WO2021198588A1 - Phytoecdysones et leurs dérivés pour leur utilisation dans le traitement d'altérations de la fonction respiratoire lors d'une infection virale - Google Patents
Phytoecdysones et leurs dérivés pour leur utilisation dans le traitement d'altérations de la fonction respiratoire lors d'une infection virale Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the invention relates to the use of phytoecdysones and semisynthetic derivatives of phytoecdysones for the treatment of alterations in respiratory function, particularly in the context of pathologies of viral origin.
- viruses responsible for these infections are numerous. These include rhinovirus, respiratory syncytial virus, influenza virus (influenza), influenza A (H1N1) virus and coronaviruses.
- ARDS represents the main cause of death in patients infected with coronaviruses (Greenland et al. 2020; Zhou et al. 2020). Therefore, it is essential to detect and treat respiratory disease as early as possible.
- the three main fatal coronavirus epidemics in the 21 st century are those of 2003 (SARS-CoV originating in the province of Guangdong, China), that of 2012 (MERS-CoV originating in the middle east) and that of 2019 (SARS -CoV2, from Hubei, China).
- SARS-CoV originating in the province of Guangdong, China
- 2012 MERS-CoV originating in the middle east
- 2019 SARS -CoV2
- respiratory failure characterized by the inability of the respiratory system to provide adequate oxygenation and elimination of carbon dioxide, is common in patients infected with coronaviruses.
- the angiotensin-2 converting enzyme (ACE2), especially expressed in pulmonary epithelial and endothelial cells, is the receptor for SARS-CoV and SARS-CoV-2, respectively responsible for SARS epidemics of 2003 and 2019 (Hoffmann et al. 2020; Wan et al. 2020; Xu et al. 2020).
- ACE2 which is part of the renin angiotensin (RAS) system, converts angiotensin II (Ang II) to angiotensin 1-7 (Ang-1-7).
- Ang-1-7 mediates anti-inflammatory, antioxidant and vasodilator effects by binding to the Mas receptor (MasR) (Magalhaes et al. 2018; Jiang et al.
- ACE converts angiotensin I (Ang I) into angiotensin II (Ang II).
- Ang II angiotensin II
- AT1 Ang II type 1 receptor
- the axes ACE / Ang II / AT1 and ACE2 / Ang-1-7 / MasR are respectively known as the “harmful” and “protective” arm of the ARS (Santos et al. 2013).
- Angiotensin 1-7 also has vasodilator properties and has hypotensive (Benter et al. 1993) and antihypertensive (Zhang et al. 2019) effects.
- Phytoecdysones represent an important family of polyhydroxylated phytosterols structurally related to insect molting hormones. These molecules are produced by many plant species and participate in their defense against insect pests. The major phytoecdysone is 20-hydroxyecdysone (20E).
- 20E is pharmacologically active in mammals. It activates the Mas receptor on the protective arm of the ARS (Dilda et al. 2019). Mas engagement by 20E is responsible for a number of preclinical beneficial activities in normal and pathological settings.
- 20-Hydroxyecdysone has anti-inflammatory effects in vivo in a mouse model of acute lung injury (ALI). Inflammatory (TNF- ⁇ , IL-2, IL-6, IL-8) and anti-inflammatory (IL-4, IL-10) cytokines in plasma are respectively reduced and increased by treatment with 20-hydroxyecdysone. Modulation of inflammation is associated with decreased lung lesions, as shown by histological examination of the lungs of treated animals (Xia et al. 2016; Song et al. 2019).
- BIO101 is an oral preparation of 20-hydroxyecdysone with a purity greater than or equal to 97%. Its method of preparation is disclosed in international patent application WO2018197731 (Lafont et al. 2018). BI0101 is a new drug candidate clinically developed in sarcopenia and Duchenne muscular dystrophy. This latter therapeutic application is the subject of international patent application WO201 8197708 (Dilda et al. 2018). Hemi-synthetic derivatives of 20-hydroxyecdysone have also been developed, as disclosed in international patent application WO2015177469 (Lafont et al. 2015), and are used for such therapeutic applications.
- ACE enzyme converting agent
- AT1 angiotensin 2 receptor antagonists
- the invention relates to a composition
- a composition comprising at least one phytoecdysone and / or at least one semisynthetic derivative of phytoecdysone, for its use in the treatment of an impairment of respiratory function resulting from an infection viral in mammals.
