CN102821762B - The intragastric administration of serpin - Google Patents

Abstract

Inventors have surprisingly discovered that by fluid bolus protease inhibitor formulation being given to the upstream that pancreas protease is incorporated into gastrointestinal position, can effectively treat shock and/or the potential multiple organ failure, MOF caused by shock.It is highly preferred that be administered directly to stomach, such as, in a certain therapeutic scheme, by need not provide significant quantity protease inhibitor to jejunum and/or such medication of ileum, effectively treat shock by nose stomach catheter.

Description

The intragastric administration of serpin

This application claims our U.S. Provisional Application No. 61/385798 He of pending trial while JIUYUE in 2010 is submitted on the 23rd The priority of the U.S. Provisional Application No. 61/529052 that on August 30th, 2011 submits to.

Invention field

Field of the present invention is compositions and the method for the treatment of shock.

Background of invention

Shock is and the wound life-threatening complication of one when relevant, and described wound includes burn, surgical operation, locally Ischemia, septicemia and the application of other critical care.Shock is a broad terms, and it describes the complication of one group of circulation, all These complication all cause general hypoxic, and ultimately result in irreversible painstaking effort due to they combined effect microcirculations Pipe is collapsed.

Shock is a kind of versatility systems response to any multiple pressure, and described pressure includes causing cell-stimulating and The thorn of the release of the interactional response medium of series (including cytokine, struvite and immune mediators and nitric oxide (NO)) Swash.During immunne response, produce oxygen-derived free radicals and superoxides to kill pathogen.But, oxygen-derived free radicals and superoxides Also damage host cell, cause the oxidation of fat, protein and nucleic acid.The biology of the medium coordinator complexity of described shock is mutual Effect and signal amplify, and cause the systemic response to local damage.

Due to the versatility of factor (including shock), therapeutic development is the most difficult.It is single that most treatment concentrates on regulation One factor (such as cytokine, NO, endotoxin) is to alleviate shock effect.It's a pity, suppress appointing of these polytropism factors What is a kind of is all invalid.Organ specific treatment can sustain life, but is not a kind of preferably selection, because they lead to Often sacrifice long-range organ dysfunction.

A kind of effective treatment molecule being proposed to be used in shock is that bactericidal/permeability increases albumen (BPI), and it is a kind of Relate to the albumen (Ammons, U.S. Patent number 6,017,881) of immunne response.Often relevant to shock Intestinal ischemia causes intestinal The destruction of mucosal permeability barrier, this makes antibacterial and/or endotoxin move to vascular system from enteric cavity.During suffering a shock, Have detected that endotoxin at portal vein, but its effect is the clearest and the most definite in shock.BPI is a kind of the most from mammal The albumen separated in the granule of forming core cell (PMNs).PMNs relates to protect body fight and invades the hemocyte of microorganism. BPI has a high degree of specificity to gram negative bacteria, and seems the work being not harmful to other pathogen or host cell With.Give weakening of the ischemic unfavorable physiological effect of enteral that rat BPI causes being catalyzed other symptom of shock.But BPI only affects one of approach of activation in shock, and therefore its application is limited.It addition, BPI discharges from enteral by attacking Enter the endotoxin after blood and antibacterial and play a role；Therefore, it cannot be used for the generation of prevention shock.

In other method, present inventors have shown that some application of tryptic effect and protease inhibitor in shock Protective effect, as in U.S. Patent number 6, those described in 534,283.Generally pancreatin is released into small intestinal for disappearing Change, have no adverse reaction.But, during suffering a shock, the permeability barrier of intestinal is to weaken, and therefore the present inventor speculates in theory The protease susceptibility loci not had under normal operation will manifest, and organizes damaged, and discharges strong as suffer a shock The albuminolysis thing of activator.The multiple protein hydrolysate being thusly-formed can be used as the medium of shock, and the present inventor is thus Think by preventing proteinase activated in small intestinal or passing through suppress at little enteral or eliminate the albumen of the activator that can produce shock Enzyme, can treat shock most effectively.Finally, inventors believe that the direct small intestinal that is administered to by protease inhibitor will in rats Can prevent shock, this can be determined by time-to-live and molecules and histologic analysis.

But, although laboratory observation seems to confirm that at least some of effect of protease inhibitor (such as circulates neutrophilic leukocyte The suppression activated, weakening of activity of myeloperoxidase), but the present inventor only considers to apply protease inhibitor to be administered directly to The possible Primary preventive intervention of small intestinal.

