WO2020048446A1 - 吡咯喹啉醌在制备用于防治急性高原反应和急性高原低氧损伤的药物中的应用 - Google Patents

吡咯喹啉醌在制备用于防治急性高原反应和急性高原低氧损伤的药物中的应用 Download PDF

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WO2020048446A1
WO2020048446A1 PCT/CN2019/104174 CN2019104174W WO2020048446A1 WO 2020048446 A1 WO2020048446 A1 WO 2020048446A1 CN 2019104174 W CN2019104174 W CN 2019104174W WO 2020048446 A1 WO2020048446 A1 WO 2020048446A1
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pqq
group
hypoxia
serum
control group
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French (fr)
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邵东
孙新强
劳学军
刘卫
张维才
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Zhejiang Medicine Co Ltd Xinchang Pharmaceutical Factory
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Zhejiang Medicine Co Ltd Xinchang Pharmaceutical Factory
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Priority to EP19857755.3A priority patent/EP3848032A4/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the present invention relates to a new use of pyrroquinoline quinone, in particular to the application of pyrroquinoline quinone in the preparation of a medicament for preventing and treating acute high altitude hypoxia injury.
  • acetazolamide can easily cause adverse reactions such as hyperchlorine metabolic acidosis, numbness of the limbs, gastrointestinal discomfort, confusion, nausea, anorexia, drowsiness, polyuria and tinnitus; 12 kinds of carbonic anhydrase have enzyme catalytic activity Isoenzymes, their tissue / organ distribution, subcellular localization, and physiological functions are quite different, and acetazamide has a strong inhibitory effect on a variety of carbonic anhydrase isoenzymes. Research on this enzyme inhibitor will mainly focus on finding carbonic anhydrase inhibitors with high selectivity and high tissue specificity.
  • Pyrroquinoline quinone is a coenzyme different from pyridine nucleotides (NAD, NADP) and riboflavin (FMN, FAD). It is an oxidoreductase co-group. As an electron donor and The receptor participates in the electronic transfer of the respiratory chain during the redox process. It has a strong ability to scavenge free radicals and has a variety of physiological functions. It stimulates organism metabolism, promotes growth and development, protects liver damage, degrades ethanol, resists oxidation, and resists radiation. Play an important role in the process. However, there are no reports on the use of pyrroquinoline quinone in the prevention and treatment of acute high altitude hypoxia injury.
  • the present invention provides an application of pyrroquinoline quinone in the preparation of a medicament for the prevention and treatment of acute altitude sickness and altitude hypoxia injury.
  • the pyrrovalline quinone of the present invention has the effect of preventing and treating acute high altitude hypoxic damage.
  • its medicinal effect is equivalent to that of acetazolamide, but acetazolamide has large toxic and side effects.
  • quinone has the advantages of low toxicity and easy acceptance by patients.
  • PQQ has been shown to improve the working ability of the plateau body, but acetazamide has not been found to have this effect.
  • Wistar rats clean grade, male, weighing 160-220g, provided by Animal Center of Academy of Military Medical Sciences.
  • Oxidative Stress SOD, CO, MDA Detection Kit (Nanjing Jiancheng Technology Co., Ltd.)
  • Adenosine triphosphate, lactic acid, liver glycogen detection kit (Nanjing Jiancheng Technology Co., Ltd.)
  • Multi-factor composite environment simulation medical scientific experimental module (AVIC Guizhou Fenglei Aviation Ordnance Co., Ltd.)
  • Healthy Wistar rats weighing 160-200g were selected, female and male, each half. After 3 days of adaptive breeding, they were randomly divided into 10 groups, each group 16 ⁇ 2. Grouping is as follows: 5 groups of the hypoxic-exposed drug experimental group were administered orally with 0.91 mg / kg, 1.83 mg / kg, 3.66 mg / kg, 7.31 mg / kg, and 14.63 mg / kg. Hypoxic exposure positive acetazolamide control group 1 (administered 0.11g / kg acetazamide); hypoxia model group 1 group, normoxic blank control group 1 group, the corresponding volume of solvent was given.
  • a normoxic PQQ control group 1 (administered with PQQ 3.66 mg / kg) and a normoxic acetazamide control group 1 (administered with 0.11 g / kg acetazamide) were set up.
  • the animals in the hypoxic exposure group were simultaneously placed in a decompression and hypoxia compound experimental chamber, the door was closed, the pressure was reduced at a speed of 10m / s, the altitude was increased to 6000m and maintained for 8h, and then 10m / The speed decreased to normal altitude, the hatch was opened, the animals were taken out, blood samples were collected (after standing for 1 hour, the supernatant was centrifuged and stored at -20 ° C), and liver tissue samples.
  • Detection indicators include weight, serum blood glucose, ATP, lactic acid, endothelin, nitric oxide, SOD, CO, MDA related to oxidative stress, and total protein, albumin, triglycerides, total cholesterol, high-density lipoprotein cholesterol, Low-density lipoprotein cholesterol, alanine aminotransferase, total bilirubin, aspartate aminotransferase, serum urea nitrogen, creatinine, uric acid, lactate dehydrogenase, creatine kinase, ⁇ -hydroxybutyrate dehydrogenase; liver ATP, liver glycogen .
  • the animals in the normoxic control group had the same experimental conditions and detection indicators except that they did not enter the decompression and hypoxia compound experimental chamber.
  • Healthy male Kunming mice weighing 18-22 g were selected, and after 3 days of adaptive breeding, they were randomly divided into 7 groups according to body weight, 10 ⁇ 1 in each group.
  • the grouping is as follows: five groups of the drug experiment group were administered orally with 1.32mg / kg, 2.64mg / kg, 5.28mg / kg, 10.56mg / kg, 21.12mg / kg drugs; the acetazamide positive drug control group 1 group, given 0.16 g / kg acetazamide; negative control group 1 was given a corresponding volume of solvent. Seven days after the administration, the exhaustive swimming test under hypoxic conditions was selected for the evaluation of the physical working ability, and the observation index was the exhaustive swimming time.
  • the swimming box is filled with water at a depth of 40cm, and the water temperature is 25 ° C.
  • the animals are placed in the swimming box, and the time from the start of swimming to exhaustion is recorded with a stopwatch.
  • Exhaustible swimming time is the time that still cannot surface after 9s of sinking.
  • nitric oxide The chemical properties of nitric oxide are very active, and the metabolism in the body quickly turns into NO 2- and NO 3- , and NO 2- is further converted into NO 3- .
  • This method uses nitrate reductase to specifically reduce NO 3- to NO. 2- , Determination of the concentration level by the color depth. Operate according to the kit instructions. After measuring the absorbance of each tube at a wavelength of 550 nm, calculate the nitric oxide content in the sample to be tested according to the formula.
  • rat endothelin Endothelin-1 capture antibody
  • specimens, standards, HRP-labeled detection antibodies in order, incubate and wash thoroughly.
  • the color is developed with the substrate TMB, and TMB is converted to blue by peroxidase catalysis, and is converted to the final yellow by the action of acid.
  • the shade of color is positively correlated with rat endothelin (endothelin-1) in the sample.
  • the absorbance (OD value) was measured with a microplate reader at a wavelength of 450 nm.
  • concentration of the standard was used as the abscissa and the corresponding OD value was used as the ordinate.
  • a linear regression curve of the standard was drawn, and the concentration of each sample was calculated according to the curve equation.
  • Malondialdehyde in the degradation products of lipid peroxide can be condensed with thiobarbitur (TBA) to form a red product with a maximum absorption peak at 532nm. Operate according to the instructions. After measuring the absorbance of each tube, calculate the malondialdehyde content in the sample to be measured according to the formula.
  • TAA thiobarbitur
  • the superoxide anion radical (O 2- ⁇ ) is generated by the xanthine and xanthine oxidase reaction system, which oxidizes hydroxylamine to form nitrite, which is purple-red under the action of a color developer , Measure its absorbance with a visible light spectrophotometer.
  • the test sample contains superoxide dismutase, it has a specific inhibitory effect on superoxide anion radicals, reducing the formation of nitrite, and the absorbance value of the measuring tube is lower than that of the control tube during colorimetric comparison. Value, the superoxide dismutase activity in the test sample can be calculated by the formula. Operate according to the instructions. After measuring the absorbance of each tube at a wavelength of 550 nm, calculate the superoxide dismutase activity in the test sample according to the formula.
  • T-AOC Total Antioxidant Capacity
  • adenosine triphosphate double antibody one-step sandwich method for enzyme-linked immunosorbent assay.
  • LC lactic acid
  • LC double antibody one-step sandwich method for enzyme-linked immunosorbent assay.
  • the color is developed with the substrate TMB, and TMB is converted to blue by peroxidase catalysis, and is converted to the final yellow by the action of acid.
  • the shade of color is positively correlated with rat lactic acid (LC) in the sample.
  • the absorbance (OD value) was measured with a microplate reader at a wavelength of 450 nm.
