1

Faculté des Sciences Pharmaceutiques et biologiques

Master 1 : Méthodes Modernes de Découverte et de

Développement de Médicaments

firazyr ®

De Blander Hadrien

22/01/2009 Tuteur : Térence Beghyn


The discovery of the Kinin-kallikrein system (KKS)
Werle : smooth muscle-
contracting substance
from an inactive
precursor. This substance
initially was called
substanz DK
(‘‘darmkontrahierende
Frey : substanz’’ or ‘‘gut-
Due to a specific contracting substance’’)
substance named
« F-substance » isolated
from human urine by
Frey and Kraut in 1928
2
…and later renamed « kallidin », and the inactive
precursor, kallidinogen
Elliott :
BK : isolated in significant
quantities from plasma
and its primary Pharmacological
structure solved characterization of
kinin receptors (B1
and B2)

1909 1926 1930 1937 1949 1959-60 1964 1977-79

Abelous and Bardier : Rocha e Silva et al.

BK : the first biologically active
IV of human urine in isolated bradykinin (BK)
peptide to be assembled by
dogs  drop in blood released from kininogens
the then newly developed
systolic pressure ( Frey, Kraut, Werle : by the venom of Bothrops
Solid Phase Peptide Synthesis
« urohypotensin » ) high concentrations of jararaca
(Merrifield)
F-substance in the
pancreas, main site of
synthesis ?
F-substance  “kallikrein”
 3
Classification of kinins receptors : • pharmacological criteria (Regoli and Barabe, 1977-79)
• molecular characterization (1991)

B1 Receptor B2 Receptor

• Inducible in pathological conditions • Constitutively expressed

LPS, cytokines (interleukins, TNFα …) …
• Down-regulation
• Not easily down regulated

The Lys118 - attracts the negative charge of the C-ter of B1-selective peptides that
The Ser111 does not repell B2-selective peptide and readily bind
lack the C-terminal Arg
…no counter-ion is available to attract B1-selective peptides
- repels the positive charge of the C-terminal Arg of B2-selective peptides
 4
Effects and Pharmacological mechanisms (B2)
 Vasodilation
Bk  One of the most powerful known vasodilators
Hypotension (particularly marked in capillaries)

 Increased vascular permeability

Edema

 Inflammation and algesic action

• Stimulation of sensory neurons  Pain
• Release of - cytokines by leukocytes
- eicosanoids from various cell types

 Action on smooth muscles

• Relaxation of venular smooth muscle
• Contraction of - smooth muscle in airways ( airway resistance)
- intestinal smooth muscle …

 Other actions
BK  the most potent stimulator of tissue-type plasminogen activator
(t-PA) release ( Fibrinolysis)
• potent stimulator of prostacyclin synthesis in the endothelial cell
which inhibits platelet function

Gαs and Gαi ERK/MAPK cascade and mitogenic signalling

 5

KKS and contact system

Pancreatic cells, intestinal, distal nephron,

endothelial, salivary, sweat, vascular smooth
muscle cells …
 6
HK
High-molecular-weight kininogen and its 6 domains

• Prekallikrein circulates in plasma as

a heterodimer complex bound to HK with 1:1 molar
Stoichiometry
• About 80 – 90% of prekallikrein is normally
complexed to HK

Bradykinin : autocrine
and paracrine action
(autacoids)
 7

What is necessary to compose a good BK-antagonist ?

 8

Stability

ACE  Pro7-Phe8 then Phe5-Ser6 T 1/2 (BK)

≈15 s
Aminopeptidases (APP)  N-ter Arg

Carboxypeptidase N (CPN)  C-ter Arg

Neutral endopeptidase (NEP)  Pro7-Phe8 then Gly4-Phe5 BK[1-4] product

In the kidney the major enzyme responsible for the metabolism of BK

H
N OH 95% of bradykinin administered
N O O
H H H intra- venously to humans is
O O O N
H2N N
O OH degraded by pulmonary ACE after a
O O N N
H
H
H H single passage
O N
N
NH H

N NH
H NH2
Bradykinin
HN NH2

Arg1 Pro2 Pro3 Gly4 Phe5 Ser6 Pro7 Phe8 Arg9

 9
Structure evolution of B2 Antagonists : From Bradykinin to Icatibant
ACE  Pro7-Phe8 The goal : Potency, selectivity and Stability !
APP  N-ter Arg

