WO2022038131A1 - Méthode de prédiction de l'évolution ou du pronostic de la réponse d'un patient souffrant d'une lésion aiguë d'un organe - Google Patents

Méthode de prédiction de l'évolution ou du pronostic de la réponse d'un patient souffrant d'une lésion aiguë d'un organe Download PDF

Info

Publication number
WO2022038131A1
WO2022038131A1 PCT/EP2021/072828 EP2021072828W WO2022038131A1 WO 2022038131 A1 WO2022038131 A1 WO 2022038131A1 EP 2021072828 W EP2021072828 W EP 2021072828W WO 2022038131 A1 WO2022038131 A1 WO 2022038131A1
Authority
WO
WIPO (PCT)
Prior art keywords
tachykinin
precursor
organ damage
subject
acute
Prior art date
Application number
PCT/EP2021/072828
Other languages
English (en)
Inventor
Manuel Vicente SALINAS-MARTIN
Original Assignee
Plus Vitech, S.L.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Plus Vitech, S.L. filed Critical Plus Vitech, S.L.
Publication of WO2022038131A1 publication Critical patent/WO2022038131A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a method to predict the progression and/or mortality of acute organ damage, particularly acute organ damage induced by viral infection.
  • the present invention relates to a method for the prediction of response of acute organ damage, particularly such damage induced by viral infection, if the subject is given a treatment (a) a NKi inhibitor, which is preferably aprepitant, fosaprepitant or maropitant, or a pharmaceutically acceptable salt of either thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof, wherein (a) and (b) may be administered alone or in combination.
  • the present invention also relates to treating patients identified to be more at risk of acute organ damage via the invention with such drugs.
  • SARS severe Acute Respiratory Syndrome
  • MERS Middle East respiratory Syndrome
  • SARS and MERS in general cause high pathogenicity and mortality rates in human populations (Song et al. 2019), in some cases causing fatal Acute Lung Injury (ALI) (2).
  • the clinical symptoms of SARS are accompanied by damage to the lungs (3) and acute renal impairment (4).
  • Both SARS and MERS are associated with virus infection, among which newly-emerging coronavirus strains, e.g. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, known more commonly as Covid-19) and influenza virus strains (e.g. H7N9) can be particularly prominent (5), as well as the influenza virus family. It can result in diffuse alveolar damage (6) (Song et al. 2019) and renal failure (4).
  • coronavirus strains e.g. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, known more commonly as Covid-19)
  • influenza virus strains e.g. H7N
  • Macroscopic examination at autopsy (3) indicates that lungs in deceased patients with fatal ALI (such as in SARS) are characterised by: haemorrhagic fluid in pleural cavity, localized haemorrhage under pleura, pleural adhesions, focal sub-pleural haemorrhage, thrombus present at pulmonary artery, lung bilateral consolidation (focal or extensive), red- coloured haemorrhagic infarct present at cut surface of lung, focal haemorrhage in mucosa, blood-stained purulent or pale red fluid in lumen, and congestion and focal haemorrhage in mucosa at the level of trachea.
  • ALI such as in SARS
  • mice in deceased patients with fatal ALI are characterised by: extensive bilateral consolidation, severe pulmonary oedema, haemorrhagic infarction, desquamative alveolitis and bronchitis with proliferation and desquamation of alveolar epithelial cells, alveolar exudation of mononuclear cells (lymphocytes and plasma cells), alveolar oedema, desquamated epithelial cells (enlarged and some had undergone fusion to form syncytia), extensive hyaline membranes in alveoli, focal necrosis with infiltration of neutrophils, monocytes, and lymphocytes, capillaries in interlobular septa and alveolar walls dilated and congested, alveolar exudates organized and fibrosed, endothelial cells of small pulmonary veins swollen and shed, oedema present in the walls of small veins and some veins showed fibri
  • the damage produced at the molecular level in articles published in patients with disease related to SARS-CoV-2 and other similar syndromes is related to the following inflammation mediators: IL-1 (7), IL-6 (7) (8) (7), IL-23 (8), INF-y (8), TNF-a (7) (8), IL-2R (9), IL-8 / CXCL8 (7) (9), TNF-a (9), IL- 10 (9).
  • the ACE2 virus binding receptor is widely expressed in the respiratory tract (11), alveolar monocytes and macrophages of the lung (12), endothelial cells of arteries and veins, mucosal cells of the intestines, tubular epithelial cells and renal tubules cells of the kidneys, cerebral neurons and immune cells, providing a variety of susceptible cells to SARS-CoV (13) (14).
  • CD209L is an alternative receptor to ACE2, for virus binding with a lower affinity (15).
  • MERS-CoV MERS-CoV
  • DPP4 dipeptidyl peptidase 4
  • CD26 CD26
  • MERS-CoV can infect several human cell lines, including lower respiratory, kidney, intestinal, and liver cells, as well as histiocytes (17), indicating that the range of MERS-CoV tissue tropism in vitro was broader than that of any other CoV.
  • MERS-CoV causes acute, highly lethal pneumonia and renal dysfunction (17).
  • NKi neurokinin 1
  • NKi inhibitors that have been approved for treating nausea and vomiting, for example acute or delayed chemotherapy-induced nausea and vomiting, or post-operative nausea and vomiting.
  • Aprepitant has also been investigated for use in treating a variety of other diseases, including depression and cancer. The latter is discussed, for example, in EP 2 837 381 Al.
  • Other NKi inhibitors are well known to those skilled in the art.
  • Gabapentinoids also known as a26 ligands, are a class of drugs that are derivatives of the inhibitory neurotransmitter y-aminobutyric acid (GABA) (i.e., GABA analogues) which block a26 subunit-containing voltage-dependent calcium channels (VDCCs), sometimes referred to as the gabapentin receptor.
  • GABA inhibitory neurotransmitter y-aminobutyric acid
  • VDCCs voltage-dependent calcium channels
  • Clinically-used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil.
  • Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome.
  • Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal.
  • Tachykinin peptides are one of the largest families of neuropeptides.
  • the Tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an Aromatic or an Aliphatic amino acid.
  • Tachykinins are from ten to twelve residues long.
  • the Tachykinin family also includes other peptides such as Neurokinin A, Neurokinin B, Neuropeptide K, Neuropeptide Gamma, and Hemokinin I, among others.
  • the Tachykinin genes in humans and others mammalians are called TAC1, TAC2, TAC3 and TAC4.
  • TAC1 encodes Neurokinin A (formerly known as substance K), Neuropeptide K (which has also been called neurokinin K), Neuropeptide Gamma, and Substance P.
  • Alpha, beta, and gamma splice forms are produced; the alpha form lacks exon 6 and the gamma form lacks exon 4. All three splice forms of TAC1 produce substance P, but only the beta and gamma forms produce the other three peptides.
  • Neuropeptide K and neuropeptide gamma are N-terminally longer versions of neurokinin A.
  • TAC3 encodes Neurokinin B.
  • TAC 4 encodes Hemokinins.
  • the present application is based on the finding that the level of Tachykinins or their precursors can be used as a way to provide a prognosis for an individual from acute organ damage, in particular where such damage is due to a viral infection, with those subjects having an increased level of one or more Tachykinin or precursor thereof being at a greater risk of a negative outcome due to the acute organ damage and in particular an increased chance of mortality.
  • those subjects with an increased level of one or more Tachykinin or a precursor thereof are those most likely to benefit from treatment, especially treatment with (a) an NKi inhibitor; and/or (b) a gabapentinoid.
  • the present invention also identifies a particular patient group for which such treatment is likely to be most beneficial.
  • the present invention provides, amongst other things, the following:
  • a method of predicting the progression of acute organ damage and/or the likelihood of mortality from acute organ damage in a subject suffering from acute organ damage comprising measuring the level of a Tachykinin or a precursor thereof in the subject.
  • a pharmaceutical composition which comprises: (a) a NKI inhibitor; and/or (b) a gabapentinoid; for use in a method for the prevention or treatment of acute organ damage, wherein the subject has increased levels of a Tachykinin or precursor thereof.
  • a method for the prevention or treatment of acute organ damage wherein the subject has increased levels of a Tachykinin or precursor thereof and the method comprises administering to the subject (a) a NKI inhibitor, and/or (b) a gabapentinoid as, optionally wherein (a) and (b) are co-administered.
  • a product comprising (a) a NK1 inhibitor and/or (b) a gabapentinoid wherein (a) and (b) are provided as a combined preparation for simultaneous, concurrent, separate or sequential use in a method for the prevention or treatment of acute organ damage wherein the subject has increased levels of a Tachykinin or precursor thereof.
  • the acute organ damage involves the lung.
  • the subject has Acute Lung Injury (ALI).
  • the subject has SARS.
  • the viral infection is infection with a coronavirus.
  • the coronavirus is the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which is the cause of COVID-19.
  • the virus is an influenza virus.
  • the subject has Middle Eastern Respiratory Syndrome (MERS).
  • Tachykinins and precursors thereof
  • the present invention is based on the measurement of Tachykinins and their precursors as an indicator of the outcome of acute organ damage and also as a way of identifying a specific patient group who the treatments outlined herein are likely to be particularly effective.
  • Tachykinins are a large family of peptides and in particular are typically neuropeptides.
  • a Tachykinin is able to bring about the contraction of gut tissue. They are found in amphibians to humans.
  • the Tachykinin is a mammalian Tachykinin.
  • the Tachykinin is a human Tachykinin.
  • the Tachykinin may be one, for instance, that comprises the consensus sequence Phe-X-Gly-Leu-Met-NH2 at its carboxyl terminus, where X is an aromatic or aliphatic amino acid.
