Icatibant: HOE 140, JE 049, JE049

Icatibant [HOE 140, JE 049] is a potent, specific and selective peptidomimetic bradykinin beta2-receptor antagonist. It has a modified peptide structure, and is the first bradykinin receptor antagonist to act on the guinea-pig trachea without demonstrating agonist effects. Icatibant was originated by Hoechst Marion Roussel (now Sanofi-Aventis). Jerini is seeking a partner for development and marketing of icatibant for the treatment of refractory ascites in liver cirrhosis, angioedema and burns. In August 2004, Aventis merged with Sanofi-Synthelabo to form Sanofi-Aventis.Icatibant has shown an excellent safety profile in phase I studies. In December 2003, Jerini demonstrated positive results in the phase IIa study. Results obtained were statistically significant and clinically relevant. At the BIO 2004 International Annual Convention (BIO-2004) [San Francisco, CA, USA; 6-9 June 2004], Jerini reported plans to initiate phase IIb trials in this indication in the second half of 2004. Positive results from an icatibant formulation comparative study, in patients with acute attacks of hereditary angioedema, were announced in August 2004; IV and SC formulations showed no difference in efficacy and safety. It was announced in September 2004 by Jerini that a pivotal study, known as For Angioedema Subcutaneous Treatment (FAST) 1, had been initiated in the US and Canada. The protocol of a European study, to be known as FAST 2, is to be submitted to the authorities in September 2004. Jerini expects to launch the product in 2006. The US FDA granted icatibant, for the treatment of hereditary angioedema, fast-track designation in July 2004. In January 2003, the European Agency for the Evaluation of Medicinal Products granted icatibant orphan drug status in Europe for the treatment of angioedema. In November 2003, Jerini announced that effective December 2003, icatibant had orphan drug status in the US for the same indication.     

Therapeutic potential of icatibant (HOE-140, JE-049)

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.     

Therapeutic potential of icatibant (HOE-140, JE-049)

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.     

Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis.

1. The novel bradykinin antagonist, HOE 140, completely blocked the fall in rabbit blood pressure caused, not only by i.v. bradykinin, but also by i.v. kallikrein. This shows that both the effects of exogenously administered bradykinin and those of endogenously released kinins are antagonized by HOE 140. 2. Acute pancreatitis was induced in rats by i.v. infusion of the cholecystokinin analogue, caerulein. This treatment resulted in massive oedema of the pancreas, increased activities of amylase and lipase in serum and a characteristic, biphasic fall in blood pressure. 3. HOE 140 prevented the caerulein-induced pancreatic oedema and the second phase of hypotension whereas NPC 349, a widely used, but short-acting, bradykinin antagonist did not show a significant inhibition. HOE 140, in contrast to its inhibitory effects on caerulein-induced pancreatic oedema and hypotension, significantly augmented the increases in amylase and lipase activities in serum. 4. It is concluded that in this model of acute pancreatitis, the release of kinins induces pancreatic oedema and hypotension. Prevention by HOE 140 of the kinin-induced oedema allows the pancreatic enzymes to leave the tissue without hindrance and thus will diminish subsequent pathological events. It is suggested that the results obtained with the highly potent and long-acting bradykinin antagonist, HOE 140, provide a pharmacological basis for a clinical trial in acute pancreatitis.     

HOE 140, a new highly potent and long-acting bradykinin antagonist in conscious rats.

The inhibitory effects of the new bradykinin antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) on depressor responses to exogenous bradykinin were investigated in conscious rats and compared with those of the bradykinin antagonist B4146 (D-Arg-Hyp-Pro-Gly-Thi-Ser-D-Pro-Thi-Arg). HOE 140 showed a 250-700-fold higher potency in vivo and a much longer biological half-life than B4146. Plasma catecholamines were not increased after application of HOE 140, indicating that this compound did not interfere with catecholamine release. HOE 140 proved to be a highly potent, specific and long-acting bradykinin B2-receptor antagonist.     

