Hemokinin-1, a legújabb tachykinin idegi és immun mediátor szerepe fájdalom, ízületi gyulladás és bőrgyulladás egérmodelljeiben

Pain is one of the most common complaints for people seeking medical help(1). While in most cases the underlying problem can be resolved, about 10-20% of pain becomes chronic(2). The currently used main groups of analgesic drugs (nonsteroidal anti-inflammatory drugs: NSAIDs, opioids and adjuvant analgesics) are not effective in every case, and long-term administration can lead to a variety of side-effects(3). Many forms of chronic pain begin with (autoimmune) inflammation; and damage to the nervous system potentially resulting in chronic pain can lead to local inflammation as well(4, 5). Nociceptors transmit the pain stimulus from the periphery to the spinal dorsal horn, where descending pathways from the brain modulate the sensation. Sensitization of nociceptors in pathological conditions can occur through both peripheral and central mechanisms. A subtype of the nociceptors is the capsaicin sensitive nerve ending which expresses the Transient Receptor Potential Vanilloid-1 (TRPV1) ion channel on its surface(6). These have a local efferent function called neurogenic inflammation when inflammatory neuropeptides are released from the nerve endings(7). Crosstalk between the nervous- and immune systems is substantial, as nociceptors release neuropeptides that regulate immune cells(8); microglia as well as other immune cells influence the developing brain(9), and lymphatic vessels have been discovered in the meninges(10, 11). Exploring these interactions and the molecules playing a role in them could advance treatment of painful pathological conditions

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1-C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a Hungarian nationwide observational study

<p>Abstract</p> <p>Background</p> <p>Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary.</p> <p>Methods</p> <p>During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy.</p> <p>Results</p> <p>Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%).</p> <p>Conclusion</p> <p>IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy.</p

Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms.

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after sciatic nerve ligation were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any alterations. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of WT, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research

Fiatalkori penisthrombosis | PENILE VEIN THROMBOSIS AT YOUNG AGE

BEVEZETÉS – A Mondor-betegség ritka megbetegedés, klasszikus formáját fôként középkorú nôknél látjuk, és a felületes mellkasi, illetve epigastrialis vénák thrombophlebitise jellemzi. Kivételes esetben atípusos lokalizációban, a felkaron, a hasfalon, a lágyékban és a penisen is kialakulhat. ESETISMERTETÉS – A hazai irodalomban elsôként a szerzôk egy fiatal férfi betegük esetét ismertetik, akinél a panaszok hátterében a fizikális vizsgálat és a Doppler-ultrahangvizsgálat penisthrombosist igazolt. Etiológiai faktorként az elvégzett familiaris thrombophiliavizsgálatok érdemi kóros eredményt nem mutattak, malignitás kizárható volt. Kiváltó okként lokális trauma, valamint korábbi hasi mûtét okozta vénás pangás szerepét feltételezték. KÖVETKEZTETÉS – A szerzôk az irodalmi adatok áttekintését követôen a thrombosis e ritka formájára, rizikófaktoraira, valamint a terápia nehézségére hívják fel a figyelmet. | INTRODUCTION – Mondor’s disease is an uncommon disorder occuring mostly in middleaged women and characterized by superficial thrombophlebitis classically involving the thoraco- epigastric veins. Rarely, cases have been reported in atypical sites (upper arms, abdomen, groin and penis). CASE REPORT – This is the first case being published in the Hungarian literature. The young male patient's complaints were caused by penile vein thrombosis which was demonstrated on physical examination and Doppler ultrasonography. Since hereditary thrombophilia and malignancy has been ruled out, we assume that local trauma and venous stasis caused by previous abdominal surgery have been the etiological factors of the disease. CONCLUSION – We give a review of the literature and would like to draw the attention to this rare type of thrombosis, its risk factors and the difficulties of the therapy