  • the concentration of the standard was used as the abscissa and the corresponding OD value was used as the ordinate.
  • a linear regression curve of the standard was drawn, and the concentration of each sample was calculated according to the curve equation.
  • GC liver glycogen
  • Blood glucose total protein, albumin, triglycerides, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, alanine aminotransferase, total bilirubin, aspartate aminotransferase, serum urea nitrogen , Creatinine, uric acid, lactate dehydrogenase, creatine kinase, ⁇ -hydroxybutyrate dehydrogenase, blood homocysteine.
  • the measurement data were processed by t test and analysis of variance.
  • the experimental results were expressed as mean ⁇ standard error (x ⁇ s).
  • the count data were analyzed by x 2 test and direct probability method P ⁇ 0.05, indicating that the differences were significant.
  • mice The weight change of mice before the simulated decompression and hypoxia tolerance at 10000m altitude (7-day test)
  • mice in the acetazamide positive drug control group decreased (P ⁇ 0.05), and there was no statistically significant difference in body weight of each drug dose group of PQQ (P> 0.05).
  • mice in the acetazamide positive drug control group decreased (P ⁇ 0.05), and there was no statistically significant difference in body weight of each drug dose group of PQQ (P> 0.05).
  • the male rats in the PQQ drug dose group I and the PQQ drug dose group IV had lower serum HDL cholesterol values (P ⁇ 0.05), and there was no statistically significant difference between the other groups (P> 0.05).
  • the serum density of high-density lipoprotein cholesterol in male rats of the PQQ drug dose group I and the PQQ drug dose group IV decreased (P ⁇ 0.05), and there was no statistically significant difference between the other groups (P > 0.05 ).
  • the serum aspartate aminotransferase activity of male rats in the PQQ drug dose group V increased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • the male rats in the PQQ drug dose group I and the acetazamide positive drug control group had lower serum aspartate aminotransferase activity, which was statistically significantly different (P ⁇ 0.05), and the other groups were not statistically significant. There was a significant difference (P> 0.05).
  • the hypoxic model group Compared with the normoxic control group, the hypoxic model group, the PQQ drug dose group IV and the PQQ drug dose group V male rats had elevated serum uric acid levels (P ⁇ 0.05); the PQQ drug dose group I, drug dose group II and vinegar There was a statistically significant difference in the reduction of the azamide-positive drug control group (P ⁇ 0.05); there was no statistically significant difference in the PQQ drug dose group III (P> 0.05).
  • the serum uric acid levels of male rats in the PQQ drug dose group I, the drug dose group II, and the acetazamide positive drug control group were reduced, and there was a statistically significant difference (P ⁇ 0.05).
  • PQQ drugs The serum uric acid level in the dose group IV increased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • the serum creatinine value of female rats in the hypoxic model group and the PQQ drug dose groups after hypoxia exposure was statistically significant (P ⁇ 0.05). Creatinine value increased (P ⁇ 0.05), and there was no statistically significant difference in other groups (P> 0.05).
  • the serum creatinine value of female rats in the PQQ drug dose group III decreased, which was statistically significant (P ⁇ 0.05).
  • the serum creatinine value of the acetazamide positive drug control group increased (P ⁇ 0.05). 0.05), there was no statistically significant difference between the other groups (P> 0.05).
  • the serum uric acid levels of female rats in the hypoxia model group, the acetazamide positive drug control group, and the acetazolamide group were statistically significantly different (P ⁇ 0.05).
  • the serum uric acid level of the PQQ drug group increased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • the serum uric acid level of male rats in the acetazamide-positive drug control group was decreased (P ⁇ 0.05), and the serum uric acid level in the PQQ drug dose group I was slightly increased (P ⁇ 0.05).
  • Statistically significant difference P> 0.05).
  • the serum endothelin-1 content of female rats in the hypoxia model group, the normoxic PQQ drug group, and the normoxetamine group was reduced (P ⁇ 0.05), and hypoxia After exposure, the serum endothelin-1 content of each drug dose group in PQQ increased, which was statistically significant (P ⁇ 0.05), and there was no statistically significant difference in the acetazamide-positive drug control group (P> 0.05).
  • the serum endothelin-1 content of the PQQ medication group increased after hypoxia exposure (P ⁇ 0.05), and there was no statistically significant difference in the acetazamide-positive control group (P> 0.05).
  • the serum lactic acid content of female rats in the hypoxia model group, the acetazamide-positive drug control group, the normoxic PQQ drug group, and the normoxacetamide group was statistically significant (P ⁇ 0.05);
  • the serum lactic acid content of the PQQ drug dose group I, II, III, and IV increased after hypoxic exposure ((P ⁇ 0.05), and the serum lactic acid content of the drug dose group V was not statistically significant compared with the normoxic control group. (P> 0.05).
  • the serum lactic acid content of the PQQ drug dose group increased after each hypoxia exposure, and there was a statistically significant difference (P ⁇ 0.05).
  • the acetazamide positive drug control There was no statistically significant difference in serum lactic acid content (P> 0.05).
  • the ATP value in the liver of male rats in the PQQ drug dose group has an increasing trend, and the increase of the IV content in the PQQ drug dose group has a statistically significant difference (P ⁇ 0.05).
  • the ATP content in the liver of male rats in the PQQ drug dose group IV and the PQQ drug dose group V increased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • the glycogen value in the liver of IV male rats in the PQQ drug dose group was increased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • the liver glycogen value of male rats in PQQ drug dose group III, PQQ drug dose group IV, and PQQ drug dose group V was increased, and there was a statistically significant difference (P ⁇ 0.05). There was no statistically significant difference in the other groups (P> 0.05).
  • the hypoglycemic model group, the PQQ drug dose group IV, the PQQ drug dose group V, and the acetazamide positive drug control group had higher glycogen values in the liver of female rats, which was statistically significant. There was no significant difference (P ⁇ 0.05) in the other groups (P> 0.05).
  • the glycogen value in the liver of female rats in the PQQ drug dose group I after hypoxia exposure was decreased (P ⁇ 0.05), and there was no statistically significant difference in the other groups (P> 0.05).
  • Acute hypoxic exposure had no significant effect on serum glucose levels in male rats, and PQQ and acetazamide intervention had no significant effect on blood glucose levels in male rats.
  • Acute hypoxic exposure did not have a significant effect on the total protein content of serum in male rats.
  • Low-dose PQQ intervention can slightly reduce the total protein content of serum in male rats exposed to hypoxia, and high-dose PQQ intervention in the total serum protein and hypoxia of rats
  • the model group was the same; no effect of acetazamide on the total protein content of serum in male rats exposed to hypoxia was found.
  • Hypoxic exposure can cause a slight increase in serum albumin
  • low-dose PQQ intervention can reduce the increase in serum albumin in male rats caused by hypoxic exposure; acetazamide has not been found to affect the total serum level of hypoxic-exposed male rats. Effect of protein content.
  • Acute hypoxic exposure had no significant effect on triglycerides in male rats, and no effect of PQQ and acetazolamide intervention on triglycerides in hypoxic rats was found.
  • Acute hypoxic exposure does not affect the total cholesterol and high density lipoprotein cholesterol content, and can slightly reduce the content of low density lipoprotein cholesterol;
  • PQQ low-dose intervention has the effect of reducing the total cholesterol and high density lipoprotein cholesterol, and has an effect on low density lipoprotein.
  • Acute hypoxic exposure did not show significant effects on alanine aminotransferase, and no effect of PQQ intervention on serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin in male rats exposed to acute hypoxia; acetazamine increased acute hypoxic exposure The effect of aspartate aminotransferase in serum of male rats had no significant effect on alanine aminotransferase and total bilirubin.
  • Acute hypoxic exposure has no significant effect on serum urea nitrogen and creatinine in male rats, which can cause a slight increase in uric acid content;
  • PQQ intervention has no significant effect on serum urea nitrogen and creatinine in male rats exposed to hypoxia, and low-dose intervention has reduced serum The effect of uric acid content;
  • acetazolamide has the effect of reducing serum uric acid level and increasing serum urea nitrogen content in rats exposed to hypoxia, and has no significant effect on serum creatinine;
  • Acute hypoxic exposure had no significant effect on serum lactate dehydrogenase, creatine kinase, and ⁇ -hydroxybutyric acid dehydrogenase activity in male rats; no intervention of PQQ and acetazolamide was found on serum lactate dehydrogenation in male rats exposed to hypoxia Effects of enzymes, creatine kinase, ⁇ -hydroxybutyrate dehydrogenase.
  • Acute hypoxic exposure can slightly increase serum homocysteine levels in male rats; no significant effects of PQQ and acetazamide intervention on serum homocysteine in male rats exposed to hypoxia can be found.
  • Acute hypoxic exposure did not have a significant effect on serum endothelin-1 and nitric oxide levels in male rats; PQQ intervention had no significant effect on the above indicators; acetazolamide slightly reduced serum endothelin- 1. The effect of nitric oxide content.