Therefore, although have the various method suffered a shock for treatment or prevention as known in the art at present, but offer is used for Treatment shock and the effective ways of shock associated conditions and compositions there are still demand.

Summary of the invention

The present inventor it has now unexpectedly been found that by fluid bolus protease inhibitor formulation is given to wherein by trypsin introduce To the upstream at gastrointestinal position, can effectively treat shock and/or the potential multiple organ failure, MOF caused by shock.More preferably Ground, is administered directly to stomach, such as, in a therapeutic scheme, by need not the protease inhibitor of offer significant quantity to jejunum And/or such medication of ileum, effectively treat shock by nose stomach catheter.Therefore, now with quick, simple and Effective manner intervention is developing or acute shock is possible.

One side in present subject matter, it is provided that a kind of in mammal treatment shock and/or by shock cause potential The method of multiple organ failure, MOF, the most in one step, described mammal is diagnosed as having shock disease.In another step In, give the protease inhibitor (normally liquid preparation) of the therapeutically effective amount of at least 20mg/kg dosage, wherein by described liquid Body preparation is administered to trypsin and discharges into the upstream at gastrointestinal position；Under a scheme, wherein give described liquid preparation With effective treatment shock and the potential multiple organ failure, MOF of described position.Therefore, it should be clear that be to be not given to substantial amounts of albumen Enzyme inhibitor, in the case of small intestinal, can start and maintain the treatment of shock.

Therefore, it is generally preferable to described position is to be administered described in harmonization of the stomach to be carried out by nasogastric tube or conduit.Give it addition, described Medicine can be carried out by oral administration solution or direct injection.Although the most every daily single whole dosed administration, but think repeatedly Divided dose also appears to be applicable.It addition, be more preferably optionally administered in separate daily dose mode, continue at least 2, In most preferably at least 7 days and most preferably at least 10 days.

In terms of the another consideration of present subject matter, described dosage is at least 25mg/kg, or at least 50mg/kg, or extremely Few 100mg/kg.Therefore, the liquid preparation being suitable for can include that concentration is the described protease suppression between 0.5mM-50mM Agent.Consider from another angle, can be to be administered between 2g-20g at daily dose.

Most typically ground, the protease inhibitor in described liquid preparation is serpin, and/or can be ammonia First naphthenic acid, FOY, ANGD, camostat, α-1 anti-trypsin, serpine (serpine) and/or MMP protease press down Preparation.When desired, described mammal the second protease inhibitor formulation can be given.Such the second protease suppresses Agent formulation then can include the protease inhibitor of identical from protease inhibitor in described liquid preparation (or different).It addition, plan Give the carrier of oxygen that described mammal effectively reduces the amount due to the organ injury caused of suffering a shock.Although stopping including various types of Gram, but the shock disease of special concern includes traumatic shock, septic shock, cardiogenic shock and hypovolemic shock. Therefore, shock disease diagnosis can great changes have taken place.Generally, however, it is preferred to described diagnosis shock disease includes measuring blood starch Enzyme and/or blood protein enzymatic activity.

In a particularly preferred aspect of present subject matter, described mammal is people, and protease inhibitor is FOY, The dosage of described protease inhibitor is at least 25mg/kg.Most preferably, administration should be and gives (once) described liquid system every day Agent at least 7 days, is typically carried out by nasogastric tube.

Each target, feature, aspect and the advantage of present subject matter is by along with preferred embodiment described below and companion With diagram (word table the most in full shows such as (like numerals represent like components) such as components) will become more clear Clear.

Accompanying drawing is sketched

Figure 1A is leukocyte (WBC) number, amylase and lipase active before and during treatment patient according to the inventive subject matter Time course figure.

Figure 1B is the X-ray figure of patient's abdominal part on the 1st, and display dispersivity intestinal obstruction and small bowel thicken.

Fig. 1 C is the X-ray figure of patient's abdominal part on the 16th, and display intestinal obstruction takes a turn for the better.

Fig. 1 D is the CT scan figure of patient's abdominal part on the 1st, does not show equal density contour between pancreas (small arrow) and liver Difference, it is inconsistent with pancreas inflammation.

