WO2015155323A1 - Br2 antagonist for use in the prevention of the hypotensive effect of patient treated with angiotensin-converting enzyme inhibitors (acei) - Google Patents

Abstract

The present invention relates to a method of preventing and/or treating the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEl) in a patient treated with ACEl, said patient being under a critical condition. More specifically, it concerns the use of a Bradykinin 2 receptor (BR2) antagonist for the prevention and treatment of the hypotensive effect of ACEl in a patient treated with ACEl undergoing emergency anaesthesia or shock resuscitation like hypovolemic shock (i.e. hemorrhagic shock (HS), or vasoplegic shock (i.e. septic shock).

Description

BR2 ANTAGONIST FOR USE IN THE PREVENTION OF THE HYPOTENSIVE EFFECT OF PATIENT TREATED WITH ANGIOTENSIN-CONVERTING ENZYME

INHIBITORS (ACEI)

RELATED APPLICATION

The present application claims priority to European Patent Application No. EP EP14305523.4, which was filed on April 10, 2014. The European patent application is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION:

The present invention relates to a method of preventing and/or treating the hypotensive effect of angiotensin- converting enzyme inhibitors (ACEI) in a patient treated with ACEI, said patient being under a critical condition. More specifically, it concerns the use of a Bradykinin 2 receptor (BR2) antagonist, for the prevention and treatment of the hypotensive effect of ACEI in a patient treated with ACEI undergoing emergency anaesthesia and/or hypovolemic (i.e. hemorrhagic) or vasoplegic (i.e. septic) shocks resuscitation.

BACKGROUND OF THE INVENTION:

Angiotensin-converting enzyme inhibitors (ACEi) are among the most frequently used therapeutic classes for the treatment of hypertension, chronic heart and chronic kidney diseases (1,2). However, ACEi are also responsible for severe hypotension during anesthesia (3). According to recent data, this perioperative hypotensive effect seems to be associated with increased renal failure and mortality (4).

Accordingly, there is a need for a new therapeutic strategy that inhibits hypotensive effect of ACEi, for patients treated with ACEi under a critical condition, particularly in case of emergency anaesthesia and/or hypovolemic (i.e. hemorrhagic) or vasoplegic (i.e. septic) shocks resuscitation.

Angiotensin-converting enzyme (ACE) not only catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) but is also responsible for bradykinin (BK) degradation. BK is a potent vasodilator (5,6), thus, the pharmacological effects of ACEi are in part mediated through the increase in BK bioavailability in addition to the reduction of Ang II formation (7). There are 2 BK receptor subtypes, Bl and B2 (B1R and B2R, respectively). Miscellaneous biologicals effects of BK are related to the activation of the B2R (8) which leads, among others, to the formation of NO (9) and vasodilator prostaglandins (10).

HOE- 140 (icatibant) is a specific and high affinity B2R antagonist blocking, with high potency, numerous B2-mediated effects (11,12). Icatibant is actually indicated for the treatment of acute attacks of hereditary angioedema in adult. But icatibant has been also previously studied in others situations. Icatibant attenuates hypotensive effect of ACEi in chronic hypertensive animal models (13-16) and inhibits BK-induced vasodilatation in a dose-dependent manner in human vascular beds in vivo (17). Icatibant exhibits a prolonged inhibitor effect: its half-life protective effect against BK-induced hypotension in rats is around 5 hours (11, 15).

Nevertheless, the ability of a B2R antagonist to rapidly and significantly inhibit chronic hypotensive effect of ACEi during critical condition, such as anesthesia or hemorrhagic shock is unknown and was unpredictable. This effect could be of great interest in ACEi treated patients during either emergency anesthesia or resuscitation. The original purpose of this invention was to study the impact of acute B2R blockade using B2R antagonist (i.e) icatibant during hemorrhagic shock (HS) in ACEi treated mice.

SUMMARY OF THE INVENTION:

By using murine models treated with ACEi, the inventors showed that B2R blockade efficiently and rapidly inhibited hypotensive effect of ACEi during hemorrhagic shock (HS). Thus, blocking B2R constitutes a new therapeutic approach for preventing the hypotensive effect of ACEi in patients under critical conditions and allows restoring rapidly (15 minutes) a normal arterial blood pressure.

The present invention provides antagonists of B2R, for a novel use in the prevention and treatment of the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition.

DETAILED DESCRIPTION OF THE INVENTION:

In a first aspect the invention provides an antagonist of the Bradykinin 2 receptor (B2R), for use in the prevention or treatment of the hypotensive effect of angiotensin- converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition.

In an embodiment, the critical condition is selected from emergency anaesthesia or shock resuscitation. In a specific embodiment, shock resuscitation is selected from the group consisting of: hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks.

In a preferred embodiment the critical condition is hemorrhagic shock or septic shock.

In still another embodiment, the antagonist of BR2 according to the invention binds to the Bradykinin 2 receptor, thereby blocking the binding of Bradykinin on B2R. To identify an antagonist able to block the interaction between Bradykinin and B2R, it may be used a test based on the effect of the B2R antagonist candidate on the induction of vasoconstriction or increasing arterial blood pressure as explained in the examples (figure 1). See also test described in Barbe F, et al .. Am. J. Physiol. 1996 Jun;270(6 Pt 2):H1985-1992 or in ref. 14, 15, 16.