  • Acute hypoxic exposure has no significant effect on serum superoxide dismutase, total antioxidants, and malondialdehyde in male rats; PQQ intervention can increase the activity of serum superoxide dismutase in male rats exposed to hypoxia and increase total serum resistance Oxide and malondialdehyde had no significant effects; acetazolamide also increased the activity of serum superoxide dismutase in male rats, and had no significant effect on serum total antioxidants and malondialdehyde.
  • Acute hypoxic exposure had no significant effect on serum ATP and lactate levels in male rats; PQQ intervention had no significant effect on the above indicators in male rats; acetazamide intervention had no significant effect on serum ATP, and had a role in reducing serum lactate content .
  • Acute hypoxic exposure did not have a significant effect on ATP and glycogen content in the liver of male rats; PQQ intervention had an effect on increasing ATP and glycogen content in the liver of male rats; acetazamide intervention had no significant effect on the above indexes in male rats influences.
  • Acute hypoxic exposure can reduce serum glucose in female rats.
  • PQQ intervention has the effect of increasing blood glucose in female rats with acute hypoxic exposure; acetazolamide intervention has no significant effect on elevated blood glucose in acute hypoxic exposure.
  • the normoxic PQQ intervention had no significant effect on the blood glucose of female rats; the normoxic acetazolamide intervention had the effect of reducing the blood glucose of female rats.
  • Acute hypoxic exposure did not have a significant effect on the total serum protein content of female rats.
  • Low-dose PQQ intervention can slightly reduce the total serum protein content of female rats exposed to hypoxic exposure.
  • High-dose PQQ intervention total serum protein and hypoxemia in rats.
  • the model group was consistent; no effect of acetazamide on the total protein content of serum in female rats was found.
  • Hypoxia exposure can cause a slight increase in serum albumin
  • low-dose PQQ intervention can reduce the increase in serum albumin in female rats caused by hypoxia exposure; acetazamide intervention also has this effect.
  • the normoxic PQQ intervention had no significant effect on the serum total protein content of female rats; normoxetamine had a slight increase in serum albumin levels in female rats.
  • Acute hypoxic exposure can reduce total cholesterol and low-density lipoprotein cholesterol in female rats, and does not affect the content of high-density lipoprotein cholesterol.
  • PQQ intervention has no significant effect on the above indicators; acetazamide intervention can increase total cholesterol, The effect of low density lipoprotein cholesterol and high density lipoprotein cholesterol content.
  • the normoxic PQQ intervention had no significant effect on the above indicators; normoxetamine had no significant effect on the amount of low-density lipoprotein cholesterol, and it could increase the total cholesterol and high-density lipoprotein cholesterol content in female rats.
  • Acute hypoxic exposure had no significant effect on alanine aminotransferase in female rats, and could slightly reduce the activity of aspartate aminotransferase.
  • PQQ intervention was not found to affect the serum alanine aminotransferase and aspartate aminotransferase activities in female rats exposed to acute hypoxia.
  • the intervention of normoxic PQQ had a slight increase in the activity of aspartate aminotransferase, and had no significant effect on alanine aminotransferase; normoxetine had no significant effect on the above indexes.
  • Acute hypoxic exposure has no significant effect on serum urea nitrogen in female rats, which can cause a slight decrease in creatinine and uric acid content;
  • PQQ intervention has no significant effect on serum urea nitrogen, creatinine, and uric acid in female rats exposed to hypoxia;
  • the normoxic PQQ intervention had no significant effect on the above indicators; normoxic acetazolamide reduced the serum uric acid level and increased the serum urea nitrogen and creatinine values in female rats.
  • Acute hypoxic exposure can reduce serum creatine kinase and ⁇ -hydroxybutyric acid dehydrogenase activity in female rats, and has no significant effect on serum lactate dehydrogenase activity; no PQQ intervention has been found on serum lactic acid in female rats with hypoxic exposure
  • Dehydrogenase, creatine kinase, and ⁇ -hydroxybutyrate dehydrogenase activity had significant effects; acetazolamide had no significant effect on the above indicators.
  • the normoxic PQQ intervention had the effect of increasing the above indexes; normoxic acetazolamide had no significant effect on the above indexes.
  • Acute hypoxic exposure can slightly reduce homocysteine levels in female rats; PQQ and acetazamide intervention have no significant effect on serum homocysteine in hypoxic exposed female rats.
  • the intervention of normoxic PQQ and acetazamide had no significant effect on the above indexes.
  • Acute hypoxic exposure can reduce serum endothelin-1 content in female rats, and no significant effect on nitric oxide content has been found;
  • PQQ intervention can increase serum endothelin-1 content in rats after acute hypoxic exposure, and Nitrogen content had no significant effect;
  • acetazolamide intervention had no significant effect on the above indicators.
  • Intervention of normoxic PQQ and acetazamide can reduce the serum endothelin-1 content in female rats, and no significant effect on nitric oxide content has been found.
  • Acute hypoxic exposure has no significant effect on serum superoxide dismutase, total antioxidants, and malondialdehyde in female rats;
  • PQQ intervention can increase serum superoxide dismutase activity in female rats exposed to hypoxia, and has a total resistance to serum Oxide and malondialdehyde had no significant effect;
  • acetazolamide also increased serum superoxide dismutase activity, and had no significant effect on serum total antioxidants and malondialdehyde.
  • Intervention with normoxic PQQ can slightly increase the effect of malondialdehyde in female rats, and has no significant effect on serum superoxide dismutase and total antioxidants; normoxetine has no significant effect on the above indicators.
  • Acute hypoxic exposure has no significant effect on serum ATP in female rats, and has a role in reducing serum lactic acid content; PQQ intervention has a role in increasing serum ATP and lactic acid content in female rats; acetazamide has no significant effect on the above indicators.
  • Normal oxygen PQQ intervention has the effect of reducing serum lactic acid content, but has no significant effect on serum ATP content; acetazamide intervention has the effect of reducing serum ATP and lactic acid content in female rats.
  • Acute hypoxic exposure can increase ATP and glycogen content in liver of female rats; PQQ and acetazolamide intervention after hypoxic exposure have no significant effect on ATP and glycogen content in liver of female rats.
  • mice exposed to 6000 meters above sea level (give 1.32mg / kg, 2.64mg / kg, 5.28mg / kg, 10.56mg / kg, 21.12mg / kg PQQ, respectively, for 7 days).
  • the results showed that the negative control
  • the mice in the control group and the acetazamide positive drug control group died earlier.
  • the exhaustion of the mice in the PQQ dose groups was delayed compared to the above two groups.
  • the negative control group and acetic nitrogen The mice in the amide-positive drug control group had almost completely died, and the mice in each dose group of PQQ died completely in about 400 minutes.

