icatibant and Abdominal-Pain

Hereditary angioedema is a rare genetic disorder, manifested by recurrent edema leading to disfigurement, organ dysfunction and life-threatening respiratory impairment that may become fatal. The hallmark of HAE is C1 esterase inhibitor deficiency, but recent evidence points at bradykinin as the main mediator that causes hyperpermeability of small vasculature, leading to accumulation of edema fluid. Current therapeutic options for HAE are limited, and consist of drugs, replacement therapy, and supportive treatment. In view of many disadvantages of the current therapeutic modalities, new approaches to the treatment of HAE are now being offered. This review summarizes our experience with a new line of medications developed for the treatment of acute exacerbations and prophylaxis of HAE--icatibant: bradykinin receptor antagonist, ecallantide: kallikrein inhibitor, and two C1 INH preparations: Berinert-P, human plasma-derived concentrate, and Rhucin: novel recombinant C1-INH produced in transgenic rabbits. Preliminary results of these studies are encouraging and may bring new hope to the patients with this distressing condition. The exact number of HAE patients in Israel is unknown and because patients are treated individually and comprehensive laboratory assessment is partial, many cases might be missed or not treated according to accepted guidelines. We offer a new specialty center for HAE patients, addressing the medical and psychosocial needs of patients and their families.

Topics: Abdominal Pain; Angioedemas, Hereditary; Bradykinin; Bradykinin Receptor Antagonists; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Kallikreins; Male; Multicenter Studies as Topic; Nausea; Peptides; Treatment Outcome

The role of bradykinin (BK) receptors in activating and sensitizing peripheral nociceptors is well known. Recently, we showed that spinal dynorphin was pronociceptive through direct or indirect BK receptor activation. Here, we explored the potential role of BK receptors in pain associated with persistent pancreatitis in rats.. Experimental pancreatitis and abdominal hypersensitivity were induced by intravenous administrations of dibutyltin dichloride (DBTC). [des-Arg-Leu]BK (B1 antagonist) and HOE 140 (B2 antagonist) were given by intraperitoneal or intrathecal injection. Dynorphin antiserum was given intrathecally. Reverse transcription-polymerase chain reaction was used to detect spinal mRNA for BK receptors.. Dibutyltin dichloride-induced pancreatitis upregulated B1 and B2 mRNA in the thoracic dorsal root ganglion and B2, but not B1, in the pancreas. No changes in spinal B1 or B2 mRNA were observed. Intraperitoneal or intrathecal administration of HOE 140 dose dependently abolished DBTC-induced abdominal hypersensitivity, whereas [des-Arg-Leu]BK was without effect by either route of administration. Antiserum to dynorphin (intrathecal) abolished DBTC-induced hypersensitivity.. These results suggest that blockade of peripheral or spinal BK B2 receptors may be an effective approach for diminishing pain associated with pancreatitis. Moreover, it is suggested that spinal dynorphin may maintain pancreatitis pain through direct or indirect activation of BK B2 receptors in the spinal cord.

Topics: Abdominal Pain; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Dynorphins; Ganglia, Spinal; Gene Expression; Immune Sera; Injections, Intraperitoneal; Injections, Intravenous; Injections, Spinal; Male; Organotin Compounds; Pain; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord

This work investigated the role of bradykinin in viscerosensitivity before and during inflammation in two models of visceral pain induced by rectal distension (RD) or "abdominal distension" (AD) in rats. RD induced both inhibition of colonic motility and an increase of abdominal spike bursts. Bradykinin receptor antagonist, Hoe 140 did not affect any of the RD-induced responses. After TNB-induced rectal inflammation, colonic inhibition and the number of abdominal contractions were enhanced. Hoe 140 selectively reduced the abdominal response to the highest distension volume, without affecting the colonic response. In AD group, acetic acid inhibited gastric emptying and increased the number of abdominal contractions, whereas the same volume of saline did not affect any of the responses. Before inflammation, Hoe 140 (1-5 mg/kg, intraperitoneally) did not affect per se abdominal and gastric emptying responses; in contrast, at 5 mg/kg, intraperitoneally, it reduced significantly (P < 0.05) both acetic acid-induced responses. We conclude that bradykinin is involved in viscerosensitivity changes related to abdominal and rectal distension in inflammatory conditions.

Topics: Abdominal Pain; Acetates; Acetic Acid; Animals; Bradykinin; Bradykinin Receptor Antagonists; Colon; Gastrointestinal Motility; Male; Peritonitis; Proctitis; Rats; Rats, Wistar; Receptors, Bradykinin; Trinitrobenzenesulfonic Acid