  • Tachykinins include Substance P, Neurokinin A, Neurokinin B, Neuropeptide K, Neuropeptide gamma, Hemokinin-1, Endokinin-A, and Endokinin B. In one embodiment, any one or more of those Tachykinins is the one measured.
  • Substance P, Neurokinin A, Neuropeptide K, and Neuropeptide gamma are all encoded by the Human TAC1 gene and in one embodiment the invention may involve any one or more of those Tachykinins or a precursor thereof.
  • the Tachykinin may be Neurokinin B, which is encoded by the TAC3 in humans.
  • the Tachykinin is Endokinin-A, or Endokinin B, both of which are encoded by the TAC4 gene in humans.
  • the Tachykinin measured is Substance P or a precursor thereof.
  • Tachykinins are synthesized as larger precursor proteins which undergo post- translational proteolytic processing to generate the mature peptide product.
  • a Tachykinin is synthesized as a prepro-proteins.
  • Reference to a precursor herein in one embodiment encompasses both the prepro and pro forms.
  • reference to a precursor of a Tachykinin just includes the pro form.
  • the “pre” portion of the precursor is usually a hydrophobic signal sequence responsible for translocation to the endoplasmic reticulum which is cleaved off, with the “pro” portion then subsequently cleaved off to give the mature Tachykinin.
  • the present invention may involve any Tachykinin, for instance one named herein, but also a precursor of a Tachykinin, for instance prepro or pro form.
  • a Tachykinin or its “pro” precursor form may be measured
  • the Tachykinin measured is Substance P, Pro- Sub stance P, or Prepro- Sub stance P.
  • the Tachykinin is Substance P or Pro-substance P and in particular Substance P itself.
  • any reference to a Tachykinin herein also encompasses its prepro and pro precursor forms and similarly any mention of Substance P encompasses its prepro and procursor forms. In a preferred instance, it encompasses Substance P and its Pro form.
  • Tachykinin or precursor is taken into account, for instance a single Tachykinin or precursor may be taken into account. In another instance, one, two, three, four, or five Tachykinin or precursors may be taken into account. In a particularly preferred instance, a single Tachykinin or precursor is taken into account, which is Substance P or a precursor thereof.
  • the invention typically involves measuring the level of a Tachykinin or its precursor or is applied to subject for which the level of a Tachykinin or its precursor has been identified as high.
  • the invention identifies that such subjects are more at risk of a negative outcome in acute organ damage, particularly where the organ damage is due to infection with a virus, and also that those subjects are more likely to benefit from the treatments set out herein.
  • the level of a Tachykinin or its precursor in a subject is important in prognosis in terms of evaluating the potential outcome in a subject suffering from acute organ damage. It is also important in identifying patients who are particularly suited to treatment with a NK1 inhibitor; and/or a gabapentinoid. It may also be used to predict the chances of successful treatment with NK1 inhibitor; and/or a gabapentinoid.
  • a method of the invention may comprise measuring the level of a Tachykinin or a precursor thereof in a subject.
  • the level may be measured, for instance, in any sample from the subject that would normally contain the Tachykinin or a precursor thereof.
  • the measurement may be performed on a sample from the subject such as on blood, plasma, or serum.
  • a method is performed on blood, or a sample obtained from blood.
  • the level is determined in serum from the subject.
  • the invention may be performed with any suitable bodily fluid from the subject.
  • a method of the invention may comprise the step of obtaining the sample from the subject.
  • a method of the invention does not involve the step of obtaining the sample from the subject and, for instance, the method is performed on a sample obtained from the subject.
  • a method of the invention may also include performing the method using a control sample from a healthy subject and comparing results for the test sample and such a control.
  • a method of the invention may involve comparing the level seen in the sample from the subject with that seen in a control and may involve determining the subject is at higher risk of progression of the acute organ damage and/or mortality if the result for the test sample is higher than that for the control.
  • the control is ideally from a healthy subject, for instance from such a healthy subject of approximately the same age and sex.
  • a method of the invention may include a positive control, for instance a sample known to be at high risk.
  • a method of the invention may include performing the method on a control which is a solution with a known level of a Tachykinin or a precursor thereof.
  • the sample may have a concentration of a Tachykinin or a precursor thereof considered to represent the reference level, as discussed further herein.
  • a method of the invention may also be performed with a negative control, for instance on a sample with no Tachykinin or a precursor thereof.
  • a method may be performed with both a known standard and such a negative control.
  • a method of the invention may also involve using a standard curve, for instance one generated using samples with serial dilutions of sample with a known level of a Tachykinin or a precursor thereof
  • the level of a Tachykinin or a precursor thereof in the sample from the subject is compared to a reference level.
  • the reference level is a set cut-off above which the subject is considered at high or higher risk of progression of the acute organ damage and/or mortality from it.
  • the reference level may be any of those discussed herein.
  • the reference level is that expected for a healthy subject who does not have acute organ damage. In particular, it is that expected for a healthy subject who does not have acute organ damage, is healthy, the same age, and the same sex.
  • a subject may be classified as at high or higher risk of progression of the acute organ damage and/or mortality if the level of Tachykinin or a precursor thereof is higher in the sample from the subject than the reference level, where the reference level is that expected for such a healthy individual.
  • the reference level is not that expected for a healthy subject, for instance it may be a particular level above that of a healthy subject.
  • the reference level may be intended to subdivide sufferers with acute organ damage into a group considered to have “high” or “higher” levels of Tachykinin or a precursor thereof and a “low” or “lower” group, with the high or higher group more likely to show progression of the acute organ failure and/or mortality, but also more likely to benefit from the treatment discussed herein.
  • the reference level may be any of the amounts discussed herein above that expected for a healthy subject.
  • the subject is considered to have an elevated level of Tachykinin or a precursor thereof if the value for them exceeds 150%, 175%, 200%, 250%, 300% or more than the value expected for a healthy subject and the reference level may be therefore one of those thresholds.
  • the subject is considered at risk or in the higher group of they have at least 150% of the amount expected for a healthy subject.
  • the subject is considered at risk if the level of Tachykinin or a precursor thereof is at least twice that expected for a healthy subject.
  • the subject is considered at higher risk if the level of the Tachykinin or a precursor thereof is at least three times the value expected for a healthy subject.
  • the subject is considered at risk if they have at least two to three times that expected for a healthy subj ect. In some instances, the subject may be considered at higher risk if the value is at least two, three, four, five, six, seven or more times greater than the that of a healthy subject. Hence, any of those thresholds may be used as the reference value.
  • the level of Tachykinin or a precursor thereof is compared to a distribution curve for the level of Tachykinin or a precursor thereof seen in sufferers of acute organ damage. In particular, the level in the sample from the subject is compared to such a curve for sufferers of acute organ damage involving the same organ.
  • the curve may be for sufferers of acute organ damage involving the same organ and viral infection.
  • the subject may be classified as at higher risk.
  • the subject is classified as at higher risk if they fall in the top two thirds.
  • the subject is classified as at risk if they fall in the top half.
  • the subject is classified at higher risk if they fall in the top third of expected values.
  • the subgroup may be defined as being at higher risk if they have levels of the Tachykinin or a precursor which is above the median value expected for subjects with the disorder.
  • a subject may be classified at risk if they fall in the highest 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15% or 10% of sufferers when ranked by the level of the Tachykinin or a precursor thereof.
  • any of those values may be used as the reference value and hence the threshold for the subj ect to be considered at risk.
  • the risk is graded accorded to how high the level of Tachykinin or a precursor is, with the higher the value the higher the risk, but at the same time more likely to benefit from the treatments set out herein.
  • the subject is graded for their value for the Tachykinin or a precursor to give a relative risk for a negative outcome without the treatment outlined herein.
  • subjects may be graded into low, medium, or high risk.
  • a method of the invention may give a “prognosis” for the subject being tested.
  • the method may give an indication of the expected evolution of a disease and in a particularly preferred embodiment give an indication of the chances of mortality.
  • a method of the invention is used to classified whether a subject falls into a higher risk group for mortality or there being a chance of the disease progressing negatively and/or having a positive outcome when given the treatments discussed herein.
  • a method of the invention may also be used to generate a “response prediction”.
  • response prediction in the context of this invention, it is meant that, for instance, the subject is more likely to benefit from the treatments set out of they are considered to have a high level of the Tachykinin or a precursor thereof.
