Olcegepant for treating sepsis

Abstract

JPEG2025535826000006.jpg58148 The present invention relates to compounds for use in methods for treating patients with severe bacterial or fungal sepsis, and disorders associated with bacterial or fungal septic shock, and conditions resulting therefrom, pharmaceutical compositions containing said compounds, and their use as medicaments for treating severe bacterial or fungal sepsis and bacterial or fungal septic shock, and conditions resulting therefrom.

Description

[Technical Field]

[0001] The present invention relates to compounds for use in the treatment of patients with systemic reactions to bacteria, fungi, or circulating bacterial or fungal products and conditions resulting therefrom, wherein the compounds [ka] or a derivative thereof (olcegepant), and relates to a method of treating patients with the above systemic reactions, a pharmaceutical composition containing the compound, and its use as a medicament for treating severe bacterial or fungal sepsis or bacterial or fungal septic shock and conditions resulting therefrom. [Background technology]

[0002] In severe bacterial or fungal sepsis or bacterial or fungal septic shock, increased vascular permeability is observed in several organs, including but not limited to the lungs, kidneys, liver, and heart. Interstitial fluid retention in these organs impairs their proper function (e.g., hypovolemia, hypotension, arrhythmias, glomerular filtration disruption, or metabolic disorders), leading to organ failure and subsequent death. Conventional antibiotics are not effective against fungal infections and are therefore not used. Sepsis, severe sepsis, and septic shock are disorders resulting from a systemic inflammatory response to infection (see Mitchell M. Levy et al., Crit Care Med. 2003 Apr;31(4):1250-6). Sepsis is a disorder that has both an infection (e.g., bacterial, fungal, abdominal trauma, intestinal perforation) and a systemic inflammatory response. This leads to increased vascular permeability in several organs, including the kidneys, liver, heart, and lungs. Severe sepsis (sepsis with organ dysfunction) is sepsis accompanied by acute organ dysfunction due to sepsis. Septic shock refers to a persistent drop in blood pressure that is not explained by other causes.

[0003] There is a need for compound formulations or dosage forms that can be used in methods for treating severe bacterial or fungal sepsis and bacterial or fungal septic shock. Unfortunately, no animal model mimics human sepsis. Many anti-inflammatory drugs, such as anti-TNF-alpha or TLR4 inhibitors, have been tested in pigs, monkeys, or healthy volunteers exposed to LPS, but have failed in septic patients. Olcegepant is a calcitonin gene-related peptide (CGRP) receptor antagonist and is described in WO98 / 11128 and in Doods et al. in the British Journal of Pharmacology 129: 420-423, 2000.

[0004] Olcegepant given as a subcutaneous bolus injection in a mouse sepsis model only rescued 2 out of 10 mice (WO2018 / 154015).

[0005] Messerer et al. reported that olcegepant given by intravenous bolus injection did not show any improvement in survival in a porcine sepsis model (British Journal of Anaesthesia 128 (5): 864-873, 2022). Surprisingly, the present invention finds that a modified release formulation of olcegepant improves survival in a murine model of polymicrobial septic shock. Summary of the Invention

[0006] The present invention relates to the use of the CGRP receptor antagonist olcegepant or a pharmaceutically acceptable salt thereof for use in treating patients diagnosed with sepsis, i.e., patients with severe bacterial or fungal sepsis and bacterial or fungal septic shock and conditions resulting therefrom, in particular conditions associated with bacterial or fungal parasitic infections. The present invention relates to olcegepant or a pharmaceutically acceptable salt thereof for use in treating patients with bacterial or fungal sepsis, severe bacterial or fungal sepsis, or bacterial or fungal septic shock, or a condition resulting therefrom selected from the group consisting of infection-related ARDS, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), peritonitis, and puerperal fever. The present invention further relates to a method for treating a patient suffering from bacterial or fungal sepsis, severe bacterial or fungal sepsis, or bacterial or fungal septic shock, or a condition resulting therefrom selected from the group consisting of infection-related acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), peritonitis, and puerperal fever, comprising the administration of olcegepant or a pharmaceutically acceptable salt thereof. [Brief explanation of the drawings]