Typically, a B2R antagonist according to the invention includes but is not limited to: i. NPC-349, HOE140, CP-0127, B9430, B9870 (peptide BR2 antagonists); ii. FR173657, LF 16-0687, Bradyzyde, MEN16132, BKM-570 (non peptide BR2 antagonists); and derived compounds.

In another aspect the invention provides a pharmaceutical composition, comprising an antagonist of B2R, for use in the prevention of the hypotensive effect of ACEIs, in a patient treated with an ACEI, said patient is under critical conditions. Definitions:

Throughout the specification, several terms are employed and are defined in the following paragraphs.

The term "bradykinin" has its general meaning in the art and refers to kinin bradykinin and lysil-bradykinin. Kinin, bradykinin and lysil-bradykinin refer to endogenous nona- and deca-peptide that are generated by cleavage of the precursor polypeptide (kininogen) by specific proteases (kallikreins) within numerous tissues of the body (Regoli, D. and Barabe, J. Pharmacol. Rev., 1980, 32, 1-46; Hall, J. M., Pharmacol. Ther., 1992, 56, 131-190; Leeb- Lundberg et al, Pharmacol. Rev. 2005, 57: 27-77). Certain enzymes of the kininase family degrade bradykinin and related peptides and thus inactivate these peptides. Kinins exert their actions through two different G protein-coupled seven transmembrane domains receptors, called Bl and B2. The term "B2-receptor" has its general meaning in the art and refers to kinin receptor type B2 or bradykinin receptor type B2 such as the B2-receptor expressed in endothelial cell. B2-receptor is a G protein-coupled receptor (GPCR)

A "receptor" or "receptor molecule" is a soluble or membrane bound/associated protein or glycoprotein comprising one or more domains to which a ligand binds to form a receptor-ligand complex. By binding the ligand, which may be an agonist or an antagonist the receptor is activated or inactivated and may initiate or block pathway signaling.

By "ligand" or "receptor ligand" is meant a natural or synthetic compound which binds a receptor molecule to form a receptor-ligand complex. The term ligand includes agonists, antagonists, and compounds with partial agonist/antagonist action.

An "agonist" or "receptor agonist" is a natural or synthetic compound which binds the receptor to form a receptor-agonist complex by activating said receptor and receptor-agonist complex, respectively, initiating a pathway signaling and further biological processes.

By "antagonist" or "receptor antagonist" is meant a natural or synthetic compound that has a biological effect opposite to that of an agonist. An antagonist binds the receptor and blocks the action of a receptor agonist by competing with the agonist for receptor. An antagonist is defined by its ability to block the actions of an agonist or/and any biological consequences of receptor activation.

The term "B2-receptor antagonist" or "bradykinin B2 receptor antagonis 'or "B2R antagonsit" has its general meaning in the art and refers to a compound that selectively blocks the action of a B2 receptor agonist (kinin bradykinin and lysil-bradykinin). As used herein, the term "selectively blocks" refers to a compound that preferentially binds to (and inactivates B2-receptor) with a greater affinity and potency, respectively, than its interaction with the other sub-types or iso forms of the bradykinin receptor family (Bl -receptor). Compounds that prefer B2-receptor, but that may also block other bradykinin receptor sub-types, as partial or full antagonists, and thus that may block multiple bradykinin receptor activities, are contemplated. Typically, a B2-receptor antagonist is a small organic molecule a peptide (or a peptide analog) or a chemical entity.

"B2R antagonist" refers to any B2R antagonist that is currently known in the art or that will be identified in the future, and includes any chemical entity that, upon administration to a patient, results in inhibition of a biological activity associated with activation of the B2R in the patient (in particularly vasoconstriction and inhibition of the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEI) as shown in the example), including any of the downstream biological effects otherwise resulting from the binding to B2R of its natural ligand. Such B2R antagonist include any agent (peptide, chemical entity (peptidic analog), ...) that may block B2R activation or any of the downstream biological effects of B2R activation.

In one embodiment of the invention, the compound which is a B2-receptor antagonist may be a peptide, such as NPC-349, HOE 140 (Icatibant/Ficazir), CP-0127 Bradicior/Deltibant), B9340, B9430 or B9870 (CU201/Breceptin), which are lead peptide B2R antagonists. Such peptides and derived compounds are described, for example, in: US5935932 (NPC349), EP0413277, EP04551133, US5648333 (HOE140), WO9217201, US5416191 (CP0127), WO9616081 (B9340, B9430), US5849863 WO9709347 (B9870).

A B2-receptor antagonist also includes peptide mimetics, metabolically and/or conformationally stabilized peptide analogs, derivatives, and pseudo-peptides with one or more non-peptide bonds, especially containing D-amino acids and/or at least one non-peptide bond. Bradykinin and related peptides, and other peptides, mimetics and/or metabolically and/or conformationally stabilized peptide analogs and/or derivatives or pseudopeptides with one or more non-peptide bonds, especially containing D-amino acids and/or at least one non- peptide bond, of the invention are useful in the prevention or treatment of the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEI) in a patient treated with an ACEI. In one embodiment, the B2-receptor antagonist may be a small chemical entity such as the following compounds: FR173657, LF16-0687 (Anatibant), Bradyzyde, MEN16132 (Fastibant), BKM-570 and derived compounds described, for example, in. EP 06223618 (FR173657) W09824783, EP0944618 (LF16-0687) Burgess GM et al (Br J Paharmacol 2000; 129: 77-86) and Dziadulewicz EK et al (J Med Chem. 2000 Mar 9;43(5):769-71) (for Bradyzyde) W02006040004 W02003103671 (MEN16132), Gera L, et al. In. Peptides 2000 (Proceedings of the 26th European Peptide Symposium); Montpellier, EDK, Paris; 2001. pages 637-8 Martinez J, Fehrentz J-A, editors. (BKM-570)

