WO2022048180A1 - 一种多肽在预防和治疗肺炎的药物中的应用 - Google Patents
一种多肽在预防和治疗肺炎的药物中的应用 Download PDFInfo
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the invention relates to the technical field of medicine, in particular to the application of a polypeptide in a medicine for preventing and treating pneumonia.
- Pneumonia is a common disease of the respiratory system. According to its onset, it can be divided into community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP).
- CAP community-acquired pneumonia
- HAP hospital-acquired pneumonia
- CAP Community-acquired pneumonia
- out-of-hospital pneumonia refers to infectious lung parenchymal inflammation outside the hospital. It is caused by pathogens, among which bacterial pneumonia is the most common. It is a common clinical lower respiratory tract infection and one of the common diseases that seriously threaten human health.
- HAP Hospital-acquired pneumonia
- Ying Xiaobo et al reported simple pneumonia pathogen infection, bacteria accounted for 31.81%, mixed infection accounted for 10.23%. After combining mixed infection with simple infection, bacteria accounted for 40.91%. It can be seen that bacterial infection occupies the first place in pneumonia (Ying Xiaobo, Wang Danmin, Song Bo, Lan Dabo. Etiological investigation of adult community-acquired pneumonia in different seasons [J]. China Public Health Administration, 2014, 30(06): 843-844+ 849.).
- the existing drugs for the treatment of pneumonia are the drugs for the treatment of pneumonia, but because the existing erythromycin and budesonide have more or less adverse reactions during the treatment process .
- Erythromycin is highly irritating.
- Oral or intravenous administration can cause gastrointestinal reactions and liver damage. Large doses or long-term use can lead to cholestasis and elevated transaminases. It is not suitable for pregnant women and those with liver insufficiency. Application, use with caution in infants and young children.
- Budesonide can cause oropharyngeal candida infection or immediate or delayed allergic reactions, including rash, contact dermatitis, urticaria, angioedema, and bronchospasm.
- drug resistance to pneumonia treatment has become a growing global concern
- Antibacterial peptides are a class of basic polypeptides, generally composed of about 12 to 50 amino acids, with broad-spectrum antibacterial properties, inhibiting or killing bacteria, fungi, viruses, parasites and tumor cells, and can promote the process of wound healing.
- antimicrobial peptides can also be used as immune effector activating molecules to regulate the function of the body's immune system, enhance the body's ability to clear pathogens, neutralize bacterial endotoxin LPS, reduce the release of inflammatory cytokines, and slow down tissue damage caused by inflammatory responses.
- antimicrobial peptides Although traditional antibiotics have obvious antibacterial effects, most of the antibacterial mechanisms are anti-microbial by hindering the synthesis of bacterial cell walls, inhibiting protein synthesis, affecting the metabolism of nucleic acids and folic acid. drug resistance. Compared with antibiotics, antimicrobial peptides have incomparable advantages in drug resistance. Antimicrobial peptides can interact with microbial cell membranes to form pores, affect osmotic pressure inside and outside cells, and then cause cell death. Because the cell membrane structure of microorganisms has evolved over hundreds of millions of years, and its structure will not change greatly in a short period of time, the antibacterial mechanism of antimicrobial peptides is not easy to cause bacteria to develop drug resistance. Therefore, antimicrobial peptides are increasingly favored as antimicrobial components.
- the antimicrobial peptide database contains 3241 kinds of antimicrobial peptides, and reports on the in vitro antibacterial activity of antimicrobial peptides are relatively common, but there are few reports on the application of antimicrobial peptides in disease treatment. This has a lot to do with the characteristics of antimicrobial peptides, the conditions under which antimicrobial peptides exert their biological activity, and the complex physiological environment of organisms.
- the three-dimensional structure of antimicrobial peptides is mainly maintained by secondary bonds such as hydrogen bonds, hydrophobic bonds, salt bonds and van der Waals forces (TCJyothi, Sharmistha Sinha, Sridevi A.Singh, A.Surolia, AGAppu Rao.Napin from Brassica juncea: Thermodynamic and structural analysis of stability[J].BBA-Proteins and Proteomics, 2007, 1774(7).), since the secondary bonds are all non-covalent bonds, they are easily affected by pH, temperature, etc. in the environment.
- vasoactive intestinal peptide is a linear cationic neuropeptide composed of 28 amino acids, and its stability is pH-dependent and temperature-dependent (Cui Xu, Han Xuan, Wang Zhimin, Cao Deying, Zheng Aiping. Study on chemical and biological stability of vasoactive intestinal peptide [J]. China Journal of New Drugs, 2011,20(19):1922-1925.).
- antimicrobial peptides such as high concentrations of monovalent and divalent cations, polyanions, serum, apolipoprotein AI and proteases (HANCOCK R EW, DIAMOND G. The role of cationic antimicrobial peptides in innate host defenses[J]. Trends in Microbiology, 2000, 8(9):402-410.).
- BMAP-27, BMAP-28 and their short synthetic fragments belong to the cathelicidin family of antimicrobial peptides.
- Mardirossian et al. evaluated the therapeutic effects of BMAP-derived peptides on cystic fibrosis-related pulmonary infections in vitro and in vivo. peptide, which did not show any therapeutic effect in a mouse model of acute pulmonary infection (Mardirossian M, Pompilio A, Crocetta V, et al. In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections [J]. Amino Acids, 2016, 48(9):1-8.).
- D-BMAP-18 showed strong antibacterial effect in vitro, but no therapeutic effect when applied to mice with acute lung infection (Mardirossian M, Pompilio A, Degasperi M, Runti G, Pacor S, Di Bonaventura G and Scocchi M (2017) D-BMAP18 Antimicrobial Peptide Is Active In vitro, Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection.Front.Chem.5:40.).
- the polypeptide of the present invention is an antibacterial polypeptide.
- the present invention provides the application of a polypeptide in a medicine for preventing and treating pneumonia, and at the same time, the present invention also provides a medicine for preventing and treating pneumonia.
- amino acid sequence of the polypeptide of the present invention is SEQ ID NO.1.
- One aspect of the present invention provides a medicament for preventing and treating pneumonia, the active ingredient of the medicament includes a polypeptide.
- the medicament of the present invention may contain the polypeptide as the sole therapeutic agent, or in combination with other adjuvants, carriers or auxiliary components.
- the medicament of the present invention may further comprise one or more therapeutic agents, or be combined with other adjuvants, carriers or auxiliary components.
- Another aspect of the present invention provides the use of a polypeptide in a medicine for preventing and treating pneumonia
- the medicine of the present invention comprises adding other pharmaceutically acceptable adjuvants, carriers or auxiliary components to prepare the polypeptide of the present invention
- the main active ingredient of the drug can be used for the prevention and treatment of pneumonia.
- Another aspect of the present invention provides the use of a polypeptide in a medicine for preventing and treating pneumonia.
- the medicine of the present invention comprises adding other pharmaceutically acceptable adjuvants, carriers or auxiliary components to prepare the polypeptide of the present invention A drug used in combination with other therapeutic agents to prevent and treat pneumonia.
- the pneumonia includes community-acquired pneumonia.
- the preparation of the present invention also includes other adjuvants, carriers or auxiliary components.
- the preparation of the present invention can be injection, (for injection) lyophilized powder, solid preparation, spray, solution, suspension, emulsion, semi-solid preparation, liquid preparation, tablet, capsule, enteric-coated tablet, pill, powder , granules, sustained release or delayed release, etc. any one or several combination formulations.
- the formulation of the present invention can be administered by any one or a combination of oral administration, parenteral administration, topical administration, injection administration, inhalation administration, and mucosal administration.
- the pharmaceutical preparation provided by the present invention further comprises one or more therapeutic agents.
- the therapeutic agent includes beta-lactams/beta-lactamase inhibitors (penicillins, cephalosporins), fluoroquinolones (moxifloxacin, gemisatha and levofloxacin), carbapenems, erythromycin, budesonide, oseltamivir, azithromycin, oseltamivir, yanshuning, trashuning, or combinations thereof.
- beta-lactams/beta-lactamase inhibitors penicillins, cephalosporins
- fluoroquinolones moxifloxacin, gemisatha and levofloxacin
- carbapenems erythromycin, budesonide, oseltamivir, azithromycin, oseltamivir, yanshuning, trashuning, or combinations thereof.