[0007] [Figure 1-1] Effect of olcegepant-PLGA in dried lung tissue in a mouse CLP model. [Figure 1-2] Effect of olcegepant-PLGA in dried liver tissue in a mouse CLP model. [Figure 1-3] Effect of olcegepant-PLGA in dried kidney tissue in a mouse CLP model. [Figure 1-4] Effect of olcegepant-PLGA in desiccated cardiac tissue in a mouse CLP model. [Figure 2-1] Effect of olcegepant-PLGA on BALF proteins in a murine streptococcal pneumonia model. [Figure 2-2] Effect of olcegepant-PLGA in dried lung tissue in a murine streptococcal pneumonia model. [Figure 3-1] Effect of olcegepant-PLGA in dried lung tissue in a mouse lung ischemia / reperfusion model. [Figure 3-2] Effect of olcegepant-PLGA on BALF proteins in a mouse lung ischemia / reperfusion model. [Figure 3-3]Effect of olcegepant-PLGA in dried cardiac tissue in a mouse lung ischemia / reperfusion model. [Figure 4-1] Effect of olcegepant-PLGA on survival compared to olcegepant in saline in a mouse CLP model. DETAILED DESCRIPTION OF THE INVENTION

[0008] In one embodiment, the present invention relates to a compound, which is the following CGRP receptor antagonist olcegepant, or a pharmaceutically acceptable salt thereof, for use in a method for treating a patient with a systemic response to and / or a condition resulting from bacteria, fungi, or circulating bacterial or fungal products. [ka]

[0009] In a particular embodiment, the invention relates to the compound olcegepant or a pharmaceutically acceptable salt thereof for use in the treatment of sepsis, wherein a patient with sepsis has a CGRP plasma concentration in the range of 30-200 pmol / L, whereas the normal range for plasma CGRP should be less than 10 pmol / L (Arnalish et al., Life Sci. 56: 75-81, 1995). In particular, the patient's systemic response is characterized by interstitial fluid retention and / or hypotension. Furthermore, the above invention is directed to the treatment of severe sepsis (i.e., sepsis-induced organ dysfunction or decreased blood flow in tissues (decreased blood pressure, increased lactate, or decreased urine output The present invention relates to a method of treating a patient with sepsis (e.g., sepsis associated with CGRP), the method comprising administering olcegepant or a pharmaceutically acceptable salt thereof, wherein the patient has a CGRP plasma concentration in the range of 30-200 pmol / L, whereas the normal range for plasma CGRP should be less than 10 pmol / L (Arnalish et al., Life Sci. 56: 75-81, 1995). In particular, the patient's systemic response is characterized by interstitial fluid retention and / or hypotension. A patient is diagnosed with sepsis when symptoms such as fever, elevated heart rate, low blood pressure, rapid breathing, low urine output, severe pain, and confusion are observed. A further embodiment of the present invention is a medicament prepared with the compound olcegepant or a salt thereof for use in the treatment of patients with bacterial, viral or fungal sepsis. Another embodiment of the present invention is a pharmaceutical composition comprising the compound olcegepant or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier, particularly for the use of olcegepant administered using a novel method for treating patients with severe bacterial or fungal sepsis or bacterial or fungal septic shock. Of particular interest are pharmaceutical compositions prepared as modified-release, particularly sustained-release, formulations of the CGRP receptor antagonist olcegepant or a pharmaceutically acceptable salt thereof, wherein the composition comprises 5-40%, particularly 5-20%, of olcegepant or a pharmaceutically acceptable salt thereof.