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Abstract

吡咯喹啉醌(PPQ)在制备用于防治急性高原反应和急性高原低氧损伤的药物中的应用。吡咯哇啉醌具有防治急性高原低氧损伤的作用，在作为防治急性高原反应药物方面，其药效与醋氮酰胺的药效相当，但醋氮酰胺毒副作用大，而吡咯喹啉醌作为一种辅酶，具有毒性低，易于被患者接受的优势。此外，通过低氧暴露条件下的小鼠力竭游泳实验，PQQ显示有提高高原体作业能力的作用特点，但未发现醋氮酰胺有此方面的作用。

Description

吡咯喹啉醌在制备用于防治急性高原反应和急性高原低氧损伤的药物中的应用 技术领域
本发明涉及一种吡咯喹啉醌的新用途，具体地说，涉及一种吡咯喹啉醌在制备用于防治急性高原低氧损伤的药物中的应用。
背景技术
高原地区的低压低氧是高原地区主要的环境因素，是高原病的主要致病因素。随着国家西部开发和青藏铁路开通，高原从业和旅游人员日渐增多，进入高原地区人员的健康维护问题也越来越受到人们关注，已成为高原药物或保健品研究工作的重要方向。
目前，治疗高原红细胞增多症需要每天服用醋氮酰胺250mg以上。但是，醋氮酰胺容易引起高氯性代谢酸中毒、四肢麻木、胃肠道不适、意识模糊、恶心、厌食、困倦、多尿和耳鸣等不良反应；由于碳酸酐酶有12种具有酶催化活性的同工酶，它们的组织/器官分布、亚细胞定位、生理功能都有较大差异，而醋氮酰胺对多种碳酸酐酶同工酶都有较强的抑制作用。有关该酶抑制剂的研究将主要集中在寻找选择性强、组织特异性高的碳酸酐酶抑制剂上。
吡咯喹啉醌(pyrroloquinoline quinone，PQQ)是一种不同于吡啶核苷酸(NAD、NADP)和核黄素(FMN、FAD)的辅酶，是一种氧化还原酶辅基，作为电子供体和受体参与氧化还原过程中的呼吸链电子传递，有很强的自由基清除能力，具有多种生理功能，在刺激生物体代谢、促生长发育、防护肝损伤、降解乙醇、抗氧化、抗辐射等过程中起重要作用。但是，目前尚无吡咯喹啉醌用于防治急性高原低氧损伤的研究及应用报道。
发明内容
为了克服现有技术上述缺陷，本发明提供了一种吡咯喹啉醌在制备用于防治急性高原反应及高原低氧损伤的药物中的应用。
本发明的吡咯哇啉醌具有防治急性高原低氧损伤的作用，在作为防治急性高原反应药物方面，其药效与醋氮酰胺的药效相当，但醋氮酰胺毒副作用大，而吡咯喹啉醌作为一种辅酶，具有毒性低，易于被患者接受的优势。此外，通过低氧暴露条件下的小鼠力 竭游泳实验，PQQ显示有提高高原体作业能力的作用特点，但未发现醋氮酰胺有此方面的作用。
具体实施方式
通过以下实施例来对本发明作进一步具体说明，但不仅限于以下实施例和实施例中的工艺参数范围。
1、材料
1.1实验动物
昆明小鼠，清洁级，雌/雄性，体重16-22g，军事医学科学院动物中心提供。
Wistar大鼠，清洁级，雄性，体重160-220g，军事医学科学院动物中心提供。
1.2主要试剂
PQQ(新昌制药，批号：150502)
醋氮酰胺，含量：99.9％，(成都优联生物技术有限公司，批号：260905091)
NO试剂盒、考马斯亮兰试剂盒(北京普尔伟业生物科技有限公司)
ET-1酶联免疫分析试剂盒北京普尔伟业生物科技有限公司)
氧化应激SOD、CO、MDA检测试剂盒(南京建成科技有限公司)
三磷酸腺苷、乳酸、肝糖原检测试剂盒(南京建成科技有限公司)
戊巴比妥钠(美国Sigma公司)
1.3主要仪器
多因素复合环境模拟医学科学实验舱(中航工业贵州风雷航空军械有限责任公司)
FlexStation 3多功能酶标仪工作站(美国Molecular Devices公司)
7180全自动血生化分析仪(日本日立株式会社)
Heraeus低温高速离心机(德国Kendro公司)
电子天平(德国Sartorius公司)
超低温冰箱(日本三洋公司)
2、PQQ抗急性高原低氧损伤实验
2.1大鼠急性减压缺氧实验
选体重160-200g健康性Wistar大鼠，雌、雄各半，适应饲养3天后，按体重随机 分成10组，每组16±2只。分组如下：低氧暴露药物实验组5组，分别灌胃给予0.91mg/kg、1.83mg/kg、3.66mg/kg、7.31mg/kg、14.63mg/kg药物。低氧暴露阳性醋氮酰胺对照1组(给予0.11g/kg醋氮酰胺)；低氧模型组1组、常氧空白对照组1组，给予相应体积的溶剂。另外设置常氧PQQ对照1组(给予PQQ3.66mg/kg)、常氧醋氮酰胺对照1组(给予0.11g/kg醋氮酰胺)。连续灌胃给药7天后，将低氧暴露组动物同时放入减压低氧复合实验舱，密闭舱门，以10m/s速度减压，上升至海拔高度6000m并维持8h后，以10m/s速度降至正常海拔高度，打开舱门，取出动物，采集血样(静置1h后，离心取上清，-20℃保存)，及肝脏组织样本。检测指标包括体重、血清血糖、ATP、乳酸、内皮素、一氧化氮、氧化应激相关的SOD、CO、MDA，及总蛋白、白蛋白、甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、谷丙转氨酶、总胆红素、谷草转氨酶、血清尿素氮、肌酐、尿酸、乳酸脱氢酶、肌酸激酶、α-羟丁酸脱氢酶；肝ATP，肝糖原。常氧对照组动物除不进入减压低氧复合实验舱外，其它实验条件和检测指标相同。
2.2小鼠高原低氧暴露条件下力竭性游泳实验
选体重18-22g健康雄性昆明小鼠，适应饲养3天后，按体重随机分成7组，每组10±1只。分组如下：药物实验组5组，分别灌胃给予1.32mg/kg、2.64mg/kg、5.28mg/kg、10.56mg/kg、21.12mg/kg药物；醋氮酰胺阳性药物对照组1组，给予0.16g/kg醋氮酰胺；阴性对照组1组，给予相应体积的溶剂。给药7天后，选择低氧条件下力竭性游泳实验进行体作业能力评价，观察指标为力竭性游泳时间。在减压低氧复合实验舱内减压低氧至海拔6000m的高度，游泳箱注水深40cm，水温25℃，动物放入游泳箱中，用秒表记录动物自游泳开始至力竭的时间，动物沉没后9s仍不能浮出水面的时间即为力竭性游泳时间。
3、检测方法
3.1血清中一氧化氮含量的测定
一氧化氮化学性质非常活泼，在体内代谢很快转为NO 2-和NO 3-，而NO 2-又进一步转化为NO 3-，本法利用硝酸还原酶特异性将NO 3-还原为NO 2-，通过显色深浅测定其浓度的高低。按试剂盒说明书进行操作，于波长550nm处测得各管吸光度值后，根据公式计算待测样本中一氧化氮的含量。
3.2血清内皮素-1含量测定
往预先包被大鼠内皮素(内皮素-1)捕获抗体的包被微孔中，依次加入标本、标准品，HRP标记的检测抗体，经过温育并彻底洗涤。用底物TMB显色，TMB在过氧化物酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。颜色的深浅和样品中的大鼠内皮素(内皮素-1)呈正相关。用酶标仪在450nm波长下测定吸光度(OD值)，以标准品浓度作横坐标，对应OD值作纵坐标，绘制出标准品线性回归曲线，按曲线方程计算各样本浓度值。
3.3氧化应激指标丙二醛、超氧化物歧化酶、总抗氧化能力的测定
丙二醛的测定：过氧化脂质降解产物中的丙二醛可与硫代巴比妥(TBA)缩合，形成红色产物，在532nm处有最大吸收峰。按说明书进行操作，测得各管吸光度值后，根据公式计算待测样本中丙二醛含量。
超氧化物歧化酶的测定：通过黄嘌呤及黄嘌呤氧化酶反应系统产生超氧阴离子自由基(O 2-·)，后者氧化羟胺形成亚硝酸盐，在显色剂的作用下呈现紫红色，用可见光分光光度计测其吸光度。当被测样品中含超氧化物歧化酶时，则对超氧阴离子自由基有专一性的抑制作用，使形成的亚硝酸盐减少，比色时测定管的吸光度值低于对照管的吸光度值，通过公式计算可求出被测样品中的超氧化物歧化酶活力。按说明书进行操作，于波长550nm处测得各管吸光度值后，根据公式计算待测样本中超氧化物歧化酶活力。
总抗氧化能力(T-AOC)的测定：利用机体中抗氧化物质，能使Fe 3+还原成Fe 2+，后者可与菲啉类物质形成稳固的络合物，并通过比色可测出其抗氧化能力高低的原理。按试剂盒说明书进行操作，于波长520nm处测得各管吸光度值后，根据公式计算待测样本中总抗氧化能力。
3.4三磷酸腺苷、乳酸、肝糖原的测定
三磷酸腺苷(ATP)的测定：采用双抗体一步夹心法酶联免疫吸附实验测定。往预先包被大鼠三磷酸腺苷(ATP)捕获抗体的包被微孔中，依次加入标本、标准品，HRP标记的检测抗体，经过温育并彻底洗涤。用底物TMB显色，TMB在过氧化物酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。颜色的深浅和样品中的大鼠三磷酸腺苷(ATP)呈正相关。用酶标仪在450nm波长下测定吸光度(OD值)，以标准品浓度作横坐标，对应OD值作纵坐标，绘制出标准品线性回归曲线，按曲线方程计算各样 本浓度值。
乳酸(LC)的测定：采用双抗体一步夹心法酶联免疫吸附实验测定。往预先包被大鼠乳酸(LC)捕获抗体的包被微孔中，依次加入标本、标准品，HRP标记的检测抗体，经过温育并彻底洗涤。用底物TMB显色，TMB在过氧化物酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。颜色的深浅和样品中的大鼠乳酸(LC)呈正相关。用酶标仪在450nm波长下测定吸光度(OD值)，以标准品浓度作横坐标，对应OD值作纵坐标，绘制出标准品线性回归曲线，按曲线方程计算各样本浓度值。
肝糖原(GC)的测定：采用双抗体一步夹心法酶联免疫吸附实验测定。往预先包被大鼠肝糖原(GC)捕获抗体的包被微孔中，依次加入标本、标准品，HRP标记的检测抗体，经过温育并彻底洗涤。用底物TMB显色，TMB在过氧化物酶的催化下转化成蓝色，并在酸的作用下转化成最终的黄色。颜色的深浅和样品中的大鼠肝糖原(GC)呈正相关。用酶标仪在450nm波长下测定吸光度(OD值)，以标准品浓度作横坐标，对应OD值作纵坐标，绘制出标准品线性回归曲线，按曲线方程计算各样本浓度值。
