TW201309325A - Administration of serine protease inhibitors to the stomach - Google Patents

Abstract

The inventors unexpectedly discovers that shock and/or potential multi-organ failure due to shock can be effectively treated by administration of liquid high-dose protease inhibitor formulations to a location upstream of where pancreatic proteases are introduced into the gastrointestinal tract. Most preferably, administration is directly to the stomach, for example, via nasogastric tube under a protocol effective to treat shock by such administration without the need of providing significant quantities of the protease inhibitor to the jejunum and/or ileum.

Description

Administration of serine protease inhibitors in the stomach

This invention relates to a composition and method for treating shock.

A shock is usually a life-threatening complication that occurs when a patient is in a trauma-related condition, such as a burn, surgery, ischemia, sepsis, or other serious condition. Shock is a broad term used to describe the cyclical syndrome, the cellular hypoxia caused by shock, and the combined effects of shock on the microcirculation leading to a ultimately irreversible cardiovascular collapse.

Shock is a multifaceted systemic response that involves responses to stimuli triggered by a cell that activates and releases a number of interacting regulators, including cytokines, inflammatory and The regulator of immunity, and nitric oxide (NO). During the immune reaction, oxygen free radicals and peroxides are formed to kill the pathogen. However, oxygen free radicals and superoxides also cause damage to host cells, leading to oxidation of lipids, proteins and nucleic acids. The medium produced during shock can coordinate the complex biological interactions and amplify the signal to produce a systemic response to local discomfort.

The development of treatment methods has become very difficult due to the multi-faceted nature of the factors that induce shock. In the past, most treatments only focused on a single cause. The regulation of children (such as cytokines, nitric oxide, endotoxin) in order to alleviate the effects of shock. Unfortunately, regardless of inhibition of any of these pleiotropic factors, it is not effective to improve the condition. Organ specific therapy, while maintaining signs of life, often sacrifices the function of the terminal organs and is not an ideal treatment.

Bactericidal/permeability-increasing protein (BPI), a protein involved in the immune response (see Amos Ammons, US Patent No. 6,017,881), which was once considered to have potential therapeutic effects. The molecule can be used to treat shock. A common shock complication, "intestinal ischemia," causes damage to the permeability barrier of the intestinal mucosa, causing the bacteria and/or endotoxin originally in the intestinal cavity to migrate into the vascular system. During the shock, although the endotoxin can be detected in the patient's portal vein, its role in shock is still unclear. Basically, the bactericidal/permeability enhancing protein is a protein obtained by separating granules of polymorphonuclear cells (PMNs) of mammals. Polymorphonuclear leukocytes are blood cells that are involved in the body against invading microorganisms. The bactericidal/permeability enhancing protein is highly specific to Gram-negative bacteria and should not cause damage to other pathogens or somatic cells. Intestinal ischemia causes other symptoms of shock, and the administration of bactericidal/permeability enhancing protein in rats reveals that physiological side effects caused by intestinal ischemia can be alleviated. However, bactericidal/permeability enhancing proteins can only inhibit one of the many pathways activated by shock, and thus their utility is limited. In addition, BPI is activated when endotoxin and bacteria are released from the intestinal lumen into the blood vessels, so it does not The method is used as a method to prevent shock.

As for other therapies, such as U.S. Patent No. 6,534,283, the inventors have demonstrated the role of pancreatic proteases in shock and the protective effects of protease inhibitors on specific uses. Under normal conditions, pancreatic digestive enzymes are released into the small intestine for digestion without side effects. However, in shock, because the intestinal wall permeability barrier is fragile, the inventors reasoned that the protease susceptible sites that would not be exposed in health would be exposed at this time, and the tissue would be destroyed, and as a shock. The protein hydrolysate of the strong activator is released. A variety of protein hydrolysates can act as regulators of shock, so the inventors believe that the most effective treatment of shock by avoiding the activation of small intestinal protease, inhibiting or excluding proteases that produce shock-inducing activators in the intestinal lumen of the small intestine. To this end, the inventors believe that the injection of protease inhibitors into the small intestine of the rat can prevent shock by analyzing the survival time and molecular and histological analysis.

However, although the experimental results confirmed that protease inhibitors have at least some effects (for example, inhibiting the activation of neutrophils in the circulatory system and attenuating the activity of bone marrow peroxidase), the inventors only considered direct administration of protease inhibition to the small intestine. The possibility of a prophylactic intervention.

