Osazepam for treatment of sepsis

Abstract

The present invention relates to compounds for use in methods for treating patients suffering from conditions associated with bacterial or fungal severe sepsis and bacterial or fungal septic shock and conditions resulting therefrom, pharmaceutical compositions containing said compounds and their use as medicaments for the treatment of bacterial or fungal severe sepsis and bacterial or fungal septic shock and the conditions resulting therefrom. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds for treating patients with a systemic response to bacteria, fungi, or circulating bacterial or fungal products and the conditions resulting therefrom, wherein the compounds are

[0002]

[0003] or derivatives thereof (oxazepam, olcegepant), and a method for treating patients suffering from said systemic response, a pharmaceutical composition containing said compounds, and their use as a medicament for treating bacterial or fungal severe sepsis or bacterial or fungal septic shock and the conditions resulting therefrom. Background Art

[0004] In bacterial or fungal severe sepsis or bacterial or fungal septic shock, an increase in vascular permeability is observed in several organs including, but not limited to, the lungs, kidneys, liver, and heart. Interstitial fluid accumulation in these organs impairs their normal function (e.g., leading to hypovolemia, hypotension, arrhythmia, glomerular filtration dysfunction, or metabolic disorders) and results in organ failure and subsequent death. Conventional antibiotics are not used for fungal infections because they are ineffective against fungal infections.

[0005] Sepsis, severe sepsis, and septic shock are conditions 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 condition having both an infection (e.g., bacterial, fungal, abdominal trauma, bowel perforation) and a systemic inflammatory response. This results in an increase in vascular permeability in several organs such as the kidneys, liver, heart, and lungs. Severe sepsis (sepsis with organ dysfunction) refers to sepsis having acute organ dysfunction caused by sepsis. Septic shock refers to persistent hypotension that cannot be explained by other causes.

[0006] There is a need for compound formulations or dosage forms for use in methods for treating bacterial or fungal severe sepsis and bacterial or fungal septic shock.

[0007] Unfortunately, there is no animal model that mimics human sepsis. A large number of anti - inflammatory drugs (such as anti - TNF - α or TLR4 inhibitors) tested in pigs, monkeys, or healthy volunteers challenged with LPS are ineffective in sepsis patients.

[0008] Olcegepant, a calcitonin gene-related peptide (CGRP) receptor antagonist, is described in WO 98 / 11128 and by Doods et al. in British Journal of Pharmacology 129:420-423, 2000.

[0009] In a murine sepsis model, olcegepant administered as a subcutaneous bolus rescued only 2 out of 10 mice (WO2018 / 154015).

[0010] Messerer et al. reported that in a porcine sepsis model, olcegepant administered as an intravenous bolus did not show any improvement in survival (British Journal of Anaesthesia 128(5):864-873, 2022).

[0011] Surprisingly, the present invention has found that a modified-release formulation of olcegepant improves survival in a murine model of polymicrobial septic shock. Summary of the Invention

[0012] The present invention relates to the use of the CGRP receptor antagonist olcegepant or a pharmaceutically acceptable salt thereof for the treatment of patients diagnosed with sepsis (i.e., patients suffering from severe bacterial or fungal sepsis and bacterial or fungal septic shock and the resulting conditions, particularly conditions associated with bacterial or fungal parasitic infections).

[0013] The present invention relates to olcegepant or a pharmaceutically acceptable salt thereof for the treatment of patients suffering from bacterial or fungal sepsis, severe bacterial or fungal sepsis, or bacterial or fungal septic shock or the resulting conditions selected from ARDS, infection-related conditions, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), peritonitis, and puerperal (childbirth) fever.

[0014] Furthermore, the present invention relates to a method for treating patients suffering from bacterial or fungal sepsis, severe bacterial or fungal sepsis, or bacterial or fungal septic shock or the resulting conditions selected from acute respiratory distress syndrome (ARDS), infection-related conditions, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), peritonitis, and puerperal (childbirth) fever, the method comprising administering olcegepant or a pharmaceutically acceptable salt thereof.