Examples of B2R antagonists include but are not limited to any of the B2R antagonists described in Whalley E.T. et al. (Exp Opin. Drug Discov. 2012 7(12) page 1129-1148) in Dziadulewicz EK (Exp Opin. Ther. Patents. 2005 15(7) page 829-589) in Fincham CI et al (Exp Opin. Ther. Patents. 2009 19(7) page 919-941) all of which are herein incorporated by reference. As used herein, the term "patient" denotes a mammal, such as a rodent, a feline, a canine, and a primate. Preferably a subject according to the invention is a human.

In the context of the present invention, the term "under critical condition" means the situation where the patient has hypotension during any medical or surgical emergencies such as emergency anaesthesia or shock resuscitation like hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks, (see Weil MH, Henning RJ. New concepts in the diagnosis and fluid treatment of circulatory shock. Thirteenth annual Becton, Dickinson and Company Oscar Schwidetsky Memorial Lecture. Anesth Analg. 1979 Mar-Apr;58(2):124-32).

In a preferred embodiment the critical condition is hemorrhagic shock and septic shock.

As used herein, the term "ACEi" or "angiotensin-converting enzyme inhibitors" means a pharmaceutical drug used primarily for the treatment of hypertension and congestive heart failure. This group of drugs causes dilatation of blood vessels, which results in lower blood pressure. ACE inhibitors inhibit angiotensin-converting enzyme (a component of the blood pressure-regulating renin-angiotensin system), thereby decreasing the tension of blood vessels and blood volume, thus lowering blood pressure. Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril.

Therapeutic methods and uses

The present invention provides for methods and compositions for use in the treatment and prevention of the hypotensive effect of ACEIs, in a patient treated with an ACEI, said patient being under a critical condition.

Inventor's work demonstrate, as shown in the Examples 1 2 and 3, the ability of B2R antagonist to rapidly suppress, with a single dose, the hypotensive effect of ACEi during critical conditions, such as anaesthesia or shock but also allows to i) have a protective affect again organ failure by preventing the increased in plasma lactate acid, a prognostic marker of morbidity and mortality during shock (19); ii/ improves tolerance to blood volume depletion and as a consequence reduces total fluid volume requirement during resuscitation.

Thus, an object of the invention is a B2R antagonist for use in the prevention of the hypotensive effect of ACEIs, in a patient treated with an ACEI, said patient is under a critical condition.

In an embodiment, the critical condition is selected from emergency anaesthesia or shock resuscitation. In a specific embodiment, shock resuscitation is selected from the group consisting of: hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks.

In a preferred embodiment the critical condition is hemorrhagic shock or septic shock. B2R antagonists according to the invention include but are not limited to: i. NPC-349, HOE140, CP-0127, B9430, B9870 (peptide BR2 antagonists); ii. FR173657, LF 16-0687, Bradyzyde, MEN16132, BKM-570 (non peptide BR2 antagonists); and derived compounds.

In first embodiment, the B2R antagonist is a peptide (or a modified peptide).

Peptide B2R antagonists that may be used in the invention include NPC-349, HOE 140 (Icatibant/Ficazir), CP-0127 (Bradicior™/Deltibant), B9340, B9430 and B9870 (CU201/Breceptin), which are lead peptide B2R antagonists. Such peptides and derived compounds are described, for example, in: US5935932 (NPC349), EP0413277, EP04551 133, US5648333 (HOE140), WO9217201, US5416191 (CP0127), WO9616081 (B9340, B9430), US5849863, WO9709347 (B9870).

A specific example of a peptide B2R antagonist that may be used according to the present invention is NPC-349 (DPhe⁷-BK substituted with P-(2-thienyl)-alanine with incorporation of an N-terminal D-arginine and 4-hydroxproline at position 3) the 'first- generation' B2R peptide antagonist. NPC-349 and derived compound are disclosed in Patent US5935932). NPC-349 has the following sequence:

(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Phe-Thi-Arg (SEQ ID N°l) Another specific example of a peptide B2R antagonist that may be used according to the present invention is HOE 140 (Icatibant / Firazyr®) Shire Pharmaceuticals) a 'second- generation' B2R peptide antagonist that successfully incorporated rigidity, stability, enhanced binding and potency and lacked partial agonist activity. In this molecule, DPhe⁷ was replaced by the conformationally constrained analog tetrahydroisoquinoline-3-carboxylic acid (DTic) and Thi⁸ by octahyroindole-2-carboxylic acid (Oic) (DArg-[Hyp³,Thi⁵,DTic⁷,Oic⁸]-BK). DTic and Oic are tertiary amides similar to proline and hydroxyproline but are resistant to endo- and exopeptidase activity and this, along with DArg at the amino terminus gave these molecules extreme stability. HOE 140 displays an impressive pharmacodynamic (PD) and pharmacokinetic (PK) profile in a vast array of in vitro and in vivo studies, including humans demonstrating high potency, stability and duration of action in most standard mammalian assay systems. HOE140 and derived compound are disclosed in patent applications EP0413277, EP04551133, US5648333. HOE140 has the following sequence:

(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Oic-Arg (SEQ ID N°2)

Another specific example of a peptide B2R antagonist that may be used according to the present invention is CP-0127 (Bradicior™/Deltibant by Cortech Inc.,), the homodimer of DArg°-[Hyp³,Thi⁵,Cys⁶,DPhe⁷,Leu⁸]-BK linked together through Cys⁶ by bis- succinimidohexane (BSH). CP-0127 had moderate potency in several assays, improved stability and efficacy in several in vivo models of trauma (Cheronis JC, et al. J Med Chem 1992;35: pages 1563-72). CP-0127 and derived compound are disclosed in Patent applications WO9217201, US5416191). CP-0127 has the following sequence:

(D)Arg-Arg-Pro-Hyp-Gly-Phe-Cys-(D)Phe-Leu-Arg (SEQ ID N°3)

|BSH

(D)Arg-Arg-Pro-Hyp-Gly-Phe-Cys-(D)Phe-Leu-Arg (SEQ ID N°3)

Another specific example of a peptidic B2R antagonist that may be used according to the present invention is B9430. B9430 (and its derivatives like B9340) comprises a-(2- indanyl)glycine (Igl) at positions 5 and 7 (Gera L, Stewart JM. Immunopharmacology 1996;33: pagesl74-7). B9430 and derived compounds which showed high potency on both BIR and B2R over a wide range of animal and human cells and bioassay systems, were highly resistant to kininases and had very long duration of action in vivo (Stewart JM, Gera L, Hanson W, et al. Immunopharmacology 1996;33:51-60). B9430 and derived compound are disclosed in Patent application WO9616081. B9430 has the following sequence:

(D)Arg-Arg-Pro-Hyp-Gly-IgI-Ser-(D)Igl-Oic-Arg (SEQ ID N°4)

Another specific example of a peptidic B2R antagonist that may be used according to the present invention is B9870 (CU201 / Breceptin), formed by crosslinking B-9430 with a suberimidyl (SUIM) linker at the amino end and which retained almost the same B2R and BIR receptor binding profile in guinea pig and human as the monomer and additionally introduced potent anticancer activity into the peptide. B9870 and derived compound are disclosed in patent applications US5849863 WO9709347). B9870 has the following sequence:

(D)Arg-Arg-Pro-Hyp-Gly-IgI-Ser-(D)Igl-Oic-Arg (SEQ ID N°4)

I SUIM

(D)Arg-Arg-Pro-Hyp-Gly-IgI-Ser-(D)Igl-Oic-Arg (SEQ ID N°4)

In the preferred embodiment, a peptidic B2R antagonist is HOE 140.

In second embodiment, the B2R antagonist is a non peptidic entity such as small chemical entity.

Non peptide antagonists that may be used in the invention include, FR173657, LF16- 0687(Anatibant), Bradyzyde, MEN16132 (Fastibant), BKM-570 and derived compounds described, for example, in. EP 06223618 (FR173657) W09824783, EP0944618 (LF16-0687) Burgess GM et al (Br J Paharmacol 2000; 129: 77-86) and Dziadulewicz EK et al (J Med Chem. 2000 Mar 9;43(5):769-71) (for Bradyzyde) W02006040004 W02003103671 (MEN16132), Gera L, et al. In. Peptides 2000 (Proceedings of the 26th European Peptide Symposium); Montpellier, EDK, Paris; 2001. p. 637-8 Martinez J, Fehrentz J- A, editors) (for BKM-570).

Additional non- limiting examples of non peptidic B2R antagonists include any of the B2R antagonists described in Dziadulewicz EK. (Exp Opin. Ther. Patents. 2005 15(7) page 829-589) in Fincham CI et al (Exp Opin. Ther. Patents 2009 19(7) page 919-941), all of which are herein incorporated by reference.

A specific example of a non peptidic B2R antagonist that may be used according to the present invention is FR173657 ((2E)-3-[6-(acetylamino)-3-pyridinyl]-N-[2-[[2, 4- dichloro-3 - [ [(2-methyl-8-quino linyl)oxy]methyl]phenyl] methylamino] -2-oxoethyl] -2- propenamide (CAS: 167838-64-4)). FR173357 and related molecules showed high affinity and selectivity for B2Rs(Aramori I, Zenkofi J, Morikawa N, et al.Mol Pharmacol 1997;51 : 171-6). In vivo, they potently inhibited BK- induced bronchoconstriction in guinea pigs, reduced carrageenan- induced paw edema, caerulein- induced pancreatitis in rats and alleviated kaolin-induced pain in mice by oral administration (Asano M. et al. Immunopharmacology 1999;43: 163-8). FR173657 and derived compound are disclosed in Patent Application EP 06223618. FR173657 has the following structure:

B₂ FR 73657

Another specific example of non peptidic B2R antagonist that is used according to the present invention is LF 16-0687 [((2S)-N-[3-[[4-(aminoiminomethyl)benzoyl]amino] propyl]- 1 -[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy] methyl] phenyl] sulfonyl] -2- pyrrolidmecarboxamide (CAS: 209 733-45-9)) (also known as Anatibant or XY2405) from Fournier Pharma; LF 16-0687 had an impressive pharmacological profile with high affinity across species (Pruneau D, et al. Immunopharmacology 1999;43: 187-94) and efficacy in multiple models of head trauma and ischemic brain injury (IBI) (Zweckberger K, et al. Neurosci Lett 2009;454(2): 115-17). LF16-0687 and derived compound are disclosed in Patent Applications W09824783, EP0944618. LF16-0687 has the following structure:

LF 16-0687

Another specific example of a non peptidic B2R antagonist is Bradyzide ((2S)-N-[2- [[2-(dimethylamino) ethyl] methylamino] ethyl]- l-[[4-[2-[[(diphenylmethyl)amino] thioxomethyl] hydrazinyl]-3-nitrophenyl]sulfonyl]-2-pyrrolidinecarboxamide (CAS: 263011- 13-8) from Novartis is an orally active molecule, highly effective in animal models of pain and is interesting in that it showed exceptional selectivity for the rat versus the human B2R (Burgess GM et al (Br J Paharmacol 2000; 129: 77-86) and Dziadulewicz EK et al (J Med Chem. 2000 Mar 9;43(5):769-71). Bradyzide has the following structure:

B₂ Bradyzide

Another suitable non peptidic B2R antagonist is MEN16132 ((also known as Fastibant); (dS)-d-amino-4-[[4-[[[2,4-dichloro-3-[[(2,4-dimethyl-8-quinolinyl)oxy]methyl] phenyl]sulfonyl]amino]tetrahydro-2H-pyran-4-yl]carbonyl]-N,N,N-trimethyl-"-oxo-l- piperazinepentanaminium chloride (CAS: 869880-33-1)) having a Ki of 10.5 nM at the human B2R and excellent efficacy in a range of animal models of inflammation (Valenti C, et al. J Pharmacol Exp Ther 2005;315:616-23). Based on these studies, MEN16132 underwent a Ph II clinical trial for knee pain in osteoarthritis. MEN16132 and derived compounds are disclosed in Patent Applications W02006040004 W02003103671). MEN16132 has the following structure:

Another suitable non peptidic B2R antagonist is BKM-570 ((aS)-4-[(2,6- dichlorophenyl)methoxy]-a-[[l-oxo-3-(2,3,4,5, 6-pentafluorophenyl)-2-propen-l-yl]amino]- N-(2,2,6,6-tetramethyl- 4-piperidinyl)benzenepropanamide (CAS: 259885- 54-6)) is a lead molecule that demonstrates impressive antitumor activity in small cell lung cancer (SCLC) SHP-77 and good activity in prostate cancer PC-3 xenografts (Gera L, et al. In:. Peptides 2000 (Proceedings of the 26th European Peptide Symposium); Montpellier, EDK,Paris; 2001. p. 637-8 Martinez J, Fehrentz J-A, editors.). BKM-570 and has the following structure:

B₂ BKM-570

Another object of the invention relates to a method for preventing or treating the hypotensive effect of angiotensin- converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition comprising administering a subject in need thereof with a therapeutically effective amount of a B2R antagonist as described above.

In the context of the invention, the term "treating" or "treatment", as used herein, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

According to the invention, the term "patient", is intended for a human or non-human mammal affected or likely to be affected with the hypotensive effect of angiotensin- converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition.

By a "therapeutically effective amount" of the antagonist or inhibitor of expression as above described is meant a sufficient amount of the B2R antagonist to treat or prevent the hypotensive effect of angiotensin- converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific polypeptide employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Preferably, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

Pharmaceutical compositions:

The B2R antagonist of the invention as above defined may be combined with pharmaceutically acceptable excipients, to form therapeutic compositions for use in preventing or treating the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEI) in a patient treated with an ACEI, whereas said patent is under critical condition.

In an embodiment, the critical condition is selected from emergency anaesthesia or shock resuscitation.

In a specific embodiment, shock resuscitation is selected from the group consisting of: hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks.

In a preferred embodiment the critical condition is hemorrhagic shock or septic shock.

In an embodiment, B2R antagonist according to the invention of the pharmaceutical composition includes but is not limited to: i. NPC-349, HOE140, CP-0127, B9430, B9870 (peptide BR2 antagonists); ii. FR173657, LF 16-0687, Bradyzyde, MEN16132, BKM-570 (non peptide BR2 antagonists); and derived compounds.

In preferred embodiment, the B2R antagonist of the pharmaceutical composition is HOE 140 and the critical condition is hemorrhagic shock.

"Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, may be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.

Preferably, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The B2R antagonist of the invention may be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

The carrier may also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms may be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions may be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Upon formulation, solutions are administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like may also be employed.

For parenteral administration in an aqueous solution, for example, the solution is suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media that may be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

The B2R antagonist of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses may also be administered.

In addition to the compounds of the invention formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations; time-release capsules; and any other form currently used.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

FIGURES:

Figure 1 Pressure targeted hemorrhagic shock

Hemodynamic impacts of HOE- 140 during pressure controlled hemorrhagic shock (HS) in chronic Angiotensin converting enzyme inhibition treated mice (ACEi); ACEi: wild type shocked mice treated with chronic ACEi; ACEI+HOE: wild type shocked mice treated with both chronic ACEi and HOE- 140; HOE: wild type shocked mice treated with HOE- 140 alone. n=5-13.*p<0.05; **p<0.01; ***p<0.001. Initial blood pressure was significantly lower in ACEi mice when compared to ACEi+HOE (figure la, mean ± SEM). The mean volume of blood withdrawal was lower in ACEi group when compared to other groups (Figure lb, box plot).