Thus, even though various methods of prevention or treatment of shock have been disclosed in the prior art, there remains a need for an effective method and composition for treating shock and shock related symptoms.

The inventors have unexpectedly discovered that by administering a high dose of a protease inhibitor formulation to trypsin injection into an upstream location of the gastrointestinal tract, it is effective to treat shock and/or potential multiple organ failure due to shock. Optimally, it is administered directly to the stomach, for example, by administering the nasogastric tube and according to the standard guidelines for effective treatment of shock according to such administration, without the need to administer a large amount of protease inhibitor to the jejunum and/or Ileum. Therefore, it is possible to intervene in the onset or acute shock in a quick, simple and effective manner.

In accordance with one aspect of the invention, a method of treating a mammalian shock and/or potential multiple organ failure due to shock, in one embodiment, the step of diagnosing the mammal having a state of shock. Another step is to administer a protease inhibitor (usually a liquid formulation) containing a therapeutically effective amount of at least 20 mg/kg, wherein the liquid formulation is administered to a location in the gastrointestinal tract and the site is released to trypsin Upstream of a location of the gastrointestinal tract; wherein, in the treatment of shock and potential multiple organ failure, the liquid formulation is administered at this location in accordance with an effective standard of care for shock. Therefore, the therapy can be continued for a period of time after the initial administration without the need to administer a high dose of protease inhibitor to the small intestine.

Therefore, the position is preferably a stomach and is preferably performed through a nasogastric tube or catheter. In addition, it may be administered by oral liquid or by direct injection. Although the administration method is preferably carried out using a single unpackaged drug per day, it is considered to be a suitable method to perform multiple administrations using the dispensed multi-agent. More preferably, the mode of administration can be selectively carried out using a dispensed single daily dose for at least two more days, more preferably at least seven days, optimally, for at least ten days.

For the purposes of the present invention, further dosages of at least 25 mg/kg, or at least 50 mg/kg, or at least 100 mg/kg are required. Therefore, suitable liquid preparations should include protease inhibitors at concentrations ranging from 0.5 millimolar (mM) to 50 millimolar. In another embodiment, the daily dose is between 2 grams and 20 grams.

Most typically, the protease inhibitor of the liquid preparation is a serine protease inhibitor, and/or tranexamic acid, mesylate mesylate (FOY), 6-mercapto- 2-naphthalene-p--6-decylhexanoyloxy dimethanesulfonate (ANGD), camostat, alpha-1 anti-trypsin, cepinine (serpine), and/or MMP protease inhibitor. In the ideal case, a second protease inhibitor formulation can be administered to the mammal. The second protease inhibitor formulation can include a protease inhibitor that is the same as or different from the protease inhibitor in the liquid formulation. In addition, mammals can be administered with an oxygen carrier at a dose effective to reduce organ damage caused by shock. Considering the type of shock, especially the symptoms of shock include traumatic shock, septic shock, cardiogenic shock, and hypovolemic shock. Therefore, the diagnosis of shock needs to consider a number of factors, and the difference is very large. Preferably, diagnosing the shock state comprises measuring a blood amylase and/or a blood protease activity.

In another preferred embodiment of the invention, the mammal is a human, the protease inhibitor is FOY; and the protease inhibitor is at least 25 mg/kg. Optimally, the method of administration is daily (once) with nasogastric The tube is administered to the liquid preparation for at least 7 days.

The subject matter of the present invention will be more apparent from the detailed description of the embodiments of the invention, the claims.

The inventors have unexpectedly discovered that different protease inhibitors can be administered in a relatively simple and high concentration manner to effectively treat morbid or acute shock states and/or multiple organ failure due to shock. Preferably, the protease inhibitor is administered directly to the stomach, preferably directly to the protease inhibitor, using a nasogastric tube (NG tube), an oral solution, a catheter, or a direct injection method. A common dosage range, between 10 and 100 mg/kg, is administered to the stomach. This mode of administration not only allows rapid and easy distribution of protease inhibitors throughout the body of the patient, but more surprisingly, it can initiate and maintain shock treatment without the need to inject high doses of the drug into the small intestine.

It is noteworthy that no adverse reactions caused by shock were observed in all treated subjects. Based on the above, the inventors expect to administer a protease inhibitor of a relatively high concentration (significantly higher than 10 mg/ml) to prevent, ameliorate or cure the shock state by oral administration or administration via an NG tube.