[0010] In one embodiment of the present invention, the CGRP receptor antagonist olcegepant can be prepared as a controlled-release or sustained-release formulation, for example, encapsulated in PLGA (poly(lactic-co-glycolic acid)) nanoparticles. Controlled-release administration involves the release of olcegepant with a delayed or extended period of time after administration. drugs The FDA-approved polymer PLGA is a biodegradable polymer composed of 75% lactic acid and 25% glycolic acid, which forms nanoparticles with a size of less than 200 nm and a negative surface charge for preparing vaccines and drugs (Lim et al., Pharmaceutics 14: 614, 2022, https: / / doi.org / 10.3390 / pharmaceutics14030614). For treating patients, such nanoparticles can be suspended in 0.1-0.4% w / v, particularly 0.25% w / v sodium carboxymethylcellulose (Na-CMC) and 0.01-0.02% v / v, particularly 0.015% v / v Tween 80 in a 0.9% sterile NaCl solution. Olcegepant can also be delivered as a controlled-release or sustained-release intravenous infusion at a rate such as 0.25 mg / 2 ml / min for at least 8 hours with physiological solutions (e.g., 0.9% saline, or lactated Ringer's solution, or 5% dextrose, or human albumin (4%-5%) in saline, or 6% hydroxyethyl starch (Hespan)) to maintain plasma concentrations in the patient below 500 nmol / L.

[0011] A further embodiment of the present invention is a pharmaceutical composition of the CGRP receptor antagonist olcegepant or a pharmaceutically acceptable salt thereof for use in treating patients with severe bacterial or fungal sepsis or bacterial or fungal septic shock, comprising 5 to 40%, particularly 5 to 20%, of olcegepant. The therapeutically effective amount of olcegepant is in the range of 0.1 to 90% by weight of the total composition, preferably 0.5 to 50% by weight of the total composition or its pharmaceutically acceptable salt.

[0012] General definition Terms not specifically defined herein should be given the meaning that one of ordinary skill in the art would give them in light of this disclosure and the context. However, as used herein, unless otherwise indicated, the following terms have the meanings indicated and in accordance with the following conventions.

[0013] As used herein, the term "pharmaceutically acceptable" is used to refer to compounds, substances, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.

[0014] For example, such salts include salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid. Such salts include acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide / hydrobromide, edetate, camsylate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulfonate, estolate, esylate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobiolate, and the like. The salts may be phosphate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfamide, sulfate, tannate, tartrate, teoclate, toluenesulfonate, triethiodide, trifluoroacetate, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine.

[0015] Further pharmaceutically acceptable salts include those derived from metal cations such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc (Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, see also 1-19) or with cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0016] Methods of Therapeutic Use Olcegepant is effective in treating bacterial and fungal sepsis, severe sepsis, and septic shock. For use in treating severe bacterial or fungal sepsis and bacterial or fungal septic shock, olcegepant can be administered via a controlled- or sustained-release formulation comprising olcegepant or a pharmaceutically acceptable salt thereof encapsulated in PLGA (poly[lactic-co-glycolic acid]). To treat patients, such nanoparticles can be suspended in 0.1-0.4%, particularly 0.25%, sodium carboxymethylcellulose (Na-CMC) and 0.01-0.02%, particularly 0.015%, Tween 80 in a 0.9% sterile NaCl solution.

[0017] Olcegepant can also be delivered as a controlled- or sustained-release intravenous infusion at a rate such as 0.25 mg / 2 ml / min for 8 hours with physiological solutions (e.g., 0.9% saline or lactated Ringer's solution, or 5% dextrose, or human albumin (4%-5%) or 6% hydroxyethyl starch (Hespan) in saline) to maintain plasma concentrations in the patient below 500 nmol / L. Routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intrasynovial injection, sublingual, transdermal, oral, topical, or by inhalation. Preferred modes of administration are oral and intravenous.