- the present invention provides the application of a polypeptide in a medicine for preventing and treating pneumonia, and at the same time, provides a kind of active ingredient that uses the polypeptide or in combination with other therapeutic agents, and adds pharmaceutically acceptable excipients. , carrier or auxiliary ingredients.
- the effect of the polypeptide of the present invention on bacterial pneumonia is better than that of the drugs currently on the market.
- the polypeptide of the present invention does not produce drug resistance, can widely prevent and treat pneumonia, and has broad application prospects.
- Figure 1 Pulmonary pathological changes in model animals.
- FIG. 3 On D8 day, the lung detection chart of each experimental group.
- Figure 4 Changes in body weight of rats in each experimental group during the test.
- the present invention provides the application of a polypeptide in a medicine for preventing and treating pneumonia.
- the present invention also provides a medicine for preventing and treating pneumonia, the medicine comprises: a polypeptide, and the amino acid sequence of the polypeptide is SEQ ID NO.1.
- One aspect of the present invention provides a medicament for preventing and treating pneumonia, the active ingredient of the medicament includes a polypeptide.
- the medicament of the present invention may contain the polypeptide as the sole therapeutic agent, or in combination with other adjuvants, carriers or auxiliary components.
- the medicament of the present invention may further comprise one or more therapeutic agents, or be combined with other adjuvants, carriers or auxiliary components.
- Another aspect of the present invention provides the use of a polypeptide in a medicine for preventing and treating pneumonia
- the medicine of the present invention comprises adding other pharmaceutically acceptable adjuvants, carriers or auxiliary components to prepare the polypeptide of the present invention
- the main active ingredient of the drug can be used for the prevention and treatment of pneumonia.
- Another aspect of the present invention provides the use of a polypeptide in a medicine for preventing and treating pneumonia.
- the medicine of the present invention comprises adding other pharmaceutically acceptable adjuvants, carriers or auxiliary components to prepare the polypeptide of the present invention A drug used in combination with other therapeutic agents to prevent and treat pneumonia.
- the pneumonia includes community-acquired pneumonia.
- the preparation of the present invention also includes other adjuvants, carriers or auxiliary components.
- the preparation of the present invention can be injection, (for injection) lyophilized powder, solid preparation, spray, solution, suspension, emulsion, semi-solid preparation, liquid preparation, tablet, capsule, enteric-coated tablet, pill, powder , granules, sustained release or delayed release, etc. any one or several combination formulations.
- the medicament of the present invention may further include other pharmaceutically acceptable adjuvants, carriers or auxiliary components, and can be prepared into pharmaceutically acceptable dosage forms as required.
- the pharmaceutically acceptable adjuvants, carriers or auxiliary ingredients include conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorbents, etc. Carriers, lubricants, etc., if necessary, flavoring agents, sweeteners, etc. can also be added.
- diluents and absorbents commonly used in pharmacy such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate etc.;
- Wetting agents and binders commonly used in pharmacy such as water, glycerin, polyethylene glycol, ethanol, propanol, starch syrup, dextrin, syrup, honey, glucose solution, Arabic mucilage, gelatin syrup, carboxymethyl Sodium cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.
- Disintegrants commonly used in pharmacy such as dry starch, alginate, agar powder, fucoidan, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester, dodecyl sulfonic acid Sodium, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oils, etc.
- lubricants such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, and the like.
- salts in the form of water- or oil-soluble or dispersible products
- pharmaceutically commonly used salts include conventional non-toxic or quaternary ammonium salts such as formed from inorganic or organic acids or bases, including acid addition salts such as acetate, hexamethylene acid salt, alginate, aspartate, benzoate, benzenesulfonate, sulfite, butyrate, citrate, cyclopentane propionate, digluconate, ethanesulfonate acid salt, glucoheptanoate, glycerophosphate, hemisulfate, lactate, oxalate, palmitate, pectate, succinate, tartrate, etc.
- acid addition salts such as acetate, hexamethylene acid salt, alginate, aspartate, benzoate, benzenesulfonate, sulfite, butyrate, citrate, cyclopentane propionate, digluconate, e
- the pharmaceutically acceptable carriers or excipients are not listed one by one, and those of ordinary skill in the art can make specific selections according to the common knowledge they have mastered.
- the formulation of the present invention can be administered by any one or a combination of oral administration, parenteral administration, topical administration, injection administration, inhalation administration, and mucosal administration.
- the optimal route of administration will be influenced by a variety of factors, including the physicochemical properties of the active molecule, the urgency of clinical presentation, and the relationship between the plasma concentration of the active molecule and the desired therapeutic effect.
- the medicament provided by the present invention further comprises one or more therapeutic agents.
- the therapeutic agents include but are not limited to beta-lactams/beta-lactamase inhibitors (penicillins, cephalosporins), fluoroquinolones (moxifloxacin) , gemifloxacin and levofloxacin), carbapenems, erythromycin, oseltamivir, azithromycin, oseltamivir, yanhuning, trashuning, or combinations thereof.
- beta-lactams/beta-lactamase inhibitors penicillins, cephalosporins
- fluoroquinolones moxifloxacin
- gemifloxacin and levofloxacin gemifloxacin and levofloxacin
- carbapenems erythromycin, oseltamivir, azithromycin, oseltamivir, yanhuning, trashuning, or combinations thereof.
- the daily dose of these pharmaceutical preparations can be appropriately changed according to the symptoms, age, body weight, sex, treatment time, therapeutic effect, administration method, etc. of the subject, as long as influenza infection can be suppressed and the side effects produced are tolerable There is no particular limitation within the range.
- the preparation is not limited to be administered once a day, and may be administered in multiple doses.
- formulations of the present invention may be prepared by any suitable method known in the art, and may be omitted or adjusted according to the requirements of the dosage form.
- polypeptides described in the present invention can be obtained by chemical synthesis, expression, separation and purification by genetic engineering technology (for specific methods, please refer to Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY , 2001).
- Example 1 In vivo therapeutic effect of polypeptide on infectious pneumonia
- Bacterial pneumonia is the most common pneumonia and one of the most common infectious diseases. It is caused by bacterial infection. Its main pathogens include Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, etc. Human health is at great risk. In this experiment, the mixed bacterial solution of Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli was instilled into the trachea to induce the rat pneumonia model. To evaluate the pharmacodynamic effect of peptides on pneumonia.
- erythromycin and budesonide are antibacterial drugs currently used to treat pneumonia, these two drugs were selected as positive controls.
- Erythromycin is produced by Dongyi Hetian Biotechnology Co., Ltd.
- budesonide is produced by AstraZeneca Co., Ltd. of Australia.
- Selected 80 SD rats, SPF grade, half male and half male randomly divided into 8 groups according to gender and body weight, 6 in blank control group and model evaluation group, 8 in blank administration group, model control group, erythromycin group , budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group, with 12 animals in each group, half male and half female.
- the animals in the blank administration group were not treated with modeling, and only inhaled high-concentration polypeptide aerosol (0.48 mg/L) through the mouth and nose every day.
- the animals in the blank control group were instilled 0.5 mL of 0.9% sodium chloride injection through the trachea, and the other groups were slightly anesthetized with ether.
- Dose treatment groups were instilled with 1 ⁇ 10 8 CFU/mL mixed bacterial solution of Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli, 0.5 mL/piece, respectively, through the trachea, and the blank control group was instilled with an equal volume of 0.9% chloride Sodium Injection.
- the specific modeling method is as follows: the rats are anesthetized by ether inhalation, lie supine on the dissection board at an angle of 30-45°, the trachea of the rat is exposed under the otoscope, and a 1mL syringe is connected to a long puncture needle and inserted into the trachea, and mixed bacteria are injected into the trachea. After the injection, the puncture needle was withdrawn, and the rats remained in the original inclined position for about 10 minutes, so that the bacterial liquid flowed into the bronchi and alveoli due to the action of gravity and caused infection to induce a rat pneumonia model.
- the MMAD of the polypeptide of the present invention in the aerosol particles of each concentration is 1-4 ⁇ m, and the GSD is in the range of 1-3, which meets the test requirements.