In contrast, in U.S. Patent No. 6,534,283, it is disclosed that a very low dose of a particular protease is directly administered into the intestine, which is hereby incorporated by reference in its entirety. For example, in the prevention of shock during cardiac surgery, one to eight hours before surgery, oral administration of 6-mercapto-2-naphthalene-p--6-mercapto 6-amidino-2-naphthyl p-guanidi-nobenzoate dimethanesulphonate (ANGD) at a dose of 0.1 to 1.0 mg/kg/hr to inhibit trypsin in the intestine of fasting patients To prevent shocks. Before surgery, an ANDG of 0.1 to 1.0 mg/kg/hr can be administered by intravenous drip (IV).

Similarly, during abdominal surgery, the catheter can be directly inserted into the intestine for preoperative and intraoperative intestinal lavage to prevent shock. The intestinal system is washed with a physiological saline solution containing glutathione and 0.5 to 5.0 mg. /kg/hr of [Ethylp-(6-guanidinohexanoyloxy)benzoate]methanesulfonate, FOY), the flow rate is controlled at a flow rate of 50 to 200 ml/min Rinse for at least 5 minutes.

It is further disclosed in the examples of U.S. Patent No. 6,534,283 that intravenous administration of alpha-2 macroglobulin to patients with traumatic shock, and for patients suspected of intestinal or pancreatic injury, preferably protease inhibitors The initial dose is administered at 1 to 10 mg/kg through the esophagus and directly into the stomach to prevent shock. Similarly, prophylactic oral medications and intestinal lavage can be combined during surgery to prevent shock. Here, preferably, the patient takes oral antitrypsin one to eight hours before the surgery, and the dose is preferably from 0.1 to 10 mg/kg/hr. Once anesthesia is performed, the catheter is inserted into the endoscope into the intestine, at the junction of the stomach and the proximal duodenum. The intestinal lavage fluid is washed with a physiological saline solution containing anti-trypsin/chymotrypsin (chymotrypsin) at a flow rate of 0.1 to 10 mg/ml/hr, after which the flow rate is maintained during the operation. Hold 0.02 to 0.5 liters / minute.

The inventors have found that, in most cases, the aforementioned doses are insufficient for the treatment of acute and/or morbid shock conditions. Conversely, it is now feasible to deliver high doses of protease inhibitors to the stomach via a nasogastric tube (NG tube) for rapid distribution for rapid treatment of acute and/or morbid shock.

For example, from the Revitalization General Hospital (approved by the Human Experimental Ethics Committee, with written consent from the patient), a 58-year-old male heart transplant patient case study was regularly followed up in the clinic and received cyclosporine, mycophenolate mofetil (mycophenolate, Cellcept), prednisolone has been treated for 4 years. The cyclosporine concentration during the patient visit was maintained at 150 to 200 mg/l at the time of the return visit, with no signs of rejection or infection. Before the hospital admission, the patient had a motorcycle accident and had a perineal trauma. The patient treated the wound by himself but worsened after a week. The patient was hospitalized and immediately sent to the intensive care unit. Despite giving more than 5 hours, a total of 2 liters of crystal and colloid fluid (crytalloid and colloid fluid) and dopamine (dopamine) 5 mg / kg / min of booster treatment, the blood pressure is still only 80/40 mm at that time Mercury column. Although the perineal debridement was performed urgently, the clinical condition did not improve. The patient is intubated and given broad-spectrum antibiotics such as teichomycin, meropenem, and caspofungin. From Figure 1A (unit of measurement: amylase: IU / ml, lipase: IV / ml; WBC: × 10 / μL) can be easily calculated, blood amylase and lipase blood chemical values continue to increase, and the belly of Figure 1B X-rays show intestinal obstruction and small bowel dilatation. At the same time, it can be seen from the abdominal CT of Fig. 1D that there is no water and edema around the pancreas. It is diagnosed as Foley's gangrene with septic shock and multiple organ failure. Due to persistent septic shock and worsening sepsis indicators, patients underwent diverting colectomy and intravenous total patient nutrition (TPN). In addition, the patient received a second extensive debridement surgery. The wound bacterial culture detected multi-drug resistant Pseudomonas aeruginosa and Bacteroides thetaiotaomicron .