[0018] Olcegepant can be administered alone or in combination with adjuvants, which enhance the stability of the compound and, in certain embodiments, facilitate administration of pharmaceutical compositions containing them, increase dissolution or dispersion, increase inhibitory activity, provide adjunctive therapy, etc., including other active ingredients. As mentioned above, dosage forms of the compounds of this invention can include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art and suitable for the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes, and cellulose-based materials. Preferred dosage forms include tablets, capsules, caplets, liquids, solutions, suspensions, emulsions, lozenges, syrups, reconstitutable powders, granules, suppositories, and transdermal patches. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements for the compounds of the invention can be selected by those skilled in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1 to 1000 mg / dose for a 70 kg patient. While a single daily dose may be sufficient, up to five doses per day can be administered. For oral administration, up to 2000 mg / day may be required. As will be appreciated by those skilled in the art, lower or higher doses may be required depending on certain factors. For example, the specific dosage and treatment regimen will depend on factors such as the patient's overall health profile, the severity and course or progression of the patient's disorder, and the judgment of the treating physician.

[0019] This article reports the lack of efficacy of olcegepant when given as a bolus injection either intravenously or subcutaneously in an animal model of sepsis. Surprisingly, it has been found that olcegepant, when given as a controlled-release or sustained-release formulation, significantly reduces vascular hyperpermeability and improves survival in animal models of sepsis. Thus, olcegepant can be used to treat severe bacterial or fungal sepsis. [Example]

[0020] CLP-induced polymicrobial sepsis in mice Cecal ligation and puncture (CLP) is a model of polybacterial sepsis that involves extrusion of fecal contents into the abdominal cavity of anesthetized animals. Two models were established: - A 24-hour acute CLP model was used to measure vascular hyperpermeability in lung, liver, kidney, and heart tissues. Vascular hyperpermeability was followed by extravasation of intravenously injected Evans Blue, which diffused and remained in the tissue. Vascular hyperpermeability was expressed as μg Evans Blue per 100 mg of dry tissue. - Chronic CLP model lasting 8 days. CLP was performed on day 0 and survival was followed for 8 consecutive days.

[0021] Acute CLP model: vascular hyperpermeability Ketamine (80 mg kg -1 , i.p.) and xylazine (10 mg kg -1 Mice were anesthetized using an intraperitoneal catheter (ip). A 1-1.5 cm midline abdominal incision was made, and the cecum was identified and tightly ligated with 4-0 (medium grade) silk suture at half the distance between the distal and proximal ends of the cecum. After moderate ligation, the cecum was thoroughly punctured once with a 21-gauge needle. A small amount of stool was expelled to confirm the wound was open. The cecum was then returned to its original position within the abdomen and closed in layers with sutures. Negative control animals underwent sham surgery: Sham-operated animals underwent an identical laparotomy, but without cecal ligation or puncture. Animals were resuscitated immediately after surgery with 1 mL of subcutaneous saline and returned to their cages. The experiment was terminated 24 hours after CLP.

[0022] Example 1: Effect of olcegepant in PLGA on an acute CLP model [ka] Olcegepant formulations in PLGA (128 mg of olcegepant encapsulated in 512 mg of PLGA nanoparticles (poly(D,L-lactic acid-co-glycolide) 75:25, designated Resomer RG 752H, manufactured by Evonik), equivalent to a total of 640 mg (20% olcegepant), suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) or its vehicle (PLGA nanoparticles suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) were administered subcutaneously (2 ml / kg) prophylactically at 30 mg / kg 2 hours before CLP or therapeutically at 10 or 30 mg / kg 2 hours after CLP. Each group contained 10 mice. Evans blue dye (0.1 mL at 40 mg / kg) was injected via the tail vein for 30 minutes, followed by euthanasia 24 hours after CLP. Lung, kidney, liver, and heart tissues were collected, and Evans blue was extracted with formamide. Evans blue dye concentrations were calculated from a standard curve and expressed as μg / 100 mg of dry lung tissue. Data were analyzed using commercially available software (Prism, version 8.3.0; GraphPad Software Inc., San Diego, CA). Different groups were compared using one-way analysis of variance (ANOVA) followed by Dunnett's test (e.g., comparing the CLP group with the treatment group). All data were expressed as mean ± SEM. The limit of significance was a p-value of less than 0.05 (p<0.05).

