WO2018152996A1

WO2018152996A1 - Use of nadph in preparation of medicine for treating cardiac hypertrophy and heart failure

Info

Publication number: WO2018152996A1
Application number: PCT/CN2017/090157
Authority: WO
Inventors: 秦正红; 盛瑞; 凌月娟; 朱路佳
Original assignee: 重庆纳德福实业集团股份有限公司
Priority date: 2017-02-21
Filing date: 2017-06-27
Publication date: 2018-08-30
Also published as: CN106902131A

Abstract

Disclosed is the use of NADPH in the preparation of a medicine for treating cardiac hypertrophy and heart failure. NADPH can improve the activity of a Na+-K+-ATP enzyme, a Ca2+-Mg2+-ATP enzyme and a total ATP enzyme in the myocardium tissue of a mouse; in addition, NADPH has no obvious influence on the blood pressure of a normal rat, and causes less adverse reactions during the treatment of heart failure and cardiac hypertrophy.

Description

Application of NADPH in the preparation of drugs for treating cardiac hypertrophy and heart failure

cross reference

This application claims priority to Chinese Patent Application No. 200910093339.4, entitled "Application of NADPH in the Preparation of Drugs for the Treatment of Cardiac Hypertrophy and Heart Failure", filed on February 21, 2017, the entire contents of which is hereby incorporated by reference. This is incorporated herein by reference.

Technical field

The invention belongs to the field of medicines, and particularly relates to the application of NADPH in preparing medicines for treating cardiac hypertrophy and heart failure.

Background technique

Reduced nicotinamide adenine dinucleotide phosphate (NADPH) is produced by the metabolism of glucose via the pentose phosphate pathway (PPP). It is the most important electron donor and biosynthesis reducing agent in the cell and can be reduced. Biosynthesis provides hydrogen ions. NADPH is a coenzyme of glutathione (GSH) reductase, which produces oxidized glutathione (GSSG) to produce reduced GSH and maintains the normal content of reduced GSH. GSH is an important antioxidant in the cell, which protects some thiol-containing proteins, fats and proteases from oxidants, especially in maintaining the integrity of erythrocyte membranes. In addition to its involvement in the biosynthesis of cholesterol, fatty acids, monooxygenases, steroids, etc., NADPH is also involved in the hydroxylation of the body and the biotransformation of drugs, poisons and certain hormones; for example, NADPH can utilize the electron donor of detoxified cells. The metabolism of the organism is reduced by metabolism in the body, and the balance of redox is maintained, which plays an important role in the oxidation defense system. NADPH can also enter the respiratory chain by means of isocitrate shuttle to produce ATP: due to the low permeability of the mitochondrial inner membrane to the substance, the NADPH produced by the mitochondria in vitro cannot be directly oxidized into the respiratory chain. H on NADPH can be delivered to NAD+ under the action of isocitrate dehydrogenase, and then energy is generated by NAD+ entering the respiratory chain. Maintenance of cellular energy metabolism and reduction of ROS (reactive oxygen species) for cell survival, Especially important for ischemia and hypoxia, it is generally believed that energy metabolism disorder and oxidative stress are important mechanisms of cardio-cerebral ischemia.

Cardiac hypertrophy, especially left ventricular hypertrophy (LVH), is the target organ response of the heart to chronic stress or volume overload. There are about 266 million patients with hypertension in China, and one-third of them with hypertension can be associated with LVH. Cardiac hypertrophy is an extremely important cardiovascular risk factor, which can increase the risk of sudden death such as coronary heart disease, congestive heart failure, stroke or transient ischemic heart attack; more importantly, cardiac hypertrophy is also chronic heart failure. One of the important mechanisms of occurrence and development.