Bradykinin B2 antagonist HOE 140 inhibits late allergic microvascular leakage in guinea pig airways

Because bradykinin has potent inflammatory actions, this molecule may be involved in the late allergic response (LAR). We investigated the role of the molecule in airway microvascular hyperpermeability during the LAR. Three weeks after ovalbumin (OVA) sensitization, animals were pretreated with bradykinin B2 receptor antagonist HOE 140 or vehicle for 30 min before the OVA inhalation challenge. The occurrence of LAR was judged by a two-fold increase in transpulmonary pressure (Ptp) from the baseline values. The microvascular permeability in the trachea was assessed by an index defined as the ratio of the area of vasculature labeled by the Monastral blue dye (area density percent). Significant microvascular hyperpermeability were observed during the LAR. The bradykinin concentrations in the bronchoalveolar lavage-fluid (BAL-f) were increased during the LAR. HOE 140 (0.1-10 mg/kg, s.c.) inhibited the airway microvascular hyperpermeability during the LAR dose-dependently. These findings suggest that bradykinin may play an important role in microvascular hyperpermeability during the LAR.     

A specific B2-bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril.

To evaluate the role of bradykinin in the antihypertrophic effect of the angiotensin-converting enzyme (ACE) inhibitor, ramipril, we investigated the influence of HOE 140, a specific B2-receptor antagonist, on the effects of ramipril on left ventricular hypertrophy (LVH) in rats with aortic banding. Ramipril at a dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and development of LVH after aortic banding; plasma ACE activity was significantly inhibited. A lower dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but prevented LVH after aortic banding. The antihypertrophic effects of the higher and the lower dose ramipril, as well as the antihypertensive action of the higher dose of ramipril were abolished by the coadministration of HOE 140 (500 micrograms kg-1 day-1). The present data show for the first time that the beneficial effects of an ACE-inhibitor on LVH in rats with hypertension caused by aortic banding can be prevented by a specific B2-receptor antagonist.     

选择性缓激肽B2受体拮抗剂——Icatibant

Icafibant（JE-049）为一新型选择性强效肽类缓激肽B2受体拮抗剂，是合成的十肽化合物，对缓激肽受体具有基本上与缓激肽一样的亲和力，其体内给药后具有良好的稳定性。Jerini公司于2001年从Aventis Pharma（Sanofi—Aventis）公司获得icatibant的全球开发权。目前，本品用于治疗严重烧伤病人水肿的研究已进入Ⅰ期临床试验，用于治疗肝硬化顽固性腹水（RAIL）的研究已进入Ⅱ期临床试验，而用于口服治疗遗传性血管水肿（HAE）的研究已进入Ⅲ期临床试验。     

Analysis of the antagonistic actions of HOE 140 and other novel bradykinin analogues on the guinea-pig ileum.

The type of antagonism exhibited by three novel bradykinin (BK) antagonists, D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]BK (HOE 140, compound I), D-Arg-[Hyp3,D-Tic7,Oic8]BK (compound II) and [Arg(Tos)1,Hyp3,Thi5,D-Tic7,Oic8]BK (compound III), was compared with that of a conventional antagonist, D-Arg-[Hyp2,Thi5,8,D-Phe7]BK (compound IV), on the guinea-pig ileum. The novel compounds induced rightward displacements of cumulative concentration-response curves to BK, accompanied by a progressive reduction of the maximum effect (Emax) without a significant decrease in the slope, whereas no reduction of Emax was observed with compound IV. Actions of substance P on the guinea-pig ileum and of vasopressin on the rat uterus remained completely unaffected. It is concluded that as the novel BK analogues show competitive as well as non-competitive inhibition in the guinea-pig ileum, but the inhibition is reversible and specific, they are dual antagonists.     

治疗遗传性血管性水肿新药艾替班特概述

艾替班特和缓激肽结构类似,与其竞争性地结合缓激肽B2受体,具有良好的药动学特性,对急性发作期遗传性血管性水肿（HAE）的患者疗效佳.同时在发病的第一时间内,患者可以安全地自我治疗.目前的文献报道提示,艾替班特治疗获得性血管性水肿（AAE）的效果与治疗HAE一样安全、有效,或许将来艾替班特也可用于AAE的治疗.     

Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Qic8]bradykinin).

HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a new B2 antagonist, was compared to R-493 (D-Arg[Hyp3-D-Phe7,Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36-9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykinin, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive even at low concentrations (7.7 x 10(-9) M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.     

EFFECTS OF HOE 140 ON SYSTEMIC DEPRESSOR RESPONSES TO BRADYKININ AND MESENTERIC VASCULAR REACTIVITY IN VIVO IN PREGNANT WISTAR-KYOTO RATS

1. To examine possible changes in vascular reactivity to exogenous bradykinin (BK) and the possible role of endogenous BK in reduced mesenteric vascular reactivity in pregnant rats. The authors studied the effects of Hoe 140 on systemic depressor responses to BK and on mesenteric vascular reactivity in in situ blood-perfused mesenteric resistance vessels of 18–20 day pregnant and age-matched non-pregnant Wistar-Kyoto rats (WKY). 2. Mean intra-arterial blood pressure (MBP) of pregnant rats was lower than non-pregnant controls. Basal mesenteric perfusion pressure (BPP) was slightly, but not significantly, reduced in the pregnant group. Neither MBP nor BPP was significantly influenced by Hoe 140 (1 mg/kg. s.c.) 3. Systemic depressor responses to BK (1–30 μg/kg, i.v.) were significantly increased in pregnant rats at 1 and 3 μg/kg. Hoe 140 completely abolished systemic depressor responses to BK in either pregnant or non-pregnant animals. 4. Mesenteric vascular responses to regional administration of noradrenaline, electrical stimulation of sympathetic nerve and angiotensin II were overall decreased in pregnant compared with non-pregnant groups, but those responses were not significantly affected by Hoe 140 in either groups. 5. The results suggested that although systemic depressor responses to exogenous BK were increased, endogenous BK does not contribute to decreased mesenteric vascular reactivity in vivo in pregnant WKY.     

Bradykinin receptors in the guinea-pig taenia caeci are similar to proposed BK3 receptors in the guinea-pig trachea, and are blocked by HOE 140.

1. Bradykinin (BK) receptors of the guinea-pig taenia caeci were compared with those of the guinea-pig trachea, a preparation proposed to possess novel BK3 receptors. 2. Bradykinin-evoked contractile responses were unaffected in both preparations by the selective BK1 receptor antagonist [des-Arg9,Leu8]-BK (1 microM-10 microM). The BK2 receptor antagonists, D-Arg-[Hyp3,D-Phe7]-BK and D-Arg-[Hyp3,Thi5,8,D-Phe7]-BK, both had low affinities (apparent pKB estimates less than 6) which did not differ significantly between the two preparations (P greater than 0.05). In contrast, the novel bradykinin receptor antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (HOE 140) potently antagonized responses to bradykinin with relatively high affinity (apparent pKB = 8.42 +/- 0.15 and 8.94 +/- 0.16 in the taenia caeci, and trachea, respectively). 3. We conclude that the bradykinin receptors in the guinea-pig taenia caeci have similar recognition properties to those present in the guinea-pig trachea, and in this respect the taenia caeci represents a useful preparation for the further study of proposed novel BK3 receptors.     

Nomifensine,clobazam and HOE 8476: Effects on aspects of psychomotor performance and cognitive ability

Summary The effects of a combination of nomifensine and clobazam (HOE 8476) were compared, on a variety of psychometric measures, with those of its separate monosubstances in a placebo controlled double-blind study with twelve normal volunteers. Assessments comprised a range of psychomotor performance tests, measures of cognitive processing ability and visual analogue rating scales — previously shown to be sensitive to the effects of psychotropic drugs. Subjects acted as their own control and were tested in the morning and afternoon following subchronic pre-dosing with each of the four treatments. When compared with placebo, nomifensine showed no significant change on any of the performance measures. HOE 8476 produced no significant changes in performance but significantly reduced self-rated anxiety. Clobazam significantly improved subjective ratings of the ease of getting to sleep and impaired choice reaction time and concept identification performance in the morning. No significant changes in the test measures were found in the afternoon following any treatment. The findings were in broad agreement with those of previous studies and demonstrated that clobazam and nomifensine, both alone and in combination, tended not to impair performance on a wide range of psychological test assessments.     