[0023] In the lungs, Evans Blue concentrations in the CLP vehicle-treated group (37 μg / 100 mg dry tissue) were significantly (p<0.05) higher than those in the sham group (15 μg / 100 mg dry tissue) (Figure 1.1). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in either the prophylactic (102% inhibition at 30 mg / kg) or therapeutic (99% inhibition at 10 mg / kg and 120% at 30 mg / kg) modes (Figure 1.1). In the liver, Evans Blue concentrations in the CLP vehicle-treated group (83 μg / 100 mg of dry tissue) were significantly (p<0.05) higher than those in the sham group (45 μg / 100 mg of dry tissue) (Figure 1.2). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in either the preventive (78% inhibition at 30 mg / kg) or therapeutic (65% at 10 mg / kg and 73% at 30 mg / kg) modes (Figure 1.2). In the kidney, Evans Blue concentrations in the CLP vehicle-treated group (80 μg / 100 mg of dry tissue) were significantly (p<0.05) higher than those in the sham group (30 μg / 100 mg of dry tissue) (Figure 1.3). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in either the preventive (74% inhibition at 30 mg / kg) or therapeutic (80% inhibition at 10 mg / kg and 77% at 30 mg / kg) modes (Figure 1.3). In the heart, Evans Blue concentrations in the CLP vehicle-treated group (39 μg / 100 mg of dry tissue) were significantly (p<0.05) higher than those in the sham group (18 μg / 100 mg of dry tissue) (Figure 1.4). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in both preventive (65% inhibition at 30 mg / kg) and therapeutic modes (96% at 10 mg / kg and 68% at 30 mg / kg) (Figure 1.4).

[0024] Example 2: Effect of olcegepant in PLGA on Streptococcus pneumonia-induced acute lung injury Mice were infected with Streptococcus pneumoniae (10 7 Mice were intratracheally inoculated with 10 or 30 mg / kg of olcegepant (CFU / 50 μL). Olcegepant formulation in PLGA (128 mg olcegepant encapsulated in 512 mg PLGA nanoparticles, equivalent to a total of 640 mg (20% olcegepant), suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) or its vehicle (PLGA nanoparticles suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) was administered subcutaneously (2 ml / kg) at 10 or 30 mg / kg 2 and 24 hours after bacterial inoculation. Mice were euthanized 48 hours after inoculation. Each group contained 10 mice. The lungs were rinsed with 0.8 ml of PBS to collect bronchoalveolar lavage fluid (BALF), which was then centrifuged at 500 rpm for 10 minutes, and the supernatant was collected and total protein was measured by absorbance at 660 nm according to the Lowry assay. Evans blue dye (0.1 mL at 40 mg / kg) was injected via the tail vein for 30 minutes, followed by euthanasia 48 hours after bacterial inoculation. Lung tissues were collected, and Evans blue was extracted with formamide. Evans blue dye concentrations were calculated from a standard curve and expressed as μg / 100 mg of dry lung tissue. Data were analyzed using commercially available software (Prism, version 8.3.0; GraphPad Software Inc., San Diego, CA). Different groups were compared using one-way analysis of variance (ANOVA) followed by Dunnett's test (e.g., comparing the S. pneumoniae group with the treatment group). All data were expressed as mean ± SEM. The limit of significance was a p-value of less than 0.05 (p<0.05). Pulmonary edema induced by intratracheal inoculation of Streptococcus pneumoniae is characterized by significant retention of bronchoalveolar lavage proteins (BALF proteins) in BALF. These proteins originate from blood-derived albumin due to increased vascular permeability and proteins derived from alveolar cell membranes in damaged lungs. In the Streptococcus pneumoniae group, BALF proteins (0.20 mg / ml BALF, Figure 2.1) were significantly higher than those in the vehicle group (0.10 mg / ml BALF, Figure 2.1). Therapeutic administration of olcegepant in PLGA significantly reduced BALF protein concentrations by 63% at 30 mg / kg (Figure 2.1). In the lungs, Evans Blue concentrations in the S. pneumoniae group (150 μg / 100 mg of dry tissue) were significantly (p<0.05) higher than those in the sham group (50 μg / 100 mg of dry tissue) (Figure 2.2). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in the treatment mode (63% at 10 mg / kg and 95% at 30 mg / kg) (Figure 2.2).