For severe septic shock and elevated amylase and lipase values, which are markers of pancreatic enzyme activity, patients were given a 3,000 mg/day dose of gabexate mesilate intravenously. At the same time, the patient stopped all feeding of the intestines, and in order to balance with body fluids, the amount of TPN was given more than 1 liter per day. However, these therapies did not reduce plasma amylase and lipase values for the next 12 hours, and they continued to rise.

Subsequently, the switching therapy was dissolved in 2,000 ml of physiological saline solution at 3,000 mg/day of gabbock mesylate, and administered continuously through a nasogastric tube. The minimum dose of dopamine was administered for two consecutive days to stabilize blood pressure. The glucose concentration was controlled by reducing the dose of subcutaneous insulin injection, and the patient's consciousness was gradually restored. On the third day, the dose of gappamate methanesulfonic acid was reduced to 300 mg/day, dissolved in 2,000 ml of saline, and the dose was maintained for the next 10 days until the patient left the intensive care unit. The amylase, lipase and white blood cell (WBC) counts were all reduced to control values (see Figure 1A) and intestinal X-rays from Figure 1C showed an improvement in intestinal obstruction. Three days after receiving intestinal mucosulfate methanesulfonic acid, the patient had been extubated. On the 13th day, reply to give immunosuppression The dosage of the preparation was less than the pre-hospital dose, and the patient was discharged one month after admission. Five months later, the patient was still alive at the time of writing this report.

Thus, in the case of an ongoing, even acute, state of shock in a mammal, especially a human, a protease inhibitor of a liquid formulation can be administered to treat a mammalian/human shock state at an effective dose of at least 20 mg/kg. (For example, in the case of an average adult, 400 mg of the drug is dissolved in 2 liters of the liquid and administered to the stomach for more than 24 hours), wherein the liquid preparation is administered to a position of the gastrointestinal tract, and the position is It refers to the release of trypsin upstream of another location in the gastrointestinal tract. In addition, liquid formulation administration is based on standard treatment guidelines for the treatment of shock, as well as the location of shock and potential multiple organ failure. Although it is not excluded that at least part of the therapeutic effect is due to the liquid preparation reaching the small intestine, it should be noted that, according to the scope of the patent application of the present invention, administration of the liquid preparation to the small intestine is not an essential part of the present invention, and One will greatly benefit the treatment and increase the speed. Therefore, it should be noted that the liquid preparation can be directly injected into the stomach through a nasogastric tube, a catheter, and can be administered orally, if the patient's condition permits.

Therefore, on the other hand, the inventors intend to prepare an agent for treating shock of a mammal and/or multiple organ failure caused by shock, according to the use of the protease inhibitor, wherein the protease inhibitor is A liquid formulation and administered to the stomach of the mammal at least once daily at a dose of at least 20 mg/kg, and at least 2 grams of protease inhibitor per day. Therefore, the inventors also want to use a protease inhibitor for the treatment of morbidity or acute shock in mammals and/or multiple devices caused by shock. Official failure, wherein the protease inhibitor is a liquid formulation and provides at least 2 grams of protease inhibitor per day at a dose of at least 20 mg/kg.

Regarding the determination that the patient is in the onset of shock and/or has acute shock, attention should be paid to shock status and/or organ failure, which may be due to various causes. For example, special considerations include trauma, septic and cardiogenic shock symptoms; shock due to surgical complications, or complications from radiation and/or chemotherapy, organ perforation Complications such as chylothorax, preoperative treatment (eg, aortic reconstruction), or severe bacterial infections (eg, Fourniers gangrene and other cSSTIs, infections caused by pneumonia, sepsis and/or bacteremia, community, Shock related to health care-related and/or hospital-acquired infections, as well as mechanical ventilation equipment, or damage caused by dialysis.

Therefore, the manner of diagnosis may vary greatly, and all known suitable diagnostic methods are envisaged here, including measuring enzyme activity in various biological fluids, especially in arterial or venous plasma, abdominal or thoracic lavage, and / Or lymph. Enzyme activity is preferred among other biochemical markers, including amylase, trypsin, chymotrypsin, kallikrein, elastase, and matrix metalloproteinases. (MMP), lipase and other enzyme activities that enter the circulatory system and ultimately lead to shock or acute shock mediators. In addition, a variety of volatile compounds are disclosed in the further patent WO2010/087874, which can be diagnosed by shock or acute shock by measuring and/or identifying the compounds. status. The entire text of the world patent WO2010/087874 is also incorporated herein by reference.