Icatibant. Attacks of hereditary angioedema: continue to use C1 esterase inhibitor

Hereditary angioedema is a severe genetic disorder due to C1 esterase inhibitor deficiency, which leads to an excess of bradykinin. It is characterised by attacks of subcutaneous or mucosal oedema, which can carry a risk of asphyxiation if the larynx is involved. The first-choice symptomatic treatment for attacks is intravenous C1 esterase inhibitor administration. Tranexamic acid is sometimes used. Icatibant, a decapeptide bradykinin B2 receptor antagonist, is now authorised in the European Union for use in this situation. We found no trials comparing icatibant versus C1 esterase inhibitor. The two principal clinical trials were both comparative trials, one versus tranexamic acid (74 patients), and the other versus placebo (56 patients). No mortality data were reported in either trial. Icatibant seemed to be more effective than tranexamic acid in relieving symptoms and also yielded a higher response rate. However, these positive results were not confirmed in the placebo-controlled trial. Both trials suffer from several biases, ruling out firm conclusions on the efficacy of icatibant, the trials were underpowered, some criteria were difficult to measure, the blinding was incomplete, and tranexamic acid was given at a lower dose than that recommended. The main adverse effects of icatibant are reactions at the injection site, which occur in almost all patients. A potential risk of cardiac disorders (especially angina) needs to be investigated. Subcutaneous administration of icatibant requires a large volume of solution (3 ml). In practice, in the absence of head-to-head comparisons, it remains to be shown whether or not icatibant has a better risk-benefit balance than C1 esterase inhibitor. Due to inconsistencies between the results and numerous biases in the two main clinical trials, the evidence supporting the efficacy of icatibant is weak. C1 esterase inhibitor remains the first-choice treatment for patients with acute attacks of hereditary angioedema.     

Icatibant,the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

Introduction: HOE-140/Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency.

Areas covered: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin–receptor interactions.

Expert opinion: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.     

Preliminary experiences with HOE 498, a novel long-acting converting enzyme inhibitor, in hypertensive patients

The effect of various doses of the new angiotensin-converting enzyme inhibitor HOE 498 was compared with that of placebo in patients with mild essential hypertension. When a single dose of 2.5 mg of the drug was given, blood pressure was not significantly reduced despite a fall in converting enzyme levels. Single doses of 5 or 10 mg did reduce blood pressure, but complete inhibition of converting enzyme was apparent only with the 10-mg dose. Acute administration of a 20-mg dose proved to be unsuitable, since this was associated with too large a fall in pressure and the occurrence of symptomatic orthostatic hypotension. Although converting enzyme and blood pressure tended to recover in part 12 h after administration of the drug, both variables remained low even after 48 h.     

Antiviral activity and pharmacokinetics of HOE 602, an acyclic nucleoside, in animal models

The acyclic nucleoside derivative HOE 602 (2-amino-9-[1,3-bis(isopropoxy)-2-propoxymethyl]purine) was evaluated for its antiviral activity in cell culture and for its therapeutic efficacy in mice infected with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) or with murine cytomegalovirus (MCMV). HOE 602 was inactive in vitro against a variety of DNA- and RNA-viruses. However it prevented symptoms and mortality in mice systemically infected with HSV-1, HSV-2 or MCMV when administered intraperitoneally or orally at a dosage of 100 mumol/kg twice per day. Pharmacokinetic studies in mice and macaques revealed that HOE 602 was converted via three metabolic steps to ganciclovir, which seemed to be the antivirally active compound. The bioavailability of ganciclovir after oral administration of HOE 602 or ganciclovir was similar in mice, while in rhesus monkeys much higher serum levels of ganciclovir were reached with HOE 602. After intraperitoneal or intravenous administration higher drug levels were obtained with ganciclovir. The excellent therapeutic efficacy in animal models, the high enteral absorption in monkeys, and the favourable physical properties will hopefully lead to an orally active drug against cytomegalovirus and severe herpes infections in man.