TWI643615B - Use of phthalides in the preparation of medicine for replacing and/or assisting hyperbaric oxygen therapy (hbot) to enhance the oxygenation level of tissue cells - Google Patents

Abstract

The present invention relates to the use of a benzoquinone compound for the preparation of a pharmaceutical composition for replacing or assisting hyperbaric oxygen therapy for improving tissue hypoxia, wherein the benzoquinone compound has the ability to increase the oxygen release capacity of hemoglobin in the blood and thereby enhance the tissue content. The effect of the degree of oxygen, wherein the benzoquinone compound can avoid side effects such as barotrauma, decompression sickness and oxygen poisoning which are common in conventional hyperbaric oxygen therapy when it is administered to a patient instead of or in combination with hyperbaric oxygen therapy. The benzoquinone compound is used to replace/assisize the regulation of 2,3-diphosphoglycerate and reduce the oxygen affinity of hemoglobin, and improve the efficiency of hemoglobin releasing oxygen to tissue cells, so that the oxygen content of the cell reaches and maintains the normal range.

Description

A benzoquinone compound for preparing a substitute/assisted hyperbaric oxygen therapy to improve tissue hypoxia Use of objects

The present invention is in the field of medicine and relates to the use of a benzoquinone compound for the preparation of a pharmaceutical composition for the replacement/assisted hyperbaric oxygen therapy to improve tissue hypoxia.

Hemoglobin (Hb) is a protein used to carry and transport oxygen in red blood cells. It can transport oxygen from respiratory organs such as the respiratory tract and lungs to various organs and surrounding cellular tissues, so that organs and surrounding areas The cellular tissue is able to obtain sufficient oxygen to maintain the normal physiological functions of the organs and surrounding tissue.

The normal adult hemoglobin is a tetramer α ₂ β ₂ composed of four subunits such as α ₁ , α ₂ , β ₁ and β _{2 ,} and the intracellular units are hydrogen bonds in the subunits (intra- Subunit hydrogen bond) and other intermolecular forces to stabilize the secondary and tertiary structures of each subunit, and inter-subunit hydrogen bonds may be formed between the subunits. So that the aforementioned four sub-units can collectively form a quaternary structure.

The quaternary structure of hemoglobin has a relaxed state of high oxygen affinity (relaxed Form, R state) and the different forms of the hypoxic affinity (tensed form, T state), when hemoglobin is transported to the lungs through the blood circulation, hemoglobin can combine with oxygen, and then carry oxygen and present R State, and transported to various organs and surrounding tissues with blood circulation, and affected by the pH, carbon dioxide concentration, 2,3-BPG concentration and other isomers of various organs and surrounding tissues, so that hemoglobin releases oxygen to various organs and surrounding areas. The tissue is converted to a T state with low affinity for oxygen.

2,3-bisphosphorglycerate (2,3-BPG) or 2,3-diphosphoglycerate (2,3-DPG), followed by 2,3-BPG) endogenous isomerism of hemoglobin The factor is the most important substance in the red blood cells of the human body except the hemoglobin responsible for carrying and transporting oxygen. 2,3-BPG through interaction between beta] ₁ and Hb and two β ₂ subunits regulate precisely configuration hemoglobin, Hb so stabilized in the smaller T-state to reduce the oxygen affinity of hemoglobin oxygen affinity of the resultant force, Helps hemoglobin release oxygen to various organs and tissue cells in the body.

Traditional hyperbaric oxygen therapy is to place the patient in a hyperbaric chamber, pressurize and maintain it at 2.0-3.0 atm, and allow people to absorb 100% oxygen through the oxygen mask to increase the oxygen concentration in the blood and improve tissue hypoxia. Promote wound healing or treat acute hypoxic conditions.

However, hyperbaric oxygen therapy, because the subject inhaled high concentrations of oxygen under high pressure, rapid pressure changes between tissues, may cause considerable side effects, including barotrauma, decompression sickness and oxygen poisoning, etc., if not properly operated or even fatal risks of.