In order to find an appropriate dose of one or more protease inhibitors, the inventors have observed from various animal models that the use of protease inhibitors to block digestive enzymes for the treatment of shock requires at least a minimum effective dose, and the least effective The dose is substantially greater than the doses considered in the '283 patent. For example, tranexamic acid is used in rats with a minimum effective dose of 100 mg/kg (administered to 350 g of rat and 17 ml of intestinal solution containing 127 mmol). Here, rats were administered 18 ml of tranexamic acid solution, which corresponds to 3.2 g of the drug dissolved in 2 liters (this is a dose suitable for humans). The maximum dose tested in rats was 1,125 mg/kg, which is equivalent to administering 36 grams of drug to humans in 2 liters of liquid and administering the dose in the lumen of the stomach or small intestine. Therefore, it is generally preferred to administer a single dose per day to humans (for example, 2 to 4 grams of FOY is dissolved in 1 to 2 liters of solution containing GoLytely (PEG) or physiological saline solution) or for multiple days (up to 14 days) ) It has proven to be very effective to administer via a nasogastric tube.

Therefore, the inventors considered the administration of one or more protease inhibitors, particularly a serine protease inhibitor, for the treatment of onset or acute shock (such as septic, cardiogenic, traumatic shock). treatment. The protease inhibitor is soluble in an acceptable water-soluble carrier (such as physiological saline, osmotic pressure PEG solution, etc.) at a dose of at least 20 mg/kg, at least 30 mg/kg, at least 40 mg. /kg, at least 50 mg/kg, at least 60 mg/kg, at least 70 mg/kg, at least 80 mg/kg, at least 90 mg / kg, at least 100 mg / kg, or even higher. As used herein, "mg/kg" refers to the number of milligrams of protease inhibitor (or other active compound) contained in a pharmaceutical composition administered per kilogram of patient's body weight. Thus, the amounts recited are for the formulation being administered, and not for the absorbable or bioavailable amount of the inhibitor (or other compound) in the patient. In addition, a suitable dose of protease inhibitor can also be considered as an effective preventive measure for shock, in which case it is preferably administered orally at a dose of at least 20 mg/kg and at least 30 mg/kg. Good, at least 50 mg / kg is better, at least 100 mg / kg is best. Therefore, the dosage can be in the range of 20 to 40 mg/kg, preferably between 40 and 60 mg/kg, more preferably between 60 and 80 mg/kg, and between 80 and 100 mg/kg. The best. Depending on the particular type of protease inhibitor, if a particular protease inhibitor is administered to a particular enteral or peritoneal membrane, the concentration is preferably between 0.5 millimolar and 50 millimolar. Such (or additional) protease inhibitors can be administered intravenously with a suitable dosage range of between substantially 5 and 500 mg/kg. On the other hand, the total daily dose of the protease inhibitor administered is preferably at least 1 gram, usually administered at least 2 grams, at least 4 grams, even up to 10 grams, 20 grams, and even in some cases. Will be higher. The total dose used on young patients will be relatively reduced.

Depending on the severity of the wound, higher doses are generally administered to those with more severe traumatic symptoms. For example, treatment of hypovolemic shock will take into account higher doses than septic shock (eg, at least 50 to 100 mg/kg versus 20 to 50 mg/kg). In general, it is better The method of administration is preferably one-time administration, and the volume of administration is suitable for administration in the stomach. For example, the total volume of the liquid formulation may be equal to or less than 2 liters. In terms of alternative selection, a suitable dosing volume includes equal to or less than 1 liter, equal to or less than 0.5 liter, equal to or less than 0.25 liter. In addition, higher doses can be administered, especially when the administration time is longer, or when the drug is administered continuously.

With regard to a suitable administration schedule, it should be noted that the liquid preparation may be administered daily in a single dose or in multiple doses per day, and in some cases even continuously. In general, the daily dosage method is preferably at least 7 days, and most often between 2 and 21 days. However, in general, the mode of administration is preferably more than at least 3 consecutive days and longer than at least 7 to 10 consecutive days. Thus, a suitable dosing cycle is carried out with selected compounds and compositions at least once a day, twice daily, three times daily, four times daily, or even more times (or consecutively) for at least two days, for a period of three. Do not apply for a period of more than seven days, or a period of between eight days and fourteen days, or even longer (for example, up to three weeks, four weeks, etc.). It should be further explained here that in addition to directly administering the drug to the stomach, other parenteral routes can be administered (for example, intravenous and/or intraperitoneal injection or lavage).