HN NH2

OH
NH
How to
H
N OH improve the
O O
N
H H
molecule ?
H H
H2N O N O O N
OH
Hoescht
H2N O O N N O
H
H
H H answer :
O O N Inspired from
S N
NH H
S
the ACE
N NH2
NH inhibitors
H
development
HN NH2

D-Arg Arg1 Pro2 Pro

Hyp3 Gly4 Thi
Phe5 Ser6 D-Phe
Pro7 Phe
Thi 8 Arg9

Vavrek and StewartBradykinin

1985
1988 (« A
(« B version »)
(NPC-349)

Antagonist/ partial agonist activity and a low potency

 10
Molecules which were later to become drugs including Tic and Oic residues : ACE inhibitors

tetrahydroisoquinoline-3-carboxylic acid (Tic) octahydroindole-2-carboxylic acid (Oic)

OH

O
O
O N O O
O O
O O O
HN NH
NH
O
NH O
O
H
H
O N N O
N O

O OH
OH
O OH H
H

Quinapril 1984 Moexipril 1982 Perindopril 1986 Trandolapril

1987

Jochen Knolle

1978 Hoescht
 11
Structure evolution of B2 Antagonists : From Bradykinin to Icatibant

The goal : Potency, selectivity and Stability !

HN NH2 Problem : NPC349 showed

B1 antagonist activity in
OH vivo, due to enzymatic removal
NH
of the C-terminal arginine
H
N OH
N O O
H H H H
N O N O O N
H2N O O N N O OH
H H H
H
O O HN
N
S N
NH H H
H S H
N NH
H NH2
CPN  C-ter Arg
HN NH2

Duration of action in
Icatibant
Vavrek 19911988
and Stewart (Hoe-140)
(NPC-349) vivo and potency

1st Generation antagonist D-Arg Arg Pro Hyp Gly Thi Ser D-Phe Thi Arg
(NPC-349) Stewart
2nd Generation antagonist D-Arg Arg Pro Hyp Gly Thi Ser D-Tic Oic Arg
(HOE-140/Icatibant) Hoescht
Next ? Icatibant is still cleaved by NEP ( BK[1–4] product in urin )  3rd generation…
 12

Conformation
• The C-terminal region plays an important role for its binding interaction to the B2 receptor

• Bulky hydrophobic unnatural amino acids force the resulting peptide in a β-turn motif
 D-Tic7-Oic8 is crucial for antagonist activity

• Pseudocyclic conformation involving a βII-turn (positions 2–5) and a βII′-turn (positions 6–9)
+ hydrogen bond between the amide hydrogen of Gly 4 and the carbonyl oxygen of D-Tic 7

• Substitution of the D-Tic7-Oic8 dipeptide in HOE 140 with constrained mimetics induced a potent B2
receptor agonist activity and even a potent and selective B1 antagonist activity

 competive antagonist in most biological assays but displays also

non-competitive properties in several tissues
 In vitro / in vivo assays
13

Potency

Selectivity
 14

Chemical Synthesis
• Laboratory

• Industrial

Solid
Phase
Peptide synthetiser (500L)
Peptide
Synthesis
 15
After 1991 … until 2001
HOE 140 has been used extensively in animals to block exogenous bradykinin.
It has also been used in various pathological states to evaluate the role of kinins in pain and
hyperalgesia and in inflammatory states (rhinitis, asthma, cystitis, pancreatitis, etc..)

Peptides having a
bradykinine
inhibiting
Activity
(new molecule Suspension of development in
Allergy, Asthma, Rhinitis and Pain
= icatibant)

1985 1988 1990 1997

Pubmed entries

 In most pathological states :

• Asthma
• Allergy
• Rheumatoid arthritis
• Endotoxic shock
• Pancreatitis
• Cancer
• Diabetes
 16

Airway diseases : Asthma and Rhinitis

Kinin formation during allergic reactions in humans

• BK administration to airways
– Bronchoconstriction only in asthmatics (enhanced B2 receptor expression in this sensitized patient
population ?)
– Sore throat and rhinitis  blocked by Icatibant

• In perennial allergic rhinitis to house-dust mite (nasal blockade)

– Icatibant : nasal blockade in allergic individuals exposed to house mite dust (Austin et al.1994)

• In seasonal allergic rhinitis to pollens (nasal blockade, rhinorrhea, sneezing)

– Inactive on nasal obstruction and albumin extravasation (Akbary & Bender,1993) (Turner et al., 2001 )

• In moderately severe asthma (double-blind, placebo controlled, 4-week clinical trial, 264 patients (Hoechst-1996) )