- a hypotensive effect can be harmful in a situation of respiratory distress linked in particular to a viral infection and a state of shock (Bitker & Burell et al. 2019; Wujtewicz et al. 2020).
- Phytoecdysones and their synthetic hemi derivatives also advantageously have no effect on peak inspiratory flow (PID), on peak expiratory flow (PEF), on respiratory rate and finally on PenH.
- the invention further meets the following characteristics, implemented separately or in each of their technically operative combinations.
- the phytoecdysones and their derivatives are advantageously purified to pharmaceutical grade.
- a phytoecdysone that can be used according to the invention is, for example, 20-hydroxyecdysone and a semisynthetic derivative of phytoecdysone that can be used is, for example, a semisynthetic derivative of 20-hydroxyecdysone.
- the composition comprises 20-hydroxyecdysone and / or at least one synthetic hemi derivative of 20-hydroxyecdysone.
- 20-hydroxyecdysone and its derivatives are advantageously purified to pharmaceutical grade.
- the 20-hydroxyecdysone used is preferably in the form of a plant extract rich in 20-hydroxyecdysone or of a composition comprising 20-hydroxyecdysone as an active agent.
- Plant extracts rich in 20-hydroxyecdysone are, for example, extracts of Stemmacantha carthamoides (also called Leuzea carthamoides), Cyanotis arachnoidea and Cyanotis vaga.
- the extracts obtained are preferably purified to pharmaceutical grade.
- the 20-hydroxyecdysone is in the form of a plant extract or a part of a plant, said plant being chosen from plants containing at least 0.5% of 20-hydroxyecdysone by dry weight of said plant, said extract comprising at least 95%, and preferably at least 97%, of 20-hydroxyecdysone.
- Said extract is preferably purified to pharmaceutical grade.
- Said extract is hereinafter called BIO101. It remarkably comprises between 0 and 0.05%, by dry weight of the extract, of impurities, such as minor compounds, liable to affect the harmlessness, availability or efficacy of a pharmaceutical application of said. extract.
- the impurities are compounds with 19 or 21 carbon atoms, such as Rubrosterone, Dihydrorubrosterone or Poststerone.
- BIO101 is produced is preferably chosen from Stemmacantha carthamoides (also called Leuzea carthamoides), Cyanotis arachnoidea and Cyanotis vaga.
- the phytoecdysone derivatives and in particular of 20-hydroxyecdysone are obtained by semisynthesis and can in particular be obtained as described in international patent application No. WO2015177469 (Lafont et al. 2015).
- the invention is aimed at the composition for its use in the treatment of an impairment of respiratory function resulting from a viral infection in mammals by a virus chosen from rhinovirus, respiratory virus. syncytial, influenza virus (influenza), influenza virus A H1 N1) and coronavirus.
- a virus chosen from rhinovirus, respiratory virus. syncytial, influenza virus (influenza), influenza virus A H1 N1) and coronavirus.
- the direct activation of the "protective" arm of the renin angiotensin system (RAS), downstream of the angiotensin-2 converting enzyme (ACE2), via the activation of the Mas receptor seems to be an option of effective treatment to restore the balance of the ARS and thus protect patients infected with an acute respiratory distress syndrome (ARDS) coronavirus.
- RAS renin angiotensin system
- ACE2 angiotensin-2 converting enzyme
- the invention is aimed at the composition for its use in the treatment of an alteration in respiratory function resulting from a viral infection by a coronavirus using ACE2 as a receptor on the surface of mammalian cells. .
- the invention relates to the composition for its use in the treatment of impaired respiratory function resulting from a viral infection with SARS-CoV in mammals.
- SARS-CoV is a coronavirus that causes severe acute respiratory syndrome.
- the invention relates to the composition for its use in the treatment of an impairment of respiratory function resulting from a viral infection by SARS-CoV2 in mammals.
- SARS-CoV2 is a type 2 coronavirus responsible for the severe acute respiratory syndrome of the COVID-19 pandemic.
- the treatment of impaired respiratory function comprises the prevention and treatment of respiratory failure in mammals suffering from viral infection.
- the treatment of impaired respiratory function comprises the prevention and treatment of acute respiratory distress syndrome in mammals affected by the viral infection.