Detailed Description Of The Invention

Inventors have surprisingly discovered that by various protease inhibitor in a very simplified manner and are administered with high concentration, can effectively treat Developing or acute shock disease and/or the multiple organ failure, MOF caused by shock.Preferably protease inhibitor is administered directly to Stomach, most preferably by nasogastric tube, oral administration solution, conduit or direct injection, dosage range typically 10-100mg/kg it Between.This administration is quickly and easily transported to patient by do not only result in protease inhibitor, moreover it is possible to unexpectedly starts and maintains Treatment, provides high amount of drug without to little enteral.

It should be noted that and expect that the side effect caused by shock disease is not all observed in the experimenter of all treatments. Based on above, the present inventor thus expects to suffer a shock disease can be (bright by using oral or NG pipe administering mode to give very high concentration Aobvious higher than 10mg/ml) protease inhibitor prevented, alleviated or reversed.

On the contrary, it should be noted U.S. Patent number 6,534,283 (they are incorporated herein by reference in full) are pointed out non- Some protease of the lowest dosage is administered directly to enteral.Such as, the prophylactic treatment preventing shock in cardiac surgical procedure needs Within 1-8 hour, to be orally administered to patient's 6-amidino groups-2-naphthyl p-guanidinobenzoic acid ester dimethanesulfonate of fasting before surgery (ANGD), dosage is 0.1-1.0mg/kg/hr, to suppress the trypsin in intestinal.Operation consent, in advance with 0.1-1.0 Mg/kg/hr speed intravenous drip ANDG.

Similarly, devise for prevention shock in abdominal surgical procedure and carry out enteric cavity filling by being inserted directly into intubating of enteral Wash, with supplementing glutathion and 0.5-5.0mg/kg/hr [p-(6-guanidine radicals acyloxy) ethyl benzoate] mesylate (FOY) Saline, with the amount of 1.5-2.5mg/kg/hr, rinse intestinal with the flow velocity of 50-200ml/min, before the operation under connecing and the phase Between at least rinse 5 minutes.

In another embodiment of ' 283 patent, plan to give α-2 macroglobulin, suspicious at traumatic shock medium-sized vein Intestinal or injury of pancreas case in, the protease inhibitor of predose 1-10mg/kg is directly administered to by esophageal tube Gastric, to prevent shock.Similarly, it was also proposed that carry out oral cavity oral prophylaxis and cleaning intestinal is prevented not in intra-operative combination Gram.Here, 1-8 hour before surgery, preferred oral gives the antitrypsin that patient dose is 0.1-10mg/kg/hr.? Carry out immediately after giving anesthetics, conduit endoscope is inserted into enteral, the intersection between harmonization of the stomach duodenum near-end. The enteric cavity saline solution of the antitrypsin/Chymotrypsin supplementing doses is rinsed, flow velocity 0.1-10mg/ml/hr, so After operating whole during with 0.02-0.5L/min flow velocity rinse.

Inventor now discovered that the dosage of aforementioned plans is the most all not enough to treat acute and/or developing Shock.On the contrary, particularly when by nose stomach (NG) pipe by high dose protease inhibitor rapid transport to gastric time, now with Acute and/or the developing shock of possible fast treating.

Such as, a research case of Cheng-Hsin general hospital (is ratified through mankind Ethics Committee, and patient is signed Written consent book) report, the 58 years old male patient accepting heart transplant operation to periodically carries out the ring spore bacterium of 4 years by a definite date The Clinical Follow-up that element, mycophenolate (mycophenolate) and prednisolone are treated is observed.Cyclosporin level is maintained at 150- About 200mg/dL, does not has the sign repelling or infecting during following up a case by regular visits to.Before carrying out this treatment, this patient suffers a car accident also And injury of perineum.Patient has processed wound voluntarily, but wound deterioration after a week.Patient is admitted to hospital and seeks medical advice and immediately enter Intensive Care Therapy Ward.Although using 2L transparent colloid fluid positive flush to process 5 hours, and 5kg/kg/min dopamine is used to carry out blood Pipe therapeutic compression, the blood pressure of this patient remains as 80/40mmHg at present.Immediately perineum is carried out urgent surgical debridement, But clinical symptoms is not improved.Implement to intubate therapy to patient, and accept broad ectrum antibiotic, including teicoplanin (teichomycin), meropenem and Caspofungin.From Figure 1A, (units of measurement is: amylase: IU/ml；Lipase: IV/ml；WBC:x10/ μ l) it can be readily seen that the hematochemistry index of amylase and fat enzyme values is rising, from figure always 1B can be seen that, abdominal cavity X-ray display small intestinal expands and with intestinal obstruction.Meanwhile, abdominal cavity CT does not finds have at pancreas Edema or the phenomenon of fluid accumulation, as Fig. 1 D visible.Diagnostic result be Fu Erni Erichsen gangrene (Fournier ' s Gangrene), accompanying infection shock and multiple organ dysfunction syndrome.Owing to persistent infection shock and deteriorated blood symptom index occurring (septic markers) has deteriorated, therefore patient receives the most again the colectomy that changes its course (diverting colectomy) He Zongying Support element intravenous injection (intravenous total parental nutrition).Additionally, patient also receives second time debridement on a large scale Art.Wound culture Pseudomonas aeruginosa (Pseudomonas aeruginosa) and bacteroides thetaiotaomicron to having multiple drug resistance (Bacteroides thetaiotaomicron) aobvious positive.