[0015] In one embodiment, the present invention relates to a compound for use in a method for treating a patient having a systemic response to bacteria, fungi, or circulating bacterial or fungal products and / or the resulting conditions, wherein the compound is the CGRP receptor antagonist oxazepam or a pharmaceutically acceptable salt thereof:

[0016]

[0017] In a particular embodiment, the above invention relates to the compound oxazepam or a pharmaceutically acceptable salt thereof for treating sepsis, wherein sepsis patients have a CGRP plasma concentration in the range of 30 to 200 pmol / L (Arnalish et al., Life Sci. 56:75 - 81, 1995), while the normal range of plasma CGRP should be below 10 pmol / L. In particular, the systemic response of the patient is characterized by interstitial fluid accumulation and / or hypotension.

[0018] Furthermore, the above invention relates to a method for treating a patient suffering from severe sepsis (i.e., sepsis accompanied by organ dysfunction or tissue hypoperfusion caused by sepsis (manifested as hypotension, elevated lactate, or Decreased urine output ))), the method comprising administering oxazepam or a pharmaceutically acceptable salt thereof, wherein sepsis patients have a CGRP plasma concentration in the range of 30 to 200 pmol / L (Arnalish et al., Life Sci. 56:75 - 81, 1995), while the normal range of plasma CGRP should be below 10 pmol / L. In particular, the systemic response of the patient is characterized by interstitial fluid accumulation and / or hypotension.

[0019] When symptoms such as fever, tachycardia, hypotension, tachypnea, oliguria, severe pain, and delirium are observed, the patient is diagnosed as suffering from sepsis.

[0020] Another embodiment of the present invention is a medicament prepared with the compound oxazepam or a pharmaceutically acceptable salt thereof for treating a patient suffering from bacterial, viral, or fungal sepsis.

[0021] Another embodiment of the present invention is a pharmaceutical composition containing the above compound oxazepam or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The composition is particularly for oxazepam administered by a new method for treating a patient suffering from bacterial or fungal severe sepsis or bacterial or fungal septic shock.

[0022] Particularly interesting is a pharmaceutical composition prepared as a modified - release preparation, particularly a sustained - release preparation, of the CGRP receptor antagonist oxazepam or a pharmaceutically acceptable salt thereof, wherein the composition contains 5 - 40%, particularly 5 - 20%, of oxazepam or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment of the present invention, the CGRP receptor antagonist oseltamivir can be formulated as a modified-release or sustained-release preparation, for example, encapsulated in PLGA (poly(lactic-co-glycolic acid)) nanoparticles. The modified-release dose is delivered after its administration Drug or extends the drug delivery time. The FDA-approved polymer PLGA is a biodegradable polymer composed of 75% lactic acid and 25% glycolic acid, forming nanospheres with a size below 200 nm and a negative surface charge, which are used to prepare vaccines and drugs (Lim et al., Pharmaceutics 14:614, 2022, https: / / doi.org / 10.3390 / pharmaceutics14030614).

[0024] For the treatment of patients, the nanoparticles can be suspended in a sterile 0.9% NaCl solution containing 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.

[0025] Oseltamivir can also be delivered as a modified-release or sustained-release intravenous infusion with a physiological solution such as 0.9% normal saline or lactated ringer's solution or 5% dextrose or human albumin (4% - 5%) / saline or 6% hydroxyethyl starch (hespan) at a rate of, for example, 0.25 mg / 2 ml / min for at least 8 hours in order to keep the plasma concentration in the patient below 500 nmol / L.

[0026] Another embodiment of the present invention is the pharmaceutical composition of the CGRP receptor antagonist oseltamivir or a pharmaceutically acceptable salt thereof for the treatment of patients suffering from severe bacterial or fungal sepsis or bacterial or fungal septic shock, the pharmaceutical composition comprising 5 - 40%, particularly 5 - 20% of oseltamivir. The therapeutically effective amount range of oseltamivir or a pharmaceutically acceptable salt thereof is 0.1 to 90 wt% of the composition as a whole, preferably in the range of 0.5 to 50 wt% of the composition as a whole. Detailed Description

[0027] General Definitions

[0028] Terms not explicitly defined herein shall be given the definitions ascribed to them by those skilled in the art based on the present disclosure and the context. However, as used in the specification, unless otherwise provided to the contrary, the following terms have the indicated definitions and follow the following conventions.

[0029] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0030] As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by preparing its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal salts or organic salts of acidic residues (such as carboxylic acids); and the like.