Heart failure refers to a syndrome in which circulatory disorders are predominant due to the absolute or relative decrease in cardiac output during normal venous return. Clinically, pulmonary circulation and/or systemic blood stasis and tissue hypoperfusion are the main features. According to the development of heart failure, acute heart failure and chronic heart failure can be divided into acute heart failure. Acute heart failure refers to acute cardiac output in a short period of time. Decreased or even lost the function of pumping blood, its rapid development, according to the severity can be expressed as fainting, cardiogenic shock, acute pulmonary edema, cardiac arrest; chronic heart failure, also known as congestive heart failure or chronic heart failure, refers to The disease-causing factors cause the heart to be under stress and/or over-loading for a long time, causing the heart to be exhausted and gradually losing compensatory function. The cardiac output is absolutely or relatively insufficient to maintain the body's metabolic needs. The causes of heart failure are multiple and complex, mainly including myocardial contraction and / or diastolic dysfunction and long-term cardiac load and ventricular filling limitation. Heart failure is actually the result of cardiac function from compensation to decompensation; In depletion, especially in chronic heart failure, the compensatory response of the body to prevent the reduction of cardiac output includes neuroendocrine reflex and myocardial configuration reconstruction. Cardiac hypertrophy is the main manifestation of cardiac reconstruction. Early cardiac hypertrophy has a certain compensatory significance for cardiac function; however, in the late stage of cardiac hypertrophy, pathological cardiac hypertrophy is accompanied by cardiomyocyte apoptosis, myocardial fibroblast proliferation and myocardial fibrosis interstitial hyperplasia, which promotes cardiac function gradually. The compensation is decompensated and participates in the occurrence and development of heart failure.

At present, the clinical treatment of cardiac hypertrophy or heart failure drugs are similar, mainly to inhibit excessive activation of neuroendocrine during heart failure or cardiac hypertrophy, to correct hemodynamic disorders, commonly used treatments include: (1) angiotensin conversion Enzyme inhibitors (ACEIs) and angiotensin II receptor I blockers (ARBs), which act by reducing the production and action of angiotensin (ACEIs), relaxing the arteries and veins, reducing the load before and after the heart, and reversing Cardiovascular remodeling and left ventricular hypertrophy; (2) Diuretics, the mechanism of action is: by eliminating excess water in the body, reducing effective circulating blood volume, reducing cardiac preload, eliminating interstitial edema or pulmonary edema, aldosterone receptors such as spironolactone Antagonists can also resist the cardiac remodeling of aldosterone; (3) calcium antagonists, the mechanism of action is: inhibition of extracellular Ca ²⁺ influx, decrease intracellular free Ca ²⁺ concentration, relax blood vessels, lower blood pressure, reduce before And / or afterload to improve cardiac function; (4) beta blockers, the mechanism of action: blocking beta receptors, inhibiting sympathetic nervous system activity and renin release, lowering blood pressure, eliminating Or partial reversal of cardiac conformation, up-regulation of beta receptors, restoring cardiac sensitivity to sympathetic neurotransmitters; (5) positive inotropic drugs, mechanisms of action such as digitalis and non-glycoactive positive inotropic drugs (including phosphodiesterase inhibitors and beta-agonists), directly strengthen myocardial contractility, increase cardiac output, reduce residual blood volume at the end of systole, reduce preload, and restore heart function. The above-mentioned drugs (1)-(4) alleviate or reverse cardiac hypertrophy and gradually improve cardiac function, and are suitable for long-term treatment of cardiac hypertrophy or chronic heart failure, but because they do not have a cardiac effect, the development of cardiac hypertrophy to heart failure The decompensation period is generally effective and cannot be used for the treatment of acute heart failure; while the category (5) drugs have more serious adverse reactions in clinical application, such as increasing the risk of arrhythmia and even increasing heart failure. mortality rate.

Currently, there is no report of NADPH for the treatment of cardiac hypertrophy and heart failure.

Summary of the invention

To this end, the present invention proposes the use of NADPH in the preparation of a medicament for the treatment of cardiac hypertrophy and heart failure.