  • the method of the invention may provide such a prediction and the likelihood of a positive outcome either if the treatments discussed herein are administered or if they are not.
  • prediction refers to an individual evaluation of any parameter that may be useful to determine the evolution of a patient and the progression of the disease.
  • the prediction of the clinical response to treatment even if it is preferred that it be correct, does not need to be correct for 100% of the subjects to be diagnosed or evaluated.
  • the term requires that a statistically significant part of the subjects can be identified as having an increased probability of having a positive response.
  • the expert in the field can easily determine if a subject is statistically significant using several statistic tools of evaluation which are well known, for example, determination of confidence intervals, determination of p-values, t Student Test, Mann-Whitney Test, etc.
  • the preferred confidence intervals are at least 50%>, at least 60%>, at least 70%>, at least 80%>, at least 90%>, at least 95%>.
  • the Pp-values are, preferably, 0.2, 0,1, or 0.05.
  • the prediction of the clinical response can be done using any criteria of valuation used in oncology and known by the expert in the field.
  • the confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%.
  • p-value is less than 0.1, than 0.05, than 0.01, than 0.005 or than 0.0001.
  • the present invention permits to correctly detect the disease in a differential form in at least 60%, more preferably in at least 70%, much more preferably in at least 80%, or even much more preferably in at least 90% of the subjects of a given group or analysed population.
  • the term “positive response” refers to a response of patients having acute organ damage which is more effective to the treatment with NK1 receptor antagonists and/or a gabapentinoid compared to other patients having acute organ damage but they do not respond in such an effective way to the treatment with NK1 receptor antagonists and/or a gabapentinoid.
  • the level of Tachykinin or a precursor thereof may be used to determine the chances of the subject having a positive response.
  • the response may be referred to the clinical result of the subject.
  • a method of the invention may be used to determine whether the subject has a higher or lower chance of a positive response. For instance, a method of the invention may classify the subject as being more likely to have a positive response when treated with NK1 receptor antagonists and/or a gabapentinoid if they fall above the reference level discussed herein.
  • the invention comprises using a reference level where, if the level of Tachykinin or a precursor thereof is above the reference level the subject is considered more likely to display a positive response.
  • the invention may be used to identify such a patient group.
  • the present invention therefore identifies a specific sub-group of patients with viral infection who are likely to be most at risk from acute organ damage and hence mortality, but also the subgroup of patients most likely to benefit from the treatments set out herein.
  • a subject being categorised as at risk may be also used to define a subject as one to apply the treatments discussed herein.
  • decreasing the chances of mortality is a particularly preferred outcome.
  • the invention may be used to identify those subjects who are less likely to have severe disease if given the treatment outlined herein.
  • Tachykinins and their precursors are peptides any suitable method for measuring their level may be employed.
  • the method of measuring the concentration of the Tachykinin or precursor thereof is an antibody based method.
  • Examples of preferred methods for assaying Tachykinin or precursor thereof can include immunological methods using an antibody capable of binding to an epitope present in the Tachykinin or precursor thereof.
  • Examples of the immunological methods include enzyme immunoassay (ELISA or EIA), fluorescence immunoassay (FIA), radioimmunoassay (RIA), luminescence immunoassay (LIA), immunoenzymatic technique, fluorescent antibody technique, immunochromatography, immunoturbidimetry, latex turbidimetry, and latex agglutination assay.
  • the method of measurement is an ELISA.
  • a sandwich ELISA may be employed.
  • the amount of Tachykinin or precursor is measured in terms of the concentration of the peptide, for instance in terms of weight of peptide per ml of sample, for example in terms of pg of peptide per ml of sample, such as pg of peptide per ml of serum from the subject.
  • the expected amount of Tachykinin or precursor thereof for a healthy subject is from 0.1 to 2.0 ng/ml. In a preferred embodiment is from 0.2 to 1.0 ng/ml, and in particular from 0.25 to 0.75 pg/ml. In a preferred embodiment those are the expected values for Substance P or a precursor thereof. In a particularly preferred embodiment they are the expected value for Substance P.
  • the concentration in a sample from a healthy subject can be measure to determine an expected value.
  • a method for diagnosing acute organ damage comprising measuring the level of a Tachykinin or precursor. Typically, if the value is above that expected it may be that acute organ damage is diagnosed. In one embodiment, any of the reference values or levels associated with the high group may be used to diagnose acute organ damage. In another embodiment, such a method may be used as part of an overall method to diagnose acute organ damage.
  • the invention is an in vitro method, particularly where the method involves measuring the level of a Tachykinin or precursor. In one embodiment, it may just be that a portion of the method is performed in vitro, such as that involving performing the measurement. As discussed further herein, the invention also provides in vivo methods and in particular the methods of treatment discussed herein. NKi inhibitors
  • NKi inhibitors are a well-known class of drug, and any suitable NKi inhibitor can be used in the present invention.
  • the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant, lanepitant, LY-686017, L-733,060, L-732,138, L -703,606, WIN 62,577, CP-122721, TAK-637, R673, CP-100263, WIN 51708, CP-96345, L-760 735, CP-122721, L-758 298, L-741 671, L-742 694, CP- 99994 or T-2328, or a pharmaceutically acceptable salt of any thereof.
  • the NKi inhibitor is aprepitant, fosaprepitant, netupitant, maropitant, vestipitant, casopitant, vofopitant, ezlopitant or lanepitant, or a pharmaceutically acceptable salt of any thereof.
  • the NKI inhibitor is aprepitant, fosaprepitant or netupitant, maropitant, or a pharmaceutically acceptable salt of any thereof.
  • the NKI inhibitor is aprepitant or its prodrug fosaprepitant, or a pharmaceutically acceptable salt of either thereof.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
  • Aprepitant is not typically formulated in the form of a pharmaceutically acceptable salt.
  • the NKi inhibitor is aprepitant.
  • Fosaprepitant is prodrug of aprepitant and has the following structure:
  • Fosaprepitant is typically provided in the form of a pharmaceutically acceptable salt, preferably in the form of the dimeglumine salt:
  • the NKi inhibitor is fosaprepitant dimeglumine.
  • Pharmaceutically acceptable salts of fosaprepitant, such as fosaprepitant dimeglumine are typically reconstituted in an aqueous solvent, such as saline, prior to administration, thereby providing an aqueous solution comprising fosaprepitant.
  • Fosaprepitant is converted in vivo to aprepitant.
  • fosaprepitant is converted to aprepitant.
  • Gabapentinoids are a well-known class of drug that are derivatives of the inhibitory neurotransmitter y-aminobutyric acid (GABA), that is they are GABA derivatives or GABA analogues. These terms may be used interchangeably herein.
  • Gabapentinoids block a26 subunit-containing voltage-dependent calcium channels (VDCCs). Any suitable gabapentinoid can be used in the present invention.
  • the gabapentinoid is gabapentin, pregabalin, mirogabalin, or a gabapentin prodrug, such as gabapentin enacarbil.
  • the gabapentinoid is gabapentin or pregabalin.
  • the gabapentinoid is a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof: wherein
  • Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group
  • R2 is a hydrogen or methyl group
  • Ri and R2 together form a C3-6 cycloalkyl group
  • R3 is a hydrogen, methyl, or carboxyl group.
  • Ci-6 alkyl group may be a straight-chain or branched-chain alkyl group.
  • Ci-6 alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • a C3-6 cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkyl groups and cycloalkyl groups are unsubstituted.
  • Ri is a Ci-6 alkyl, phenyl, or C3-6 cycloalkyl group
  • R2 is a hydrogen or methyl group
  • R3 is a hydrogen, methyl, or carboxyl group.
  • Ri is a Ci-6 alkyl group, more preferably a -(CH2)o-2-iC4H9 group and most preferably an -iC4H9 group (i.e., an isobutyl group).
  • R2 is hydrogen
  • R3 is hydrogen
  • a particularly preferred compound of formula (I) is one in which Ri is an -iC4H9 group and R2 and R3 are both hydrogen.
  • Compounds of formula (I) can contain one or several asymmetric carbon atoms.
  • the invention includes the individual diastereomers or enantiomers, and the mixtures thereof.
  • the individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
  • a particularly preferred compound of formula (I) is pregabalin, i.e. (3S)-3- (aminomethyl)-5-methylhexanoic acid.
  • a particularly preferred gabapentinoid is pregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • Pregabalin has the following structure:
  • Another preferred compound of formula (I) is 4-methylpregabalin.
  • another particularly preferred gabapentinoid is 4-methylpregabalin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • Ri and R2 together form a C3-6 cycloalkyl group; and R3 is a hydrogen, methyl, or carboxyl group.
  • Ri and R2 together form a cyclopentyl or cyclohexyl group, more preferably a cyclohexyl group.
  • R3 is hydrogen.
  • another particularly preferred compound of formula (I) is one in which Ri and R2 together form a cyclohexyl group and R3 represents hydrogen.
  • This compound is gabapentin.
  • a particularly preferred gabapentinoid is gabapentin or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • An example of a prodrug of gabapentin is gabapentin enacarbil.
  • Gabapentin has the following structure:
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, hydrosulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, mandelic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines such as meglumine, aralkyl amines or heterocyclic amines.