Therefore, the main object of the present invention is to provide a benzoquinone compound for use in the preparation of a pharmaceutical composition for replacing/assisting hyperbaric oxygen therapy for improving tissue hypoxia, wherein the benzoquinone compound The substance has the effect of increasing the oxygen release rate of a donor's hemoglobin. The use of the invention can improve the oxygenation balance curve of hemoglobin, thereby improving the blood oxygen content and improving the hypoxia of the tissue without excessively increasing the partial pressure of oxygen, thereby avoiding the disadvantages of the existing hyperbaric oxygen therapy. .

The benzoquinone compound is used to replace/assisize the 2,3-diphosphoglycerate of the donor, and assists the hemoglobin to enhance the ability to release oxygen to the tissue cells, so that the recipient does not change or excessively change the partial pressure of oxygen. It can improve the blood oxygen level in tissue cells and improve the hypoxia of tissues.

The benzoquinone compound is any compound containing a structural feature of a phenylhydrazine functional group. As shown in FIG. 8, the ring is a phenylhydrazine functional molecular structure characterized by an inner ring oxygen atom and an adjacent ketone. .

The benzoquinone compound of the invention can not only replace and supplement the 2,3-BPG of the donor, but also synergistically with 2,3-BPG, and has the effect of increasing the oxygen release efficiency of hemoglobin (Fig. 1). .

Hemoglobin has a high affinity with oxygen and is usually expressed by P ₅₀ . P ₅₀ is the partial pressure of oxygen required to achieve an oxygen saturation of 50%. P ₅₀ normal adult is about 3.59kPa (27mmHg). Increased blood PCO ₂ , decreased pH, or increased 2,3-BPG content in red blood cells can reduce hemoglobin oxygen affinity, shift the oxygenation equilibrium curve to the right, and increase P ₅₀ (Figure 2); conversely, when hemoglobin is An increase in oxygen affinity causes the oxygenation equilibrium curve to shift to the left and P _{50 to} decrease.

Under normal conditions, the PO ₂ (oxygen partial pressure) of human cells is about 9.9-19 mmHg ( J. Cell. Mol. Med. , 15, 1239-1253 (2011)), but it is fixed by observing the hemoglobin oxygenation equilibrium curve. The effect of different concentrations of 2,3-BPG on oxygen saturation under oxygen partial pressure (Fig. 3) can better understand the effect of 2,3-BPG on the oxygen release rate of hemoglobin. After applying 12 mM 2,3-BPG (Fig. 3 purple curve), the oxygen saturation of hemoglobin is about 80% of hemoglobin without 2,3-BPG after the oxygen partial pressure is fixed at 20 mmHg (Fig. 3 gray curve). Reduced to 35%, that is, the oxygen release rate increased from 20% to 65%.

In a preferred embodiment, the benzoquinone compound can function as a 2,3-BPG to effectively increase the P ₅₀ value of hemoglobin, ie, reduce the oxygen affinity of hemoglobin, and the higher concentration of the benzoquinone compound, The higher the P ₅₀ , the lower the affinity for oxygen (Figure 4).

In another embodiment, under no presence of phthalides, it requires about 4mM of 2,3-BPG the hemoglobin P ₅₀ reaches 18.8mmHg; and after administration of phthalides, 0.6-1.2mM of only about 2,3-BPG can reach a near or higher P ₅₀ (Figure 5).

In another embodiment, as shown in FIG. 6, in the case of 2,3-BPG with PO ₂ =20 mmHg/1.2 mM, the oxygen saturation is about 60%, but after the administration of the additional benzoquinone compound, The oxygen saturation drops to about 47%, which means that the oxygen release rate increases from 40% to 53%. Therefore, it can be confirmed that the benzoquinone compound can assist the 2,3-BPG of the donor, and the hemoglobin can release more oxygen under the condition of constant oxygen partial pressure.