- the invention relates to the composition for its use in the treatment of at least one or more of the alterations of the respiratory function in the mammal affected by the viral infection, chosen from hypoxia and the decrease in the ability to remove CO2.
- the treatment of the impairment of the respiratory function comprises the treatment of the respiratory muscle function.
- the invention is aimed at the composition for its use in mammals in the treatment of an alteration in respiratory function linked to the evolution of at least one of the parameters chosen from:
- the phytoecdysones are administered at a dose of between 1 and 15 milligrams per kilogram per day in humans.
- the term “phytoecdysone” is understood here to mean both phytoecdysones in general and their derivatives, 20-hydroxyecdysone (in particular in the form of an extract) and its derivatives.
- the phytoecdysones are administered at a dose of 200 to 1000 mg / day, in one or more intakes, in an adult human, and a dose of 5 to 350 mg / day, in one or more intakes, in the human child or infant.
- the term “phytoecdysone” is understood here to mean both phytoecdysones in general and their derivatives, 20-hydroxyecdysone (in particular in the form of an extract) and its derivatives.
- the composition comprises at least one compound considered to be a phytoecdysone derivative, said at least one compound being of general formula (I): [Chem. 1] in which :
- Q is a carbonyl group
- R 1 is chosen from: a (Ci-C6) W (Ci-C6) group; a (Ci-C6) W (Ci-C6) W (Ci-C 6 ) group; a (Ci-C6) W (Ci-C6) CC> 2 (Ci-C6) group; a (CI-C6) A group, A representing a heterocycle optionally substituted by a group of OH, OMe, (C1-C6), N (CI-C6), C02 (C1-C6) type; a CH2Br group;
- W being a heteroatom chosen from N, O and S, preferably O and even more preferably S.
- (C1-C6) any alkyl group of 1 to 6 carbon atoms, linear or branched, in particular, methyl, ethyl, n-propyl, iso -propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, n-hexyl.
- it is a methyl, ethyl, iso-propyl or t-butyl group, in particular a methyl or ethyl group, more particularly a methyl group.
- Y is a hydroxyl group
- R 1 is chosen from: a (Ci-C6) W (Ci-C6) group; a (Ci-C6) W (Ci-C6) W (Ci-C 6 ) group; a (Ci-C6) W (Ci-C6) CC> 2 (Ci-C6) group; a (CI-C6) A group, A representing a heterocycle optionally substituted by a group of OH, OMe, (OI-OQ), N (OI-OQ), C02 (CI-Ce) type; W being a heteroatom chosen from N, O and S, preferably O and more preferably S.
- the composition comprises at least one compound chosen from the following compounds: No. 1: (2S, 3R, 5R, 10R, 13R, 14S, 17S) -2,3,14-trihydroxy-10 , 13-dimethyl-17- (2-morpholinoacetyl) -2,3,4,5,9,11, 12,15,16,17-decahydro-1 H-cyclopenta [a] phenanthren-6-one, no.
- n ° 6 2- [2-oxo-2 - [(2S, 3R, 5R, 10R, 13R, 14S, 17S) -2,3,14-trihydroxy-10,13-dimethyl-6-oxo-2, 3,4,5,9,11,12,15,16,17-decahydro-1 H-cyclopenta [a] phenanthren-17-yl] ethyl] sulfanylacetate; n ° 7: (2S, 3R, 5R, 10R, 13R, 14S, 17S) -17- (2-ethylsulfanylacetyl) -2,3,14- trihydroxy-10,13-dimethyl-2,3,4,5, 9,11,12,15,16,17-decahydro-1 H-cyclopenta [a] phenanthren-6-one; n ° 8: (2S,
- the composition comprises at least one compound considered to be a phytoecdysone derivative, said at least one compound being of formula (II): [Chem. 2]
- the compound of formula (II) is hereinafter called BI0103.
- composition is incorporated into an acceptable pharmaceutical formulation which can be administered orally.
- acceptable pharmaceutical which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and which is acceptable for veterinary use as well as human pharmaceutical.
- Figure 1 is a diagram illustrating the scientific rationale for activating the ACE2 / Ang 1-7 / Mas arm in patients with coronavirus using ACE2 as a receptor.
- FIG. 2A represents a graph illustrating the absence of an antihypertensive effect of BIO101 in spontaneously hypertensive animals.
- the effects of BIO101 alone were evaluated after single oral administration.