[0031] For example, such salts include salts 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 can be acetate, ascorbate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bromide / hydrobromide, edetate, camphorsulfonate, carbonate, chloride / hydrochloride, citrate, edisylate, ethanedisulfonate, estolate, esylate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothiocyanate, lactate, lactobionate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, mucate, naphthalenesulfonate, nitrate, oxalate, pamoate, pantothenate, phenylacetate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, tannate, tartrate, teoclate, toluenesulfonate, triethyl iodide, trifluoroacetate, ammonium salt, benzathine, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, glucosamine salt, and procaine salt.

[0032] Further pharmaceutically acceptable salts may be formed with cations from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (see also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19) or with cations from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane.

[0033] Method for therapeutic use

[0034] Oxazepam can be effective in treating bacterial and fungal infections, severe sepsis, and septic shock.

[0035] For use in treating bacterial or fungal severe sepsis and bacterial or fungal septic shock, oxazepam can be administered via a modified-release or sustained-release formulation comprising oxazepam or a pharmaceutically acceptable salt thereof encapsulated in PLGA (polylactic-co-glycolic acid). For treating a patient, the nanoparticles can be suspended in a sterile 0.9% NaCl solution of 0.1-0.4%, particularly 0.25% sodium carboxymethylcellulose (Na-CMC) and 0.01-0.02%, particularly 0.015% Tween 80.

[0036] Oxazepam can also be delivered as a modified-release or sustained-release intravenous infusion with a physiological solution such as 0.9% saline or lactated Ringer's solution or 5% dextrose or human albumin (4%-5%) / saline or 6% hydroxyethyl starch (hespan) at a rate such as 0.25 mg / 2 ml / min for 8 hours in order to keep the plasma concentration in the patient below 500 nmol / L.

[0037] Routes of administration include but are not limited to intravenous, intramuscular, subcutaneous, intra-articular, by infusion, sublingual, transdermal, oral, topical, or by inhalation. Preferred routes of administration are oral and intravenous.

[0038] Oxazepam can be administered alone or in combination with adjuvants (including other active ingredients) that enhance compound stability, facilitate the administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjuvant therapy, etc.

[0039] As described above, the dosage forms of the compounds of the present invention may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable for the dosage forms. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffering 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, Lea and Febiger eds. (1990)). The dosage levels and requirements for the compounds of the present invention can be selected by those of ordinary skill in the art from the available methods and techniques applicable to a particular patient. In some embodiments, the dosage level range for a 70 kg patient is about 1 - 1000 mg / dose. Although one dose per day may be sufficient, up to 5 doses per day may be administered. For oral doses, 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 specific factors. For example, the specific dose and treatment regimen will depend on factors such as the general health of the patient, the severity and course of the patient's condition or its management, and the judgment of the attending physician.

[0040] The literature reports that oxazepam lacks efficacy when administered as an intravenous or subcutaneous bolus in septic animal models.

[0041] Surprisingly, in septic animal models, oxazepam administered as a modified-release or sustained-release formulation significantly reduces hypervascular permeability and improves survival. Thus, oxazepam can be used to treat severe bacterial or fungal sepsis.

[0042] Example

[0043] CLP-induced polymicrobial sepsis in mice

[0044] Cecal ligation and puncture (CLP) is a polymicrobial sepsis model that involves extruding fecal contents from the abdominal cavity of an animal under anesthesia.

[0045] Two models were implemented:

[0046] - In the 24-hour CLP acute model, increased vascular permeability in the lung, liver, kidney, and heart tissues was measured. The increased vascular permeability led to the extravasation and diffusion of intravenously injected Evans blue and its accumulation in the tissues. The increased vascular permeability was expressed as the number of micrograms of Evans blue per 100 mg of dry tissue.

[0047] - In the 8-day CLP chronic model. CLP was performed on day 0 and the survival rate was followed for 8 consecutive days thereafter.

[0048] CLP acute model: Increased vascular permeability

[0049] Mice were anesthetized with ketamine (80 mg / kg -1 , i.p.) and xylazine (10 mg / kg -1 , i.p.). A 1-1.5 cm midline abdominal incision was made, the cecum was located and tightly ligated (moderately) with 4-0 silk suture at half the distance between the distal pole and the base of the cecum. After moderate ligation, the cecum was punctured once thoroughly with a 21-gauge needle. A small amount of feces was extruded to ensure the wound was patent. Then the cecum was returned to its original position in the abdomen and sutured layer by layer with sutures. For negative control animals, sham surgery was performed: Sham-operated animals underwent the same laparotomy but without cecal ligation or puncture. The animals were immediately resuscitated with 1 mL of subcutaneous saline after surgery and returned to their cages. The experiment was terminated 24 hours after CLP.