– « Long-term » anti-inflammatory effect

– Relatively modest improvement in pulmonary performance
– No bronchodilation
– No impact on frequency of rescue medication

“ Administered locally in all these studies, the short duration of action

possibly due to mucociliary clearance may partly explain the reason
for these discouraging results ”
(Proud,1998)
 17
Pain
BK is one of the few mediators of inflammation that directly stimulates afferent nerves

• B2 receptor  on non-myelinated sensory neurons (nociceptors)

• In rats, antinociceptive effect of the B1/B2 receptor antagonist
– In provoked hyperalgesia, icatibant was effective at the beginning, but that the B1 receptor ligand
progressively became the best analgesic in a few days after lesion initiation (Perkins et al. 1993)

Analgesic profile of B2 receptor antagonist :

• Initial inflammatory response = pain inducer

B1
B2
Analgesic profile of B1 receptor antagonist :
(in the periphery and the CNS ):
• Longer term inflammation and pain
(sometimes in the absence of inflammation)

• Hoe 140 was completely ineffective against the abdominal constriction response induced by Zymosan, kaolin and
acetic acid
In contrast, morphine, ibuprofen and indomethacin had similar potencies (John S. Shaw & Susannah C. Farmer 1993)
 18
After 1991 … until 2001
HOE 140 has been used extensively in animals to block exogenous bradykinin.
It has also been used in various pathological states to evaluate the role of kinins in pain and
hyperalgesia and in inflammatory states (rhinitis, asthma, cystitis, pancreatitis, etc..)

Peptides having a
bradykinine
inhibiting
Activity
(new molecule Suspension of development in
Allergy, Asthma, Rhinitis and Pain
= icatibant)

1985 1988 1990 1997 1999 2000


Pubmed entries

 In most pathological states :

• Asthma
• Allergy
• Rheumatoid arthritis
• Endotoxic shock
• Pancreatitis
• Cancer
• Diabetes
 19

Phase IIa trial in

liver cirrhosis

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed
exclusive worldwide
development and
commercialization
rights to icatibant
from Aventis

Phase I trials in
liver cirrhosis
 Refractory ascites in liver cirrhosis and 20

Hepato-Renal Syndrome
Cirrhosis : significant abnormalities in their fluid and electrolyte balance
 ascites and edema

5–10%

Advanced cirrhosis + severe urinary sodium retention …and no answer to diuretics

Refractory ascites

liver transplantation

Phase IIa (randomized, crossover, placebo-controlled)  Icatibant met all the primary endpoints :
- improved sodium and potassium excretion
- urine flow
- body weight
 21

Phase IIa trial in

liver cirrhosis

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed Phase I trials in

exclusive worldwide edema with
development and severe burns
commercialization ………………
rights to the drug the FDA granted
from Aventis Orphan Drug
status for the
treatment of
edema in severe
Phase I trials in
burn patients
liver cirrhosis

Icatibant indications in :
- edema with severe burns
- ascites in liver cirrhosis
…no longer listed on the
Jerini’s pipeline
 still capillary leak syndrome
 22

Capillary Leak Syndrome (CLS)

…it was assumed that development in these indications had been subsumed into the preclinical CLS program

• Since 1960 ~100 cases worldwide have been

•described
leakage of plasma to the extra-vascular compartment

Recurrent episodes of hypovolemic shock

+ hemo-concentration, generalized edema…

organ failure, cardiovascular collapse and death

• no evident etiology

Icatibant ability to block the vascular permeability increase in patients

May 2008, preclinical studies in CLS were underway

Icatibant is currently being tested in several preclinical CLS models
 23
EU and US phase IIb
studies in osteoarthritis
pain

Phase IIa trial in Phase IIa trials for

liver cirrhosis osteoarthritis pain
Use of bradykinin-B2
receptor
antagonists for
treating osteoarthritis

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed Phase I trials in

exclusive worldwide edema with
development and severe burns
commercialization ………………
rights to the drug the FDA granted
from Aventis Orphan Drug
status for the
treatment of
edema in severe
Phase I trials in
burn patients
liver cirrhosis

Icatibant indications in
edema with severe
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline  still capillary
leak syndrome
 24
Efficacy and Safety Study of Intra-Articular Multiple Doses of Icatibant
in Patients With Painful Knee Osteoarthritis

Phase IIa :
 Icatibant  quick and sustained pain relief in a phase II study in patients with osteoarthritis of the knee