- Each group was given the first administration 2 hours after modeling. After the start of the experiment, 7.16 mg/mL and 71.6 mg/mL of polypeptide solution were atomized into aerosol particles with target concentrations of 0.07 and 0.48 mg/L, respectively. kg, 3.7 mg/kg, and the corresponding drug concentrations are 0.07 and 0.48 mg/L, respectively) animals were given aerosol particles of corresponding concentrations through oral and nasal inhalation, 10 min/time, 3 times a day, for 7 consecutive days; blank given The drug group (the cumulative dose was 22.2 mg/kg, the corresponding drug concentration was 0.48 mg/L) was given 0.48 mg/L of polypeptide aerosol particles by oral and nasal inhalation every day, 20 min/time, 3 times a day, for 7 consecutive times.
- the blank control group and the model control group were inhaled 0.9% sodium chloride solution for the same duration by the same method; the erythromycin group and the budesonide group were respectively given 5 mg/mL erythromycin solution and 0.05 mg erythromycin solution for the same duration by the same method. /mL of budesonide suspension, and the body weight of each group of rats was measured daily.
- pathological changes such as vascular congestion in the alveolar wall, thickening of the alveolar wall, doubling of the alveolar structure, and infiltration of a large number of inflammatory cells can be seen.
- the pathological score is 3.0 ⁇ 0.6.
- the experimental procedure of gross anatomy and pathological examination the rats to be tested were anesthetized by intraperitoneal injection of 20% ulose (1000 mg/kg), and the rats in each group were first tested for lung function with a pulmonary function tester. Then, blood was collected from the abdominal aorta, and the partial pressure of oxygen (PaO 2 ) and the partial pressure of carbon dioxide (PaCO 2 ) in the blood of the rats were measured by a blood gas analyzer, and then the left lower lobe lung tissue was taken, which was fixed in formalin, embedded, and Sections, HE staining, and pathological changes were observed under light microscope.
- PaO 2 partial pressure of oxygen
- PaCO 2 carbon dioxide
- the forced vital capacity (FVC) on D4 day, tidal volume on D8 day, and FEV200/FVC decreased significantly, and the respiratory rate (f) on D4 increased by 37%, indicating that the early stage of pneumonia was caused by The ventilation function of the lungs is limited, and the body will increase the respiratory rate to maintain a constant ventilation volume.
- the tidal volume (VT) of the erythromycin group, the budesonide group, the low-dose polypeptide treatment group, and the high-dose polypeptide treatment group on D4 showed an increasing trend, and the respiratory frequency (f) showed a decreasing trend (trending to normal). ), but no significant difference; no significant change in minute ventilation (MV).
- the FVC, FEV200 and FEV200/FVC of the high-dose polypeptide treatment group increased significantly
- the FEV200/FVC of the erythromycin group and the low-dose polypeptide treatment group increased significantly.
- the f, mv, FVC, and FEV200 of the erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group on D8 day showed an upward trend compared with the model control group, but there was no statistical difference.
- the tidal volume in the erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group increased significantly
- the FEV200 in the erythromycin group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group increased significantly.
- /FVC were significantly increased.
- VT, f, mv, FVC, FEV200 and FEV200/FVC there was no significant difference in VT, f, mv, FVC, FEV200 and FEV200/FVC in the blank administration group compared with the blank control group.
- VT, f, MV, FVC, FEV200, FEV200/FVC between the low-dose polypeptide treatment group and the high-dose polypeptide treatment group on D4, but the VT, FVC, and FEV200 in the high-dose polypeptide treatment group were not statistically different.
- the respiratory rate showed a decreasing trend; compared with the erythromycin group and the budesonide group, the respiratory rate decreased.
- MV, FVC, FEV200, FEV200/FVC were not significantly different, and there was no trend of increasing or decreasing.
- the high-dose peptide treatment group showed better efficacy than erythromycin and budesonide on D4, and there was no difference in the efficacy on D8, which indicated that the onset time of 3.7 mg/kg polypeptide was earlier than 18 mg/kg erythromycin and 0.18 mg/kg budesonide.
- the pH of the erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group on D8 showed an increasing trend, but there was no statistical difference;
- the PaCO2 in arterial blood in the budesonide group, the low - dose polypeptide treatment group and the high - dose polypeptide treatment group increased significantly, and the PaO2 in the erythromycin group increased significantly increased by 37.17% (vs the model control group), but there was no statistical difference.
- polypeptide, erythromycin and budesonide can significantly regulate pH, PaCO 2 , PaO 2 in arterial blood of rats with bacterial infection pneumonia, and the pharmacodynamic effect of low-dose polypeptide (0.54mg/kg) is comparable to that of red erythromycin.
- the pharmacodynamic effects of pycnogenol solution (18mg/kg) and budesonide suspension (0.18mg/kg) were equivalent.
- the lungs of the blank control group had no obvious abnormality; on D4 day, the alveolar structure of the model control group was destroyed, the alveolar wall was significantly thickened, the blood vessels in the alveolar wall were congested, and a large number of inflammatory cells were infiltrated. On D4 day, erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group showed thickening of alveolar wall, slight congestion of blood vessels in alveolar wall, infiltration of inflammatory cells, and abnormal alveolar structure. The model control group was significantly improved.
- the alveolar wall of the model control group was obviously thickened, and the blood vessels in the alveolar wall were slightly congested and inflammatory cells were infiltrated.
- the lung tissue lesions in the erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group were significantly improved, and the lung tissue in the erythromycin group and high-dose polypeptide treatment group tended to be normal. No obvious abnormality was found in the lung tissue microscopic examination of the blank drug group, indicating that the cumulative dose of 22.2 mg/kg polypeptide aerosol inhaled by the rat through the mouth and nose showed no lung histopathological changes related to the test substance.
- the inhibition rates of Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae were different in each administration group, among which the erythromycin group, the polypeptide low-dose treatment group, and the polypeptide high-dose treatment group inhibited Escherichia coli
- the rates were 85.58%, 71.19%, and 92.16%, respectively, while the inhibition rate of budesonide against Escherichia coli was -20.55%; erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group
- the inhibition rates against Staphylococcus aureus were 87.41%, 48.74%, 80.56%, and 90.99%, respectively; the inhibition rates against Streptococcus pneumoniae were 74.14%, 61.73%, 84.14%, and 90.49%, respectively.
- the number of Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae in the lungs of the animals in the budesonide group on D8 day decreased, but there was no statistical difference;
- the number of Staphylococcus aureus in the lungs was significantly reduced, but there was no statistical difference;
- the numbers of Escherichia coli and Streptococcus pneumoniae in the lungs of the erythromycin group, the low-dose polypeptide treatment group, and the high-dose polypeptide treatment group were significantly reduced (P ⁇ 0.05 or P ⁇ 0.01).
- the inhibition rates of erythromycin group, budesonide group, low-dose polypeptide treatment group, and high-dose polypeptide treatment group against Escherichia coli were 91.69%, 7.58%, 85.77%, and 96.57%, respectively;
- the inhibition rates were 96.66%, 83.43%, 96.75%, and 97.43%, respectively;
- the inhibition rates against Streptococcus pneumoniae were 95.77%, 72.65%, 94.95%, and 98.74%, respectively.
- erythromycin, budesonide group and polypeptide administered by oral and nasal inhalation can significantly inhibit the replication of Staphylococcus aureus and Streptococcus pneumoniae in the lung tissue, but budesonide can inhibit the bacterial infection of the large intestine in the lungs of rats.
- Escherichia coli had no obvious inhibitory effect.
- the high-dose polypeptide treatment group (3.7mg/kg) had better efficacy than erythromycin solution (18mg/kg) and budesonide suspension (0.18mg/kg).
- the model control group had no significant difference in body weight; compared with the model control group, there was no significant difference in the erythromycin group, budesonide group, polypeptide low-dose treatment group, and polypeptide high-dose treatment group; Compared with the blank control group, there was no significant difference in the body weight of the blank administration group.
- the oral and nasal inhalation of polypeptide has a significant therapeutic effect on bacterial pneumonia induced by mixed bacteria, and the results of the high-dose polypeptide treatment group are better than those of the erythromycin group and the budesonide group.
- the polypeptide of the present invention is composed of 19 amino acids, and the degradation products are natural amino acids, which do not produce drug residues.
- the sterilization mechanism of the polypeptide is that it carries a strong positive charge and adsorbs to the surface of the bacteria, causing a sudden change in the local potential of the cell wall. A high potential difference is formed, and finally the cell wall is broken down to form a perforation.
- the polypeptide molecules accumulate to a certain amount, the formed holes will be further enlarged and the integrity of the cell membrane will be destroyed, thereby causing the outflow of intracellular substances and the death of the bacteria. Its unique sterilization mechanism It is determined that the polypeptide is not easy to produce drug resistance, has good advantages, and has broad application prospects.