[0050] Example 1: The effect of oxazepam / PLGA on the CLP acute model

[0051]

[0052] The oxazepam / PLGA formulation (128 mg of oxazepam encapsulated in 512 mg of PLGA nanoparticles ((poly(lactic-co-glycolic acid) copolymer) 75:25 called Resomer RG 752H, prepared by Evonik), equivalent to a total of 640 mg (20% oxazepam) and suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80) or its vehicle (PLGA nanoparticles suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80)) was administered subcutaneously (2 ml / kg) prophylactically at 30 mg / kg 2 h before CLP or therapeutically at 10 or 30 mg / kg 2 h after CLP. Each group included 10 mice.

[0053] Twenty-four hours after CLP, Evans blue dye (0.1 mL at 40 mg / kg) was injected via the respective tail vein 30 minutes before anesthesia. Lung, kidney, liver, and heart tissues were collected, and Evans blue was extracted into formamide. The concentration of Evans blue dye was 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., comparison of the CLP group with the treatment groups). All data are expressed as mean ± SEM. A p-value less than 0.05 (p < 0.05) was considered the significance threshold.

[0054] In the lung, the concentration of Evans blue in the CLP vehicle-treated group (37 μg / 100 mg dry tissue) was significantly (p < 0.05) higher than that in the sham-operated group (15 μg / 100 mg dry tissue) (Figure 1.1). Oxazepam / PLGA significantly (p < 0.05) decreased the concentration of Evans blue in the preventive model (102% inhibition at 30 mg / kg) or the therapeutic model (99% inhibition at 10 mg / kg and 120% inhibition at 30 mg / kg) (Figure 1.1).

[0055] In the liver, the concentration of Evans blue in the CLP vehicle-treated group (83 μg / 100 mg dry tissue) was significantly (p < 0.05) higher than that in the sham-operated group (45 μg / 100 mg dry tissue) (Figure 1.2). Oxazepam / PLGA significantly (p < 0.05) decreased the concentration of Evans blue in the preventive model (78% inhibition at 30 mg / kg) or the therapeutic model (65% at 10 mg / kg and 73% at 30 mg / kg) (Figure 1.2).

[0056] In the kidney, the concentration of Evans blue in the CLP vehicle-treated group (80 μg / 100 mg dry tissue) was significantly (p < 0.05) higher than that in the sham-operated group (30 μg / 100 mg dry tissue) (Figure 1.3). Oxazepam / PLGA significantly (p < 0.05) decreased the concentration of Evans blue in the preventive model (74% inhibition at 30 mg / kg) or the therapeutic model (80% inhibition at 10 mg / kg and 77% inhibition at 30 mg / kg) (Figure 1.3).

[0057] In the heart, the Evans blue concentration in the CLP vehicle-treated group (39 μg / 100 mg dry tissue) was significantly (p < 0.05) higher than that in the sham-operated group (18 μg / 100 mg dry tissue) (Figure 1.4). Oxazepam / PLGA significantly (p < 0.05) decreased the Evans blue concentration in the prophylactic model (65% inhibition at 30 mg / kg) and the therapeutic models (96% at 10 mg / kg and 68% at 30 mg / kg) (Figure 1.4).

[0058] Example 2: Effect of Oxazepam / PLGA on Acute Lung Injury Induced by Streptococcus pneumoniae

[0059] Mice were inoculated intratracheally with Streptococcus pneumoniae (10 7 CFU / 50 μL). Oxazepam / PLGA formulation (128 mg oxazepam encapsulated in 512 mg PLGA nanoparticles, equivalent to a total of 640 mg (20% oxazepam)) was administered subcutaneously (2 ml / kg) at 10 or 30 mg / kg therapeutically 2 h and 24 h after bacterial inoculation and suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80) or its vehicle (PLGA nanoparticles suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80)). Mice were euthanized 48 h after inoculation. Ten mice were included in each group. Lungs were flushed with 0.8 ml PBS to facilitate collection of bronchoalveolar lavage fluid (BALF), which was then centrifuged at 500 rpm for 10 min and the supernatant was collected for determination of total protein by Lowry measurement of absorbance at 660 nm.