- Six SH rats were used in cross-treatments (crossover treatment) with a minimum elimination period of 72 hours between treatments. Prior to treatment, the animals were fitted with telemetry instruments for blood pressure measurements.
- the animals received the treatments following: vehicle, or BIO101 at 5 mg / kg, or BIO101 at 50 mg / kg, or Enalapril at 50 mg / kg.
- FIG. 2B represents a graph illustrating the absence of a hypotensive effect of BIO101 in hypertensive animals already treated with an antihypertensive agent: Enalapril.
- Enalapril is a converting enzyme inhibitor (ACE).
- ACE converting enzyme inhibitor
- the effects of BIO101 alone were evaluated after repeated administration in animals treated for 4 days with Enalapril (30 mg / kg * day).
- Six SH rats were used in cross-treatments (cross-over treatment) with a minimum elimination period of 72 hours between treatments. Prior to treatment, the animals were fitted with telemetry instruments for blood pressure measurements. For the experiment described in FIG.
- the animals received the following treatments: Enalapril at 30 mg / kg for 4 days, or Enalapril at 30 mg / kg + BI0101 at 5 mg / kg for 4 days, or Enalapril at 30 mg / kg / kg + BI0101 at 50 mg / kg for 4 days.
- FIG. 3A represents a graph illustrating the effects of BIO101 on the mean arterial pressure evaluated after single oral administration.
- Four beagle dogs were used in cross-treatments (crossover treatment) with a elimination period of at least 72 hours between treatments. Prior to treatment, the animals were fitted with telemetry instruments for blood pressure measurements. For the experiment described in Figure 3A, the animals received the following oral treatments: vehicle, or BIO101 at 30 mg / kg, or BIO101 at 120 mg / kg, or BIO101 at 500 mg / kg.
- FIG. 3B represents a graph illustrating the effects of BIO101 on heart rate evaluated after single oral administration.
- Four beagle dogs were used in cross-treatments (crossover treatment) with a minimum elimination period of 72 hours between treatments. Prior to treatment, the animals were fitted with telemetry instruments for heart rate measurements. For the experiment described in FIG. 3B, the animals received the following oral treatments: vehicle, or BIO101 at 30 mg / kg, or BIO101 at 120 mg / kg, or BIO101 at 500 mg / kg.
- FIG. 4A represents a graph illustrating the absence of effects of BIO101 on the peak inspiratory flow (PID) after oral administration of single doses. Eight rats were used in cross-treatments (cross-over treatment) with a minimum elimination period of 72 hours between treatments.
- PID peak inspiratory flow
- the animals received the following oral treatments: vehicle, or BIO101 at 100 mg / kg, or BIO101 at 300 mg / kg, or BIO101 at 1000 mg / kg.
- the respiratory parameters are measured by plethysmography for 4 h 30 min.
- Figure 4B is a graph illustrating the lack of effect of BI0101 on peak expiratory flow (PEF) after oral administration of single doses.
- Eight rats were used in cross-treatments (cross-over treatment) with a elimination period of at least 72 hours between treatments.
- the animals received the following oral treatments: vehicle, or BIO101 at 100 mg / kg, or BIO101 at 300 mg / kg, or BIO101 at 1000 mg / kg.
- the respiratory parameters are measured by plethysmography for 4 h 30 min.
- Figure 4C is a graph illustrating the lack of effect of BI0101 on respiratory rate after oral administration of single doses.
- Eight rats were used in cross-treatments (crossover treatment) with a elimination period of at least 72 hours between treatments.
- the animals received the following oral treatments: vehicle, or BIO101 at 100 mg / kg, or BIO101 at 300 mg / kg, or BIO101 at 1000 mg / kg.
- the respiratory parameters are measured by plethysmography for 4 h 30 min.
- FIG. 4D represents a graph illustrating the absence of effect of BI0101 on Penh after oral administration of single doses.
- Eight rats were used in cross-treatments (cross-over treatment) with a minimum elimination period of 72 hours between treatments. For this experiment, the animals received the following oral treatments: vehicle, or BIO101 at 100 mg / kg, or BIO101 at 300 mg / kg, or BIO101 at 1000 mg / kg.
- the respiratory parameters are measured by plethysmography for 4 h 30 min.