- drug pharmaceutical preparation
- preparation preparation containing active pharmaceutical ingredients and optionally a pharmaceutically acceptable carrier therein.
- pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal to be treated with it.
- pharmaceutically acceptable carrier refers to non-toxic solid, semi-solid or liquid fillers, diluents, adjuvants, wrapping materials or other formulation auxiliaries.
- the carrier used can be adapted to the corresponding administration form, and the carrier known to those skilled in the art can be used to formulate injections, (for injection) lyophilized powders, solid preparations, sprays, solutions, suspensions, semi-solid preparations, Liquid preparations, tablets, capsules, enteric-coated tablets, pills, powders, granules, sustained release or delayed release, etc. any one or a combination of preparations.
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Abstract
涉及医药技术领域，具体涉及一种多肽在预防和治疗肺炎的药物中的应用，所述多肽可有效预防和治疗肺炎，也可添加其他治疗剂、辅料、载体或辅助性成分制成以所述多肽和其他治疗剂为主要活性成分的药物，用于预防和治疗肺炎。还公开了该多肽及其药物在预防和治疗肺炎中的应用，所述药物对肺炎具有较好的抑制和治疗作用，可有效作用于致病菌引起的肺炎，有效预防，也可提高肺炎的治疗效果。与现有技术相比，所述多肽及其药物具有安全性高、无耐药性的效果，有效预防和治疗肺炎，具有较高价值的应用前景。
Description
本发明涉及医药技术领域，具体涉及一种多肽在预防和治疗肺炎的药物中的应用。
肺炎是呼吸系统的常见病，按其发病场所，可分为社区获得性肺炎(community-acquired pneumonia,CAP)和医院获得性肺炎(Hospital acquired pneumonia,HAP)。
社区获得性肺炎(community-acquired pneumonia,CAP)是一种异质性疾病，也称院外获得性肺炎，是指在医院外罹患的感染性肺实质炎症，多由细菌、病毒、真菌及非典型病原体所引起，其中以细菌性肺炎患者最为多见，是临床常见的下呼吸道感染，也是人类健康受到严重威胁的常见疾病之一。
医院获得性肺炎(Hospital acquired pneumonia,HAP)指入院前无感染指征，于住院48h后发生肺炎的患者(汤琳民,楼娟花,胡瑱臻.ICU医院获得性肺炎感染病原菌耐药性及危险因素分析[J].实用药物与临床,2016,19(03):367-370.)，多由细菌感染引起。因其传播性强、易加重患者病情及疾病负担等特点，近年来引起了临床与预防界学者的广泛关注(黄芳,陈兴峰,王燕萍.医院获得性肺炎的流行病学特点及预防措施研究[J].中华医院感染学杂志,2018,28(13):2053-2055.)。
应晓波等报道单纯肺炎病原体感染，细菌占31.81％，混合感染占10.23％。将混合感染与单纯感染合并后，细菌占40.91％。可见细菌感染在肺炎占首位(应晓波,王丹民,宋波,兰大波.不同季节成人社区获得性肺炎病原学调查[J].中国公共卫生管 理,2014,30(06):843-844+849.)。
随着检测方法学的进步，同一个患者合并的多种致病原可被同时检测出来，越来越多的混合感染被识别、发现，并且合并细菌感染的CAP患者病死率较单病原体感染者显著增加(Burk M,El-Kersh K,Saad M,et al.Viral infection in community-acquired pneumonia:a systematic review and meta-analysis.EurRespir Rev,2016,25(140):178-188.)。
现有的用于治疗肺炎的药物，红霉素、布地奈德等是治疗肺炎的药物，但是由于现有红霉素、布地奈德在治疗过程中，均出现了或多或少的不良反应。红霉素的刺激性强，口服或静脉给药均可引起胃肠道反应，还会带来肝损害，大剂量或长期应用可导致胆汁瘀积和转氨酶升高等，孕妇及肝功能不全者不宜应用，婴幼儿慎用。布地奈德可引起口咽部念珠菌感染或速发或迟发的过敏反应，包括皮疹，接触性皮炎，荨麻疹，血管神经性水肿和支气管痉挛。另外，肺炎治疗的耐药性也成为日益关注的全球性问题
故研发一款对肺炎的主要病原体作用范围广且无耐药性，无不良反应的药物制剂以在初期的肺炎治疗中发挥重要的治疗作用迫在眉睫。
抗菌肽是一类碱性多肽，一般由12～50个左右氨基酸组成，具有广谱抗菌性，对细菌、真菌、病毒、寄生虫和肿瘤细胞有抑制或杀灭作用，可促进伤口愈合过程。此外，抗菌肽还能作为免疫效应活化分子，调节机体免疫系统的功能，增强机体清除病原体的能力，中和细菌内毒素LPS，降低炎性细胞因子的释放，减缓炎症反应引起的组织损伤。传统抗生素虽抗菌效果明显，但抗菌机理大多通过阻碍细菌细胞壁的合成、抑制蛋白质的合成、影响核酸、叶酸的代谢等来进行抗微生物，微生物很容易通过基因突变来改变代谢途径，进而对抗生 素产生耐药性。相对于抗生素，抗菌肽在耐药性方面具有不可比拟的优点，抗菌肽可通过与微生物细胞膜作用，形成孔洞，影响细胞内外渗透压，进而使细胞死亡。由于微生物的细胞膜结构是经亿万年进化而来，其结构不会在短时间内做出较大改变，所以，抗菌肽的这种抗菌机理不易使细菌产生耐药性。因此，抗菌肽作为抗微生物成分受到越来越多的青睐。
目前，抗菌肽数据库(APD,http://aps.unmc.edu/AP/)收录3241种抗菌肽，对抗菌肽的体外抗菌活性报道较为常见，但抗菌肽应用于疾病治疗的报道较少，这与抗菌肽自身特性、抗菌肽发挥生物活性的条件以及生物体复杂的生理环境都有较大关系。
抗菌肽自身的三维空间结构主要靠氢键、疏水键、盐键及范德华力等次级键维持(T.C.Jyothi,Sharmistha Sinha,Sridevi A.Singh,A.Surolia,A.G.Appu Rao.Napin from Brassica juncea:Thermodynamic and structural analysis of stability[J].BBA-Proteins and Proteomics,2007,1774(7).)，由于次级键都是非共价键，易受环境中pH、温度等的影响，因而蛋白多肽的结构域易发生变化，引起三维结构的构象发生改变，造成变性从而导致稳定性较差或功能丧失(Dipesh Shah,Thomas P.Johnston,Ashim K.Mitra.Thermodynamic parameters associated with guanidine HCl-and temperature-induced unfolding of bFGF[J].International Journal of Pharmaceutics,1998,169(1).)。如血管活性肠肽(vasoactive intestinal peptide,VIP)，是一种由28个氨基酸组成的直链阳离子神经肽，其稳定性具有pH依赖性和温度依赖性(崔旭,韩璇,王志敏,曹德英,郑爱萍.血管活性肠肽化学及生物学稳定性研究[J].中国新药杂志,2011,20(19):1922-1925.)。
同时，抗菌肽在体内半衰期过短、易被高盐离子失活、易被蛋白 酶水解等也制约了其在制药领域的应用。GOLDMAN等人报道：部分抗菌肽的抗菌作用和溶液中的Na+浓度存在负相关性,当NaCl浓度为150mmol/L(生理盐浓度)时即失去活性(GOLDMAN M J,et a.l Human beta-defensin-1is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis[J].Cel,l 1997,88(4):553-560.)。HANCOCK等人报道：许多因素会降低抗菌肽的活性，如高浓度的一价和二价阳离子、聚阴离子(polyanion)、血清、阿朴脂蛋白A-I(apolipoprotein A-I)和蛋白酶等(HANCOCK R EW,DIAMOND G.The role of cationic antimicrobial peptides in innate host defences[J].Trends in Microbiology,2000,8(9):402-410.)。