Serious septic shock and amylase and lipase level value are raised (with the pancreatin that exists as label), quiet Arteries and veins injection gabexate mesilate (gabexate mesilate), dosage is 3000mg/ day.Meanwhile, patient stops all of enteral Feed, give the body fluid balance that the total nutrient of vein (total parental nutrition) of more than 1L keeps positive every day.But these Treatment does not reduce blood plasma amylase and the level value of lipase in 12 hours subsequently, and contrary two kinds of values continue to rise High.

Then treatment turning to enteral feeding gabexate mesilate, is persistently fed by nasogastric tube to stomach, dosage is 3000mg/ day, it is dissolved in 2000ml normal saline.In two days, the dopamine of blood pressure lowest dose level is stable, glucose level Can usually be controlled by the islets of langerhans of the less dosage of subcutaneous injection, and patient's level of consciousness increases.At the 3rd day, by gabexate first sulphur The decrease in dose of hydrochlorate, to 300mg/ day (fluid volume 2000ml), maintains this level 10, then by patient from Intensive Care Therapy Ward is produced.Amylase, lipase and leukocyte (WBC) counting are all reduced to control level (see Figure 1A), abdominal cavity X-ray Display intestinal obstruction is alleviated, as can be seen in Fig. 1 C.After enteral gabexate mesilate is treated three, remove stomach tube. At the 13rd day, recover to use IDT, but dosage decreased compared with the front time of being in hospital, 1 month in hospital After, patient discharge (discharged from the ward).After leaving hospital 5 months, i.e. writing this report now, this patient is still Alive.

It is to be understood, therefore, that be once diagnosed to be the mammal/people suffering from shock disease, should be by giving in liquid preparation The protease inhibitor of therapeutically effective amount to treat the developing and the most acute shock of mammal (the especially mankind) sick Disease, its dosage is that at least 20mg/kg is (such as, common in the input of 24 hours periods by the 2L fluid containing 400mg inhibitor The gastric of adult), wherein described liquid preparation is administered to a certain position of gastrointestinal, wherein this position is in trypsin Discharge into the upstream at position in gastrointestinal tract, and wherein described liquid preparation is administered under a scheme, with effective treatment shock Potential multiple organ dysfunction syndrome with described position.Although being not excluded at least some of therapeutic effect is due to described liquid preparation stream Enter or flow through small intestinal and produce, it should be noted that be not required to give described liquid preparation according to the therapy of subject of the present invention Little enteral, this measure significantly promotes treatment and accelerates treatment speed.It is noted, therefore, that described liquid preparation can pass through nose stomach Pipe, conduit, direct injection or even drink (when patient condition allow such be administered time) directly give stomach.

Therefore, from the point of view of another angle, protease inhibitor is used for making a kind of medicine by the present inventor's expectation, is used for controlling Treat mammal shock and/or the multiple organ dysfunction syndrome caused of suffering a shock, wherein described protease inhibitor is made liquid preparation Form, is administered to mammal stomach the most once every day, and dosage is at least 20mg/kg, and is provided that at least 2g every day The amount of protease inhibitor.Therefore, suffer a shock during the present inventor is also desirable that the development that protease inhibitor is used for treating mammal Or acute shock and/or the multiple organ dysfunction syndrome that caused by shock, wherein described protease inhibitor is configured to liquid solution Preparation, to give stomach, dosage is at least 20mg/kg, and is provided that the amount of at least 2g protease inhibitor every day.