Phase IIb :
o To compare icatibant treatment with steroid treatment and placebo

: Icatibant (3 weekly intra-articular injections of 500 µg each) 

 pain relief in patients with knee OA
 rapid in onset
 lasts up to 3 months following treatment
 no gastrointestinal or cardiovascular side effects
 25
EU and US phase IIb
studies in osteoarthritis
pain
………………………..
Discontinued due to lack
of efficacy

Phase IIa trials for

osteoarthritis pain
Phase IIa trial in
liver cirrhosis Use of bradykinin-B2
receptor
antagonists for
treating osteoarthritis

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed Phase IIa Phase I trials in

exclusive worldwide proof-of- edema with
development and concept trial severe burns
commercialization was initiated ………………
rights to the drug in HAE the FDA granted
from Aventis Orphan Drug
status for the
Jerini received treatment of
European edema in severe
Phase I trials in Orphan Drug burn patients
liver cirrhosis designation
for icatibant
(FDA  for
angioedema
Icatibant indications in
edema with severe
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline  still capillary
leak syndrome
 26
Hereditary Angioedema
• Autosomal dominant transmission
• 1 in 10 000 to 1 in 150 000 persons (500 to 1000 touched in France)
• Intense, massive, localized edema without concomitant pruritus
• Mortality rates ~ 15-33%, resulting from laryngeal edema and asphyxiation

 Bradykinin released during acute attacks ( symptoms) by directly causing

- increased vascular permeability (edema, swelling, and ascites)
- vasodilation (congestion, erythema, and hypotension)
- contraction of nonvascular smooth muscle (cramps, spasms and pain)

The symptoms of HAE are caused by the extravasation of plasma into the deeper cutaneous
or mucosal layers as a result of one or more locally released vasoactive peptides.
 27

Barium study performed in a patient during an laryngeal edema

abdominal attack
 28

 2 types (possibly X-linked “type III” HAE primarly women and exacerbated by estrogens)

No correlation between defiency and

severity of symptoms

 C1 Inhibitor (C1-INH)

• Hepatic Glycoprotein
• Serpin family = 20% of all plasma proteins
• Serine Protease Inhibitors
• Suicide substrate

More than 200 different mutations of the C1INH reported in HAE patients
 29

Trauma
General pattern
FXII

FXIIf
FXIIa

FXI FXIa Fibrin Fibrin

degradation

Plasminogen

Plasmin
Prékallikrein Kallikrein

HMWK

Bradykinin

• Vasodilation
• Nonvascular Smooth
Muscle Contraction
• Increased Capillary
Permeability, Fluid
Extravasation, and
Edema
MAC : Membrane attack complex
 30
Treatments
Acute Long term Short term prophylaxis
treatment
Antifibrinolytic agents prophylaxis
Antifibrinolytic agents C1-inh concentrate
(ex :Tranexamic acid) (ex :Tranexamic acid)

C1-inh concentrate Antifibrinolytic agents

Synthetic attenuated androgens

Synthetic attenuated androgens
Fresh frozen plasma

Fresh frozen plasma

 Phase II Studies in HAE
31

Proof-of-concept study
• 20 acute HAE attacks (10 cutaneous, 3 abdominal, 7 combined) were treated with Icatibant as follows (n=4 each group) :

Posology Time of relief

0.4mg/kg over 2hr i.v 1.5 h
0.4mg/kg over 0.5hr i.v 1.4 h
0.8mg/kg over 0.5hr i.v 1.1 h

30mg s.c 0.5 h

45mg s.c 0.6 h

 no difference in efficacy between the two treatment forms

rapid relief of symptoms after administration
 safe and well tolerated

Pharmacokinetics, safety and local tolerability of subcutaneous formulation :

 24 healthy subjects (subcutaneous injection)
 good bioavailability (about 90% )
 rapid absorption (Cmax reached after about 30 min)
 low variability

Studies for HAE by sc administration

 32
EU and US phase IIb
studies in osteoarthritis
pain
………………………..
Discontinued due to lack
of efficacy

Phase IIa trials for

Phase IIa trial in osteoarthritis pain
liver cirrhosis Use of bradykinin-B2
receptor Kos and Jerini
antagonists for in agreement
treating osteoarthritis for the
development,
marketing and
distribution of
icatibant

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed Phase IIa Phase I trials in Phase III trial

exclusive worldwide proof-of- edema with FAST-2
development and concept trial severe burns
commercialization was initiated ………………
rights to the drug in HAE the FDA granted
from Aventis Orphan Drug
status for the
Jerini received treatment of
European edema in severe
Phase I trials in Orphan Drug burn patients
liver cirrhosis designation
for icatibant
(FDA  for Sept : Phase III HAE
angioedema trials designated
FAST-1 Icatibant indications in
edema with severe
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline  still capillary
leak syndrome
 FAST 1 33