BMAP-27、BMAP-28及其短合成片段属于Cathelicidin家族抗菌肽，Mardirossian等人评估了BMAP衍生肽在体内外对囊性纤维化相关肺部感染的治疗作用，结果表明，体外抗菌活性高的多肽，在急性肺部感染小鼠模型中未显示任何治疗效果(Mardirossian M,Pompilio A,Crocetta V,et al.In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections[J].Amino Acids,2016,48(9):1-8.)。研究者将原因归集于为多肽遇肺部蛋白酶而被快速降解，为提高多肽稳定性，研究者合成了具蛋白酶抗性的D型BMAP-18多肽做进一步研究，同样的，D-BMAP-18在体外表现出较强抗菌作用，当应用于急性肺部感染的小鼠时，无治疗作用(Mardirossian M,Pompilio A,Degasperi M,Runti G,Pacor S,Di Bonaventura G and Scocchi M(2017)D-BMAP18 Antimicrobial Peptide Is Active In vitro,Resists to Pulmonary Proteases but Loses Its Activity in a Murine Model of Pseudomonas aeruginosa Lung Infection.Front.Chem.5:40.)。
本发明所述多肽为一种抗菌多肽，申请人在研究中惊讶的发现了本发明所述多肽在动物体内具有较好的抗菌效果，故其可用于生产预防和治疗肺炎的药物，具有极大的应用和研究前景。现有技术中未公开其可用于预防和治疗肺炎的报道。
发明内容
针对现有技术的不足，本发明提供了一种多肽在预防和治疗肺炎的药物中的应用，同时，本发明还提供了一种预防和治疗肺炎的药物。
本发明所述多肽的氨基酸序列为SEQ ID NO.1。
本发明的一方面提供了一种预防和治疗肺炎的药物，该药物的活性成分包括多肽。
本发明所述的药物可包含多肽作为唯一治疗剂，或者与其他辅料、载体或辅助性成分组合。
本发明所述的药物也可进一步包含一种或多种治疗剂，或者与其他辅料、载体或辅助性成分组合。
本发明另一个方面提供了一种多肽在预防和治疗肺炎的药物中的应用，本发明所述药物包括添加了其他药学上可接受的辅料、载体或辅助性成分制成以本发明所述多肽为主要活性成分的药物，可用于预防和治疗肺炎。
本发明再一个方面提供了一种多肽在预防和治疗肺炎的药物中的应用，本发明所述药物包括添加了其他药学上可接受的辅料、载体或辅助性成分制成以本发明所述多肽和其他治疗剂组合的药物，可用于预防和治疗肺炎。
优选的，所述肺炎包括社区获得性肺炎。
优选的，本发明所述的制剂还包括其他辅料、载体或辅助性成分。
本发明所述制剂可以是注射剂、(注射用)冻干粉、固体制剂、 喷雾剂、溶液、混悬液、乳液、半固体制剂、液体制剂、片剂、胶囊、肠溶片、丸剂、粉剂、颗粒剂、持续释放或延迟释释放等任一一种或几种的组合形式制剂。
优选的，本发明所述制剂可以通过口服、非胃肠施用、局部施用、注射给药、吸入给药、粘膜给药任一一种或几种的组合形式给药。
优选的，本发明提供的药物制剂进一步包含一种或多种治疗剂。
优选的，本发明所述的药物，其中所述的治疗剂包括β-内酰胺类/β-内酰胺酶抑制剂(青霉素类、头孢菌素类)、氟喹诺酮类(莫西沙星、吉米沙星和左氧氟沙星)、碳青霉烯类、红霉素、布地奈德、奥司他韦、阿奇霉素、奥司他韦、炎琥宁、穿琥宁或它们的组合。
综上所述，本发明提供了一种多肽在预防和治疗肺炎的药物中的应用，同时，提供了一种以所述多肽或与其他治疗剂组合为有效成分，添加药学上可接受的辅料、载体或辅助性成分而制成的药物。与现有技术相比，本发明所述的多肽对细菌性肺炎的作用效果比现有市场上在用的药物的治疗效果好。并且本发明所述多肽不产生耐药性，可广泛预防和治疗肺炎，具有广阔的应用前景。
图1：造模动物的肺部病理变化图。
图2：D4天时，各试验组肺脏检测图。
图3：D8天时，各试验组肺脏检测图。
图4：试验过程中，各试验组大鼠体重变化图。
本发明提供了一种多肽在预防和治疗肺炎的药物中的应用。
同时，本发明还提供了一种预防和治疗肺炎的药物，所述药物包 括：多肽，所述多肽的氨基酸序列为SEQ ID NO.1。
本发明的一方面提供了一种预防和治疗肺炎的药物，该药物的活性成分包括多肽。
本发明所述的药物可包含多肽作为唯一治疗剂，或者与其他辅料、载体或辅助性成分组合。
本发明所述的药物也可进一步包含一种或多种治疗剂，或者与其他辅料、载体或辅助性成分组合。
本发明另一个方面提供了一种多肽在预防和治疗肺炎的药物中的应用，本发明所述药物包括添加了其他药学上可接受的辅料、载体或辅助性成分制成以本发明所述多肽为主要活性成分的药物，可用于预防和治疗肺炎。
本发明再一个方面提供了一种多肽在预防和治疗肺炎的药物中的应用，本发明所述药物包括添加了其他药学上可接受的辅料、载体或辅助性成分制成以本发明所述多肽和其他治疗剂组合的药物，可用于预防和治疗肺炎。
优选的，所述肺炎包括社区获得性肺炎。
优选的，本发明所述的制剂还包括其他辅料、载体或辅助性成分。
本发明所述制剂可以是注射剂、(注射用)冻干粉、固体制剂、喷雾剂、溶液、混悬液、乳液、半固体制剂、液体制剂、片剂、胶囊、肠溶片、丸剂、粉剂、颗粒剂、持续释放或延迟释释放等任一一种或几种的组合形式制剂。
本发明所述药物可进一步包括药学上可接受的其他辅料、载体或辅助性成分，根据需要可制备成药学上可接受的剂型。所述药学上可接受的辅料、载体或辅助性成分，包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等，必要时，还可加入香味剂、甜味剂等。
具体如药学上常用的稀释剂和吸收剂，例如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；药学上常用的湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等。
药学上常用的崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等。
药学上常用的润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。
药学常用的盐(水溶性或油溶性或可分散性产物形式)包括如从无机或有机酸或碱形成的常规无毒盐或季铵盐，包括酸加成盐，例如乙酸盐、已二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、亚硫酸盐、丁酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、乙磺酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、乳酸盐、草酸盐、棕榈酸盐、果胶酸盐、琥珀酸盐、酒石酸盐等。
关于药学上可接受的载体或辅料不再一一例举，本领域普通技术人员可根据所掌握的公知常识进行具体选择。
优选的，本发明所述制剂可以通过口服、非胃肠施用、局部施用、注射给药、吸入给药、粘膜给药任一一种或几种的组合形式给药。最佳的给予途径将受多种因素的影响，这些因素包括活性分子的物理化学性质、临床表现的紧急性、以及活性分子的血浆浓度与所希望的治疗效果之间的关系。
优选的，本发明提供的药物进一步包含一种或多种治疗剂。
优选的，本发明所述的药物，其中所述的治疗剂包括但不限于β-内酰胺类/β-内酰胺酶抑制剂(青霉素类、头孢菌素类)、氟喹诺酮类(莫西沙星、吉米沙星和左氧氟沙星)、碳青霉烯类、红霉素、奥司他韦、阿奇霉素、奥司他韦、炎琥宁、穿琥宁或它们的组合。
另外，这些药物制剂的一天的给药量可以根据给药对象的症状、年龄、体重、性别、治疗时间、治疗效果、给药方法等适当变更，只要可以抑制流感感染且产生的副作用在可允许的范围内就无特别限制。该制剂不限于一天给药一次，可以分多次给药。
本发明的制剂可以通过本领域已知的任何合适的方法制备，可根据剂型要求进行删减或调整。
本领域技术人员可以根据所需要制备的剂型，按照本领域该剂型的一般技术常识和要求，选择合适的辅料，在多肽的基础的上，加入适当的辅料和添加剂，并按照常规的制剂技术来制备，可以制成片剂、粉剂、液体等剂型。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。
本发明中所述多肽可通过化学合成，也可以通过基因工程技术表达、分离纯化得到(具体方法可参见Sambrook et al.，Molecular Cloning：A Laboratory Manual，Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NY，2001)。
若未特别指明，实施例中所用的技术手段为本领域技术人员所熟知的常规手段，实施例中，加入的各试剂等除特别说明外，均为市售。
本部分实施例进一步说明本发明的内容，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的修改或替换，均属于本发明的范围。
实施例1多肽对感染性肺炎的体内治疗效果
细菌性肺炎是最常见的肺炎，也是最常见的感染性疾病之一，为 细菌感染所致，其主要致病菌包括肺炎链球菌、金黄色葡萄球菌、大肠埃希菌等，对儿童及老年人的健康威胁极大。本实验选用气管滴注金黄色葡萄球菌、肺炎链球菌、大肠埃希菌的混合菌液，诱导大鼠肺炎模型，通过观察多肽经口鼻吸入给药对混合细菌感染所致肺炎模型的影响，评价多肽对肺炎的药效作用。
由于红霉素、布地奈德是目前用来治疗肺炎的抗细菌药物，故选用这两种药物为阳性对照品。红霉素由东易和天生物科技有限公司生产，布地奈德由澳大利亚阿斯利康有限公司生产。