For determining that patient is the most just occurring shock symptom and/or having acute shock, it should be noted that shock disease and/or organ decline Exhaust and can be caused by many reasons.Such as, the disease of special concern includes wound, septicemia, cardiogenic shock, surgical complications Shock that the complication of the shock, radiation and/or the chemotherapy that cause causes, organ perforation, chylothorax, preoperative anesthesia are (such as large artery trunks Rebuild), serious antibacterial infect (infection, septicemia and/or bacteremia as relevant to pneumonia in Fu Erni Erichsen gangrene, group The infection that body, health center and/or hospital are subject to), mechanichal respirator or dialysis caused by damage.

Therefore, diagnostic method can great changes have taken place, it is generally recognized that all known diagnostic modes are the most all identified For being suitable, it is included in different biofluid (especially tremulous pulse or venous plasma, ascites, chest hydrops, and/or lymph Liquid) enzymatic activity measure.Other be suitable for biochemical marker in, particularly preferred enzymatic activity be amylase, trypsin, The activity of Chymotrypsin, kallikrein, elastoser, MMP, lipase and other digestive enzyme, and enter circulation System causes in development or the medium of acute shock.As selection, or a kind of other method is, in development or acute shock Disease also by measuring and/or can differentiate that some volatile compounds determine, as being incorporated herein by reference Compound described in WO2010/087874.

For the suitable amount of one or more protease inhibitor, the present inventor observes in various animal models: use egg White enzyme inhibitor blocks the shock treatment of digestive enzyme needs the effective dose that at least some of protease inhibitor is minimum, this minimum dose Amount is significantly higher than the projected dose in the patent of ' 283.Such as, rat being used tranexamic acid, minimum effective dose is 100mg/kg (127mM is dissolved in intestinal juice, 17ml, gives 350g rat).It is dissolved in 18cc fluid here, give rat Tranexamic acid.The equivalent concentration of 2L (being considered suitable as human dose) is 3.2g.The maximal dose of rat test is 1125mg/kg, it is equivalent to people's dosage of the 36g in the 2L liquid being administered in harmonization of the stomach enteric cavity.Therefore, it is generally preferable to In people, enter with single dose/day (such as, 2-4g be dissolved in 1-2L contain the Foy in Polyethylene Glycol (GoLytely) (PEG) or saline) Row is administered, and is had shown that it is that very effective-NG pipe is administered continuously many days (up to 14 days) by one.

It is to be understood, therefore, that inventor's design gives one or more protease inhibitor, particularly serine protease and presses down Preparation is used for treating developing or acute shock (such as septicemia, heart source property, traumatic), wherein protease inhibitor with Pharmaceutically the form in the aqueous solution (such as normal saline, iso-osmotic PEG solution etc.) of acceptable carrier is administered, and dosage is at least 20mg/kg, at least 30mg/kg, at least 40mg/kg, at least 50mg/kg, at least 60mg/kg, at least 70mg/kg, extremely Few 80mg/kg, at least 90mg/kg, at least 100mg/kg are the highest.Expression " mg/kg " used herein refers to often The milligram number of protease inhibitor described in the compositions that kg patient body weight is given (or other reactive compound).Therefore, on State the amount enumerating the preparation that quantity refers in particular to give, and the most described inhibitor (or other compound) is absorbed or raw The available amount of thing.Additionally, also design gives suitable protease inhibitor and is used as a kind of effective preventive measure, this In the case of, it being administered preferred oral, dosage is at least 20mg/kg, more preferably at least 30mg/kg, even more desirably at least 50 Mg/kg, most preferably at least 100mg/kg.Therefore, dosage scope can be between 20-40mg/kg, more preferably 40- Between 60mg/kg, between even more preferably 60-80mg/kg, most preferably between 80-100mg/kg.Press down according to protease The particular type of preparation is different, if enteral or peritoneal administration, concentration should be preferably between 0.5mM-50mM.When vein carries During for medicine (additional) protease inhibitor, suitable dosage range is by between typically 5-500mg/kg.From another angle Seeing, the accumulated dose of the protease inhibitor given every day is preferably at least 1g, and more typical is at least 2g, at least 4g, the highest Reach 10g, up to 20g, the highest.The total consumption of department of pediatrics should correspondingly reduce.