3.5血生化指标和血同型半胱氨酸测定
利用全自动血生化分析仪进行血糖、总蛋白、白蛋白、甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、谷丙转氨酶、总胆红素、谷草转氨酶、血清尿素氮、肌酐、尿酸、乳酸脱氢酶、肌酸激酶、α-羟丁酸脱氢酶、血同型半胱氨酸测定。
4、统计分析
计量资料采用t检验和方差分析对数据进行处理，实验结果以均值±标准误(x±s)表示；计数资料采用x 2检验和直接概率法P＜0.05表示差异有显著性。
5、PQQ抗急性高原低氧损伤小鼠实验结果
5.1小鼠模拟10000m高原急性减压缺氧耐受力实验
5.1.1单次给药实验
表1模拟10000m高原急性减压缺氧耐受力实验前小鼠体重(单次给药实验)
Figure PCTCN2019104174-appb-000001
从表1中可知，实验前雄性、雌性小鼠分别各组间的体重均未见统计学上显著性差异(P＞0.05)。
5.1.2给药3天实验
表3模拟10000m高原急性减压缺氧耐受力实验前小鼠体重(给药3天实验)
Figure PCTCN2019104174-appb-000002
从表3中可知，实验前雄性、雌性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。
5.1.3给药7天实验
表5模拟10000m高原急性减压缺氧耐受力实验前小鼠体重变化(给药7天实验)
Figure PCTCN2019104174-appb-000003
从表5中可知，实验前雄性、雌性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。给药7天后，雄性、雌性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。
表7模拟10000m高原急性减压缺氧耐受力实验前雄性小鼠体重变化(给药7天雄性小鼠重复实验)
Figure PCTCN2019104174-appb-000004
从表7中可知，实验前雄性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。给药7天后，与对照组相比，醋氮酰胺阳性药物对照组小鼠下降(P<0.05),各PQQ药物剂量组体重未见统计学上显著性差异(P＞0.05)。
5.1.4给药14天实验
表9模拟10000m高原急性减压缺氧耐受力实验前小鼠体重变化(给药14天实验)
Figure PCTCN2019104174-appb-000005
*P＜0.05，**P＜0.01vs.阴性对照组
从表9中可知，与阴性对照组相比，给药前雄性、雌性各组间小鼠体重均未见统计学上显著性差异(P＞0.05)。给药7天后，雄性、雌性醋氮酰胺阳性药物对照组与其相应的阴性对照组相比体重较低，有统计学上显著性差异(P＜0.05)；各PQQ药物剂量组体重与其阴性对照组相比未见统计学上显著性差异(P＞0.05)。给药14天后，雄性、雌性醋氮酰胺阳性药物对照组与其阴性对照组相比体重减低，有统计学上显著性差异(P＜0.05)；雌性小鼠PQQ药物剂量组Ⅲ和Ⅴ的体重与雌性阴性对照组相比减低，有统计学上显著性差异(P＜0.05)，其他PQQ药物剂量组雌性和雄性小鼠的体重与其相应的阴性对照组相比均未见统计学上显著性差异(P＞0.05)。
6、小鼠密闭缺氧耐受力实验结果
6.1雄性小鼠密闭缺氧耐受力实验
表11雄性小鼠密闭缺氧耐受力实验前体重变化
Figure PCTCN2019104174-appb-000006
*P＜0.05，**P＜0.01vs.阴性对照组
从表11中可知，实验前雄性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。给药3天后，与对照组相比，醋氮酰胺阳性药物对照组小鼠下降(P<0.05),PQQ各药物剂量组体重未见统计学上显著性差异(P＞0.05)。
6.2雌性小鼠密闭缺氧耐受力实验
表14雌性小鼠密闭缺氧耐受力实验体重变化
Figure PCTCN2019104174-appb-000007
*P＜0.05，**P＜0.01vs.阴性对照组
从表14中可知，实验前雌性小鼠各组间的体重均未见统计学上显著性差异(P＞0.05)。给药3天后，与对照组相比，醋氮酰胺阳性药物对照组小鼠下降(P<0.05),PQQ各药物剂量组体重未见统计学上显著性差异(P＞0.05)。
7、PQQ抗急性高原低氧损伤大鼠实验结果
7.1大鼠急性减压缺氧实验前体重变化
表17大鼠急性减压缺氧实验前体重变化
Figure PCTCN2019104174-appb-000008
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表17中可知，与常氧对照组和低氧模型组相比，给药灌胃7天后，雄性大鼠醋氮酰胺阳性药物对照组体重均下降，有统计学上显著性差异(P＜0.05)，其他各组未见统计学上显著性差异(P＞0.05)。与常氧对照组和低氧模型组相比，灌胃前及灌胃7天后的雌性大鼠体重各组均未见统计学上显著性差异(P＞0.05)。
7.2 PQQ对急性高原低氧暴露大鼠血糖影响
表18 PQQ对急性高原低氧暴露雄性大鼠血糖影响
Figure PCTCN2019104174-appb-000009
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表18中可知，与常氧对照组和低氧模型组相比，低氧模型组和PQQ各药物剂量组雄性大鼠的血糖值无统计学上显著性差异(P>0.05)。
表19 PQQ对急性高原低氧暴露雌性大鼠血糖影响
Figure PCTCN2019104174-appb-000010
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表19中可知，与常氧对照组相比，低氧模型组、低氧暴露后PQQ药物剂量组Ⅴ、醋氮酰胺阳性药物对照组和常氧醋氮酰胺组的雌性大鼠血糖值降低，有统计学上显著性差异(P＜0.05)，其他各组与常氧对照组相比无统计学上显著性差异(P>0.05)。与低氧模型组相比，PQQ各药物剂量组和醋氮酰胺阳性药物对照组的雌性大鼠血糖值均升高，有统计学上显著性差异(P<0.05)。
7.3 PQQ对急性高原低氧暴露大鼠蛋白代谢影响
表20 PQQ对急性高原低氧暴露雄性大鼠蛋白代谢影响
Figure PCTCN2019104174-appb-000011
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表20中可知，与常氧对照组相比，低氧模型组和PQQ各药物剂量组(PQQ药物剂量组Ⅰ除外)雄性大鼠的血清总蛋白无统计学上显著性差异(P＞0.05)；PQQ药物剂量组Ⅰ与常氧对照组相比血清总蛋白値降低，有统计学上显著性差异(P<0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ和PQQ药物剂量组Ⅱ血清总蛋白値降低，有统计学上显著降低(P<0.05)，其他各PQQ药物剂量组均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和PQQ药物剂量组Ⅰ，Ⅲ，Ⅳ，Ⅴ组雄性大鼠的血清白蛋白値升高(P<0.05),PQQ药物剂量组Ⅱ与常氧对照组相比无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ和PQQ药物剂量组Ⅱ血清白蛋白値降低，有统计学上显著性差异(P<0.05)，其他各PQQ药物剂量组无统计学上显著性差异(P>0.05)。
表21 PQQ对急性高原低氧暴露雌性大鼠蛋白代谢影响
Figure PCTCN2019104174-appb-000012
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表21中可知，与常氧对照组相比，PQQ药物剂量组Ⅱ，Ⅲ雌性大鼠血清总蛋白降低(P<0.05)，常氧醋氮酰胺组有统计学上显著性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅱ，Ⅲ的血清总蛋白降低(P<0.05)，而其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组、低氧暴露后PQQ药物剂量组Ⅳ和常氧醋氮酰胺组的雌性大鼠血清白蛋白値升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅱ、PQQ药物剂量组Ⅲ和醋氮酰胺阳性药物对照组降低(P<0.05)，其他各组无统计学上显著性差异(P>0.05)。
7.4 PQQ对急性高原低氧暴露大鼠脂代谢影响
表22 PQQ对急性高原低氧暴露雄性大鼠脂代谢影响
Figure PCTCN2019104174-appb-000013
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表22中可知，与常氧对照组及低氧模型组相比，各药物干预组雄性大鼠的血清甘油三酯含量均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅰ、PQQ药物剂量组Ⅱ和PQQ药物剂量组Ⅳ的雄性大鼠血清总胆固醇值降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ的雄性大鼠血清总胆固醇值降低(P<0.05)，PQQ药物剂量组Ⅴ升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅰ和PQQ药物剂量组Ⅳ的雄性大鼠血清高密度脂蛋白胆固醇值降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ和PQQ药物剂量组Ⅳ雄性大鼠血清高密度脂蛋白胆固醇值降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，各组雄性大鼠的血清低密度脂蛋白胆固醇值均有降低，除醋氮酰胺阳性药物对照组外，其他各组有统计学上显著性差异(P<0.05)。与低氧模型组相 比，各药物处理组雄性大鼠的血清低密度脂蛋白胆固醇值均未见统计学上显著性差异(P＞0.05)。