Therefore, the use of the present invention is to utilize a benzoquinone compound for the preparation of a pharmaceutical composition for improving hypoxia of hyperbaric oxygen therapy; by shifting the oxygenation balance curve of hemoglobin to the right, the oxygen delivery and release efficiency of hemoglobin is improved, thereby avoiding Traditional hyperbaric oxygen therapy is commonly used for side effects such as barotrauma, decompression sickness and oxygen poisoning. Moreover, the benzoquinone compound and 2,3-BPG have the synergistic effect of assisting hemoglobin to release oxygen.

Figure 1 is a graph showing the degree of addition of a benzoquinone compound to 2,3-BPG; A: Z-decalactone; B: Yanchuan azlactone I.

Figure 2 is an oxygenation equilibrium curve of hemoglobin at different concentrations of 2,3-BPG (0.2-12 mM), showing that the higher the concentration of 2,3-BPG, the more the oxygenation equilibrium curve of hemoglobin shifts to the right, and P _The higher the ₅₀ value.

Figure 3 shows the oxygenation curve of hemoglobin at different concentrations of 2,3-BPG (0.2-12 mM) and its corresponding oxygen saturation to human brain tissue, general cells, and alveoli under different physiological oxygen partial pressure conditions. The fraction is regulated by 2,3-BPG regulation.

Figure 4 shows that the P ₅₀ of hemoglobin increases as the concentration of different benzoquinone compounds increases, representing a decrease in oxygen affinity for hemoglobin and an increase in oxygen release rate.

Figure 5 shows that even in the case of a lower content of 2,3-BPG, different phthalides help regulation of hemoglobin, Hb so reach the normal P _50.

Figure 6 shows that the oxygen balance curve of hemoglobin is coordinated by 2,3-BPG and benzoquinones, indicating that benzoquinones can assist 2,3-BPG to reduce hemoglobin in the oxygen partial pressure. Rate, increase the rate of oxygen release.

7A to 7L are structural formulas of 12 kinds of benzoquinones; 7A: Z-butenyl benzoquinone; 7B: Z-decalactone; 7C: sedative lactone A; 7D: sulphate lactone H; 7E: Yangchuan azlactone I; 7F: Yanchuan azlactone F; 7G: E-butenyl phenylhydrazine; 7H: E-decalactone; 7I: 3-butylphthalide; 7J: 3-butene Base-4 mercaptobenzoquinone; 7K: 6,7-didecyl ligustilide; 7L: 6,7-epoxy licapionide.

Fig. 8 is a schematic view showing the molecular structure of a functional group of a phenylhydrazine compound.

In order to more clearly understand the technical content, features, and advantages of the present invention, The following embodiments are described in detail with reference to the drawings, but the following examples are not intended to limit the invention.

The benzoquinone compound of the present invention is any compound containing a structural feature of phenylhydrazine, such as Z-butylidenephthalide (Fig. 7A) and Z-decrolactone (Z-). Ligustilide) (Fig. 7B), senkynnolide A (Fig. 7C), senkynnolide H (Fig. 7D), senkynnolide I (Fig. 7E), ocean Ligustrum lactone F (Fig. 7F), E-butylidenephthalide (Fig. 7G), E-ligustilide (Fig. 7H), 3-butyl 3-butylphthalide (Fig. 7I), 3-butylidene-4-hydrophthalide (Fig. 7J), 6,7-didecyl ligustilide (6) , 7-dihydroxyligustilide) (Fig. 7K), and 6,7-epoxyligustilide (Fig. 7L).

Hemoglobin has a high affinity with oxygen and is usually expressed by P ₅₀ . P ₅₀ is the partial pressure of oxygen required to achieve an oxygen saturation of 50%. P ₅₀ normal adult is about 3.59kPa (27mmHg). Increased blood PCO ₂ , decreased pH, or increased 2,3-BPG content in red blood cells can reduce hemoglobin oxygen affinity, shift the oxygenation equilibrium curve to the right, and increase P ₅₀ (Figure 2); conversely, when hemoglobin is An increase in oxygen affinity causes the oxygenation equilibrium curve to shift to the left and P _{50 to} decrease.