Figure 2 Volume targeted hemorrhagic shock

Targeted volume hemorrhagic shock (HS) protocol assesses the impact of HOE-140 on HS outcome in chronic Angiotensin-converting enzyme inhibitors (ACEi) treated mice. WT: wild type shocked mice; ACEi: wild type shocked mice treated with chronic ACEi; ACEi+HOE: wild type shocked mice treated with both chronic ACEi and HOE-140. n=8-10 * p<0.005, ** p< 0.001. HOE 140 allowed restoring the mean arterial blood pressure during anesthesia and HS in ACEi shocked mice. Min shock: minimal mean arterial blood pressure during shock. Mean shock: mean arterial blood pressure during shock

Figure 3 Biological consequence of hemorrhagic shock

Determination of blood lactate after volume controlled hemorrhagic shock in mice. WT: wild type shocked mice; ACEi: wild type shocked mice treated with chronic ACEi; ACEi+HOE: wild type shocked mice treated with both chronic ACEi and HOE-140. n = 6-8.* p<0.005.

Figure 4: Determination of blood lactate acid after volume targeted hemorrhagic shock (VTS).

Sham: Sham-operated animals underwent the same anesthetic and surgical procedures, but neither hemorrhage nor fluid resuscitation was performed; Control : (or WT) control shocked mice; ACEi: shocked mice treated with chronic ACEi; ACEi + HOE: shocked mice treated with both ACEi and a single shot of icatibant; HOE: shocked mice treated with a single shot of icatibant. n = 6-8.* p<0.05.

Figure 5: Impact of acute B2R blockade on liver failure after volume targeted hemorrhagic shock (VTS)

Sham: Sham-operated animals underwent the same anesthetic and surgical procedures, but neither hemorrhage nor fluid resuscitation was performed; Control : control shocked mice;

ACEi: shocked mice treated with chronic ACEi; ACEi + HOE: shocked mice treated with both ACEi and a single shot of icatibant; HOE: shocked mice treated with a single shot of icatibant. n = 8-10.* p<0.05, ** p<0.001.

EXAMPLE 1:

Material & Methods Animals. C57/BL6 wild-type mice were obtained from Harlan (Harlan France, Gannat, France). Animal experimentations were performed according to national and institutional animal care and ethical guidelines and were approved by local board. Protocol Design. Based on recently published HS model (18), the hemodynamic and biological effects of icatibant in ACEi treated mice were studied by a dual protocol: 1) a pressure targeted hemorrhagic shock protocol (PTS) and 2) a volume targeted hemorrhagic shock protocol (VTS). The aim of PTS was to determine the hemodynamic impact of icatibant compared to the inventors' previous investigations whereas the objective of VTS was to assess the impact of icatibant on HS outcome in ACEi treated mice.

Experimental groups were performed using 18 wk-old mice randomly assigned as follows: 1/ Wild type (WT) shocked mice (WT, n = 13 for PTS and n = 10 for VTS), 21 WT shocked mice treated with 7 days of ACEi (ACEi, n = 5 for PTS and 8 for VTS) and 3/ WT shocked mice treated with 7 days of ACEi and a single shot of icatibant before anesthesia, (ACEi+HOE, n = 6 for PTS and n = 8 for VTS). Experimental groups were identical for the 2 protocols. ACEi (Ramipril, Aventis Pharma, Germany) was given at a dose of lmg/kg/j in drinking water 7 days before shock and icatibant (Aventis Pharma, Germany) was administrated at a dose of 250 μg/kg subcutaneously just before anesthesia. After shock procedure, mice were sacrificed at 2 days for PTS and at 3 hours for VTS.

WT and Control are the same group (without anaesthetic and surgical proceeding)

Hemorrhagic Shock Protocols. HS was induced as previously described (18). Briefly, animals were anesthetized with ketamine and xylazine (125 mg/kg and 10 mg/kg, respectively) and intubated using an intratracheal canula. Mechanical ventilation (9 mL/kg, 150 breath/min) was carried out with a specific ventilator Minivent 845 (Hugo Sachs Elektronik, March-Hugstetten, Germany). The left jugular vein and femoral artery were catheterized and anesthesia was maintained with ketamine (20 mg/kg/hr) until the end of shock. Animal body temperature was continuously monitored and maintained at 37°C. All along the procedure, femoral arterial blood pressure was monitored using a blood pressure analyzer (IOX, EMKA technologie, France).

- Pressure targeted HS (PTS). Blood was withdrawn through the femoral arterial line until the targeted arterial blood pressure (MAP) of 35 mmHg was reached. Blood was stored in 0.15 mL of heparinized serum. MAP was maintained at 35 ± 5 mmHg for 2 hours by successive blood withdrawal or replacement (by steps of 0.025 mL). - Volume targeted HS (VTS). A systematic blood volume of 0.30 mL was withdrawn through the femoral arterial line. This volume was the mean volume withdrawal in ACEi treated mice during PTS. As in PTS, blood was stored in 0.15 mL of heparinized serum.