Icatibant (30mg) vs.Placebo (56 patients)

VAS (Visual Analog Scale) :

Time to Almost Complete Relief (VAS)

• Double blind randomization Primary Endpoint (VAS) Secondary Endpoint
Icatibant Comparator p Icatibant Comparator p
FAST-1 2.5 h 4.6 h 0.131 8.5 h 35.2 h 0.035

: « due to an unexpectedly high response to placebo

in patients with abdominal pain. »

Time to first improvement of symptoms (not VAS)

Patient reported Physician reported
Icatibant Comp p Icatibant Comp p
FAST-1 0.8 h 16.9 h <0.001 1.0 h 5.2 h <0.001
 FAST 2 34

Icatibant (30mg) vs. Tranexamic acid (74 patients)

Time to Almost Complete Relief (VAS)

Primary Endpoint (VAS) Secondary Endpoint
Icatibant Comparator p Icatibant Comparator p
FAST-1 2.5 h 4.6 h 0.131 8.5 h 35.2 h 0.035
FAST-2 2.0 h 12.0 h <0.001 10.0 h 35.5 h <0.001

Combined Analysis 2.0 h 8.0 h <0.001

Time to first improvement of symptoms (not VAS)

Patient reported Physician reported
Icatibant Comp p Icatibant Comp p
FAST-1 0.8 h 16.9 h <0.001 1.0 h 5.2 h <0.001
FAST-2 0.8 h 7.9 h <0.001 1.5 h 6.9 h <0.001
Combined 0.8 h 8.0 h <0.001 1.3 h 6.3 h <0.001
 35
Laryngeal Attacks
Time to Relief Laryngeal Attacks

the vocal cords  not visible

due to a severe supraglottic oedema, leading
to dysphonia, dyspnoea as well as dysphagia
Bas et al. (2006)

• A 59-year-old patient
• 4 episodes laryngeal (particularly)
significant relief of symptoms

The other attacks were successfully treated

complete recovery

Laryngeal oedema
(endoscopic finding)
 36

Advantages Inconvenients
• Active in all types of attacks (cutaneous, abdominal, laryngeal) • Not for oral administration
• Excellent systemic safety demonstrated to date • Access
• Ease of use: subcutaneous administration
• Pre-filled syringe (stable in solution at room temperature >1 year)
• Synthetic product (not plasma-derived, not recombinant)

European Commission Approval (July 2008)

Non-approvable letter for HAE (April 2008)

« …Because the protocol developed by Jerini pooled numerical data from multiple types of attacks, the data analysis
may have led to difficulties with adequate comparisons »
 37

Avis
29 octobre 2008

• D'après les résultats des essais cliniques il n’est pas attendu d'impact pour la spécialité
FIRAZYR en termes populationnel sur la morbi-mortalité et la qualité de vie des patients.

• Les éléments disponibles ne permettent pas de présumer que la spécialité FYRAZYR

apportera une réponse supplémentaire au besoin identifié. Ce d’autant que le produit n’est pas
auto-administrable par le patient.

• En conséquence, en l’état actuel des connaissances, il n’est pas attendu d’intérêt de santé
publique pour la spécialité FIRAZYR dans cette indication.

• SMR
important
•Amélioration du SMR
mineure (ASMR IV) dans la prise en charge des crises d’angio-oedème
héréditaire.

• Recommandations de la Commission de la Transparence :

- Mise à disposition de FIRAZYR en seringue auto-injectable par les patients

Phase IIa trial in
liver cirrhosis
Use of bradykinin-B2
receptor
antagonists for
treating osteoarthritis
38
EU and US phase IIb
studies in osteoarthritis
pain
………………………..
Discontinued due to lack
of efficacy
Phase IIa trials for
osteoarthritis pain Kos returned the rights
to the product to Jerini
(for asthma)
acquired Jerini
Kos and Jerini the product did not
in agreement appear on Jerini's
for the pipeline in May 2008
development,
marketing and
distribution of
icatibant Use of kinin antagonists