According to the order of severity of wound, generally believe that high dose is more preferably for more serious wound.Example As, it is contemplated that hypovolemic shock will need higher dosage (such as, at least 50-100mg/kg than the treatment of septic shock Contrast 20-50mg/kg).The most described general administration is to be administered consistent volume single-dose with stomach.Such as, liquid The cumulative volume of preparation can equal to or less than 2L.On the other hand, be suitably administered volume and include equal to or less than 1L, equal to or Less than 0.5L, equal to or less than 0.25L.It addition, may be used without larger volume, particularly administration time is longer or is administered continuously Time.

For suitable dosage regimen, it should be noted that liquid preparation can be supplied to patient with single dose every day or multiple dose, and The most even can successive administration.Additionally, generally preferably during a few days, more typically during 2-21 day, often It is administered.Generally, however, it is preferred to be administered continuously at least 3, more typically at least 7-10 day.Therefore, suitably it is administered Scheme include every day 1 time, every day 2 times, three times a day, every day 4 times, the most repeatedly (or continuously), the persistent period is at least 2 days, during 3-7 day, during 8-14 day, even more long-time (such as, up to 3 weeks, 4 weeks etc.), give predetermined chemical combination Thing and compositions.Additionally, it is to be noted that except direct stomach is administered, it is possible to use various parenteral (such as, vein Injection and/or lumbar injection or lavation).

About protease inhibitor, it should be clear that be all known and pharmaceutically acceptable protease inhibitor is all thought It is applicable to the purposes of the present invention, can be used alone or use with any rational combination of other medicines.Particularly suitable albumen Enzyme inhibitor includes the compound of synthesis, such as 6-amidino groups-2-naphthyl-p-guanidinobenzoic acid ester dimethanesulfonate (ANGD), adds shellfish Ester monomethyl sulfonate (FOY), fluorophosphoric acid diisopropyl ester (DFP), to (amidino groups-phenyl) Fumette (APMSF), ammonia first ring Acid, 4-(2-amino-ethyl) benzene sulfonyl fluorine (AEBSF), camostat (Camostate) (FOY-305), and there is protease press down The various naturally isolated single or combined protein matter of system activity, if serine protease inhibitor is (such as SERPIN A1- A13, B1-13, C1 etc.), alpha1-antitrypsin, alpha2-macroglobulin etc..Therefore, from another viewpoint, it should be noted that It is specially to contemplate serpin.But, also contemplate have non-serine protease specific various its Its protease inhibitor, as cysteine proteinase, serine/threonine protein enzyme, aspartic protease, hydroxyproline enzyme and/ Or matrix metalloproteinase.

Have expected from other that compound of protease inhibiting activity includes ACE inhibitor, one or more can suppress and/or slow Solve digestive enzyme and/or the medicine (it can directly give stomach, intestinal and/or anus) of inactive medium obtained, various hiv protease Inhibitor (such as Saquinavir, ritonavir, indinavir, viracept see nelfinaivr, amprenavir), some diabetes medicament (as Januvia, sitagliptin；Vildagliptin；Egelieting (alogliptin)；BMS-477118), one or more DPP-IV inhibitor, Ulinastatin and MMP inhibitor (synthesis is with natural, such as TIMPs), and various antibiotic, including imipenum, U.S. Luo Peinan injectable powder, ciprofloxacin, Levoquin, trovafloxacin, Zosyn, tigecycline injection (Tygasil), head His pyridine, Cefotaxime, Ceftriaxone, cefotetan, Cefoxitin, unasyn, cefobid, Ancef, Linezolid, Da Tuo of spore Mycin, vancomycin class antibiotics etc. and their generic equivalent.Therefore, it is also clear that the second albumen can be given Enzyme inhibitor, it can belong to one species with the first protease inhibitor, it is possible to being not belonging to one species, it can or can not To be administered directly to stomach.

It should be clear that according to specific protease inhibitor, carrier can have the biggest change.Generally, however, it is preferred to carry Body is a kind of isotonic aqueous solution carrier preferably comprising electrolyte.Additionally, other composition can include glycols, especially PEG (such as Polyethylene Glycol-3350), and pharmaceutically acceptable cosolvent.Therefore, can be by intended inhibitor and other medicines suspendible Or be dissolved in Polyethylene Glycol or normal saline.Such as, directly stomach can be given by 0.5-2L solution, if intravenous injection It is administered, needs instillation 3-10 hour (such as more than 8 hours).