表23 PQQ对急性高原低氧暴露雌性大鼠脂代谢影响
Figure PCTCN2019104174-appb-000014
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表23中可知，与常氧对照组相比，低氧模型组和低氧暴露后PQQ各药物剂量组的雌性大鼠血清总胆固醇值降低(P<0.05)，低氧暴露后醋氮酰胺阳性药物对照组无统计学上显著性差异，而常氧醋氮酰胺组血清总胆固醇值升高，有统计学上显著性差异(P<0.05)，醋氮酰胺阳性药物对照组和常氧PQQ药物组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅲ的雌性大鼠血清总胆固醇值降低(P<0.05)，醋氮酰胺阳性药物对照组升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅱ和PQQ药物剂量组Ⅲ的雌性大鼠血清高密度脂蛋白胆固醇值降低(P<0.05)，醋氮酰胺阳性药物对照组和常氧醋氮酰胺组升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅲ雌性大鼠血清高密度脂蛋白胆固醇值降低(P<0.05)，醋氮酰胺阳性药物对照组升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和各低氧暴露后药物干预组的雌性大鼠血清低密度脂蛋白胆固醇值降低(P<0.05)，常氧PQQ药物组和醋氮酰胺组血清低密度脂蛋白胆固醇值无统计学上显著性差异(P＞0.05)。与低氧模型组相比，醋氮酰胺阳性药物对照组的雌性大鼠低密度脂蛋白胆固醇值升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
7.5 PQQ对急性高原低氧暴露大鼠肝功能影响
表24 PQQ对急性高原低氧暴露雄性大鼠肝功能影响
Figure PCTCN2019104174-appb-000015
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表24中可知，与常氧对照组相比，PQQ药物剂量组Ⅴ和醋氮酰胺阳性药物对照组雄性大鼠血清谷丙转氨酶活性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各用药组雄性大鼠的谷丙转氨酶活性均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅴ的雄性大鼠血清谷草转氨酶活性，升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ和醋氮酰胺阳性药物对照组的雄性大鼠血清谷草转氨酶活性降低，有统计学上显著性差异(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组及低氧模型组相比，各组雄性大鼠的总胆红素均未见统计学上显著性差异(P＞0.05)。
表25 PQQ对急性高原低氧暴露雌性大鼠肝功能影响
Figure PCTCN2019104174-appb-000016
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
表25中可知，与常氧对照组及低氧模型组相比，各组雌性大鼠的谷丙转氨酶均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和醋氮酰胺阳性药物对照组雌性大鼠的血清谷草转氨酶活性降低(P<0.05)，常氧PQQ药物组升高(P<0.05)。与低氧模型组相比，各药物干预组血清谷草转氨酶活性均无统计学上显著性差异(P＞0.05)。
7.6 PQQ对急性高原低氧暴露大鼠肾功能影响
表26 PQQ对急性高原低氧暴露雄性大鼠肾功能影响
Figure PCTCN2019104174-appb-000017
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表26中可知，与常氧对照组及低氧模型组相比，醋氮酰胺阳性药物对照组雄性大鼠的血清尿素氮含量升高(P<0.05)，其他各组均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅰ雄性大鼠的血清肌酐值降低(P<0.05)，醋氮酰胺阳性药物对照组血清肌酐值升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组、PQQ药物剂量组Ⅳ和PQQ药物剂量组Ⅴ雄性大鼠血清尿酸水平升高(P<0.05)；PQQ药物剂量组Ⅰ、药物剂量组Ⅱ和醋氮酰胺阳性药物对照组的降低，有统计学上显著性差异(P<0.05)；PQQ药物剂量组Ⅲ的无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ、药物剂量组Ⅱ和醋氮酰胺阳性药物对照组雄性大鼠的血清尿酸水平降低，有统计学上显著性差异(P<0.05)，PQQ药物剂量组Ⅳ血清尿酸水平升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
表27 PQQ对急性高原低氧暴露雌性大鼠肾功能影响
Figure PCTCN2019104174-appb-000018
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表27中可知，与常氧对照组相比，低氧暴露后PQQ药物剂量组Ⅰ、醋氮酰胺阳性药物对照组和常氧醋氮酰胺组雌性大鼠的血清尿素氮含量升高(P<0.05)，其他各组均未见统计学上显著性差异(P＞0.05)。与低氧模型组相比，醋氮酰胺阳性药物对照组雌性大鼠的血清尿素氮有统计学上显著性升高(P<0.05)，其他各组均未见统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和低氧暴露后PQQ各药物剂量组雌性大鼠血清肌酐值降低，有统计学上显著性差异(P<0.05)，常氧醋氮酰胺组血清肌酐值升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅲ雌性大鼠的血清肌酐值降低，有统计学上显著性差异(P<0.05)，醋氮酰胺阳性药物对照组血清肌酐值升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组、醋氮酰胺阳性药物对照组和常氧醋氮酰胺组雌性大鼠血清尿酸水平降低，有统计学上显著性差异(P<0.05)，常氧PQQ药物组血清尿酸水平升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，醋氮酰胺阳性药物对照组雄性大鼠的血清尿酸水平降低(P<0.05)，PQQ药物剂量组Ⅰ血清尿酸水平略升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
7.7 PQQ对急性高原低氧暴露大鼠心肌酶活性影响
表28 PQQ对急性高原低氧暴露雄性大鼠心肌酶活性的影响
Figure PCTCN2019104174-appb-000019
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表28中可知，与常氧对照组及低氧模型组相比，各组雄性大鼠的乳酸脱氢酶均未见统计学上显著性差异(P＞0.05)。
与常氧对照组及低氧模型组相比，各组雄性大鼠的肌酸激酶均未见统计学上显著性差异(P＞0.05)。
与常氧对照组及低氧模型组相比，各组雄性大鼠的α-羟丁酸脱氢酶均未见统计学上 显著性差异(P＞0.05)。
表29 PQQ对急性高原低氧暴露雌性大鼠心肌酶活性的影响
Figure PCTCN2019104174-appb-000020
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表29中可知，与常氧对照组相比，常氧PQQ药物组乳酸脱氢酶活性升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和各低氧暴露后药物组雌性大鼠的血清肌酸激酶活性降低(P<0.05)，常氧PQQ药物组血清肌酸激酶活性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组、低氧暴露后药物剂量组Ⅳ、药物剂量组Ⅴ和阳性醋氮酰胺对照组雌性大鼠的血清α-羟丁酸脱氢酶活性降低，有统计学上显著性差异(P<0.05)，常氧PQQ药物组血清α-羟丁酸脱氢酶活性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均无统计学上显著性差异(P＞0.05)。
7.8 PQQ对急性高原低氧暴露大鼠血清同型半胱氨酸影响
表30 PQQ对高原低氧暴露雄性大鼠血清同型半胱氨酸影响
Figure PCTCN2019104174-appb-000021