- Figure 5 shows the pharmacokinetic profiles of BIO101 in Syrian hamster plasma. These are graphs representing the plasma concentrations as a function of time after a single oral administration (PO) of BIO101 at 50 mg / kg formulated in 4000 cP 0.5% methylcellulose medium in water (Figure 5A) or after a single intraperitoneal (IP) administration at 10 mg / kg formulated in 0.9% NaCl medium (FIG. 5B).
- PO oral administration
- IP intraperitoneal
- Figure 6 shows the timing diagram of the study of the treatment of impaired respiratory function in Syrian hamsters infected with the SARS-CoV-2 virus as well as the various parameters studied.
- Respiratory function is assessed by whole body plethysmography before inoculation and 5 days after viral infection.
- the pulmonary infectious viral load is quantified.
- FIG. 7 represents a histogram illustrating the quantification of the pulmonary viral load of the different groups of control animals not infected with SARS-CoV-2 (control), infected with SARS-CoV-2 and treated with the vehicle (SARS-CoV-2 + vehicle) or infected with SARS- CoV-2 treated with BIO101 IP (SARS-CoV-2 + BIO101).
- FIG. 8A is the schematic representation of a plot of the recording of a breathing cycle (inspiration then expiration) and of the various data that can be recorded by whole body plethysmography.
- DIP Peak inspiratory flow
- DEP Peak expiratory flow
- PTE Tele-expiratory pause
- TE Expiration time
- Tl Inspiration time
- TR expiration time required to expire 65% of the total volume d 'air.
- FIG. 8B represents the Penh values of the non-controlled control groups.
- FIG. 9 represents different respiratory parameters measured by whole body plethysmography of the different groups of control animals not infected with SARS-CoV-2 (control), infected with SARS-CoV-2 and treated with the vehicle ( SARS-CoV-2 + vehicle) or infected with SARS-CoV-2 treated with BIO101 IP (SARS-CoV-2 + BIO101).
- the parameters measured are: inspiration time in milliseconds ( Figure 9A), expiration time in milliseconds ( Figure 9B), tele-expiratory pause in milliseconds ( Figure 9C) with * p ⁇ 0.05, and
- the study concerns adults aged 18 and over, suffering from a SARS-CoV-2 infection proven by PCR, during the last 28 days and who have developed severe manifestations, during the last 7 days, defined as: signs of respiratory decompensation by one of the following parameters: a respiratory rate greater than or equal to 25 respiratory cycles (inspiration and expiration) per minute and / or arterial oxygen saturation less than or equal to 92% in air ambient or with 3 liters of oxygen per minute.
- BI0101 is administered orally daily.
- BIO101 is a plant extract chosen from plants containing at least 0.5% of 20-hydroxyecdysone by dry weight of said plant, said extract comprising at least 97% of 20-hydroxyecdysone.
- the effect of treatment with BIO101 on patients affected by the SARS-CoV2 coronavirus is evaluated after 7, 14 and 28 days on the basis of the following measurements:
- the effect of the treatment is also evaluated using parameters such as the sequential assessment score for respiratory failure (SOFA, Zhou et al. 2020), the pulmonary severity index (PSI, Liu et al. 2020) and medical imaging which allows the level of progression of exudative inflammatory pathology to be graded.
- SOFA sequential assessment score for respiratory failure
- PSI pulmonary severity index
- medical imaging which allows the level of progression of exudative inflammatory pathology to be graded.
- BIO101 The effect of BIO101 on the plasma level of pro-inflammatory and anti-inflammatory cytokines is also evaluated.
- BIO101 at doses of 5 and 50 mg / kg does not induce a decrease in the mean arterial pressure of hypertensive animals, whatever the dose used (FIG. 2A). BIO101 therefore has no anti-hypertensive effect.
- Enalapril an ACE inhibitor, has antihypertensive activity.
- BIO101 on the respiratory parameters by plethysmography in vigilant rats after oral administration at doses of 100, 300 and 1000 mg / kg.
- single oral administration of BIO101 at 100, 300 or 1000 mg / kg had no effect on peak inspiratory flow (PID, Figure 4A), on peak expiratory flow ( DEP, Figure 4B), on the respiratory rate (Figure 4C) and finally on the PenH (Figure 4D).
- a pharmacokinetic study of BI0101 was previously carried out in healthy hamsters, without viral infection, in order to determine which route of administration made it possible to obtain plasma exposure in hamsters, similar to the plasma exposure found in male, after oral administration at 350 mg bid of BI0101 for 14 days in a phase 1 clinical study.