For protease inhibitors, currently known pharmaceutically acceptable protease inhibitors can be used herein in a single or rational combination. Particularly suitable protease inhibitors include synthetic compounds such as 6-mercapto-2-naphthalene-p--6-decylhexanoyloxy dimethanesulfonate (ANGD), plus mebyl benzoic acid sulfonate (FOY), diisopropyl fluorophosphate (DFP), p-(decylphenyl)methanesulfonyl fluoride (APMSF), tranexamic acid 4-(2-aminoethyl)sulfonyl fluoride (AEBSF), methanesulfonic acid camostat Camostate (FOY -305), and various natural isolated proteins or recombinant proteins with protease inhibitor activity, such as serpins (eg, Sepin A1-A13, B1-13, C1, etc.), Alpha 1-anti-pancreas Protease (alpha 1-antitrypsin), alpha 2-macruglobulin, etc. Therefore, from one aspect, it should be noted that serine protease inhibitors can be specifically considered. However, other non-serine proteases such as cysteine proteases, threonine proteases, aspartate proteases, glutamate proteases may also be considered. And/or other various inhibitors of matrix metalloproteinases that are specific.

In addition, it is contemplated that a compound having inhibitory protease activity includes an ACE inhibitor, one or more agents that inhibit and/or potentiate the activity of the digestive enzyme and/or a drug that inactivates the regulator (which can be directly administered to the stomach, intestine, and / or anal), various HIV protease inhibitors (eg, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir) Amprenavir)), certain diabetes drugs (eg, sinuvia phosphate, sitagliptin, vildagliptin, alogliptin, saxagliptin), One or more DPP-IV inhibitors, ulinastatin and matrix metalloproteinase inhibitors (MMP inhibitors) (such as synthetic and natural metalloproteinase tissue inhibitors (TIMPs)) and various antibiotics, including Merrem, Imipenem, Cipro, Levoquin, Tello Trovan, Zosyn, Tygasil, Fortaz, Claforan, Rocephin, Cefotetan, Mefoxin ), Unaysn, Cefobid, Cefazoline (Ancef), Zyvox, Cubicin, vancomycin antibiotics, etc. A comparable drug. Thus, a second protease inhibitor, which may be the same as or different from the first protease inhibitor or of the same type as the first protease inhibitor, may be administered and administered to the stomach either directly or indirectly.

The vectors used vary greatly depending on the particular protease inhibitor. Generally, the carrier is preferably an isotonic aqueous solution carrier, and preferably contains an electrolyte. Also, other ingredients such as glycols, especially PEG (e.g., polyethylene glycol-3350), and pharmaceutically acceptable co-solvents may be added. Therefore, this inhibitor and other drugs can be suspended or dissolved in PEG or physiological saline. For example, 0.5 to 2 liters of the drug can be directly administered to the stomach and intravenously instilled for 3 to 10 hours (for example, more than 8 hours).

In addition, the patient may be administered other pharmaceutically active agents, preferably based on established dosages and standard treatment guidelines. For example, suitable other pharmaceutically active agents include various lipase inhibitors, amylase inhibition Agents, albumin, and/or cytotoxic lipid-binding proteins, all of which can be co-administered with a protease inhibitor or administered separately.

In addition, the inventors have also discovered that oxygen carriers (i.e., one or more compounds that can carry and release oxygen) used during treatment help to reduce damage to organs. The oxygen carrier is preferably suitable or considered suitable as a blood substitute. Thus, particularly suitable oxygen carriers include various perfluorocarbon-based carriers (eg, oxygent, oxycyte, PHER-O2, perftoran, etc.) and hemoglobin-based carriers. Particularly suitable (for example, hempure, oxyglobin, hemospan, polyheme, dextran hemoglobin, hemotech, etc.), and the above is usually made into a liquid before being loaded with oxygen.