  • a prodrug of a compound of formula (I) is a structural analogue of a compound of formula (I) which is transformed in the body into a compound of formula (I) or a species which mimics the biological activity of the compound of formula (I).
  • a prodrug of pregabalin is a structural analogue of pregabalin which is transformed in the body into pregabalin itself or a species which mimics the biological activity of pregabalin.
  • a prodrug of gabapentin is a structural analogue of gabapentin which is transformed in the body into gabapentin itself or a species which mimics the biological activity of gabapentin.
  • in the body is meant within the human or animal body following administration of the prodrug to the human or animal.
  • the compound of formula (I) is not typically formulated as a prodrug.
  • the gabapentinoid used in the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example pregabalin or gabapentin or a pharmaceutically acceptable salt thereof. More preferably, the gabapentinoid used in the present invention is a compound of formula (I), for instance pregabalin or gabapentin.
  • the patient to be treated is a mammal.
  • the patient is a human.
  • the patient may have a confirmed or suspected viral infection, which may be a coronavirus infection or an influenza infection.
  • the subject has a coronavirus infection.
  • the coronavirus may be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), Middle East respiratory syndrome-related coronavirus (MERS-CoV), or any related or similar virus.
  • the subject has Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
  • the subject has Covid- 19, alpha, beta, gamma, or delta strain of Covid- 19. In one preferred embodiment, the subject has the delta strain of Covid- 19. In another preferred embodiment, the subject has Severe acute respiratory syndrome coronavirus (SARS-CoV). In another preferred embodiment, the subject has Middle East respiratory syndrome-related coronavirus (MERS-CoV). In another preferred embodiment, the subject is infected with an influenza virus.
  • the influenza virus may be a type A, B, C or D influenza.
  • the influenza virus is a type A or B influenza virus.
  • the influenza virus is a type A influenza virus.
  • the influenza virus is a type H7N9 influenza virus.
  • influenza virus is a type A(H1N1) influenza virus. In one embodiment, the influenza virus is a type A(H3N2) virus. In one embodiment, any of the methods described herein may comprise diagnosing what virus the individual is infected with, for instance a method may comprise testing whether a subject is infected with one of the viruses discussed herein. In another embodiment, the subject may have already been diagnosed with such a viral infection.
  • the patient may not (yet) exhibit overt symptoms of viral infection, but will typically exhibit one or more symptoms of a disease associated with viral infection, particularly symptoms affecting the respiratory system.
  • the patient may be exhibiting one or more symptoms of the coronavirus disease COVID-19.
  • Symptoms may include fever, cough, shortness of breath or difficulty breathing, loss of smell and/or taste, tiredness, aches, runny nose, sore throat.
  • Confirmation of a viral infection may be made by any suitable assay.
  • rRT-PCR real-time reverse-transcription polymerase chain reaction
  • Treatment is preferably administered to the patient prior to any respiratory symptom becoming severe.
  • Patients who are particularly likely to develop severe symptoms are older people, people with suppressed immunity, and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer. Treatment is particularly suitable for such patients.
  • Treatment is preferably administered to prevent, arrest or reverse acute lung injury (ALI) in the patient.
  • ALI may be characterised by alveolar-capillary membrane injury, inflammation, and/or increased permeability pulmonary edema.
  • the present invention may involves the use of (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or gabapentin, or a pharmaceutically acceptable salt of either thereof, alone or in any combination.
  • a NKi inhibitor which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof
  • a gabapentinoid which is preferably pregabalin and/or gabapentin, or a pharmaceutically acceptable salt of either thereof, alone or in any combination.
  • the invention may be used to identify the chance of a positive outcome with such a pharmaceutical composition. It also provides the pharmaceutical composition for use in a method of treatment, wherein the subject to be treated has been identified as having high level of a Tachykinin or precursor thereof as discussed herein.
  • the NKi inhibitor and the gabapentinoid are here
  • the present invention provides a pharmaceutical composition that comprises: (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and/or (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; including for use in the treatment or prevention of acute organ damage, particularly when induced by viral infection, where the subject to be treated has been identified as having a high level of a Tachykinin or precursor thereof as discussed herein.
  • Pharmaceutical compositions according to the invention will typically further comprise one or more pharmaceutically acceptable excipients or carriers.
  • the present invention extends to situations where the active ingredients discussed above are co-administered. More than one NKi inhibitor and/or more than one gabapentinoid may be co-administered.
  • the active ingredients can be present either in a single pharmaceutical composition or in separate pharmaceutical compositions, including in separate pharmaceutical compositions optimized for administration either by the same mode or a different mode.
  • the active ingredients may both be administered intravenously, orally, or by inhalation, either in a single pharmaceutical composition or, more preferably, in separate pharmaceutical compositions.
  • the product comprising (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof; as a combined preparation for simultaneous, concurrent, separate or sequential use, the product may comprise either a single pharmaceutical composition that comprises both (a) and (b) (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a) and a second (i.e., separate) pharmaceutical composition that comprises (b).
  • the product may comprise either a single pharmaceutical composition that comprises both (a) and each of the gabapentinoids (i.e. a unit dosage form) or alternatively, and preferably, a first pharmaceutical composition that comprises (a), a second (i.e., separate) pharmaceutical composition that comprises the first gabapentinoid, e.g. pregablin, and a third (i.e., separate) pharmaceutical composition that comprises the second gabapentinoid, e.g. gabapentin, and so on for any further gabapentinoid.
  • Co-admini strati on of the active ingredients according to the present invention includes simultaneous, separate and sequential administration.
  • administration of the pharmaceutical compositions may be oral (as syrups, tablets, capsules, lozenges, controlled-release preparations, fast-dissolving preparations, etc), by injection (subcutaneous, intradermal, intramuscular, intravenous, etc.), or by inhalation (as a dry powder, a solution, a dispersion, etc.).
  • aprepitant is preferably delivered orally, whereas fosaprepitant is preferably administered intravenously.
  • Pregabalin and gabapentin are both typically delivered orally.
  • the pharmaceutical compositions of the present invention may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycolate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glyco
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • the pharmaceutical compositions typically take the form of an aqueous injectable solution.
  • suitable aqueous carriers that may be employed in the injectable pharmaceutical compositions of the invention include water, buffered water and saline.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • the pharmaceutical composition may take the form of a dry powder, which will typically comprise the active ingredient and a carrier such as lactose, and be delivered via an inhaler.
  • the pharmaceutical composition may for example be formulated as aqueous solutions or suspensions and be delivered as an aerosol from a pressurised metered dose inhaler, with the use of a suitable liquefied propellant.
  • Suitable propellants include fluorocarbon or hydrogen-containing chlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes.
  • Pharmaceutical compositions comprising of the invention may be prepared by any suitable method known to those of skill in the art.
  • compositions of the invention may comprise additional active ingredients, such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
  • additional active ingredients such as an additional therapeutic or prophylactic agent intended, for example, for the treatment of the same condition or a different one, or for other purposes such as amelioration of side effects.
  • the compositions of the invention do not contain any further active ingredients (i.e. the pharmaceutical compositions contain only (a) a NKi inhibitor, which is preferably aprepitant or fosaprepitant, or a pharmaceutically acceptable salt thereof, and (b) a gabapentinoid, which is preferably pregabalin and/or or gabapentin, or a pharmaceutically acceptable salt of either thereof.
  • Suitable dosages of the active ingredients used in the present invention may easily be determined by a skilled medical practitioner.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • Administration may be in single or multiple doses. Multiple doses may be administered via the same or different routes and to the same or different locations. Dosage and frequency may vary depending on the half-life of the drugs in the patient and the duration of treatment desired.
  • NKi inhibitors such as aprepitant and fosaprepitant, and pharmaceutically acceptable salts thereof, are currently approved for use in treating nausea and vomiting in patients, including those suffering from cancer who may also be suffering from nausea and vomiting as a result of chemotherapy and/or surgery . It is thus preferred in the present invention that the NKi inhibitor is not prescribed and/or administered to the patient for the purpose of treating nausea and vomiting, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
  • Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome.
  • Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. It is thus preferred in the present invention that the gabapentinoid is not prescribed and/or administered to the patient for the purpose of treating any of these indications, but instead is prescribed and/or administered to the patient for the treatment or prevention of acute lung damage, particularly when induced by viral infection.
  • kits or devices may comprise an antibody against the Tachykinin or precursor thereof. It may comprise further elements for performing a method of the invention, for instance a negative and/or positive control samples. It may include a Tachykinin or precursor thereof, for instance in the form of a solution of known concentration, to allow for the production of a standard curve.
  • an antibody against the a Tachykinin or precursor thereof is present in the kit.
  • the antibody is human, humanized or synthetic. In other more preferred implementation, the antibody is monoclonal.
  • the antibody is marked by a fluorochrome.
  • the fluorochrome is selected from the list that includes Fluorescein (FITC), tetramethylrhodamine and derived, Phycoerythrin (PE), PerCP, Cy5, Texas, allophycocyanin, or any of their combinations.
  • the kit of the present invention includes the necessary means to compare the quantity detected with a reference quantity.
  • the kit can also include, without any type of limitations, tampons, agents to prevent contamination, inhibitors of protein degradation, etc.
  • the kit can include all the supports and necessary containers for its activation and its optimization.
  • the kit includes as well the instructions to implement any of the methods of the invention.
  • the indefinite articles “a” and “an” refer to one or two or more (i.e., at least one) object(s) grammatically represented by the indefinite articles.
  • a factor means one factor or two or more factors.
  • the present invention is applied to SARS- CoV-2 infection (Covid-19) infection.
  • the invention may be used to predict the likely severity of Covid- 19 infection in a subject in terms of organ damage, particularly lung damage.
  • the present invention may be applied to a subject who has tested positive for a coronavirus, but has not yet developed serious symptoms of the coronavirus infection.
  • the invention is employed on patients at the time that they are admitted to hospital. It may be that the present invention is used to select the subjects to treat with the drugs discussed herein or any given coronavirus treatment.
  • Tachykinin or precursor thereof may be used to predict those subjects who are displaying a so-called cytokine storm and/or as a marker of macrophage activation
  • measuring a Tachykinin or precursor may be used to identify individuals at risk, or actually displaying, a cytokine storm and/or macrophage activation that is likely to be damaging to the subject.
  • Example 1 The analysis in the blood of the Tachykinins, in particular of Substance P predicts the progression of disease and survival in SARS- and MERS-type Acute Lung Injury (ALT).
  • ALT Acute Lung Injury
  • Tachykinins specifically substance P
  • ALI SARS-type Acute Lung Injury
  • New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All 30 subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation). 3 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used as a control to which the mixture of water and sodium hypochlorite was not administered, to determine Substance P values under baseline conditions.
  • Substance-P (SP) (Substance-P ELISA Kit, abl33029, Abeam Inc., Cambridge, MA, USA) was measured using serum, which was extracted prior to treatment (day 3), from a blood sample of rabbits, according to the protocol provided by the manufacturer and as previously described (18).
  • Group 3 level> 3 times the mean level of Sub
  • the animals were monitored for 30 days.
  • Table 1 show that the measurement of substance P in blood is of use to predict the response to predict progression and survival of SARS-type ALI.
  • Example 2 The analysis in the blood of the pro-Tachykinins, in particular of proSubstance P predicts the progression of disease and survival in SARS- and MERS-type Acute Lung Injury (ALI).
  • ALI Acute Lung Injury
  • Tachykinins specifically substance P
  • ALI SARS-type Acute Lung Injury
  • New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All 30 subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation). 3 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used as a control to which the mixture of water and sodium hypochlorite was not administered, to determine Substance P values under baseline conditions.
  • Pro-Tachykinin was measured were measured using an antibody (ELISA procedure) that recognize the specific part of the sequence “1 mkilvalavf flvstqlfae eiganddlny wsdwydsdqi keelpepfeh llqriarrpk 61 pqqffglmgk rdadssiekq vallkalygh gqishkrhkt dsfvglmgkr alnsvayers 121 amqnyerrr” (NCBI Reference Sequence: NP_001095168) (19) (20).
  • the animals were monitored for 30 days.
  • Example 3 The analysis in the blood of the Tachykinins, in particular of Substance P predicts the response to treatment with NKi inhibitors, such as Aprepitant.
  • Tachykinins is a good method for predicting the response to treatment and prevention with NKI receptor antagonists, such as Aprepitant of SARS-type Acute Lung Injury (ALI).
  • SARS and MERS especially those induced by viruses and more especially, those induced by viruses of the COVID or Influenza type is characterized by haemorrhagic fluid in pleural cavity, localized haemorrhage under pleura, pleural adhesions and focal sub-pleural haemorrhage, thrombus present at pulmonary artery, lung bilateral consolidation (focal or extensive), red-coloured haemorrhagic infarct present at cut surface of lung and focal haemorrhage in mucosa, blood-stained purulent or pale red fluid in lumen, congestion and focal haemorrhage in mucosa at the level of trachea.
  • ALI Aprepitant of SARS-type Acute Lung Injury
  • New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used in this example. All 27 subjects were administered an aerosol of a solution consisting of a mixture of water and sodium hypochlorite (55 g sodium hypochlorite per litre of water) at a rate of 5 mL of said solution by inhalation three times a day for 7 days (days 1 to 7 of experimentation). 3 New Zealand albino rabbits (New Zealand White Rabbit) with an initial average weight about 3 kg were used as a control to which the mixture of water and sodium hypochlorite was not administered, to determine Substance P values under baseline conditions.
  • Substance-P (SP) (Substance-P ELISA Kit, abl33029, Abeam Inc., Cambridge, MA, USA) was measured using serum, which was extracted prior to treatment (day 3), from a blood sample of rabbits, according to the protocol provided by the manufacturer and as previously described (18).
  • the samples were then allowed to cool to room temperature over 10 minutes. Endogenous peroxidase activity was blocked by treatment with 3% hydrogen peroxide over 30 min at room temperature. After washing the samples with 0.05 M Tris buffer, they were incubated with 10 % non-immune pig serum over 30 minutes at room temperature. In order to verify the expression of proteins, the samples were incubated in the presence of antibodies diluted 1 : 1000 at 4 °C overnight. After this time they were washed in 0.05M Tris buffer at room temperature. Subsequently, Envision System-HRP (Dako) reagents were added for 30 min at room temperature.
  • Envision System-HRP Dako
  • the total number of cells and the number of cells displaying immunostaining were counted in each one of the fields in order to subsequently determine the percentage of cells displaying said immunostaining.
  • the sections (slides) stained with hematoxylin/eosin the area occupied by fibrosis was assessed.
  • the antibodies used in immunohistochemical assays were ACE2 sc-390851 (Santa Cruz Biotechnologies, Monoclonal Mouse) as previously described (21) and DPP4 (CD26) sc-52642 (Santa Cruz Biotechnologies, Monoclonal Mouse).
  • Table 3 show a reduction of all the macroscopic findings in autopsy after treatment with NK1 receptor antagonists Aprepitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Table 4 show a reduction of all the microscopic findings in autopsy after treatment with NK1 receptor antagonists Aprepitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS and MERS-inducing coronavirus.
  • the results shown in Table 5 show a reduction of all the biomarkers, such as ACE2 and CD26, which are the ones that serve as the binding target of the virus (coronavirus) to the human cell in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Example 4 The analysis in the blood of the Tachykinins, in particular of Substance P predicts the response to treatment with NKi inhibitors, such as Maropitant.
  • New Zealand albino rabbits (New Zealand White Rabbit) were treated under conditions similar to those described in Example 1 and similar to what is described in example 1 and 3 New Zealand albino rabbits (New Zealand White Rabbit) were used as a control (mixture of water and sodium hypochlorite was not administered) to determine Substance P values under baseline conditions, and Substance-P (SP) was measured.
  • the antibodies used in immunohistochemical assays were ACE2 sc-390851 (Santa Cruz Biotechnologies, Monoclonal Mouse) and DPP4 (CD26) sc-52642 (Santa Cruz Biotechnologies, Monoclonal Mouse) as previously described as described in example 3.
  • Macroscopic autopsy findings in cases treated with the drug Maropitant The results shown in Table 6 show a reduction of all the macroscopic findings in autopsy after treatment with NK1 receptor antagonists Maropitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Table 7 show a reduction of all the microscopic findings in autopsy after treatment with NK1 receptor antagonists Maropitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Table 8 Immunohistochemical expression in cases treated with the drug Maropitant.
  • NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS and MERS-inducing coronavirus.
  • the results shown in Table 8 show a reduction of all the biomarkers, such as ACE2 and CD26, which are the ones that serve as the binding target of the virus (coronavirus) to the human cell in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Example 5 The analysis in the blood of the Tachykinins, in particular of Substance P predicts the response to treatment with Gabapentinoids, such as Pregabalin.