- BIO101 The pharmacokinetic study of BIO101 was performed using female Syrian hamsters, 6-7 weeks old.
- the BIO101 molecule was administered either orally (PO, gavage) at a dose of 50 mg / kg of body weight, or intraperitoneally (IP), at a dose of 10 mg / kg of body weight.
- PO orally
- IP intraperitoneally
- the blood samples were centrifuged and the plasmas collected.
- a calibration curve is carried out with 9 standards (from 10,000 ng / mL to 10 ng / mL) and three quality controls (from 4000 ng / mL to 40 ng / mL).
- the dilution of the standards is carried out in hamster plasma.
- a part of each sample (standard solutions, or quality control) is transferred to a 96-well plate (200 ⁇ L).
- 4 ⁇ L of an internal standard is added (Cyasterone at 10 ⁇ g / mL in MeOH). Samples are prepared by deproteinization with the addition of 4 volumes of MeOH (80 ⁇ l). After centrifugation, the supernatants of the samples are transferred to a 96-well plate (150 ⁇ l) before injection.
- LC-MS / MS analysis is carried out with a 1260 Infinity HPLC chain, and a QQQ6420 mass spectrometer with an ESI source in positive mode (MRM).
- the injection volume is 5pL.
- BIO101 is eluted on a C18 reversed phase column (2.1 * 50 mm, particles 3.5 ⁇ m; Fortis) with a gradient of acetonitrile and water (containing 0.1% formic acid) and a flow rate of 0.3 mL / min.
- the assay of the plasma samples made it possible to determine the pharmacokinetic parameters, namely the Cmax, which corresponds to the maximum concentration observed after administration of the molecule, the Tmax which is the time required to reach the maximum concentration after administration of the molecule and the AUC: the area under the curve which corresponds to the plasma exposure.
- BIO101 allows a plasma exposure very close to that found in humans after oral administration of BIO101 for 14 days, at 350 mg bid (3841 ng.h / ml).
- BIO101 in order to test the efficacy of BI0101 in hamsters, after viral infection with SARS-CoV-2, the IP administration of BIO101 was chosen.
- a stock inoculum was prepared, with a titre of 10 6 TCID 50 / mL of the strain BetaCov / Belgium / Sart-Tilman / 2020/1 (Misset et al., 2020) from SARS-CoV-2.
- An inoculum consisting of 100 microliters of this stock was inoculated into each hamster, ie 50 microliters in each nostril. Inoculation was performed under brief general anesthesia with isoflurane. Animals waking up from anesthesia after 90 seconds or less.
- BIO101 was administered daily, for 7 days, intraperitoneally (IP) at 10 mg / kg formulated in 0.9% NaCl medium.
- VeroE6 cells are seeded (7.5 ⁇ 10 3 cells per 100 ⁇ l in DMEM / 10% FBS culture medium) then left to incubate overnight. The next day the cells are visualized under a light microscope to confirm that the cells are evenly distributed and have reached about 75% confluence.
- serial dilutions (1:10) of lung homogenates are prepared in infection medium (DMEM / FBS2%). After removing the growth medium from the cells, the various preparations of pulmonary homogenates are transferred to the previously prepared VeroE6 cell mats. The cells are incubated for 2 hours at 37 ° C. then 100 ⁇ L of infection medium is added to each well. The plates are incubated at 37 ° C.
- the viral titer is calculated according to the standard method of Reed and Muench. For example, a titer expressed as 10 3 TCID50 / mL in 5 days in the VeroE6 cell line can be translated as: 1 mL of pulmonary homogenate diluted to 1: 1000 will infect 50% of cells in 5 days when using the Vero E6 cell line. Seven days after the inoculation of SARS-CoV-2, a pulmonary viral load is still detectable in the lungs of infected hamsters.
- Penh is an important index to define because its variations evolve in parallel with those of the respiratory resistance and it therefore represents a predictive parameter of the changes in the resistive properties of the respiratory system (Hamelmann et al., 1997; Bergren; , 2001; Onclinx et al., 2003).
- Penh is significantly increased in the group of hamsters infected with SARS-CoV-2 treated with the vehicle , compared to the uninfected control group (respectively 0.63 ⁇ 0.11 versus 0.28 ⁇ 0.01; p ⁇ 0.01).