In order to solve the above technical problems, the present invention is achieved by the following technical solutions:

According to one aspect of the present application, the present invention provides the use of NADPH for the preparation of a medicament for the treatment of cardiac hypertrophy.

According to another aspect of the present application, the present invention also provides the use of NADPH for the preparation of a medicament for treating heart failure.

Preferably, in the above use of the invention, the medicament comprises a pharmaceutically effective amount of NADPH and a pharmaceutically acceptable carrier.

Further preferably, in the above application of the present invention, the carrier is selected from the group consisting of commonly used pharmaceutical excipients, or physiological saline, or distilled water.

Further preferably, in the above application of the present invention, the drug is NADPH according to a conventional process, and a conventional excipient is added to prepare a clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, plaster, suppository. , aerosol, ointment or injection.

Further preferably, in the above application of the present invention, the administration mode of the drug is at least one selected from the group consisting of oral administration, injection administration, sublingual administration, rectal administration, transdermal administration, and spray inhalation.

The above technical solution of the present invention has the following advantages over the prior art:

(1) The present invention has found that NADPH not only has a significant cardiac effect, but also has a mitigating effect on cardiac hypertrophy, and thus can be used as a drug for treating cardiac hypertrophy and heart failure;

(2) The present inventors further found that NADPH can increase the activity of Na ⁺ -K ⁺ -ATPase, Ca ²⁺ -Mg ²⁺ -ATPase and total ATPase in myocardial tissue of mice, suggesting that NADPH may pass The above mechanism exerts a mitigating effect on cardiac hypertrophy;

(3) In addition, NADPH has no significant effect on the blood pressure of normal rats, and the adverse reactions in the treatment of cardiac hypertrophy and heart failure are small.

DRAWINGS

In order to make the content of the present invention easier to understand, the present invention will be further described in detail below with reference to the accompanying drawings, in which:

Fig. 1(a) shows the effect of NADPH on the cardiac contractile force of the in situ frog heart in Experimental Example 1, and the numerical value indicates the percentage of contractile force compared with normal; Fig. 1(b) shows the experimental example 1. The effect of NADPH on cardiac output of isolated in situ frog heart; Fig. 1(c) shows the effect of NADPH on the heart rate of in situ frog heart in experimental example 1; Fig. 1(d) shows the experiment The effect of NADPH on the cardiac contractility of isolated in situ frog hearts in Example 1, mean ± standard deviation, N = 8-10; compared with the normal group, ^* P < 0.05, ^** P <0.01; compared to low ^{^{calcium, # P <0.05, ## P}} <0.01, ### P <0.001;

Fig. 2(a) shows the effect of NADPH on ISO-induced cardiac hypertrophy in Experimental Example 2; Figure 2(b) shows the HE staining map of each group of mice in Experimental Example 2; Figure 2(c) shows The effect of NADPH on ISO-induced cardiac hypertrophy center weight index in experimental example 2; the wet weight of the heart and left ventricle was measured, and the heart weight index (HWI=HW/BW) and left heart index (LVWI=LVW/BW) were calculated. Mean ± standard deviation; compared with the control group, ^### P<0.001; compared with the ISO group, ^* P < 0.05, ^** P < 0.01, ^*** P <0.001; N (L) is NADPH 1mg/kg, N(M) represents NADPH 2mg/kg, and N(H) represents NADPH 4mg/kg;

Fig. 3(a) shows the electrocardiogram of each group of mice in Experimental Example 2; Fig. 3(b) shows the effect of NADPH on the R wave amplitude of the electrocardiogram of ISO-induced mice in Experimental Example 2; Standard deviation; compared with the control group, ^### P<0.001; N(L) indicates NADPH 1 mg/kg, N(M) indicates NADPH 2 mg/kg, and N(H) indicates NADPH 4 mg/kg. Kg;

Figure 4 is the effect of NADPH on cardiac function in mice in Experimental Example 2; N(L) indicates NADPH 1 mg/kg, N(M) indicates NADPH 2 mg/kg, and N(H) indicates NADPH 4 mg/kg. Kg;