[0025] Example 3: Effect of olcegepant in PLGA on pulmonary ischemia-reperfusion Mice were anesthetized and mechanically ventilated. A left thoracotomy was performed, and the left pulmonary hilum, including the bronchus, pulmonary artery, and pulmonary vein, was occluded with forceps for 90 minutes to induce left pulmonary ischemia. Upon removal of the forceps, the left lung was reperfused and reventilated for 90 minutes. Time-matched sham-operated controls underwent a thoracotomy without hilar occlusion. Evans blue dye (0.1 mL at 40 mg / kg) was injected through the tail vein for 30 min, respectively, after which reperfusion was terminated. At the end of the reperfusion period, bronchoalveolar lavage fluid (BALF) was collected using 3 × 0.5 mL of PBS. Mice were perfused with PBS containing 5 mM EDTA. Left and right lungs and hearts were collected and assessed for Evans blue content. Evans blue dye (0.1 mL at 40 mg / kg) was injected via the tail vein for 30 minutes, followed by euthanasia. Lung and heart tissues were collected, and Evans blue was extracted with formamide. Evans blue dye concentrations were calculated from a standard curve and expressed as μg / 100 mg of dry lung tissue. A formulation of olcegepant in PLGA (128 mg of olcegepant encapsulated in 512 mg of PLGA nanoparticles, equivalent to a total of 640 mg (20% olcegepant), suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) or its vehicle (PLGA nanoparticles suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) was administered subcutaneously (2 ml / kg) at 3, 10, or 30 mg / kg prophylactically, followed by ischemia 1 hour later. In the obstructed left lung, Evans Blue concentrations at 7 μg / 100 mg dry tissue were significantly (p<0.05) higher than Evans Blue in the sham group (2 μg / 100 mg dry tissue) (Figure 3.1). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in the prophylactic mode (45% inhibition at 3 mg / kg, 60% at 10 mg / kg, and 65% at 30 mg / kg) (Figure 3.1). In BALF, the Evans Blue concentration of 1.8 μg / ml was significantly (p<0.05) higher than that in the Sham group (0.4 μg / ml) (Figure 3.2). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentration in the prophylactic mode (54% at 10 mg / kg and 63% at 30 mg / kg) (Figure 3.2). In the heart, Evans Blue concentrations at 3.2 μg / 100 mg of dry tissue were significantly (p<0.05) higher than Evans Blue in the sham group (1.5 μg / 100 mg of dry tissue) (Figure 3.3). Olcegepant in PLGA significantly (p<0.05) reduced Evans Blue concentrations in the prophylactic mode (80% at 10 mg / kg and 93% at 30 mg / kg) (Figure 3.3).

[0026] Example 4: Chronic CLP model: survival rate On day 0, ketamine (80 mg kg -1 , i.p.) and xylazine (10 mg kg -1 Mice were anesthetized using an intraperitoneal catheter (ip). A 1-1.5 cm midline abdominal incision was made, and the cecum was identified and tightly ligated with 4-0 (medium grade) silk suture halfway between the distal and proximal ends of the cecum. After moderate ligation, the cecum was thoroughly punctured once with a 21-gauge needle. A small amount of stool was expelled to confirm the wound was open. The cecum was then returned to its original position within the abdomen and closed in layers with sutures. Negative control animals underwent sham surgery: Sham-operated animals underwent an identical laparotomy, but without cecal ligation or puncture. Animals were resuscitated immediately after surgery with 1 mL of subcutaneous saline and returned to their cages. A formulation of olcegepant in PLGA (128 mg of olcegepant encapsulated in 512 mg of PLGA nanoparticles, corresponding to a total of 640 mg of formulation (20% olcegepant), suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) or its vehicle (PLGA microparticles suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution) was administered subcutaneously at 30 mg / kg therapeutically (2 ml / kg) 2 hours after CLP induction and once daily on days 1 through 6. Olcegepant solubilized in saline was also tested and its efficacy compared to that of olcegepant encapsulated in PLGA. Olcegepant in saline was administered therapeutically at 30 mg / kg subcutaneously (2 ml / kg) 2 hours after CLP induction and once daily from days 1 to 6. Each group contained 10 mice.