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表30中可知，与常氧对照组相比，低氧模型组、PQQ药物剂量组Ⅱ、药物剂量组Ⅲ和药物剂量组Ⅴ雄性大鼠的血清同型半胱氨酸水平升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各药物干预组均无统计学上显著性差异(P＞0.05)。
表31 PQQ对急性高原低氧暴露雌性大鼠血清同型半胱氨酸影响
Figure PCTCN2019104174-appb-000022
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表31中可知，与常氧对照组相比，低氧模型组和低氧暴露后PQQ药物剂量组Ⅴ雌性大鼠血清同型半胱氨酸水平降低(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，低氧暴露后PQQ药物剂量组Ⅱ雌性大鼠的血清同型半胱氨酸水平升高(P<0.05)，其他各组均无统计学上显著性差异(P＞0.05)。
7.9 PQQ对急性高原低氧暴露大鼠内皮功能影响
表32 PQQ对急性高原低氧暴露雄性大鼠内皮功能影响
Figure PCTCN2019104174-appb-000023
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表32中可知，与常氧对照组相比，低氧模型组和各药物干预组雄性大鼠的血清内皮素-1含量均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅱ和醋氮酰胺阳性药物对照组血清内皮素-1含量降低(P<0.05)，其他组无统计学上 显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组和各药物干预组雄性大鼠的血清一氧化氮含量均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，醋氮酰胺阳性药物对照组血清一氧化氮含量降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
表33 PQQ对急性高原低氧暴露雌性大鼠内皮功能影响
Figure PCTCN2019104174-appb-000024
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表33中可知，与常氧对照组相比，低氧模型组、常氧PQQ药物组和常氧醋氮酰胺组雌性大鼠的血清内皮素-1含量降低(P<0.05)，低氧暴露后PQQ各药物剂量组血清内皮素-1含量升高，有统计学上显著性(P<0.05)，醋氮酰胺阳性药物对照组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各低氧暴露后PQQ用药组血清内皮素-1含量升高(P<0.05)，醋氮酰胺阳性药物对照组无统计学上显著性差异(P＞0.05)。
与常氧对照组和低氧模型组相比，低氧暴露后PQQ药物剂量组Ⅰ雌性大鼠的血清一氧化氮含量降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
7.10 PQQ对急性高原低氧损伤大鼠氧化应激指标影响
表34 PQQ对急性高原低氧暴露雄性大鼠氧化应激指标影响
Figure PCTCN2019104174-appb-000025
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表34中可知，与常氧对照组和低氧模型组相比，PQQ药物剂量组Ⅰ，Ⅱ，Ⅲ，Ⅳ和醋氮酰胺阳性药物对照组雄性大鼠血清超氧化物歧化酶活性升高(P<0.05)，药物剂量组Ⅴ无统计学上显著性差异(P＞0.05)。
与常氧对照组和低氧模型组相比，PQQ药物剂量组Ⅲ雄性大鼠的血清总抗氧化物值升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅴ雄性大鼠血清丙二醛値升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均无统计学上显著性差异(P＞0.05)。
表35 PQQ对急性高原低氧暴露雌性大鼠氧化应激指标影响
Figure PCTCN2019104174-appb-000026
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表35中可知，与常氧对照组相比，低氧暴露后PQQ药物剂量组Ⅰ，Ⅱ，Ⅲ，Ⅳ和醋氮酰胺阳性药物对照组雌性大鼠血清超氧化物歧化酶活性升高(P<0.05)，药物剂量组Ⅴ和常氧PQQ药物组、常氧醋氮酰胺组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，低氧暴露后PQQ各药物剂量组雌性大鼠的超氧化物歧化酶活性升高，有统计学上显著性差异(P<0.05)。
与常氧对照组相比，低氧暴露后PQQ药物剂量组Ⅱ和药物剂量组Ⅳ雌性大鼠的总抗氧化物有统计学上显著性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各组均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧暴露后PQQ药物剂量组Ⅰ、药物剂量组Ⅴ和常氧PQQ药物组雌性大鼠的血清丙二醛値有统计学上显著性升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ和药物剂量组Ⅴ雌性大鼠的血清丙二醛値升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
7.11 PQQ对急性高原低氧损伤大鼠血清能量代谢指标影响
表36 PQQ对急性高原低氧暴露雄性大鼠血清ATP和乳酸的影响
Figure PCTCN2019104174-appb-000027
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表36中可知，与常氧对照组和低氧模型组相比，各组雄性大鼠的血清ATP含量均无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，各组雄性大鼠的血清乳酸含量均无统计学上显著性差异(P＞0.05)。与低氧模型组相比，醋氮酰胺阳性药物对照组雄性大鼠的血清乳酸含量降低(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。
表37 PQQ对急性高原低氧暴露雌性大鼠血清ATP和乳酸的影响
Figure PCTCN2019104174-appb-000028
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表37中可知，与常氧对照组相比，各低氧暴露后PQQ药物剂量组血清ATP含量升高，有统计学上显著性差异(P<0.05)。与低氧模型组相比，各低氧暴露后PQQ药物剂量组血清ATP含量升高(P<0.05)，醋氮酰胺阳性药物对照组无统计学上显著性差异(P＞0.05)。常氧醋氮酰胺组雌性大鼠的血清ATP含量降低，有统计学上显著性差异(P<0.05)。
与常氧对照组相比，低氧模型组、醋氮酰胺阳性药物对照组、常氧PQQ药物组和常氧醋氮酰胺组雌性大鼠的血清乳酸含量降低，有统计学上显著性(P<0.05)；低氧暴露后PQQ药物剂量Ⅰ，Ⅱ，Ⅲ，Ⅳ组血清乳酸含量升高((P<0.05)，药物剂量组Ⅴ血 清乳酸含量与常氧对照组相比无统计学上显著性差异(P＞0.05)。与低氧模型组相比，各低氧暴露后PQQ药物剂量组血清乳酸含量升高，有统计学上显著性差异(P<0.05)，醋氮酰胺阳性药物对照组血清乳酸含量无统计学上显著性差异(P＞0.05)。
7.12 PQQ对急性高原低氧暴露大鼠肝脏能量代谢指标影响
表38 PQQ对急性高原低氧暴露雄性大鼠肝脏ATP和糖原的影响)
Figure PCTCN2019104174-appb-000029
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表38中可知，与常氧对照组相比，PQQ药物剂量组雄性大鼠肝脏中的ATP值均有升高趋势，其中PQQ药物剂量组Ⅳ含量升高有统计学上显著性差异(P<0.05)。与低氧模型组相比，PQQ药物剂量组Ⅳ和PQQ药物剂量组Ⅴ雄性大鼠肝脏中的ATP含量升高(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，PQQ药物剂量组Ⅳ雄性大鼠肝脏中的糖原值升高(P<0.05)，其他各组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅲ、PQQ药物剂量组Ⅳ和PQQ药物剂量组Ⅴ雄性大鼠肝脏中的糖原值升高，有统计学上显著性差异(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。
表39 PQQ对急性高原低氧暴露雌性大鼠肝脏ATP和糖原的影响
Figure PCTCN2019104174-appb-000030
*P＜0.05，**P＜0.01vs.常氧对照组，#P＜0.05，##P＜0.01vs.低氧模型组
从表39中可知，与常氧对照组相比，低氧模型组、低氧暴露后PQQ药物剂量组Ⅳ、PQQ药物剂量组Ⅴ和醋氮酰胺阳性药物对照组雌性大鼠肝脏中的ATP含量升高(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，PQQ药物剂量组Ⅰ雌性大鼠肝脏中的ATP含量降低(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。