Under normal conditions, the PO ₂ (oxygen partial pressure) of human cells is about 9.9-19 mmHg ( J. Cell. Mol. Med. , 15, 1239-1253 (2011)), but it is fixed by observing the hemoglobin oxygenation equilibrium curve. The effect of different concentrations of 2,3-BPG on oxygen saturation under oxygen partial pressure (Fig. 3) can better understand the effect of 2,3-BPG on the oxygen release rate of hemoglobin. After applying 12 mM 2,3-BPG (Fig. 3 purple curve), the oxygen saturation of hemoglobin is about 80% of hemoglobin without 2,3-BPG after the oxygen partial pressure is fixed at 20 mmHg (Fig. 3 gray curve). Reduced to 35%, that is, the oxygen release rate increased from 20% to 65%.

In a preferred embodiment, the benzoquinone compound can function as a 2,3-BPG to effectively increase the P ₅₀ value of hemoglobin, ie, reduce the oxygen affinity of hemoglobin, and the higher concentration of the benzoquinone compound, The higher the P ₅₀ , the lower the affinity for oxygen (Figure 4).

In another embodiment, under no presence of phthalides, it requires about 4mM of 2,3-BPG the hemoglobin P ₅₀ reaches 18.8mmHg; and after administration of phthalides, 0.6-1.2mM of only about 2,3-BPG can reach a near or higher P ₅₀ (Figure 5).

In another embodiment, as shown in FIG. 6, in the case of 2,3-BPG with PO ₂ =20 mmHg/1.2 mM, the oxygen saturation is about 60%, but after the administration of the additional benzoquinone compound, The oxygen saturation drops to about 47%, which means that the oxygen release rate increases from 40% to 53%. Therefore, it can be confirmed that the benzoquinone compound can assist the 2,3-BPG of the donor, and the hemoglobin can release more oxygen under the condition of constant oxygen partial pressure.

In one embodiment, the benzoquinone compound can be used together with other compounds capable of stabilizing the oxygenated hemoglobin in the T state and effectively reducing the affinity of hemoglobin for oxygen, thereby improving the oxygen release efficiency of the hemoglobin of the donor.

In another preferred embodiment, the benzoquinone compound can be administered to a subject in combination with assisted hyperbaric oxygen therapy, including orally or by injection, to reduce intracavitary pressure during hyperbaric oxygen therapy and to reduce interstitial oxygen. The change in the partial pressure.

In summary, the use of the present invention provides a use of a benzoquinone compound for the preparation of a pharmaceutical composition for improving hypoxia, which is a method for improving hypoxic oxygen release in a subject. The effect. The benzoquinone compound is used to replace/assisize the 2,3-diphosphoglycerate of the donor, by shifting the oxygen balance curve of hemoglobin to the right, The effect of improving the blood oxygen level in tissue cells and improving the hypoxia of tissues can be avoided by changing or not excessively changing the partial pressure of oxygen, and the disadvantages of the existing hyperbaric oxygen therapy can be avoided.

While the invention has been described in connection with the preferred embodiments described above, it is not intended to limit the scope of the invention. The technical scope of the invention is protected, and therefore the scope of the invention is defined by the scope of the appended claims.

Claims (1)

Use of a benzoquinone compound and 2,3-diphosphoglycerate for preparing a pharmaceutical composition for improving hypoxic hypoxia by Hyperbaric oxygen therapy (HBOT), wherein the benzoquinone compound has an increase The effect of the oxygen release rate of the hemoglobin of the subject, wherein the benzoquinone compound is selected from the group consisting of Z-butylidenephthalide, Z-ligustilide , senkyunolide A, senkyunolide H, senkyunolide I, senkyunolide F, E-butenyl phenyl hydrazine (E) -butylidenephthalide), Z-ligustilide, 3-butylphthalide, 3-butylidene-4-hydrophthalide, 6 , 7-dihydroxyligustilide, and 6,7-epoxyligustilide, wherein the benzoquinone compound has 2,3-di Phosphoglycerate multiply acts on the hemoglobin to increase the oxygen release rate of the hemoglobin.