选取SD大鼠80只，SPF级，雌雄各半，按性别及体重随机分8组，空白对照组和模型评价组均为6只，空白给药组8只，模型对照组、红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组，每组各12只，雌雄各半。
空白给药组动物不做造模处理，每日仅经口鼻吸入高浓度多肽气溶胶(0.48mg/L)。空白对照组动物经气管滴注0.5mL的0.9％氯化钠注射液，其余各组用乙醚轻微麻醉后，模型对照组、红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组分别经气管滴入1×10
8CFU/mL金黄色葡萄球菌、肺炎链球菌、大肠埃希菌的混合菌液，0.5mL/只，空白对照组滴入等体积的0.9％氯化钠注射液。
具体造模方法如下：大鼠用乙醚吸入麻醉，呈30-45°角倾斜仰卧于解剖板上，耳镜下暴露大鼠气管，用1mL的注射器连接穿刺长针插入气管内，并注入混合细菌0.5mL/只，注射完毕后抽出穿刺针，大鼠仍保持原倾斜位置约10min，使菌液由于重力的作用流入支气管和肺泡内而引起感染，以诱导大鼠肺炎模型。
实验开始前分别将7.16mg/mL、71.6mg/mL的多肽低剂量治疗组、多肽高剂量治疗组溶液雾化生成药物浓度分别为0.07、0.48mg/L的气溶胶颗粒。
1.对雾化的气溶胶颗粒浓度进行验证
首次给药前，对气溶胶颗粒的雾化进行验证：采用滤膜采集任一暴露口气溶胶颗粒，采样流量1L/min，采样时间5min，测定雾化后的气溶胶中供试品的含量，采用安德森采样器采集2个浓度的气溶胶颗粒，采样流量1L/min，采样时间3～5min(低剂量5min，高剂量3min)，检测并计算各浓度气溶胶颗粒中多肽的中值粒径(MMAD)和标准偏差(GSD)，每日使用气溶胶质量浓度检测仪对各给药组给药过程中的气溶胶颗粒浓度进行监测。气溶胶中受试物含量与粒径分布结果见表1
表1气溶胶中受试物含量与粒径分布
由表1可知，首次给药前，各浓度气溶胶颗粒中本发明所述多肽的MMAD在1～4μm，GSD均在1～3范围内，符合试验要求。
2.进行给药试验
各组于造模后2h进行首次给药。实验开始后，每天将7.16mg/mL、71.6mg/mL的多肽溶液雾化成目标浓度分别为0.07、0.48mg/L的气溶胶颗粒，多肽低剂量治疗组、多肽高剂量治疗组(0.54mg/kg、3.7mg/kg，对应药物浓度分别为0.07、0.48mg/L)动物分别经口鼻吸入给予相应浓度的气溶胶颗粒，10min/次，1日3次，连续给药7天；空白给药组(累积剂量为22.2mg/kg，对应药物浓度为0.48mg/L)每日经口鼻吸入给予0.48mg/L的多肽气溶胶颗粒，20min/次，1日3次，连续给药7天；空白对照组、模型对照组按相同方法吸入同等时长0.9％氯化钠溶液；红霉素组、布地奈德组按相同方法分别给予同等时长的5mg/mL的红霉素溶液与0.05mg/mL的布地奈德悬液，并且每日对每组大鼠的体重进行检测。
2.1对造模动物进行验证
经气管滴入肺炎链球菌、金黄色葡萄球菌、大肠埃希菌混合菌液24h后，为验证是否造模成功，对模型评价组6只动物进行解剖，取肺脏，福尔马林固定、包埋、切片、HE染色，光镜下观察肺脏病理变化，以6只大鼠中至少5只肺脏产生明显病理变化，视为造模成功。结果显示，6只动物均出现肺泡结构被破坏，肺泡壁明显增厚，可见肺泡壁血管充血，炎症细胞大量浸润等病理变化，表明经气管滴注混合细菌诱导大鼠肺炎造模成功，该批造模动物可用于后续试验，具体肺部的病理变化见图1。
由图1可见肺泡壁血管充血、肺泡壁增厚、肺泡结构倍破坏、炎症大量细胞浸润等病理变化，该病理评分为3.0±0.6。
2.2肺功能检测、大体解剖检查及病理性检测
2.2.1试验设计
除空白给药组外，其余各组D4天，随机选取出一半动物，进行肺功能检测以及大体解剖检查和病理学检测，并每组选取3只动物肺 脏进行细菌培养计数；D8天对剩余动物进行肺功能检测以及大体解剖检查和病理学检测，并每组选取3只动物肺脏进行细菌培养计数(空白对照组、空白给药组不做检查)。
2.2.2试验步骤
2.2.2.1大体解剖检查和病理性检测
大体解剖检查和病理学检测的实验步骤：将待检测的大鼠的腹腔注射20％乌来糖(剂量为1000mg/kg)麻醉，各组大鼠先用肺功能检测仪检测大鼠肺功能。然后腹主动脉采血，采用血气分析仪，测定大鼠血液中氧分压(PaO
2)与二氧化碳分压(PaCO
2)后，取左侧下叶肺组织，福尔马林固定、包埋、切片、HE染色，光镜观察病理改变。
2.2.2.2细菌计数
细菌培养的实验步骤：除空白给药组外，其余每组中随机抽取6只动物(首次末次解剖各随机挑选3只)，取左侧中叶肺组织，用0.9％氯化钠注射液冲洗，按重量加入1倍的0.9％氯化钠注射液研磨成匀浆，接种于肉膏汤琼脂培养基中于37℃培养16～18h，进行细菌分离，将分离培养的各菌悬液按照10倍梯度稀释为10
-1、10
-2、10
-3、10
-4、10
-5、10
-6、10
-7、10
-8，即9ml生理盐水加1ml菌悬液为10
-1，依此类推。选取适当浓度的0.1ml菌液放于选择性培养基上，轻轻推开菌液，进行24h-48h培养，然后用细菌计数仪进行细菌计数，根据其稀释浓度计算每ml菌液的菌数。与模型对照组相对比，计算各组的抑制率。
2.2.3试验结果及分析
各实验数据及结果如下：
(1)不同阶段各实验组对大鼠肺功能的影响结果见表2。
表2不同给药阶段各实验组对大鼠肺功能的影响
如表2所示，与空白对照组比较，模型对照组，D4天用力肺活量(FVC)、D8天潮气量、FEV200/FVC显著减小，D4呼吸频率(f)增加37％，说明肺炎早期由于肺的通气功能受限，机体会通过增加呼吸频率，进而维持通气量的恒定。
与模型对照组比较，D4天红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组潮气量(VT)呈增加趋势，呼吸频率(f)呈降低趋势(趋于正常)，但无显著性差异；每分通气量(MV)无显著变化。与模型对照组比较，多肽高剂量治疗组的FVC、FEV200、FEV200/FVC显著增加，红霉素组、多肽低剂量治疗组的FEV200/FVC显著增加。
与模型对照组比较，D8天红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组f、mv、FVC、FEV200较模型对照组呈上 升趋势，但无统计学差异。与模型对照组比较，红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组潮气量均显著增加，红霉素组、多肽低剂量治疗组、多肽高剂量治疗组FEV200/FVC均显著增加。空白给药组较空白对照组VT、f、mv、FVC、FEV200、FEV200/FVC均无显著差异。与红霉素组比较，D4天多肽低剂量治疗组、多肽高剂量治疗组VT、f、MV、FVC、FEV200、FEV200/FVC虽无统计学差异，但多肽高剂量治疗组VT、FVC、FEV200较红霉素组与布地奈德组呈增大趋势，呼吸频率较较红霉素组与布地奈德组呈减小趋势；D8天多肽低剂量治疗组、多肽高剂量治疗组VT、f、MV、FVC、FEV200、FEV200/FVC较红霉素组与布地奈德组无相差不大，无增大或减小趋势。
由此可知，多肽高剂量治疗组在D4天时表现出优于红霉素与布地奈德的药效作用，D8天药效作用无差别，这表明3.7mg/kg的多肽的起效时间早于18mg/kg红霉素与0.18mg/kg布地奈德。
(2)各不同实验组对大鼠动脉血气的影响结果见表3。
表3各实验组对大鼠动脉血气的影响
如表3所示，与空白对照组比较，D4天模型对照组动脉血中pH显著降低、PCO
2显著增加，PaO
2下降30.16％，但无统计学差异。与模型对照组比较，D4天红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组PO
2虽有一定程度的升高，但无统计学差异；多肽低剂量治疗组、多肽高剂量治疗组动脉血中pH显著升高、PaCO
2显著降低，布地奈德组动脉血中pH呈升高趋势，PaCO
2呈降低趋势，但无统计学差异。
与空白对照组比较，D8天模型对照组动物动脉血中pH、PaCO
2 无统计学差异，PaO
2显著降低；空白给药组pH、PaCO
2、PaO
2较空白对照组无明显差异，表明连续7天经口鼻吸入给予累计剂量为22.2mg/kg多肽对大鼠血液中的pH、PaCO
2、PaO
2无明显影响。与模型对照组比较，D8天红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组pH虽呈升高趋势，但无统计学差异；红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组动脉血中PaCO
2显著降低，布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组PaO
2显著升高，红霉素组PaO2升高了37.17％(vs模型对照组)，但无统计学差异。
与红霉素组比较，D4、D8天多肽低、高剂量组大鼠血液中的pH、PaCO2、PaO2无明显差异；与布地奈德组比较，D4、D8天多肽低、高剂量组大鼠血液中的pH、PaCO2、PaO2无明显差异。
由上数据表明，多肽、红霉素、布地奈德均能显著调节细菌感染性肺炎大鼠动脉血中pH、PaCO
2、PaO
2，且低剂量多肽(0.54mg/kg)药效作用与红霉素溶液(18mg/kg)以及布地奈德悬液(0.18mg/kg)药效作用相当。
(3)对D4、D8的大鼠肺脏进行病理学研究