2001 2002 2003 2004 2005 2006 2007 2008

Jerini licensed Phase IIa Phase I trials in Phase III trial the FDA issued a
exclusive worldwide proof-of- edema with FAST-2 non-approvable
development and concept trial severe burns letter
commercialization was initiated ………………
rights to the drug in HAE the FDA granted
Dec : Jerini and The drug was
from Aventis Orphan Drug
Abbott, following approved by the
status for the
Jerini received its acquisition of EMEA for HAE
treatment of
European Kos were also under the
edema in severe
Phase I trials in Orphan Drug developing an
burn patients trademark Firazyr
liver cirrhosis designation inhaled
for icatibant formulation of
(FDA  for Sept : Phase III HAE icatibant for the
angioedema trials designated potential
FAST-1 Icatibant indications in
treatment of
edema with severe
asthma
burns, as well
as ascites in liver
cirrhosis were no longer
listed on the Company’s
pipeline  still capillary
leak syndrome
 39

Non peptide B2 antagonists

(1993)
Random screening

Ki = 64 nM

Ki ~ µM
not specific for BK
(1997)
(1997)

= Anatibant

Ki = 20 nM Ki = 0.67 nM

Anatibant : Brain oedema (head trauma or stroke) : No safety issues

2008 : Phase I clinical study in patients with severe traumatic brain injury Pharmacokinetics
 Bradykinin and cancer 40

BK  important growth factor for small-cell lung cancer and prostate cancer

3rd Generation antagonist :

B-9430 No action on tumor growth

B-9870
Suim = suberimidyl moiety
1997 -C(=NH)-(CH2)6-C(=NH)-

J. Stewart

- Blocked the proliferation of tumour-derived cell lines (activation of c-Jun kinase, caspase 3 ( apoptosis) and
antagonizes BK-induced calcium signalling )
- Dual B1R and B2R antagonist / partial agonist in lung cancer cell lines + "biased agonist" action
- Icatibant  lower efficacy (minor activation of endocytosis and ERK kinase activation)
- Idem for Hoe 140 dimer (B-9872)
2008 : Phase I Clinical : small cell and non small cell lung cancer

(Lung cancer cell line) (Prostate cancer cell line)

 41

Bibliography
• Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies
• Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies
• Inhibition of the response to nasal provocation with bradykinin by HOE-140: efficacy and duration of action
• Nonpeptide antagonists for kinin receptors
• A non-peptide antagonist unusually selective for the human form of the bradykinin B2 receptor
• Review : Kallikrein–kinin in infection and cancer
• The design of non peptide human bradykinin B2 receptor antagonists employing the Benzodiazepine peptidomimetic scaffold
• Knee osteoarthritis: a role for bradykinin?
• Hereditary Angioedema by the New england journal
• C1inhibitor deficiency: consensus document
• Hereditary and acquired angioedema: Problems and progress: Proceedings of the third C1 esterase inhibitor deficiency workshop and beyond
• Hereditary angioedema: Optimal therapy
• Current and future therapy for hereditary angioedema
• What future for the new therapies?
• Bradyzide, a potent non-peptide B2 bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesia
• Synthesis and Structure-Activity Relationships of Potent New AngiotensinConverting Enzyme Inhibitors Containing Saturated Bicyclic Amino Acids’
• The Kallikrein-Kinin System: Current and Future Pharmacological Targets
• The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins
• International Union of Pharmacology. XLV.Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological
Consequences
• La bradykinine par M/S
• The Role of Plasma High Molecular Weight Kininogen in Experimental Intestinal and Systemic Inflammation
• Bradykinin receptors and their antagonists
• Antagonist, partial agonist and antiproliferative actions of B-9870 (CU201) as a function of the expression and density of the bradykinin B1 and B2
receptors
• CHMP ASSESSMENT REPORT FOR Firazyr
• The Kallikrein-Kinin System: Current and Future Pharmacological Targets
• Role of kinins in seasonal allergic rhinitis: Icatibant, a bradykinin B2 receptor antagonist, abolishes the hyperresponsiveness and nasal eosinophilia
induced by antigen
• Inhibition of bradykinin-induced vasodilation in human forearm vasculature by icatibant, a potent B2-receptor antagonist
• Reduction by Hoe 140, the B2 kinin receptor antagonist, of antigen-induced nasal blockage
• Efficacy and tolerability of Icatibant (Hoe 140) in patients with moderately severe chronic bronchial asthma
• Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant
• Bradykinin antagonists modified with dipeptide mimetic b-turn inducers
• Bradykinin receptor ligands: therapeutic perspectives
• Bradykinin antagonists as new drugs for prostate cancer
• Combination cancer chemotherapy with one compound: Pluripotent bradykinin antagonists
• …………………………..
• …………………………………and more