Direct administration of oxygen to the small intestine cavity reduces oxygen consumption and increases ATP production of the mucosal barrier, thereby protecting the barrier function of the epithelial mucosa and enhancing the repair of the barrier of the epithelial mucosa after increased permeability. Therefore, under hypoxic conditions, oxygen supplementation is considered to interfere with the disrupted gastrointestinal mucosal barrier, minimizing digestive enzyme leakage, thereby reducing tissue destruction and multiple organ failure. Therefore, oxygen is generally delivered to the lumen of the intestine via an artificial oxygen carrier, either as a preventive measure for intestinal hypoxia or as an acute or chronic intervention to reduce tissue hypoxia.

Therefore, it is more generally believed that oxygen carriers can be used in the treatment of onset or acute shock to reduce multiple organ failure and mortality, for the expected or unintended reduction of blood flow into the intestine during surgery, and for deficiency Oxygen related Various forms of intestinal complications. It is worth noting that there are currently no methods available in the prior art for selective (eg, revascularization, intestinal resection, tumor resection, etc., which require interruption of blood flow into the intestine) or non-selective (due to trauma) The clinical condition of the disease or the associated disease that reduces blood flow to the intestine maintains the oxygen content in the mucosal barrier. The oxygen carrier can be used as a simple means to solve the above problems.

For example, in a common application during surgery or in the treatment of an ongoing or acute shock, an oxygen-carrying artificial blood product (for example, a carrier oxygen perfluorodecalin (C10F18), CAS) is used. No. 306-94-5, 95% cis-trans isomer mixture) is saturated with oxygen and stored in an airtight container before or before treatment by a conventional method. Thereafter, prior to or during intestinal ischemia and/or shock, the oxygen carrier solution can be administered orally to the intestinal lumen, or administered by the nasogastric tube to the stomach, or administered by a catheter to the duodenum. It should be noted that perfluorodecalin is a component of Fluosol, a component of an artificial blood product developed by Green Cross Corporation (Japan). A typical known use of perfluorodecalin is to locally provide additional oxygen to a particular site and accelerate wound healing. In addition, organs and tissues can be stored in an oxygenated perfluorodecalin solution prior to transplantation (for example, before the transplant, it can be used in a "two-layer method"). Perfluorodecalin and the University of Wisconsin solution to preserve organs.)

The inventors have demonstrated in a mammalian (rat) model with a severe ischemic small intestine that the administration of oxygen carriers to the intestine by preventing digestive enzymes It is feasible to enter the intestinal wall to reduce intestinal damage. More specifically, it was verified in an animal model of ischemia for 30 minutes, and the animal model was administered a saturated perfluorodecalin solution (230 g rat, 7 ml) with oxygen for 10 minutes. Therefore, it should be noted that in humans and other mammals in the stomach, duodenum, jejunum, ileum perfusion (or other exposures), the method can be treated as a single or supplement. Of course, the volume of the oxygen carrier can be adjusted to allow close contact with the entire stomach, duodenum, jejunum, and/or ileum.

The most common mode of administration for humans is oral, through the stomach cannula, through the catheter to the stomach and / or the small intestine. Therefore, the dose of the oxygen carrier is significantly different depending on the mode of administration. When administered to humans, the dosage is at least 100 ml, preferably at least 250 ml, more preferably at least 500 ml, and at least 1,000 ml is optimal. And the administration can be administered in a single dose, or in multiple doses, or even continuous administration, and the administration period can be only a single to several days. Further, the oxygen carrier may be administered with a protease inhibitor in an alternating schedule of protease inhibitors, or the oxygen-carrying system and the protease inhibitor may be administered separately.

However, the oxygen carrier is preferably co-administered with a protease inhibitor, in particular the protease inhibitor is soluble or dispersible in the oxygen carrier. Thus an oxygen carrier solution can include a protease inhibitor at a concentration between 0.5 and 50 millimoles (or even higher). Viewed from another aspect, the prepared oxygen carrier solution contains a protease inhibitor at a dose of at least 20 mg/kg, at least 30 mg/kg, at least 40 mg/kg, at least 50 mg/kg, at least 60 mg/ Kilograms, at least 70 mg/kg, at least 80 mg/kg, at least 90 mg/kg, at least 100 mg/kg, or even higher. Therefore, the dose range of the drug is between 20 and 40 mg / kg. Yes, 40 to 60 mg/kg is preferred, 60 to 80 mg/kg is preferred, and 80 to 100 mg/kg is preferred. Viewed from another aspect, the total daily dose of the protease inhibitor in the oxygen carrier used for administration is preferably at least 1 gram, and usually at least 2 grams, at least 4 grams, or even up to 10 grams, 20 grams, And in some cases even higher. The total amount used in young patients will be relatively reduced. Likewise, mixtures of aqueous carriers and oxygen carriers containing protease inhibitors are also listed herein.