At the end of 2 hours shock in the 2 protocols, the blood previously stored and a lactated Ringer's solution (twice the initial blood volume) was infused to provide appropriate fluid resuscitation.

Hemodynamic analysis. MAP (Mean Arterial Blood Pressure) was reported during anesthesia, just before shock (MAPi), at the beginning of the shock (MAPis), during shock with the measurement of the lowest MAP (MAPmin), and at the end of the resuscitation (MAPf). The average mean MAP during shock was also reported (MAPm). In the PTS protocol, blood volume withdrawn was systematically reported.

Biological analysis. At the end of the procedure, a catheter was introduced into the abdominal aorta and blood was collected. Biological analysis was performed on whole blood. Lactic acid, a prognostic marker of severity, was measured to evaluate organ failure.

Statistical methods. Data are provided as means ± SEM. Comparisons between groups were performed using the nonparametric Kruskal-Wallis one-way analysis of variance followed by a post hoc Dunn's test. Results with p < 0.05 were considered as statistically significant. Analyses were performed using GraphPad Prism 4 (Graphpad Software Inc, San Diego, CA).

Results

Hemodynamic impact of HOE- 140 during HS.

In PTS protocol (Fig la and lb), MAPi in WT, ACEi, and ACEi+HOE groups were

75.1±9.5, 67.2±13.5, and 81.2±9.8 mmHg, respectively. ACEi group exhibited significantly lower MAPi when compared to ACEi+HOE group. At the end of the resuscitation, MAPf in WT, ACEi, and ACEi+HOE mice were 55.7+5.5, 42.0+3.2, and 48.6+6.0 mmHg, respectively. As expected, no difference in MAP during HS was observed between groups (Figure la).

Means blood withdrawn during PTS protocol were 612+118 μΐ in the WT group, 402+117 μΐ in the ACEi group, and 631+124 μΐ in the ACEi+HOE group. The mean blood volume withdrawal was lower in ACEi group when compared to other group (Figure lb). Icatibant attenuated also hypotensive effects of ACEi during HS. In VTS protocol (Figure 2), MAPi in WT, ACEi, and ACEi+HOE groups were 74.8±9.4, 63.1=1=8.4, and 73.0±8.8 mmHg, respectively. MAPmin and MAPm of these same groups were 32.7±9.5 and 42.4±9.4, 22.1±8.3 and 30.1±8.3, and 30.7±8.8 and 38.3±8.8 mmHg, respectively. At each time, MAP was significantly lower in ACEi group, when compared to WT and ACEi+HOE groups. No difference for MAP was observed between WT and ACEi+HOE group. Interestingly, icatibant allowed restoring the MAP during anesthesia and HS in ACEi shocked mice.

Biological impact of HOE- 140 during HS.

Three hours after VTS, lactate acid was significantly higher in the ACEi group compared to others groups (Figure 3).

Conclusions

The results show that acute B2R blockade significantly attenuates deleterious hypotensive effect of ACEi during HS mice. This beneficial effect of B2R blockade is quickly reached and sustainable with a single shot of icatibant, a highly specific B2R antagonist. This hemodynamic effect of icatibant on HS mice pre-treated for 7 days with ACEi was validated by 2 protocols (PTS and VTS). The results also support that the beneficial hemodynamic effect of icatibant in ACEi treated mice could reduce plasma lactate acid, a prognostic marker of severity during shock.

EXAMPLE 2: Confirmation of the results

The inventors confirm the previous results adding new groups: HOE alone and Sham (control mice with the same anesthetic and surgical procedure) and 2 additional subject for the group ACEi+ HOE

Results obtained evidenced that a) MAP was significantly higher in ACEi + HOE group, when compared to ACEi group and b) Lactate acid was significantly higher in the ACEi group compared to ACEi + HOE groups, are fully consistent with the results obtained on the previous dataset (figure 4).

These additional data strengthen that acute B2R blockade significantly attenuates the deleterious hemodynamic effect of ACEi and have a protective effect against organ failure by preventing the increased in plasma lactate acid, a prognostic marker of morbidity and mortality during shock (19). Results

Icatibant increases tolerance to blood volume depletion

In PTS protocol, in anesthetized mice before shock, MAPi in control, ACEi, ACEi + HOE and HOE groups were 75.1 ± 9.5, 67.2 ± 13.5, 81.2 ± 9.8, and 79.2 ± 10.5 mmHg, respectively. ACEi group exhibited significantly lower MAPi when compared to ACEi + HOE group only (p<0.01). At the end of the resuscitation, MAPf in control, ACEi, ACEi + HOE, and HOE mice were 55.7 ± 5.5, 42.0 ± 3.2, 48.6 ± 6.0, and 59.4±7.2 mmHg, respectively. MAPf was significantly lower in ACEi group when compared to HOE group only (p<0.05). As expected, no difference in MAP was observed between groups during HS.

Means blood volume withdrawal during PTS protocol were 612 ± 118 μΐ in control group, 402 ± 117 μΐ in ACEi group, 631 ± 124 μΐ in ACEi + HOE group, and 773 ± 63 μΐ in HOE group. The mean blood volume withdrawal was significantly lower in ACEi group when compared to other groups (p<0.01 and p<0.001).