Additionally, it is desirable to other pharmaceutically active substances can be given patient, established dosage is preferably used and to prescription Case.Such as, be suitable for other pharmaceutically active substances include various lipase inhibitor, amylase inhibitor, albumin and/or Cytotoxic lipid binding protein, can be by all these materials and described protease inhibitor drug combination or separately medication.

Additionally, it has further been found by the present inventors that and use the carrier of oxygen (the most one or more can to carry and discharge over the course for the treatment of The compound of oxygen) contribute to being down to organ injury minimum.It is suitable for or thinks being suitable as blood it is further preferred that the carrier of oxygen should be those The material of liquid succedaneum.Therefore, the particularly suitable carrier of oxygen includes various perfluocarbon base carrier (such as, perflubron breast Agent, oxycyte, PHER-O2, perftoran etc.) and hemoglobin base carrier (such as, black nurse galloping you, glutamer 200 (oxyglobin), hemospan, PolyHeme, dextran hemoglobin, hemotech etc.), all above-mentioned things Matter was typically formulated as liquid before carrying oxygen.

Think that oxygen directly gives enteric cavity can be reduced oxygen consumption to greatest extent, strengthen ATP generation in mucosal barrier, thus protect Protect the barrier function of epithelial, and strengthen the barrier reparation after epithelial permeability raises.It is therefore contemplated that this delivery of supplemental oxygen is lacking May interfere with the damage of harmonization of the stomach intestinal mucosal barrier in the case of oxygen, and the escape of digestive enzyme is preferably minimized, thus by disorganization Produce with multiple organ failure, MOF and be preferably minimized.Therefore, it is usually directed to deliver oxygen by artificial oxygen carrier and enters enteric cavity, or as pre- The preventive measure of phase intestinal anoxia, or also can reduce histanoxia to greatest extent as one urgency or chronic measure.

Therefore, more commonly thinking, the carrier of oxygen can be used for treating development of shock or acute shock, reduces multiple organ dysfunction syndrome And mortality rate, and can be used for wherein flowing to blood either intentionally or unintentionally (the intentionally or non-intentionally) minimizing of enteric cavity Surgical operation, and can be used for any type of intestinal tract complication relevant to anoxia.It should be noted that current this area The method that there is no alternative (for example, it is desired to interrupt leading to the surgical operation of intestinal blood flow, such as reconstructive vascular operation, Gastrointestinal diseases Excision, tumorectomy etc.) or non-selective (owing to wound or disease cause the blood flowing to intestinal to reduce) the clinical setting phase Between, maintain the oxygen in mucosal barrier.Now use the carrier of oxygen can provide a kind of straightforward procedure solving problems.

Such as, in intra-operative or a kind of typical case's application in treatment development of shock or acute shock, many institutes are used Known method, and the artificial blood goods that oxygen can be carried by a kind of (such as, carrier of oxygen perfluorodecalin (C10F18), CAS 306- 94-5, the cis and trans isomer mixture of 95%) use oxygen saturation, and before surgery or it is saved in sealing container before treatment In.Then intestinal ischemia and/or shock before or period, described carrier of oxygen solution can be orally administered to enteric cavity, pass through NG Pipe enters stomach, or is inserted in duodenum by conduit.It should be pointed out that, that perfluorodecalin is a kind of one-tenth in Fluosol Point, it is the artificial blood goods developed by green cross company (Japanese).In commonly known application, perfluorodecalin can topical application To specific position, to provide extra oxygen to carry out accelerating wound healing.Additionally, can will organize with organ long term storage in oxygen containing In perfluorodecalin, (such as, " two-layer method " uses perfluorodecalin and University of Wisconsin solution to preserve organ until they are moved Plant).

Present inventors have demonstrated that such method feasibility in mammal (rat) model suffer from serious intestinal ischemia, The wherein intestinal administration carrier of oxygen, makes Gut Injury be preferably minimized by stoping digestive enzyme to enter intestinal wall.More particularly, feasible Property demonstration carry out in the model of ischemia 30min, first saturated 10min in oxygen, process with perfluorodecalin solution (rat of 230g is administered 7ml).It is noted, therefore, that Stomach duodenum, sky can be used in people and other mammals Intestinal and ileal irrigation (or other way of contact) are as independent or replacement therapy.More typically, the volume of the adjustable carrier of oxygen makes Obtain the carrier of oxygen to be in close contact fully with Stomach duodenum, jejunum and/or ileum.