[0060] Forty-eight hours after bacterial inoculation and 30 min before euthanasia, Evans blue (0.1 mL at 40 mg / kg) was injected via the respective tail vein. Lung tissues were collected and Evans blue was extracted into formamide. The concentration of the Evans blue dye was calculated from the standard curve and expressed as μg / 100 mg 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 by one-way analysis of variance (ANOVA), followed by Dunnett's test (e.g., CLP group compared with the treated group). All data are expressed as mean ± SEM. A p-value less than 0.05 (p < 0.05) was considered the significance threshold.

[0061] In BALF, pulmonary edema induced by intratracheal inoculation of Streptococcus pneumoniae was characterized by a marked accumulation of bronchoalveolar lavage protein (BALF protein). The source of these proteins was albumin from the blood due to excessive vascular permeability and proteins from damaged alveolar cell membranes. In the Streptococcus pneumoniae group, BALF protein (0.20 mg / ml BALF, Figure 2.1) was significantly higher than that in the vehicle group (0.10 mg / ml BALF, Figure 2.1). Oxazepam / PLGA administered therapeutically at 30 mg / kg significantly reduced the BALF protein concentration by 63% (Figure 2.1).

[0062] In the lung, the Evans blue concentration in the Streptococcus pneumoniae group (150 μg / 100 mg dry tissue) was significantly (p < 0.05) higher than that in the sham-operated group (50 μg / 100 mg dry tissue) (Figure 2.2). Oxazepam / PLGA significantly (p < 0.05) reduced the Evans blue concentration in the treatment model (63% inhibition at 10 mg / kg and 95% inhibition at 30 mg / kg) (Figure 2.2).

[0063] Example 3: Effect of Oxazepam / PLGA on Lung Ischemia-Reperfusion

[0064] Mice were anesthetized and mechanically ventilated. A left thoracotomy was performed and the hilar region of the left lung (including the bronchus, pulmonary artery, and pulmonary vein) was occluded with a clamp for 90 min to induce lung ischemia of the left lung. After removal of the clamp, the left lung was reperfused and ventilation was restored for 90 min. In time-matched sham-operated animals used as controls, thoracotomy was performed without occluding the hilum.

[0065] Evans blue dye (0.1 mL at 40 mg / kg) was injected via the respective tail vein 30 minutes before the end of reperfusion.

[0066] At the end of the reperfusion period, bronchoalveolar lavage (BALF) was performed with 3 x 0.5 mL PBS. Mice were perfused with PBS containing 5 mM EDTA. The left and right lungs and the heart were collected for evaluation of Evans blue content. Evans blue (0.1 mL at 40 mg / kg) was injected via the respective tail vein 30 minutes before euthanasia. Lung and heart tissues were collected and Evans blue was extracted into formamide. The concentration of the Evans blue dye was calculated from the standard curve and expressed as μg / 100 mg of dry lung tissue. Oxazepam / PLGA formulation (128 mg oxazepam encapsulated in 512 mg PLGA nanoparticles, equivalent to a total of 640 mg (20% oxazepam)) was administered prophylactically subcutaneously (2 ml / kg) at 3, 10 or 30 mg / kg 1 h before ischemia and suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80 or its vehicle (PLGA nanoparticles suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80)).

[0067] In the occluded left lung, the Evans blue concentration was 7 μg / 100 mg of dry tissue, significantly (p < 0.05) higher than the Evans blue concentration in the sham-operated group (2 μg / 100 mg of dry tissue) (Figure 3.1). Oxazepam / PLGA significantly (p < 0.05) decreased the Evans blue concentration in the prophylactic model (45% inhibition at 3 mg / kg, 60% inhibition at 10 mg / kg and 65% inhibition at 30 mg / kg) (Figure 3.1).

[0068] In BALF, the Evans blue concentration was 1.8 μg / ml, significantly (p < 0.05) higher than the Evans blue concentration in the sham-operated group (0.4 μg / ml) (Figure 3.2). Oxazepam / PLGA significantly (p < 0.05) decreased the Evans blue concentration in the prophylactic model (54% inhibition at 10 mg / kg and 63% inhibition at 30 mg / kg) (Figure 3.2).

[0069] In the heart, the Evans blue concentration was 3.2 μg / 100 mg of dry tissue, significantly (p < 0.05) higher than the Evans blue concentration in the sham-operated group (1.5 μg / 100 mg of dry tissue) (Figure 3.3). Oxazepam / PLGA significantly (p < 0.05) decreased the Evans blue concentration in the prophylactic model (80% at 10 mg / kg and 93% at 30 mg / kg) (Figure 3.3).