  • New Zealand albino rabbits (New Zealand White Rabbit) were treated under conditions similar to those described in Example 1 and 3 New Zealand albino rabbits (New Zealand White Rabbit) were used as a control (mixture of water and sodium hypochlorite was not administered) to determine Substance P values under baseline conditions, and Substance-P (SP) was measured.
  • New Zealand White Rabbit 3 New Zealand albino rabbits (New Zealand White Rabbit) were used as a control (mixture of water and sodium hypochlorite was not administered) to determine Substance P values under baseline conditions, and Substance-P (SP) was measured.
  • SP Substance-P
  • the antibodies used in immunohistochemical assays were ACE2 sc-390851 (Santa Cruz Biotechnologies, Monoclonal Mouse) as previously described as described in example 3.
  • Table 9 show a reduction of all the macroscopic findings in autopsy after treatment with the gabapentinoid drug Pregabalin (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with gabapentinoids in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Table 10 show a reduction of all the microscopic findings in autopsy after treatment with gabapentinoid drug Pregabalin (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with gabapentinoids in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS and MERS-inducing coronavirus.
  • the results shown in Table 9 show a reduction of all the biomarkers, such as ACE2 and CD26, which are the ones that serve as the binding target of the virus (coronavirus) to the human cell in the samples derived from the groups with different serum values of Substance P.
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Example 6 The analysis in the blood of the Tachykinins, in particular of ProTachykinins (Pro-Substance P) predicts the response to treatment with NKi inhibitors, such as Aprepitant.
  • New Zealand albino rabbits (New Zealand White Rabbit) were treated under conditions similar to those described in Example 1, 3 New Zealand albino rabbits (New Zealand White Rabbit) were used as a control (mixture of water and sodium hypochlorite was not administered) to determine Pro-Substance P values under baseline conditions, and Pro- Substance-P (SP) was measured.
  • SP Pro- Substance-P
  • the antibodies used in ELISA assays were those that recognize the specific part of the sequence of pro-substance P “1 mkilvalavf flvstqlfae eiganddlny wsdwydsdqi keelpepfeh llqriarrpk 61 pqqffglmgk rdadssiekq vallkalygh gqishkrhkt dsfvglmgkr alnsvayers 121 amqnyerrr” (NCBI Reference Sequence: NP_001095168) (19) (20).
  • Macroscopic autopsy findings in cases treated with the drug Apr epitant orally show a reduction of all the macroscopic findings in autopsy after treatment with NK1 receptor antagonists Aprepitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Pro- Tachykinins (Pro- Sub stance P).
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Microscopic autopsy findings in cases treated with the drug Aprepitant are of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Table 2 show a reduction of all the microscopic findings in autopsy after treatment with NK1 receptor antagonists Aprepitant (presence of all unfavourable pathological macroscopic findings in autopsy) in the samples derived from the groups with different serum values of Pro- Tachykinins (Pro- Sub stance P).
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • NK1R antagonists inhibits lung cell expression of targets necessary for the binding of SARS and MERS-inducing coronavirus.
  • the results shown in Table 3 show a reduction of all the biomarkers, such as ACE2 and CD26, which are the ones that serve as the binding target of the virus (coronavirus) to the human cell in the samples derived from the groups with different serum values of Pro- Tachykinins (Pro- Sub stance P).
  • the measurement of substance P in blood is of use to predict the response to treatment with NK1 receptor antagonists in the sense that it prevents the development and progression of SARS- and MERS-type ALI.
  • Example 7 The level of tachykinins such as Substance P, Pro-Substance P and Hemokinin 1 predict the response to acute lung injury and induced pneumonia in a model of CO VID
  • LPS lipopolysaccharide
  • ophthalmic lubricant is applied, the anaesthetised animal is placed in an upright position and the mouse's tongue is gently pulled with blunt forceps.
  • Lipopolysaccharide diluted in PBS (3 pg/g wt; Total volume: 50 ul) is pipetted into the oral cavity with a P200 pipette, on the dorsum of the tongue, while the nose is covered with a gloved finger, thus forcing the mouse to breathe through the mouth.
  • the nose is uncovered, and the tongue is released after at least two breaths have been completed, when no fluid is visible in the oral cavity.
  • the animal is then placed in a dish, which is kept at 37°C by a heating plate, until it recovers from anaesthesia, as previously described (Allen 2014).
  • mice were sacrificed. Organs were removed and fixed in formaldehyde (4%) for histological studies. After fixation, the organs were dehydrated by treatment with increasing concentrations of ethanol and finally in xylene. Then, the samples were embedded in paraffin creating a cell block.
  • the histogram allows obtaining an objective and reproducible numerical value of the light intensity of an image.
  • the light intensity in the histogram is measured from 0 to 255, with "0" corresponding to dark images, without light and the value "255" to white images with maximum light intensity.
  • the histological preparations of the lungs are studied, knowing that normal lungs have abundant alveolar spaces that appear white and the areas of lung parenchyma appear pink (due to eosin staining).
  • Histological automated segmentation has been validated as a method to globally assess the damage induced by acute lung injury (Conti 2010).
  • the histogram allows obtaining an objective and reproducible numerical value of the light intensity of an image.
  • the light intensity in the histogram is measured from 0 to 255, with "0" corresponding to dark images, without light and the value "255" to white images with maximum light intensity.
  • the histological preparations of the lungs are studied, knowing that normal lungs have abundant alveolar spaces that appear white and the areas of lung parenchyma appear pink (due to eosin staining). Therefore, in a normal lung parenchyma, abundant well-ventilated alveolar spaces are present, meaning that many “white” spaces will be seen and will present a mean value of intensity in the highest histogram (closer to 255).
  • the specific antibodies used were: 1) for substance P the Anti -Sub stance P antibody (ab216414), 2) for prosubstance P a specific antibody that recognizes the sequence “1 mkilvalavf flvstqlfae eiganddlny wsdwydsdqi keelpepfeh llqriarrpkk 61 pqqffgl vallkalygh gqishkrhkt dsfvglmgkr alnsvayers amqnyerrr 121 "(NCBI Reference sequence: NP 001095168) and for hemoquinina 1 antibody recognizing a specific sequence 1 mlpllallll igpsvcttag dreelafgae aeswvtvnlk gipvp
  • paraffin blocks were cut on a microtome to a thickness of 5 microns, which were placed on slides suitable for performing immunohistochemistry. Subsequently, samples were dewaxed by immersion in xylene and then were hydrated through a series of solutions containing decreasing concentrations of ethanol, to be finally immersed in water. Then, these samples were subjected to pressure cooker treatment at lOx citrate buffer at pH 6.0, to obtain an increased exposure of antigens. Subsequently, the samples were cooled at room temperature for 10 minutes. Endogenous peroxidase activity was blocked with hydrogen peroxide of 3% for 30 min at room temperature.
  • cytokine storm It is known in the state of the art that the pathophysiological mechanism by which the infection by the SARS-CoV-2 virus and other SARS-inducing viruses produce Acute Lung Damage or COVID-19 disease is mediated by the storm release of cytokines, the so-called cytokine storm. It is also known in the state of the art that macrophages are the end effector of this cytokine storm and are responsible for this acute lung damage. The cytokines induce an "activation" state in macrophages that puts them in a position to attack both foreign elements and the lung parenchyma, inducing pneumonia, lung consolidation, and acute lung damage (Otsuka 2020, Ombrello 2021, McGonagle 2021). Morphologically, macrophages can be easily recognized in histological slides and, in these, activation signs such as signs of phagocytosis and more specifically of hemophagocytosis (phagocytosis of the red blood cells themselves).
  • Table 13 shows the raw data from the histogram measurements of the 6 cases corresponding to group 1 of mice with lung damage induced by exposure to the LPS agent (both right and left lungs in each case are considered).
  • Table 14 shows the relationship between the induced lung damage and the expression of the biomarkers Substance P, Pro-Substance P and Hemokinin 1.
  • Normal Pulmonary Parenchima mean value ⁇ Standard Deviation (Mean ⁇ SD) of the light intensity in the image histogram in a selection of lung parenchyma considered normal from the histological point of view (both in the right lung and in the left lung) of each of the 6 in group 1 (considered as a light intensity control of the normal lung parenchyma).
  • C Pulmonar Parenchima with Consolidated Pneumonia: mean value ⁇ Standard Deviation (Mean ⁇ SD) of light intensity in the image histogram in a selection of lung parenchyma with consolidated pneumonia (extreme degree of pneumonia / inflammation / lung damage) the histological point of view (both in the right lung and in the left lung) of each of the 6 in group 1 (considered as a control of light intensity of the lung parenchyma in extreme degree of pneumonia / lung damage).
  • F factor it is the percentage value of what E supposes, with respect to D, which means which is the value of the luminosity in each specific case within the possible range. It allows obtaining a quantitative and objective data of luminosity that is correlated with the degree of affectation / inflammation / consolidation / lung damage. A higher F Factor value equates to more lung damage. Table 14.
  • NCBI ProTachykinin- 1 preproprotein [Oryctolagus cuni cuius] NCBI Reference Sequence: NP 001095168.1 [Internet], Available from: https://www.ncbi.nlm.nih.gOv/protein/NP_001095168. l