- the Penh value (0.35 ⁇ 0.02) is significantly lower when compared to the animals infected and treated with the vehicle (p ⁇ 0.05) (FIG. 8B).
- TEP tele-expiratory pause
- Figure 8A and 9C Another parameter of the respiratory cycle was evaluated. This is the tele-expiratory pause (TEP) ( Figure 8A and 9C).
- the TEP corresponds to the expiratory flow plateau at the end of expiration.
- the bronchioles are at least partially obstructed, therefore resistance to flow is increased, which slows emptying and prolongs TEP (Menachery et al., 2015).
- the length of the TEP therefore provides a measure of the difficulty in exhaling at the end of the tidal volume and this difficulty is proportional to the degree of obstruction of the lower airways (either by a luminal obstacle or simply because the inflammatory edema of the wall narrows the section area).
- the expiratory pause time significantly increases in hamsters infected with SARS-CoV-2 compared to hamsters of the uninfected control group (respectively 18.8 ⁇ 1.6 msec versus 12.4 ⁇ 0.5 msec; p ⁇ 0.01).
- this expiratory pause time was significantly lower (12.6 ⁇ 0.3 msec; p ⁇ 0.01) compared to infected animals treated with the vehicle.
- BIO101 The daily administration of BIO101 for 5 days restores the expiratory pause time of the treated animals (95% CI: 11.9-13.4), to a level comparable to that found in the uninfected control animals (CI 95%: 11.3-13.4) ( Figure 9C).
- BIO101 administered intraperitoneally at a dose of 10 mg / kg * day, provides plasma exposure of BIO101 in hamsters similar to that obtained in patients exposed to 350 mg of BI0101 twice daily for 14 days. In addition, 7 days post infection, BI0101 had no significant effect on pulmonary viral load.
- this study demonstrates significant beneficial effects of treatment with BIO101, on the respiratory parameters of hamsters infected with SARS-CoV-2, in particular on indicators which measure the resistance of the respiratory tract to air passage (Penh, PTE).
- the viral disease has been shown to increase the resistance of the airways, which is expected in acute lung infections.
- This study on respiratory function performed by whole body plethysmography reveals that BIO101 significantly attenuates this dysfunction (Penh, PTE) but also the prolongation of the expiration time during the disease, which confirms the attenuation of PTE.
- Bitker L, Burrell LM. Classic and nonclassic renin-angiotensin Systems in the critically ill. Crit. Clin Care 2019; 35: 213-227.
- Angiotensin-converting enzyme 2 / angiotensin- (1-7) / Mas axis protects against lung fibrosis by inhibiting the MAPK / NF-kB pathway. Am J Respir Cell Mol Biol. 2014; 50 (4): 723-736.
- the angiotensin-converting enzyme 2 / angiotensin (1-7) / Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA / Rho kinase pathway. Antioxid Redox Signal.
- Onclinx C Relationship between total pulmonary resistance and Penh according to the anatomical location of the airway obstruction (in-depth dissertation). University of Liège, Faculty of veterinary medicine: Liège, (2003).
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WO2018197708A1 (fr) | 2017-04-28 | 2018-11-01 | Biophytis | Utilisation de 20-hydroxyecdysone et ses dérivés dans le traitement des myopathies |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2024134105A1 (fr) | 2022-12-23 | 2024-06-27 | Biophytis | Phytoecdysones pour leur utilisation dans le traitement de pathologies respiratoires inflammatoires |
FR3143975A1 (fr) | 2022-12-23 | 2024-06-28 | Biophytis | Phytoecdysones pour leur utilisation dans le traitement de pathologies respiratoires inflammatoires |
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AU2021250695A1 (en) | 2022-10-27 |
FR3108504A1 (fr) | 2021-10-01 |
KR20230011278A (ko) | 2023-01-20 |
US20230128105A1 (en) | 2023-04-27 |
CN115776892A (zh) | 2023-03-10 |
JP2023519710A (ja) | 2023-05-12 |
MX2022012262A (es) | 2023-01-18 |
EP4125922A1 (fr) | 2023-02-08 |
CA3173112A1 (fr) | 2021-10-07 |
FR3108504B1 (fr) | 2023-03-31 |
IL296757A (en) | 2022-11-01 |
BR112022019679A2 (pt) | 2022-12-20 |
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