[0070] Example 4: Chronic model of CLP: Survival rate

[0071] On day 0, ketamine (80 mg kg -1, i.p.) and xylazine (10 mg / kg -1 , i.p.) to anesthetize the mice. A 1-1.5 cm midline abdominal incision was made, the cecum was located and tightly ligated (moderately) with 4-0 silk suture at half the distance between the distal pole and the base of the cecum. After moderate ligation, the cecum was punctured once thoroughly with a 21-gauge needle. A small amount of feces was extruded to ensure the wound was open. Then the cecum was returned to its original position in the abdomen and sutured in layers with sutures. For the negative control animals, sham surgery was performed: sham-operated animals underwent the same laparotomy but without cecal ligation or puncture. The animals were immediately resuscitated with 1 mL of subcutaneous saline after surgery and returned to their cages.

[0072] The oxazepam / PLGA formulation (128 mg of oxazepam encapsulated in 512 mg of PLGA nanoparticles, equivalent to a total of 640 mg (20% oxazepam) and suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80) or its vehicle (PLGA nanoparticles suspended in a sterile 0.9% NaCl solution of 0.25% sodium carboxymethylcellulose ((Na-CMC) and 0.015% Tween 80)) was therapeutically administered subcutaneously (2 mL / kg) at 30 mg / kg 2 h after CLP induction and once daily from day 1 to day 6.

[0073] Oxazepam dissolved in physiological saline was also tested to compare its efficacy with that of oxazepam encapsulated in PLGA. Oxazepam in physiological saline was therapeutically administered subcutaneously (2 mL / kg) at 30 mg / kg 2 h after CLP induction and once daily from day 1 to day 6.

[0074] Each group included 10 mice.

[0075] No deaths were observed in the sham-operated group of mice within 8 days, while all mice in the CLP group died on day 3. Oxazepam / PLGA significantly reduced the mortality rate on day 8, with a survival rate of 70% (7 out of 10 mice still survived on day 8) (Figure 4.1). Oxazepam dissolved in physiological saline slightly reduced the mortality rate on day 8, with a survival rate of 20% (2 out of 10 mice still survived on day 8) (Figure 4.1), which is consistent with the data described in patent WO 2018 / 154015, where oxazepam dissolved in physiological saline and administered subcutaneously twice daily at 100 mg / kg saved 20% of the mice on day 4 (2 out of 10 mice still survived on day 4) in a mouse CLP model.

Claims

1. A compound or a pharmaceutically acceptable salt thereof for treating a patient having a systemic response to bacteria, fungi, or circulating bacterial or fungal products and / or the conditions resulting therefrom, wherein said compound is a CGRP receptor antagonist 2. The compound according to claim 1, wherein the systemic response of the patient is characterized by interstitial fluid accumulation and / or hypotension.

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

4. A medicament for treating a patient having a systemic response to bacteria, fungi, or circulating bacterial or fungal products, said medicament being prepared with the compound or a salt thereof according to claim 1.

5. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, which comprises 5 - 40% of oxazepam or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6, which comprises 5 - 20% of oxazepam or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, which is prepared as a physiological solution for slow release such as 0.9% normal saline, or lactated Ringer's solution, or 5% glucose, or human albumin (4% - 5%) / saline or 6% hydroxyethyl starch (hespan).

9. The pharmaceutical composition according to claim 7, which is prepared as a slow release formulation comprising oxazepam encapsulated in PLGA nanoparticles.

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

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

12. The pharmaceutical composition according to claim 5 for treating a patient suffering from severe bacterial or fungal sepsis or bacterial or fungal septic shock.

13. The pharmaceutical composition according to claim 5, for use in a method for treating a patient having a CGRP plasma concentration of 30 to 200 pmol / L and suffering from bacterial or fungal severe sepsis or bacterial or fungal septic shock, said pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in an amount ranging from 0.1 to 90 wt% of the composition as a whole, preferably ranging from 0.5 to 50 wt% of the composition as a whole.

14. The pharmaceutical composition according to claim 13, for use in a method for treating a patient having a CGRP plasma concentration of 30 to 200 pmol / L compared to a health condition in which the CGRP plasma concentration is less than 10 pmol / L.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 5, for use in a method for treating or preventing bacterial or fungal severe sepsis and bacterial or fungal septic shock.

Images