in patients with epidermal growth factor receptor inhibitor-induced rash. Ten healthy subjects applied topical 0.1% vitamin K1 to healthy and tape stripped skin every 12 hours for five doses. Vitamin K1 levels were measured by ELISA in serum and plasma at 0, 26, and 50 hours. Vitamin K1 levels ranged between 0 to 8.22ng/ml. Bivariate correlative analyses showed no association between mean vitamin K1 concentration and time (r=0.008, p=0.930). Using a range of vitamin K1 concentrations (2.5 to 100ng/ml) that encompassed and exceeded the levels detected in our healthy subjects, we evaluated the ability of vitamin K1 to reverse cetixumab-induced Epidermal Growth Factor Receptor inhibition in A549 lung cancer cells. Vitamin K1 did not significantly change phosphorylated-Epidermal Growth Factor Receptor levels in cetuximab-treated cells (p>0.670). In conclusion, systemic vitamin K1 levels up to 100ng/ml would not interfere with epidermal growth factor receptor inhibitor therapy. Our next step is to test the effectiveness of our 0.1% topical VK1 formulation for Epidermal Growth Factor Receptor Inhibitor-induced rash in patients receiving epidermal growth factor receptor inhibitor therapy in a randomized, placebo-controlled, blinded study.