It is obvious to those skilled in the art that the present invention is not limited by the scope of the present invention. Therefore, the spirit of the subject matter of the present invention is not limited by the scope of the appended patent application. In addition, in the interpretation of the specification and the scope of patent application, it is necessary to have a broad interpretation consistent with the context. The term "comprises and includes" shall mean an element, a component, or a reference element, component, step, or use, or combination thereof, as represented in a non-exclusive manner. Other components, components, or ambiguous steps. Where a component described in the scope of the patent application is selected from at least one of the group consisting of A, B, C, ..., and N, the meaning of the article should be interpreted as requiring at least only the group. One, not A plus N, or B plus N, etc.

Figure 1A depicts white blood cell (WBC) counts, amylase and lipase activity of a patient prior to and during treatment in accordance with the present invention. Figure 1B shows the abdominal X-ray image of the patient on the first day, showing diffuse intestinal obstruction and intestinal wall thickening; Figure 1C is the abdominal X-ray image of the patient on the 16th day, showing intestinal obstruction Improved; and Figure 1D is a CT scan of the abdomen on the first day of the patient. There is no contrast zone between the pancreas (small arrow) and the liver, indicating an equal density, which is inconsistent with pancreatitis.

Claims (20)

A method for treating at least one shock in a mammal and potential multiple organ failure caused by shock, comprising the steps of: diagnosing the mammal having a state of shock; and administering a therapeutically effective amount of a protease inhibitor The protease inhibitor is in a liquid preparation, and one of the liquid preparations is at least 20 mg/kg, wherein the liquid preparation is administered to a position in the gastrointestinal tract, wherein the position is released to the gastrointestinal tract by trypsin Upstream of another location, and the liquid formulation is administered according to a standard treatment regimen that is effective for treating shock and potential multiple organ failure at this location. The method of claim 1, wherein the location is a stomach and the administering step is performed via a nasogastric tube or catheter. The method of claim 1, wherein the location is a stomach, and the administering step is performed by an oral solution or direct injection. The method of claim 1, wherein the administering step is administered daily in a single unpacked dose. The method of claim 1, wherein the administering step is administered selectively for a minimum of 2 days in a single daily dose. The method of claim 1, wherein the dosage is at least 50 mg/kg. The method of claim 1, wherein the dosage is at least 100 mg/kg. The method of claim 1, wherein the liquid formulation comprises the protease inhibitor at a concentration between 0.5 millimoles and a concentration of 50 millimoles. The method of claim 1, wherein the administering step is carried out at a daily dose of from 2 to 20 grams. The method of claim 1, wherein the protease inhibitor in the liquid preparation is a serine protease inhibitor. The method of claim 1, wherein the protease inhibitor is selected from the group consisting of tranexamic acid, butyl sulfamate, 6-mercapto-2-naphthalene-p--6- A group consisting of decyl hexanoyloxy dimethanesulfonate, carostat, alfa-1 antitrypsin, pirin, and matrix metalloproteinase protease inhibitors. The method of claim 1, further comprising the step of administering a second protease inhibitor formulation to the mammal. The method of claim 12, wherein the second protease inhibitor formulation is the same as the protease inhibitor in the liquid formulation. The method of claim 1, further comprising: administering to the mammal a dose of one of the oxygen carriers, the dosage system being effective to reduce organ damage caused by shock. The method of claim 1, wherein the shock state is traumatic shock, septic shock, cardiogenic shock, hypovolemic shock, shock caused by surgical intervention or exposure to radiation Shock. The method of claim 1, wherein the step of diagnosing the state of shock comprises measuring the activity of a blood amylase or the activity of a hemoproteinase. The method of claim 1, wherein the mammalian system is a human. The method of claim 17, wherein the dosage is at least 25 mg/kg, and the protease inhibitor in the liquid formulation is gbesulfame methanesulfonate. The method of claim 18, wherein the administering step is to administer the liquid preparation daily for at least 7 days. The method of claim 19, wherein the administering step comprises administering the liquid formulation via a nasogastric tube.