Most typically ground, therefore human administration can be administered orally, by gastric intubation, entered stomach and/or little by conduit The modes such as intestinal are carried out.Therefore, it should be clear that be the described carrier of oxygen that is every time administered volume can great changes have taken place.But, typically The volume preferably giving people is at least 100ml, more generally at least 25ml, even more typically at least 500ml, allusion quotation It is at least 1000ml type.Administration can be administered or multiple dose administration according to single dose, or the mode being even administered continuously is entered OK, and can just for one day or in several days be administered.Additionally, should be clear that can giving the described carrier of oxygen and protease inhibitor Administration carry out simultaneously, or carry out in an alternating manner with the administration of protease inhibitor, or with the administration of protease inhibitor Separately carry out.

When preferably with protease inhibitor co-administered, should be clear that especially can by described protease inhibitor dissolve or It is dispersed in the carrier of oxygen.It is therefore contemplated that carrier of oxygen solution will include that concentration protease between 0.5-50mM (or higher) presses down Preparation.From a different perspective, carrier of oxygen solution can be configured to a kind of preparation that can give protease inhibitor, described albumen The dosage of enzyme inhibitor be at least 20mg/kg, at least 30mg/kg, at least 40mg/kg, at least 50mg/kg, at least 60 Mg/kg, at least 70mg/kg, at least 80mg/kg, at least 90mg/kg, at least 100mg/kg are the highest.Cause This, the dosage range given can be between 20-40mg/kg, more preferably between 40-60mg/kg, even more preferably exists Between 60-80mg/kg, and most preferably between 80-100mg/kg.From another viewpoint, in the carrier of oxygen given every day The accumulated dose of protease inhibitor will be preferably at least 1g, the most at least 2g, at least 4g, the most up to 10g, height To 20g and the highest.Pediatric drugs accumulated dose will reduce accordingly.Similarly, suppress with protease Within the water-solubility carrier of agent and the mixture of the carrier of oxygen are included in the present invention the most significantly.

Those skilled in the art it should be clear that under without departing substantially from idea of the invention, except discussed above those it Outward, also can much modify.Therefore, in addition to appending claims, subject of the present invention is not restricted by.This Outward, explaining in the specification and claims, should by all terms by consistent with this context the most wide in range in the way of Explain.Particularly, term " includes " and " comprising " should be interpreted that the key element of non-exclusive mode, component or step, table Bright cited key element, component or step there may be, or used, or with other key element not being explicitly mentioned, Component or step combination.When the claim of described description refers to that at least one is selected from A, B, C ... and during the key element of N, should The key element being construed to herein only to need in this group rather than A are added N, or B adds N etc..

Claims (9)

1. giving a single-dose liquid preparation for individual stomach, it comprises:

Polyethylene Glycol, at least the 4 of therapeutically effective amount G tranexamic acid and the pharmaceutically acceptable aqueous carrier containing electrolyte, the volume of wherein said preparation is 0.25-2 liter.

2. the liquid preparation of claim 1, Polyethylene Glycol therein is PEG-3350.

3. comprise the single-dose liquid preparation of Polyethylene Glycol, at least 4 g tranexamic acids of therapeutically effective amount and the pharmaceutically acceptable aqueous carrier containing electrolyte in preparation for treating the purposes at least one shock and the medicine of potential multiple organ failure, MOF that caused by shock, wherein said medicine is formulated for being administered to the stomach of individuality, and the volume of wherein said preparation is 0.25-2 liter.

4. the purposes of claim 3, wherein said Polyethylene Glycol is PEG-3350.

5. the purposes of claim 3, wherein said medicine is formulated for by nasogastric tube or catheter drug delivery.

6. the purposes of claim 3, wherein said medicine is formulated for oral or direct injection.

7. the purposes of claim 3, tranexamic acid therein is present in described medicine with the amount that can give the tranexamic acid of at least 20 mg/kg dosage.

8. the purposes of claim 3, wherein said shock is traumatic shock, septic shock, cardiogenic shock, hypovolemic shock or is exposed to radiation-induced shock.

9. the purposes of claim 3, wherein said shock is that surgery gets involved the shock caused.