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention se rapporte au traitement ou à la prévention d'une lésion aiguë d'un organe, en particulier une lésion induite par une infection virale, faisant intervenir (a) un inhibiteur de NK1, qui est de préférence l'aprépitant ou le fosaprépitant, ou un sel pharmaceutiquement acceptable de l'un ou de l'autre, et/ou (b) un gabapentinoïde, qui est de préférence la prégabaline et/ou la gabapentine, ou un sel pharmaceutiquement acceptable de l'une et/ou de l'autre, (a) et (b) pouvant être administrés seuls ou en association.
PCT/EP2021/072828 2020-08-19 2021-08-17 Méthode de prédiction de l'évolution ou du pronostic de la réponse d'un patient souffrant d'une lésion aiguë d'un organe WO2022038131A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20382760.5 2020-08-19
EP20382760 2020-08-19

Publications (1)

Publication Number Publication Date
WO2022038131A1 true WO2022038131A1 (fr) 2022-02-24

Family

ID=72234791

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/072828 WO2022038131A1 (fr) 2020-08-19 2021-08-17 Méthode de prédiction de l'évolution ou du pronostic de la réponse d'un patient souffrant d'une lésion aiguë d'un organe

Country Status (1)

Country Link
WO (1) WO2022038131A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022253748A1 (fr) * 2021-06-03 2022-12-08 Plus Vitech, S.L. Combinaisons pour le traitement du vph
WO2024122680A1 (fr) * 2022-12-08 2024-06-13 경상국립대학교병원 Procédé de fourniture d'informations pour la prédiction de symptômes cliniques d'un patient atteint d'un syndrome de détresse respiratoire aiguë
WO2024139979A1 (fr) * 2022-12-27 2024-07-04 上海数因信科智能科技有限公司 Utilisation de vofopitant pour le traitement de la sclérodermie
WO2024139978A1 (fr) * 2022-12-27 2024-07-04 上海数因信科智能科技有限公司 Utilisation de vofopant pour le traitement de la fibrose pulmonaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003167A1 (fr) 1996-07-24 1998-01-29 Warner-Lambert Company Isobutylgaba et ses derives utilises pour le traitement de la douleur
EP2837381A1 (fr) 2011-12-13 2015-02-18 Servicio Andaluz De Salud Utilisation d'agents modificateurs de l'environnement péritumoral pour le traitement du cancer

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998003167A1 (fr) 1996-07-24 1998-01-29 Warner-Lambert Company Isobutylgaba et ses derives utilises pour le traitement de la douleur
EP2837381A1 (fr) 2011-12-13 2015-02-18 Servicio Andaluz De Salud Utilisation d'agents modificateurs de l'environnement péritumoral pour le traitement du cancer

Non-Patent Citations (40)

* Cited by examiner, † Cited by third party
Title
"Kalopanax pictus, Hericium erinaceus, and Astragalus membranaceus in experimentally induced in vitro and in vivo osteoarthritis models", NUTRIENTS, vol. 10, no. 3, 2018
"NCBI", Database accession no. NP-001095168.1
ALLEN IC: "The utilization of oropharyngeal intratracheal PAMP administration and bronchoalveolar lavage to evaluate the host immune response in mice", J VIS EXP, vol. 86, 2 April 2014 (2014-04-02), pages 51391
AMRAIE RNAPOLEON MAYIN WBERRIGAN JSUDER EZHAO G ET AL.: "CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells", BIORXIV PREPR SERV BIOL [INTERNET, 23 June 2020 (2020-06-23), pages 064099, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/32607506>
ANONYMOUS: "To Determine the Efficacy of Neurokinin 1 Receptor Antagonist as a Therapeutic Tool Against Cytokine Storm and Respiratory Failure in Covid-19 Patients - Full Text View - ClinicalTrials.gov", 1 July 2020 (2020-07-01), XP055863555, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT04468646> [retrieved on 20211119] *
BORCZUK ACSALVATORE SPSESHAN SVPATEL SSBUSSEL JBMOSTYKA MELSOUKKARY SHE BDEL VECCHIO CFORTAREZZA F: "COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City", MOD PATHOL, vol. 33, no. 11, November 2020 (2020-11-01), pages 2156 - 2168, XP037277812, DOI: 10.1038/s41379-020-00661-1
CHU KHTSANG WKTANG CSLAM MFLAI FMTO KF ET AL.: "Acute renal impairment in coronavirus-associated severe acute respiratory syndrome", KIDNEY INT., vol. 67, no. 2, 2005, pages 698 - 705
CONTI GTAMBALO SVILLETTI GCATINELLA SCARNINI CBASSANI FSONATO NSBARBATI AMARZOLA P: "Evaluation of lung inflammation induced by intratracheal administration of LPS in mice: comparison between MRI and histology", MAGMA, vol. 23, no. 2, April 2010 (2010-04-01), pages 93 - 101, XP019785382
DING YWANG HSHEN HLI ZGENG JHAN H ET AL.: "The clinical pathology of severe acute respiratory syndrome (SARS): A report from China", J PATHOL., vol. 200, no. 3, 2003, pages 282 - 9
EHRENTRAUT HWEISHEIT CKFREDE SHILBERT T: "Inducing Acute Lung Injury in Mice by Direct Intratracheal Lipopolysaccharide Instillation", J VIS EXP., vol. 149, 6 July 2019 (2019-07-06)
GU JKORTEWEG C: "Pathology and Pathogenesis of Severe Acute Respiratory Syndrome. ASIPJournalCMEProgram Review", AM J PATHOL., vol. 170, 2007, pages 1136 - 47
GUO YKORTEWEG CMCNUTT MAGU J: "Pathogenetic mechanisms of severe acute respiratory syndrome", VIRUS RES., vol. 133, no. 1, 2008, pages 4 - 12, XP022520308, DOI: 10.1016/j.virusres.2007.01.022
HUANG CWANG YLI XREN LZHAO JHU Y ET AL.: "Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China", LANCET [INTERNET, vol. 395, no. 10223, February 2020 (2020-02-01), pages 497 - 506, XP086050317, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/32607506> DOI: 10.1016/S0140-6736(20)30183-5
JEFFERS SATUSELL SMGILLIM-ROSS LHEMMILA EMACHENBACH JEBABCOCK GJ ET AL.: "CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus", PROC NATL ACAD SCI USA., vol. 101, no. 44, 2004, pages 15748 - 53
KUBA KIMAI YRAO SGAO HGUO FGUAN B ET AL.: "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury", NAT MED, vol. 11, no. 8, 2005, pages 875 - 9, XP037065952, DOI: 10.1038/nm1267
LEONARDO LORENTE ET AL: "Serum substance P levels are associated with severity and mortality in patients with severe traumatic brain injury", CRITICAL CARE, BIOMED CENTRAL LTD LONDON, GB, vol. 19, no. 1, 27 April 2015 (2015-04-27), pages 192, XP021221736, ISSN: 1364-8535, DOI: 10.1186/S13054-015-0911-Z *
LIU LWEI Q FAUALVAREZ XALVAREZ X FAUWANG HWANG H FAUDU YDU Y FAUZHU HZHU H FAU: "Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques. PG - 4025-30 LID - 10.1128/JVI.02292-10 [doi", J VIROL., April 2011 (2011-04-01), pages 4025 - 30
MAGERT HJHEITLAND AROSE MFORSSMANN WG: "Nucleotide sequence of the rabbit gamma-preproTachykinin I cDNA", BIOCHEM BIOPHYS RES COMMUN [INTERNET, vol. 195, no. 1, 31 August 1993 (1993-08-31), pages 128 - 31, XP024767918, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/8363593> DOI: 10.1006/bbrc.1993.2019
MATOS IONE M ET AL: "Effects of tachykinin NK 1 or PAF receptor blockade on the lung injury induced by scorpion venom in rats", EUROPEAN JOURNAL OF PHARMACOLOGY, 1 January 1999 (1999-01-01), Amsterdam, pages 293 - 300, XP055864980, Retrieved from the Internet <URL:https://www.sciencedirect.com/science/article/pii/S0014299999003829/pdfft?md5=f2e9e8323ca33f56cf8a8618783ffd12&pid=1-s2.0-S0014299999003829-main.pdf> [retrieved on 20211123], DOI: 10.1016/S0014-2999(99)00382-9 *
MATUTE-BELLO GFREVERT CWMARTIN TR: "Animal models of acute lung injury", AM J PHYSIOL LUNG CELL MOL PHYSIOL., vol. 295, no. 3, September 2008 (2008-09-01), pages L379 - 99
MCGONAGLE DSHARIF KO'REGAN ABRIDGEWOOD C: "The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease", AUTOIMMUN REV, vol. 19, no. 6, June 2020 (2020-06-01), pages 102537
MEHBOOB RIFFAT ET AL: "SARS-Corona Virus-2 May Initially Infect Brainstem through Trigeminal Ganglion-Latency May Be Present-A New Perspective", 30 June 2020 (2020-06-30), XP055864324, Retrieved from the Internet <URL:https://www.preprints.org/manuscript/202007.0015/v1/download> [retrieved on 20211122], DOI: 10.20944/preprints202007.0015.v1 *
MEYERHOLZ DKLAMBERTZ AMMCCRAY PB: "Dipeptidyl Peptidase 4 Distribution in the Human Respiratory Tract Implications for the Middle East Respiratory Syndrome", AM J PATHOL [INTERNET, vol. 186, no. 1, 2016, pages 78 - 86, Retrieved from the Internet <URL:http://dx.doi.org/10.1016/j.ajpath.2015.09.014>
MUNOZ MIGUEL ET AL: "Involvement of substance P and the NK-1 receptor in human pathology", AMINO ACIDS., vol. 46, no. 7, 1 July 2014 (2014-07-01), AU, pages 1727 - 1750, XP055830200, ISSN: 0939-4451, Retrieved from the Internet <URL:https://link.springer.com/content/pdf/10.1007/s00726-014-1736-9.pdf> DOI: 10.1007/s00726-014-1736-9 *
OBOHO IKTOMCZYK SMAL-ASMARI AMBANJAR AAAL-MUGTI HALORAINI MS ET AL.: "2014 MERS-CoV Outbreak in Jeddah — A Link to Health Care Facilities", N ENGL J MED [INTERNET, vol. 372, no. 9, 26 February 2015 (2015-02-26), pages 846 - 54, Retrieved from the Internet <URL:http://www.nejm.org/doi/10.1056/NEJMoa1408636>
OMBRELLO MJSCHULERT GS: "COVID-19 and cytokine storm syndrome: are there lessons from macrophage activation syndrome?", TRANSL RES, vol. 232, June 2021 (2021-06-01), pages 1 - 12, XP086566898, DOI: 10.1016/j.trsl.2021.03.002
OTSUKA R, SEINO KI: "Macrophage activation syndrome and COVID-19", INFLAMM REGEN, vol. 40, 6 August 2020 (2020-08-06), pages 19
QIN CZHOU LHU ZZHANG SYANG STAO Y ET AL.: "Dysregulation of immune response in patients with COVID-19 in Wuhan, China", CLIN INFECT DIS, 2020, pages 2019
QINFEN ZJINMING CXIAOJUN HHUANYING ZJICHENG HLING F ET AL.: "The life cycle of SARS coronavirus in Vero E6 cells.", J MED VIROL., vol. 73, no. 3, 2004, pages 332 - 7
ROBINSON PREMA ET AL: "Substance P Receptor Antagonism: A Potential Novel Treatment Option for Viral-Myocarditis", BIOMED RESEARCH INTERNATIONAL, vol. 2015, 1 January 2015 (2015-01-01), pages 1 - 12, XP055864333, ISSN: 2314-6133, Retrieved from the Internet <URL:http://downloads.hindawi.com/journals/bmri/2015/645153.pdf> DOI: 10.1155/2015/645153 *
SONG ZXU YBAO LZHANG LYU PQU Y ET AL.: "From SARS to MERS, thrusting coronaviruses into the spotlight", VIRUSES, vol. 11, no. 1, 2019
SONG ZXU YBAO LZHANG LYU PQU YZHU HZHAO WHAN YQIN C: "From SARS to MERS, Thrusting Coronaviruses into the Spotlight", VIRUSES, vol. 11, no. 1, 14 January 2019 (2019-01-14), pages 59
STARK CJATREYA CD.: "Molecular advances in the cell biology of SARS-CoV and current disease prevention strategies", VIROL J, vol. 2, 2005, pages 1 - 8
TSANG KWHO PLOOI GCYEE WKWANG TCHAN-YEUNG M ET AL.: "A cluster of cases of severe acute respiratory syndrome in Hong Kong", N ENGL J MED, vol. 348, no. 20, 15 May 2003 (2003-05-15), pages 1977 - 85, Retrieved from the Internet <URL:http://www.ncbi.nlm.nih.gov/pubmed/12671062>
VERNOOY JHDENTENER MAVAN SUYLEN RJBUURMAN WAWOUTERS EF: "Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils", AM J RESPIR CELL MOL BIOL., vol. 24, no. 5, May 2001 (2001-05-01), pages 569 - 76
VERNOOY JHDENTENER MAVAN SUYLEN RJBUURMAN WAWOUTERS EF: "Long-term intratracheal lipopolysaccharide exposure in mice results in chronic lung inflammation and persistent pathology", AM J RESPIR CELL MOL BIOL., vol. 26, no. l, January 2002 (2002-01-01), pages 152 - 9, XP002439920
WANG GANG ET AL: "Potential role of serum substance P as a favorable biomarker of functional outcome in acute spontaneous intracerebral hemorrhage", CLINICA CHIMICA ACTA, ELSEVIER BV, AMSTERDAM, NL, vol. 510, 10 July 2020 (2020-07-10), pages 111 - 116, XP086284861, ISSN: 0009-8981, [retrieved on 20200710], DOI: 10.1016/J.CCA.2020.07.014 *
WONG SIMON S ET AL: "Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation", AMERICAN JOURNAL OF PHYSIOLOGY - LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, AMERICAN PHYSIOLOGICAL SOCIETY, US, vol. 287, no. 4, 1 October 2004 (2004-10-01), pages L859 - L866, XP002468167, ISSN: 1040-0605, DOI: 10.1152/AJPLUNG.00388.2003 *
YUE YNABAR NRSHI CSKAMENYEVA OXIAO XHWANG IY ET AL.: "SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death", CELL DEATH DIS [INTERNET, vol. 9, no. 9, 2018, Retrieved from the Internet <URL:http://dx.doi.org/10.1038/s41419-018-0917-y>
ZULLI ABURRELL LMWIDDOP REBLACK MJBUXTON BFHARE DL: "Immunolocalization of ACE2 and AT2 receptors in rabbit atherosclerotic plaques", J HISTOCHEM CYTOCHEM, vol. 54, no. 2, 2006, pages 147 - 50