与常氧对照组相比，低氧模型组、PQQ药物剂量组Ⅳ、PQQ药物剂量组Ⅴ和醋氮酰胺阳性药物对照组雌性大鼠肝脏中的糖原值升高，有统计学上显著性差异(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。与低氧模型组相比，低氧暴露后PQQ药物剂量组Ⅰ雌性大鼠肝脏中的糖原值降低(P<0.05)，其他组无统计学上显著性差异(P＞0.05)。
7.13 PQQ对小鼠高原低氧条件下作业能力影响的力竭游泳实验
表40雄性小鼠力竭游泳实验体重变化
Figure PCTCN2019104174-appb-000031
*P＜0.05，**P＜0.01vs.阴性对照组
从表40中可知，与阴性对照组相比，灌胃给药前雄性小鼠的体重未见统计学上显著性差异(P＞0.05)。灌胃给药7天后，与阴性对照组相比，醋氮酰胺阳性药物对照组、PQQ药物剂量组Ⅰ、PQQ药物剂量组Ⅱ和PQQ药物剂量组Ⅲ雄性小鼠的体重减低，有统计学上显著性差异(P＜0.05)；PQQ药物剂量组各组间无统计学上显著性差异(P＞0.05)。
8、实验结果小结
8.1 PQQ抗大鼠急性高原低氧损伤的实验
8.1.1 PQQ抗雄性大鼠急性高原低氧损伤的实验
PQQ干预7天不影响雄性大鼠体重，醋氮酰胺给药可导致雄性大鼠体重下降。
急性低氧暴露对雄性大鼠血清血糖值无显著影响，PQQ和醋氮酰胺干预对雄性大鼠血糖值无显著影响。
急性低氧暴露对雄性大鼠血清总蛋白含量未发现有显著影响，低剂量PQQ干预可轻度降低低氧暴露雄性大鼠血清总蛋白量，高剂量PQQ干预大鼠血清总蛋白量与低氧模型组一致；未发现醋氮酰胺对低氧暴露雄性大鼠血清总蛋白含量影响。低氧暴露可致血清白蛋白量轻度增高，低剂量PQQ干预可降低低氧暴露所致的雄性大鼠血清白蛋白量增高的作用；未发现醋氮酰胺对低氧暴露雄性大鼠血清总蛋白含量影响。
急性低氧暴露对雄性大鼠甘油三酯无显著影响，未发现PQQ和醋氮酰胺干预对低氧暴露大鼠甘油三酯的影响。急性低氧暴露不影响总胆固醇、高密度脂蛋白胆固醇含量，可轻度降低低密度脂蛋白胆固醇含量；PQQ低剂量干预有降低总胆固醇、高密度脂蛋白胆固醇量的作用，对低密度脂蛋白胆固醇量无显著影响；醋氮酰胺干预对以上指标无显著影响。
急性低氧暴露对谷丙转氨酶未发现有显著影响，未发现PQQ干预对急性低氧暴露雄性大鼠血清谷丙转氨酶、谷草转氨酶和总胆红素的影响；醋氮酰胺有增加急性低氧暴露雄性大鼠血清谷草转氨酶的作用，对谷丙转氨酶和总胆红素无显著影响。
急性低氧暴露对雄性大鼠血清尿素氮、肌酐无显著影响，可致尿酸含量轻度增加；PQQ干预对低氧暴露雄性大鼠血清血清尿素氮、肌酐无显著影响，低剂量干预有降低血清尿酸含量的作用；醋氮酰胺有减低低氧暴露大鼠血清尿酸水平，升高血清尿素氮含量的作用，对血清肌酐无显著影响；
急性低氧暴露对雄性大鼠血清乳酸脱氢酶、肌酸激酶、α-羟丁酸脱氢酶活性无显著影响；未发现PQQ和醋氮酰胺干预对低氧暴露雄性大鼠血清乳酸脱氢酶、肌酸激酶、α-羟丁酸脱氢酶的影响。
急性低氧暴露可轻度升高雄性大鼠血清同型半胱氨酸水平；未发现PQQ和醋氮酰胺干预对低氧暴露雄性大鼠血清同型半胱氨酸有显著影响。
急性低氧暴露对雄性大鼠血清内皮素-1、一氧化氮含量未发现有显著影响；PQQ干预对以上指标无显著影响；醋氮酰胺有轻度降低低氧暴露雄性大鼠血清内皮素-1、一氧化氮含量的作用。
急性低氧暴露对雄性大鼠血清超氧化物歧化酶、总抗氧化物、丙二醛无显著影响；PQQ干预可升高低氧暴露雄性大鼠血清超氧化物歧化酶活力，对血清总抗氧化物、丙二醛无显著影响；醋氮酰胺也有升高雄性大鼠血清超氧化物歧化酶活力的作用，对血清总 抗氧化物和丙二醛无显著影响。
急性低氧暴露对雄性大鼠血清ATP和乳酸含量未发现有显著影响；PQQ干预对雄性大鼠血清以上指标无显著影响；醋氮酰胺干预对血清ATP无显著影响，有降低血清乳酸含量的作用。
急性低氧暴露对雄性大鼠肝脏ATP和糖原含量未发现有显著影响；PQQ干预有升高雄性大鼠肝脏ATP和糖原含量的作用；醋氮酰胺干预对雄性大鼠肝脏以上指标无显著影响。
8.1.2 PQQ抗雌性大鼠急性高原低氧损伤的实验
PQQ干预7天不影响雌性大鼠体重，醋氮酰胺对雌性大鼠体重无显著影响。
急性低氧暴露可降低雌性大鼠血清血糖值，PQQ干预有升高急性低氧暴露雌性大鼠血糖的作用；醋氮酰胺干预对急性低氧暴露血糖升高无显著影响。常氧PQQ干预对雌性大鼠血糖无显著影响；常氧醋氮酰胺组干预有降低雌性大鼠血糖的作用。
急性低氧暴露对雌性大鼠血清总蛋白含量未发现有显著影响，低剂量PQQ干预可轻度降低低氧暴露雌性大鼠血清总蛋白量，高剂量PQQ干预大鼠血清总蛋白量与低氧模型组一致；未发现醋氮酰胺对雌性大鼠血清总蛋白含量影响。低氧暴露可致血清白蛋白量轻度增高，低剂量PQQ干预可降低低氧暴露所致的雌性大鼠血清白蛋白量增高的作用；醋氮酰胺干预也有此作用。常氧PQQ干预对雌性大鼠血清总蛋白含量无显著影响；常氧醋氮酰胺有轻度升高雌性大鼠血清白蛋白量的作用。
急性低氧暴露可减低雌性大鼠总胆固醇、低密度脂蛋白胆固醇量，不影响高密度脂蛋白胆固醇含量，PQQ干预对以上指标无显著影响；醋氮酰胺干预有升高雌性大鼠总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇含量的作用。常氧PQQ干预对以上指标未发现有显著影响；常氧醋氮酰胺对低密度脂蛋白胆固醇量无显著影响，可升高雌性大鼠总胆固醇和高密度脂蛋白胆固醇含量。
急性低氧暴露对雌性大鼠谷丙转氨酶无显著影响，可轻度降低谷草转氨酶活性；未发现PQQ干预对急性低氧暴露雌性大鼠血清谷丙转氨酶、谷草转氨酶活性的影响。常氧PQQ干预有轻度增加谷草转氨酶活性的作用，对谷丙转氨酶无显著影响；常氧醋氮酰胺对以上指标无显著影响。
急性低氧暴露对雌性大鼠血清尿素氮无显著影响，可致肌酐、尿酸含量轻度减低；PQQ干预对低氧暴露雌性大鼠血清尿素氮、肌酐、尿酸无显著影响；醋氮酰胺有降低低 氧暴露雌性大鼠血清尿酸水平，增加血清尿素氮、肌酐值的作用。常氧PQQ干预对以上指标未发现有显著影响；常氧醋氮酰胺有降低雌性大鼠血清尿酸水平，增加血清尿素氮、肌酐值的作用。
急性低氧暴露可减低雌性大鼠血清肌酸激酶、α-羟丁酸脱氢酶活性，对血清乳酸脱氢酶活性未发现有显著影响；未发现PQQ干预对低氧暴露雌性大鼠血清乳酸脱氢酶、肌酸激酶、α-羟丁酸脱氢酶活性的有显著影响；醋氮酰胺对以上指标无显著影响。常氧PQQ干预有升高以上指标的作用；常氧醋氮酰胺对以上指标未发现有显著影响。
急性低氧暴露可轻度降低雌性大鼠同型半胱氨酸水平；PQQ和醋氮酰胺干预对低氧暴露雌性大鼠血清同型半胱氨酸无显著影响。常氧PQQ、醋氮酰胺干预对以上指标无显著影响。
急性低氧暴露可减低雌性大鼠血清内皮素-1含量，未发现对一氧化氮含量有显著影响；PQQ干预可升高急性低氧暴露后大鼠血清内皮素-1的含量，对一氧化氮含量无显著影响；醋氮酰胺干预对以上指标无显著影响。常氧PQQ、醋氮酰胺干预可减低雌性大鼠血清内皮素-1含量，未发现对一氧化氮含量有显著影响。
急性低氧暴露对雌性大鼠血清超氧化物歧化酶、总抗氧化物、丙二醛无显著影响；PQQ干预可升高低氧暴露雌性大鼠血清超氧化物歧化酶活力，对血清总抗氧化物、丙二醛无显著影响；醋氮酰胺也有升高血清超氧化物歧化酶活力的作用，对血清总抗氧化物和丙二醛无显著影响。常氧PQQ干预可轻度升高雌性大鼠丙二醛的作用，对血清超氧化物歧化酶、总抗氧化物的无显著影响；常氧醋氮酰胺对以上指标无显著影响。
急性低氧暴露对雌性大鼠血清ATP无显著影响，有降低血清乳酸含量的作用；PQQ干预有升高雌性大鼠血清ATP和乳酸含量的作用；醋氮酰胺对以上指标无显著影响。常氧PQQ干预有降低血清乳酸含量的作用，对血清ATP含量无显著影响；醋氮酰胺干预有降低雌性大鼠血清ATP和乳酸含量的作用。
急性低氧暴露可升高雌性大鼠肝脏ATP和糖原含量；低氧暴露后和常氧PQQ、醋氮酰胺干预对雌性大鼠肝脏ATP和糖原含量均无显著影响。
8.2 PQQ提高小鼠高原低氧条件下作业能力的力竭游泳实验
暴露于海拔6000米雄性小鼠力竭游泳实验(分别给予1.32mg/kg、2.64mg/kg、5.28mg/kg、10.56mg/kg、21.12mg/kgPQQ，给药7天)结果显示，阴性对照组和醋氮酰胺阳性药物对照组的小鼠死亡开始较早，PQQ各剂量组小鼠力竭游泳死亡开始时间较以上 两组延迟；暴露于海拔6000米180分钟后，阴性对照组和醋氮酰胺阳性药物对照组小鼠已经基本完全死亡，至400分钟左右PQQ各剂量组小鼠完全死亡。雄性小鼠阴性对照组、阳性醋氮酰胺对照组、PQQ以上5个剂量组小鼠力竭游泳存活时间(分)133.38±110.94、130.64±79.46、199.21±98.54、273.10±63.07、173.15±116.32、195.04±59.81、263.20±48.27；存活时间增加率依次为0％、2.10％、52.49％、109.05％、32.54％、49.30％、101.47％。该实验结果提示，给予PQQ可延长小鼠力竭游泳存活时间，具有提高小鼠高原低氧暴露条件下体作业能力的作用。
本发明通过上面的实施例进行举例说明，但是，应当理解，本发明并不限于这里所描述的特殊实例和实施方案。在这里包含这些特殊实例和实施方案的目的在于帮助本领域中的技术人员实践本发明。任何本领域中的技术人员很容易在不脱离本发明精神和范围的情况下进行进一步改进和完善，因此本发明只受到本发明权利要求的内容和范围的限制，其意图涵盖所有包括在由附录权利要求所限定的本发明精神和范围内的备选方案和等同方案。

Claims (2)

  1. 吡咯喹啉醌在制备用于防治急性高原反应的药物中的应用。
  2. 吡咯喹啉醌在制备用于防治急性高原低氧损伤的药物中的应用。
PCT/CN2019/104174 2018-09-03 2019-09-03 吡咯喹啉醌在制备用于防治急性高原反应和急性高原低氧损伤的药物中的应用 Ceased WO2020048446A1 (zh)

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