[0027] No mortality was observed in the sham group over 8 days, while all mice in the CLP group died on day 3. Olcegepant in PLGA significantly reduced mortality, with a survival rate of 70% on day 8 (7 out of 10 mice were still alive on day 8) (Figure 4.1). Olcegepant solubilized in saline slightly reduced mortality, with a survival rate of 20% on day 8 (2 out of 10 mice were still alive on day 8) (Figure 4.1), consistent with data from patent WO2018 / 154015, in which olcegepant solubilized in saline and administered subcutaneously at 100 mg / kg twice daily in a mouse CLP model rescued 20% of mice on day 4 (2 out of 10 mice were still alive on day 4).

Claims

1. A compound for use in treating patients with a systemic response to and / or conditions resulting from bacteria, fungi, or circulating bacterial or fungal products, comprising a CGRP receptor antagonist 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 10. The compound of claim 1, wherein the systemic response of the patient is characterized by interstitial fluid retention and / or hypotension.

3. 10. The compound of claim 1 for use in a method for treating a patient having a CGRP plasma concentration of 30 to 200 pmol / L.

4. 10. A medicament for treating a patient with a systemic reaction to bacteria, fungi, or circulating bacterial or fungal products, the medicament being prepared with a compound of claim 1 or a salt thereof.

5. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

6. 6. The pharmaceutical composition according to claim 5, comprising 5 to 40% of olcegepant or a pharmaceutically acceptable salt thereof.

7. 7. The pharmaceutical composition according to claim 6, comprising 5 to 20% of olcegepant or a pharmaceutically acceptable salt thereof.

8. 8. The pharmaceutical composition of claim 7, formulated as a physiological solution for sustained release, such as 0.9% saline, or lactated Ringer's solution, or 5% dextrose, or human albumin (4%-5%) in saline, or 6% hydroxyethyl starch (Hespan).

9. 8. The pharmaceutical composition of claim 7, prepared as a sustained release formulation comprising olcegepant encapsulated in PLGA nanoparticles.

10. 10. The pharmaceutical composition of claim 9, wherein the PLGA nanoparticles are suspended in 0.1-0.4% sodium carboxymethylcellulose (Na-CMC) and 0.01-0.02% Tween 80 in 0.8-1.0% sterile NaCl solution.

11. 11. The pharmaceutical composition of claim 10, wherein the PLGA nanoparticles are suspended in 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.015% Tween 80 in 0.9% sterile NaCl solution.

12. 6. The pharmaceutical composition of claim 5 for use in a method for treating a patient with severe bacterial or fungal sepsis or bacterial or fungal septic shock.

13. 6. The pharmaceutical composition according to claim 5, for use in a method for treating patients with severe bacterial or fungal sepsis or bacterial or fungal septic shock and having a CGRP plasma concentration of 30 to 200 pmol / L, comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the range of 0.1 to 90% by weight of the total composition, preferably in the range of 0.5 to 50% by weight of the total composition.

14. 14. The pharmaceutical composition of claim 13 for use in a method for treating a patient with a CGRP plasma concentration of 30-200 pmol / L compared to a healthy state where the CGRP plasma concentration is less than 10 pmol / L.

15. 10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, for use in a method for the treatment or prevention of severe bacterial or fungal sepsis and bacterial or fungal septic shock.

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