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022253748A1 (fr) * 2021-06-03 2022-12-08 Plus Vitech, S.L. Combinaisons pour le traitement du vph
WO2024122680A1 (fr) * 2022-12-08 2024-06-13 경상국립대학교병원 Procédé de fourniture d'informations pour la prédiction de symptômes cliniques d'un patient atteint d'un syndrome de détresse respiratoire aiguë
WO2024139979A1 (fr) * 2022-12-27 2024-07-04 上海数因信科智能科技有限公司 Utilisation de vofopitant pour le traitement de la sclérodermie
WO2024139978A1 (fr) * 2022-12-27 2024-07-04 上海数因信科智能科技有限公司 Utilisation de vofopant pour le traitement de la fibrose pulmonaire

Similar Documents

Publication Publication Date Title
WO2022038131A1 (fr) Méthode de prédiction de l&#39;évolution ou du pronostic de la réponse d&#39;un patient souffrant d&#39;une lésion aiguë d&#39;un organe
US20130316337A1 (en) Methods of Diagnosing and Treating an Inflammatory Response
US9808501B2 (en) Compositions and methods for treating and preventing hyperlipidemia, fatty liver, atherosclerosis and other disorders associated with metabolic syndrome
WO2021191108A1 (fr) Traitement ou prévention d&#39;un dommage d&#39;organe aigu induit par une infection virale avec un inhibiteur de nk1 et/ou un gabapentinoïde
JP7454908B2 (ja) メトホルミンのバイオマーカーとしての増殖分化因子１５
Gu et al. Fractalkine neutralization improves cardiac function after myocardial infarction
US11052073B1 (en) Sphingosine kinase 2 inhibitor for treating coronavirus infection
De Luca et al. Pharmacological therapies for pediatric and neonatal ALI/ARDS: an evidence-based review
Lear et al. KIAA0317 regulates pulmonary inflammation through SOCS2 degradation
ES2353835T3 (es) Biomarcadores para evaluar la función hepática.
EP3406242B1 (fr) Antagoniste du tlr4 destiné à être utilisé dans le traitement de l&#39;augmentation des taux plasmatiques d&#39;ammoniac
Shi et al. Direct factor Xa inhibition attenuates acute lung injury progression via modulation of the PAR-2/NF-κB signaling pathway
CN111094981B (zh) Pct和pro-adm作为监测抗生素治疗的标记物
JP2022521390A (ja) 術後有害事象の診断または予後
US10272133B2 (en) Compositions and methods for treating and preventing hyperlipidemia, fatty liver, atherosclerosis and other disorders associated with metabolic syndrome
Wang et al. Effects of extracellular histones on left ventricular diastolic function and potential mechanisms in mice with sepsis
US20230160893A1 (en) Pro-adrenomedullin for prognosing disease progression in severe acute respiratory syndrome (sars)
US11471448B2 (en) Sphingosine kinase 2 inhibitor for treating coronavirus infection in moderately severe patients with pneumonia
US20230346784A1 (en) Method for treating complement mediated disorders caused by betacoronaviruses
CN111065927B (zh) 作为危重患者的治疗监测标记物的pro-adm
Fragni Identification of novel readouts to assess anti-fibrotic efficacy of new compounds in a bleomycin-induced pulmonary fibrosis mouse model
Bianchi Biomarkers in COVID-19 pandemic: implications for acute phase assessment and chronic management
El Kenani Mechanisms underlying low flow-low gradient aortic stenosis
JP2023520941A (ja) Ｓａｒｓ－ｃｏｖ－２感染リスク評価方法
Boccherini Douze quatuors pour deux violons, viola et violoncelle, oeuvre 39

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21765863

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21765863

Country of ref document: EP

Kind code of ref document: A1