由图2、图3可知，空白对照组的肺脏未出现明显异常；D4天，模型对照组肺泡结构被破坏，肺泡壁明显增厚，可见肺泡壁血管充血，炎症细胞大量浸润。D4天，红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组均可见肺泡壁增厚，肺泡壁血管有微量充血，炎症细胞浸润，肺泡结构异常，上述病理改变较模型对照组明显改善。
D8天，模型对照组肺泡壁增厚明显，可见肺泡壁血管少量充血，炎症细胞大量浸润。D8天，红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组肺组织病变明显改善，其中红霉素组、多肽高剂量治疗组肺组织趋于正常。空白给药组肺组织镜检，未见明显异 常，表明大鼠经口鼻吸入累计剂量为22.2mg/kg多肽气溶胶未见与受试物相关的肺组织病理学改变。
(4)各实验组肺炎模型大鼠肺组织中细菌数见表4。
表4各实验组肺炎模型大鼠肺组织中细菌数
如表4所示，与模型对照组比较，D4天各给药组动物肺组织中大肠埃希菌、金黄葡萄球菌、肺炎链球菌数目均有大幅度的降低，但仅多肽高剂量治疗组肺炎链球菌数目较模型对照组显著减少(P<0.05)，其余各组肺脏中上述细菌数目无统计学差异。此外，各给药组对大肠埃希菌、金黄葡萄球菌、肺炎链球菌的抑制率有所不同，其中红霉素组、多肽低剂量治疗组、多肽高剂量治疗组对大肠埃希菌的抑制率分别为85.58％、71.19％、92.16％，而布地奈德对大肠埃希菌的抑制率为-20.55％；红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组对金黄葡萄球菌的抑制率分别为87.41％、48.74％、80.56％、90.99％；对肺炎链球菌的抑制率分别为74.14％、61.73％、84.14％、90.49％。
与模型对照组比较，D8天布地奈德组动物肺脏中大肠埃希菌、金黄葡萄球菌、肺炎链球菌数目呈降低趋势，但无统计学差异；红霉素组、多肽低、高剂量组动物肺脏中的金黄色葡萄球菌数目有大幅度降低，但无统计学差异；红霉素组、多肽低剂量治疗组、多肽高剂量 治疗组肺脏中大肠埃希菌、肺炎链球菌数目显著减少(P<0.05或P<0.01)。D8天红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组对大肠埃希菌的抑制率分别为91.69％、7.58％、85.77％、96.57％；对金黄葡萄球菌的抑制率分别为96.66％、83.43％、96.75％、97.43％；对肺炎链球菌的抑制率分别为95.77％、72.65％、94.95％、98.74％。
与红霉素组比较，D4、D8天多肽高剂量治疗组动物肺脏中大肠埃希菌、金黄葡萄球菌、肺炎链球菌均呈下降趋势，但无统计学差异；与布地奈德组比较，D4、D8天多肽低剂量治疗组、多肽高剂量治疗组动物肺脏中大肠埃希菌、金黄葡萄球菌、肺炎链球菌均呈下降趋势，但无统计学差异，表明多肽高剂量治疗组(3.7mg/kg)对大肠埃希菌、金黄葡萄球菌、肺炎链球菌抑制作用优于红霉素溶液(18mg/kg)以及布地奈德悬液(0.18mg/kg)。
由上述结果分析，经口鼻吸入给予红霉素、布地奈德组、多肽均能显著抑制金黄葡萄球菌、肺炎链球菌在肺脏组织内的复制，但布地奈德对细菌感染大鼠肺脏中大肠埃希菌无明显抑制作用，于此同时，多肽高剂量治疗组(3.7mg/kg)药效作用优于红霉素溶液(18mg/kg)以及布地奈德悬液(0.18mg/kg)。
3.实验过程中，每天记录大鼠的体重，详见图4。
由图4可知，与空白对照组比较，模型对照组体重无显著差异；与模型对照组比较，红霉素组、布地奈德组、多肽低剂量治疗组、多肽高剂量治疗组无显著差异；与空白对照组比较，空白给药组的体重无显著差异。
由此可知，多肽低剂量治疗组合多肽高剂量治疗组的给药均不影响大鼠的体重。
综上所述，多肽经口鼻吸入给药对混合菌诱导的细菌性肺炎具有 显著治疗作用，且多肽高剂量治疗组的结果优于红霉素组以及布地奈德组。
同时，SD大鼠经口鼻吸入给予累计剂量22.2mg/kg的多肽溶液，连续7天，未见肺组织相关病理学改变，且肺功能指标、肺泡灌洗液中WBC、Neu、TNF-α、IL-6较空白对照组无明显差异。
并且本发明所述多肽为19个氨基酸组成，降解产物为天然氨基酸，不产生药物残留，同时，由于多肽的杀菌机理是其携带强大的正电荷吸附到菌体表面，使胞壁局部电位骤变形成高电位差，最终击穿胞壁形成穿孔，多肽分子积累到一定数量时，进一步扩大已经形成的孔洞，破坏细胞膜的完整性，从而使胞内物质外流，菌体死亡，其独特的杀菌机理决定了多肽不易产生耐药性，具有较好的优势，具有广阔的应用前景。
在本文中，“药物”、“药物制剂”、“制剂”未特别说明，可以互换使用，指的是包含药物有效成分的制品，并任选其中还包含药学上可接受的载体。其中，“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。“药学上可接受的载体”指无毒固态、半固态或液态填充剂、稀释剂、佐剂、包裹材料或其他制剂辅料。所用载体可与相应的给药形式相适应，可使用本领域技术人员所知晓的载体配成注射剂、(注射用)冻干粉、固体制剂、喷雾剂、溶液、混悬液、半固体制剂、液体制剂、片剂、胶囊、肠溶片、丸剂、粉剂、颗粒剂、持续释放或延迟释释放等任一一种或几种的组合形式制剂。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。
Claims (6)
- 一种多肽在预防和治疗肺炎的药物中的应用，其特征在于，所述多肽的氨基酸序列为SEQ ID NO.1。
- 一种预防和治疗肺炎的药物，其特征在于，所述药物包括：多肽，所述多肽的氨基酸序列为SEQ ID NO.1。
- 根据权利要求2所述的药物，其特征在于，所述药物还包括药学上可接受的其他辅料、载体或辅助性成分。
- 根据权利要求2或3所述的药物，其特征在于，所述药物还可进一步包括一种或多种治疗剂。
- 根据权利要求2或3所述的药物，其特征在于，所述药物可以通过口服、非胃肠施用、局部施用、注射给药、吸入给药、粘膜给药任一一种或几种的组合形式给药。
- 根据权利要求4所述的药物，其特征在于，所述药物可以通过口服、非胃肠施用、局部施用、注射给药、吸入给药、粘膜给药任一一种或几种的组合形式给药。
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| JP2023514973A JP2023540541A (ja) | 2020-09-04 | 2021-05-12 | 肺炎を予防・治療する薬物におけるポリペプチドの応用 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2944195A1 (en) * | 2014-05-15 | 2015-11-18 | Monier Tadros | Negatively charged matrix and use thereof |
| WO2017091734A2 (en) * | 2015-11-25 | 2017-06-01 | Indiana University Research And Technology Corporation | Bacteriocidal peptides and uses thereof |
| CN108771028A (zh) * | 2018-05-28 | 2018-11-09 | 南京千济诺生物科技有限公司 | 一种动物饲料添加剂及其制备方法与应用 |
| CN111214644A (zh) * | 2020-03-16 | 2020-06-02 | 中国人民解放军第四军医大学 | 芬母多肽在制备抑制ii型单纯疱疹病毒感染药物中的应用 |
| CN111375051A (zh) * | 2018-12-29 | 2020-07-07 | 江苏吉锐生物技术有限公司 | 一种多肽在制备预防和治疗人乳头瘤病毒感染制剂的应用 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668832B (zh) * | 2017-03-30 | 2020-08-14 | 浙江瀛康生物医药有限公司 | 一种多肽在制备治疗肠道病毒感染药物的应用 |
-
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2021
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- 2021-05-12 EP EP21863250.3A patent/EP4209226A4/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2944195A1 (en) * | 2014-05-15 | 2015-11-18 | Monier Tadros | Negatively charged matrix and use thereof |
| WO2017091734A2 (en) * | 2015-11-25 | 2017-06-01 | Indiana University Research And Technology Corporation | Bacteriocidal peptides and uses thereof |
| CN108771028A (zh) * | 2018-05-28 | 2018-11-09 | 南京千济诺生物科技有限公司 | 一种动物饲料添加剂及其制备方法与应用 |