Figure 5 is a graph showing the effect of NADPH on the ATPase content in myocardial tissue of mice in Experimental Example 2; N(L) indicates NADPH 1 mg/kg, and N(M) indicates NADPH 2 mg/kg, and N(H) indicates For NADPH 4mg/kg;

Figure 6 is the effect of NADPH on the blood pressure of normal rats in Experimental Example 3; NS indicates normal saline, SBP indicates systolic blood pressure, DBP indicates diastolic blood pressure, MBP indicates mean arterial pressure, mean ± standard difference.

Experimental example

Each of the following experiments exemplifies the technical effects described in the present invention.

Experimental Example 1 Experiment of the cardiac effect of NADPH on in situ frog heart

(1) Experimental materials

蟾蜍 (60～80g) was provided by the Experimental Animal Center of Suzhou University Medical College, and the experimental animal use license number: SYXK (Su) 2002-0037;

Animal feeding environment: room temperature 22 ° C, humidity 50-60%, good ventilation, artificial day and night (12h / 12h), free access to food and water;

The source of exogenous NADPH drugs can be obtained by artificial synthesis, semi-synthesis, and biological extraction;

(2) Experimental method

The medulla was fixed on the frog plate, the left and right aorta and inferior vena cava were separated, the inferior vena cava was inserted into the venous cannula, the left aorta was inserted into the arterial cannula, and the right aorta was ligated with Ren's solution (1000 mL: NaCl 6.5 g). , KCl 0.14g, CaCl ₂ 0.12g, NaHCO ₃ 0.2g, NaH ₂ PO ₄ 0.01g, glucose 1g, double distilled water) rinse the heart, frog heart clamps the apex, connect the Medlab operating system through the tension transducer, record Normal frog heart beat curve, heart rate and cardiac output, switch into the same amount of low calcium Ren's solution (CaCl ₂ content is 1/2 of Ren's solution) to perfuse the heart, when the heart contraction is significantly weakened, add NADPH to the venous cannula (Purity >97%, Roche, 10621706001), recording changes in heart beat curve, heart rate, and cardiac output.

(3) Experimental results

The effect of NADPH on isolated in situ frog hearts is shown in Figures 1(a), 1(b), 1(c), and 1(d).

It can be seen from Fig. 1(a), 1(b), 1(c), and 1(d) that the heart deficiencies are significantly reduced and the cardiac output is decreased after perfusion of the low-calcium solution. After adding 5μg/mL NADPH or 10μg/mL NADPH to Calcium solution, the contraction amplitude of the isolated frog heart can be significantly increased, the cardiac output is increased, but the heart rate has no significant effect; after 20 minutes of administration, the cardiac effect begins to appear. , the maintenance time is up to 2h.

(4) Experimental conclusion

NADPH can significantly increase the contraction amplitude of the isolated frog heart and increase the cardiac output, but has no significant effect on the heart rate; that is, NADPH has a significant cardiac effect.

Experimental Example 2 Mouse Cardiac Hypertrophy Model Experiment

(1) Experimental materials

SPF grade ICR mice (male, weight 18 ~ 22g) were provided by the Experimental Animal Center of Suzhou University Medical College, experimental animal production license number: XCYK (Su) 2002-2009;

ATPase kit (A070-6), purchased from Nanjing Jiancheng Bioengineering Research Institute;

Isoproterenol (ISO) and captopril (Cap) were purchased from Shanghai Maclean Biochemical Technology Co., Ltd.;

Chloral hydrate is purchased from Sinopharm Chemical Reagent Co., Ltd.;

Electrocardiograph (Kenz, ECG-103).