Icatibant significantly increases MAP

In VTS protocol, MAPi in control, ACEi, ACEi + HOE, and HOE groups were 74.8 ± 9.4, 63.1 ± 8.4, 73.0 ± 8.8, and 80.1 ± 10.5 mmHg, respectively. MAPmin and MAPm in the same groups were 32.7 ± 9.5 and 42.4 ± 9.4, 22.1 ± 8.3 and 30.1 ± 8.3, 30.7 ± 8.8 and 38.3 ± 8.8, and 43.3 ± 8.5 and 52.3 ± 6.9 mmHg, respectively. At each time, MAP was significantly lower in ACEi group, when compared to control, ACEi + HOE, and HOE groups. No difference for MAP was observed between control and ACEi + HOE groups.

In VTS protocol, no deaths were observed in sham, control and HOE group whereas, 4 of 12 and 2 of 10 mice died in ACEi and ACEi + HOE groups. There was a tendency but not significant lower mortality in ACEi + HOE group when compared to ACEi group (p = 0.673).

One hour after VTS, blood lactate was significantly higher in the ACEi group when compared to others groups particularly between ACEi and ACEi + HOE groups (Figure 4).

Discussion

We report here, for the fist time, that acute B2R blockade by icatibant attenuates the deleterious hypotensive effect of prolonged ACEi treatment during HS in mice. The beneficial effect of icatibant on arterial blood pressure was demonstrated by two different protocols.

ACEi is a valuable therapy for the management of hypertension, cardiac failure and chronic kidney diseases (20). Growing evidence indicates that antihypertensive and cardioprotective effects of ACEi are partially related by the increase in endogenous BK bioavailability. This leads to an enhanced B2R activation (12). Hemodynamic effect of B2R antagonism by icatibant has been previously studied during ACEi treatment in hypertensive, heart failure and diabetic animal models (14, 16) and in normal men (21, 22). These different studies confirm that:

BK is involved in the regulation of arterial blood pressure and ii/ B2R antagonism attenuates the effect of ACEi on MAP. In our study, we extended these observations to critical condition (HS) such as volume and pressure targeted shock. Our results demonstrate that B2R blockade by icatibant exerts a significant protective effect on systemic hemodynamic.

During HS, acute B2R blockade significantly attenuates the worsening hypotensive effect of ACEi in mice. This beneficial effect of B2R blockade is quickly reached and sustainable with a single shot of icatibant. Both VTS and PTS results support that icatibant in ACEi treated mice i/ prevents the increased in plasma lactate acid, a prognostic marker of morbidity and mortality during shock (19); ii/ improves tolerance to blood volume depletion and as a consequence reduces total fluid volume requirement during resuscitation.

This benefit could be of high interest in ACEi-treated patients during both emergency anesthesia and resuscitation.

EXAMPLE 3: Liver protection of BR2 blockade

The inventors seek to access the impact of B2R blockade on multi-organ failure (liver, kidney and intestine) induced by the HS in ACEi treated mice. The first result showed that icatibant prevents the increased in the liver enzymes proved by the measurement of Alanine Aminotransferase, a biomarker of liver failure (figure 5). REFERENCES:

Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

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Claims

CLAIMS:

1. An antagonist of the Bradykinin 2 receptor (BR2) for use in the prevention or treatment of the hypotensive effect of angiotensin-converting enzyme inhibitors (ACEi) in a patient treated with an ACEi, whereas said patent is under critical condition.

2. The antagonist of BR2 for use according to Claim 1, wherein critical conditions is selected from emergency anaesthesia or shock resuscitation.

3. The antagonist of BR2 for use according to Claim 2, wherein shock resuscitation is selected from the group consisting of: hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks.

4. The antagonist of BR2 for use according to any one of Claims 1 to 3, wherein critical conditions is hemorrhagic shock or septic shock.

5. The antagonist of BR2 for use according to any one of Claims 1 to 4, which is selected from the group consisting of: i. ; NPC-349, HOE140, CP-0127, B9430, B9870 ii. FR173657, LF16-0687, Bradyzyde, MEN16132, BKM-570.

6. The antagonist of BR2 according to any one of Claim 1 to 5, wherein the antagonist of BR2 is HOE 140 and critical condition is hemorrhagic shock.

7. A pharmaceutical composition, comprising an antagonist of BR2 according to any one of Claims 1-4, for use in the prevention of the hypotensive effect of ACEIs, in a patient treated with an ACEI, said patient is under critical conditions.

8. The pharmaceutical composition for use according of Claim 7, wherein critical conditions is selected from emergency anaesthesia or shock resuscitation.

9. The pharmaceutical composition for use according to Claim 8 wherein shock resuscitation is selected from the group consisting of: hypovolemic (i.e. hemorrhagic), or vasoplegic (i.e. septic) shocks.

10. The pharmaceutical composition for use according to any one of Claim 7 to 9, wherein critical conditions is hemorrhagic shock or septic shock.

11. The pharmaceutical composition for use according to any one of Claim 7 to 10, wherein the antagonist of BR2 is selected from the group consisting of i.; NPC-349, HOE140, CP-0127, B9430, B9870; ii. FR173657, LF16-0687, Bradyzyde, MEN16132, BKM-570.

12. The pharmaceutical composition for use according to any one of Claim 7 to 11, wherein the antagonist of BR2 is HOE 140 and critical condition is hemorrhagic shock.