| CN111375051A (zh) * | 2018-12-29 | 2020-07-07 | 江苏吉锐生物技术有限公司 | 一种多肽在制备预防和治疗人乳头瘤病毒感染制剂的应用 |
| CN111214644A (zh) * | 2020-03-16 | 2020-06-02 | 中国人民解放军第四军医大学 | 芬母多肽在制备抑制ii型单纯疱疹病毒感染药物中的应用 |
Non-Patent Citations (16)
| Title |
|---|
| BURK MEL-KERSH KSAAD M ET AL.: "Viral infection in community-acquired pneumonia: a systematic review and meta-analysis", EURRESPIR REV, vol. 25, no. 140, 2016, pages 178 - 188 |
| CUI XUHAN XUANWANG ZHI-MINCAO DE-YINGZHENG AI-PING: "Study on chemical and biological stability of vasoactive intestinal peptide [J", CHINESE JOURNAL OF NEW DRUGS, vol. 20, no. 19, 2011, pages 1922 - 1925 |
| DIPESH SHAHTHOMAS P. JOHNSTONASHIM K. MITRA: "Thermodynamic parameters associated with guanidine HCl- and temperature-induced unfolding of bFGF[J", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 169, no. 1, 1998 |
| DMYTRO P. YEVTUSHENKO, SANTOSH MISRA: "Transgenic Expression of Antimicrobial Peptides in Plants: Strategies for Enhanced Disease Resistance, Improved Productivity, and Production of Therapeutics", SMALL WONDERS: PEPTIDES FOR DISEASE CONTROL, 31 December 2012 (2012-12-31), XP055906734 * |
| GOLDMAN M J ET AL.: "Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis[1", CEL, vol. 88, no. 4, 1997, pages 553 - 560, XP001120536, DOI: 10.1016/S0092-8674(00)81895-4 |
| HAINES LEE R., THOMAS JAMIE M., JACKSON ANGELA M., EYFORD BRETT A., RAZAVI MORTEZA, WATSON CRISTALLE N., GOWEN BRENT, HANCOCK ROBE: "Killing of Trypanosomatid Parasites by a Modified Bovine Host Defense Peptide, BMAP-18", PLOS NEGLECTED TROPICAL DISEASES, vol. 3, no. 2, 1 February 2009 (2009-02-01), pages e373, XP055906738, DOI: 10.1371/journal.pntd.0000373 * |
| HANCOCK R EWDIAMOND G: "The role of cationic antimicrobial peptides in innate host defences [J", TRENDS IN MICROBIOLOGY, vol. 8, no. 9, 2000, pages 402 - 410, XP008106997, DOI: 10.1016/S0966-842X(00)01823-0 |
| HUANG FANGCHEN XING-FENGWANG YAN-PING: "Epidemiological characteristics and preventive measure study of hospital acquired pneumonia [J", CHINESE JOURNAL OFNOSOCOMIOLOGY, vol. 28, no. 13, 2018, pages 2053 - 2055 |
| JUNG CHIAU-JING, LIAO YOU-DI, HSU CHIH-CHIEH, HUANG TING-YU, CHUANG YU-CHUNG, CHEN JENG-WEI, KUO YU-MIN, CHIA JEAN-SAN: "Identification of potential therapeutic antimicrobial peptides against Acinetobacter baumannii in a mouse model of pneumonia", SCIENTIFIC REPORTS, vol. 11, no. 1, 1 December 2021 (2021-12-01), XP055906693, DOI: 10.1038/s41598-021-86844-5 * |
| MARDIROSSIAN MPOMPILIO ACROCETTA V ET AL.: "In vitro and in vivo evaluation of BMAP-derived peptides for the treatment of cystic fibrosis-related pulmonary infections [J", AMINO ACIDS, vol. 48, no. 9, 2016, pages 1 - 8, XP036034678, DOI: 10.1007/s00726-016-2266-4 |
| SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS |
| See also references of EP4209226A4 |
| T.C. JYOTHISHARMISTHA SINHASRIDEVI ASINGH, ASUROLIA, A.G.APPU RAO: "Napin from Brassica juncea: Thermodynamic and structural analysis of stability [J", BBA - PROTEINS AND PROTEOMICS, vol. 1774, no. 7, 2007, XP022133617, DOI: 10.1016/j.bbapap.2007.04.008 |
| TANG LIN-MINLOU JUAN-HUAHU ZHEN-ZHEN: "Analysis of pathogen resistance and risk factors in ICU hospitalized patients with HAP [J", PRACTICAL DRUGS AND CLINICS, vol. 19, no. 03, 2016, pages 367 - 370 |
| YANG SUNGTAE; LEE CHUL WON; KIM HAK JUN; JUNG HYUN-HO; KIM JAE IL; SHIN SONG YUB; SHIN SUNG-HEUI: "Structural analysis and mode of action of BMAP-27, a cathelicidin-derived antimicrobial peptide", PEPTIDES, ELSEVIER, AMSTERDAM, NL, vol. 118, 18 June 2019 (2019-06-18), AMSTERDAM, NL , XP085779242, ISSN: 0196-9781, DOI: 10.1016/j.peptides.2019.170106 * |
| YING XIAO-BOWANG DAN-MINSONG BOLAN DA-BO: "Etiological investigation of adult community-acquired pneumonia in different seasons [J", CHINA PUBLIC HEALTH ADMINISTRATION, vol. 30, no. 06, 2014, pages 843 - 844 |
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| CN114129705A (zh) | 2022-03-04 |
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| EP4209226A4 (en) | 2024-04-24 |
| JP2023540541A (ja) | 2023-09-25 |
| US20230330178A1 (en) | 2023-10-19 |
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