(2) Experimental method

1) Isoproterenol-induced cardiac hypertrophy in mice

Isoproterenol (ISO) is a non-selective beta-adrenergic receptor agonist. Long-dose administration can increase myocardial contractility and oxygen consumption, and promote intracellular cyclic adenosine monophosphate (cAMP) and sugar. The original synthesis increases the synthesis of total protein and non-shrinking protein in cardiomyocytes, causing cardiac hypertrophy, especially left ventricular hypertrophy.

ICR mice were randomly divided into 6 groups: normal control group, model control group - ISO group, positive control group - ISO + Captopril (Cap) 100 mg / kg, ISO + NADPH 1 mg / kg group, ISO + NADPH 2 mg /kg group, ISO+NADPH 4mg/kg group.

The administration methods of each group were as follows: normal control group was injected subcutaneously (sc) with equal volume of normal saline daily; other groups were injected subcutaneously (sc) ISO twice times, each time 1 mg/kg, 2 times interval 8 h, ISO+ The NADPH 1 mg/kg group, the ISO+NADPH 2 mg/kg group, and the ISO+NADPH 4 mg/kg group were sc ISO every morning. After 4 hours, the corresponding dose of NADPH was intraperitoneally injected. The positive control group was sc ISO every morning, and the corresponding dose was intraperitoneally injected 4 hours later. Cap, model control group was intraperitoneally injected with equal volume of normal saline; continuous administration for 14 days.

2) Mouse echocardiography

The mice were intraperitoneally injected with 4% chloral hydrate 10 mg/kg to remove the chest hair of the mice. The high-resolution small animal ultrasound imaging system (VISUΛLSONICS, VEVO2100) was used. The probe frequency was 8 MHz, placed on the left side of the sternum, and the standard left was selected. The short-axis and long-axis sections of the papillary muscle were combined with M-mode and Doppler ultrasound to measure the ejection fraction (EF) and left ventricular short-axis shortening (FS) of the systolic and diastolic phases of the mouse, respectively. The indoor diameter (LVID), left ventricular posterior wall thickness (LVPW), left ventricular anterior wall thickness (LVAW), and left ventricular volume (LVvol) were averaged over three consecutive cardiac cycles.

3) Determination of mouse electrocardiogram

The mice were intraperitoneally injected with 4% chloral hydrate 10 mL/kg anesthetized, and the needle electrode red was connected with (R) right upper limb, yellow (L) left upper limb, green (LF) left lower limb, black (RF) right lower limb, and electrocardiogram was used. The instrument detects the II lead electrocardiogram with a frequency of 50 Hz and a paper speed of 25 mm/s.

4) Determination of mouse heart weight index

After 14 days of administration, the body weight (BW) of the mice was measured, the anesthesia was sacrificed, the heart was opened by chest, the residual blood was washed with physiological saline, the filter paper was blotted and photographed, and the heart weight (HW) and left were weighed. Left ventricle weight (LVW), calculated heart weight index (HWI=HW/BW) and left heart index (LVWI=LVW/BW). Part of the left ventricle was fixed with 4% neutral formaldehyde, and some left ventricles were stored at -80 °C.

5) HE staining of mouse myocardial tissue

The left ventricular tissue of the apex was fixed in 4% neutral formaldehyde solution, dehydrated with gradient ethanol, embedded in paraffin, sectioned, and stained with HE. The photograph was taken under an optical microscope.

6) Determination of biochemical indicators in mice

The supernatant of the left ventricular tissue of the mice was taken, and the levels of Na ⁺ -K ⁺ , Ca ²⁺ -Mg ²⁺ and T-ATPase in the myocardial tissue were determined by a kit.

(3) Experimental results

The effect of NADPH on reducing ISO-induced cardiac hypertrophy in mice is shown in Figures 2(a), 2(b), and 2(c).

As can be seen from Fig. 2(a), the heart of the model control group was significantly larger than the normal control group, the positive control group, the ISO+NADPH 1 mg/kg group, the ISO+NADPH 2 mg/kg group, and the ISO+NADPH 4 mg/kg group heart. It has been reduced.

It can be seen from Fig. 2(b) that the pathological examination showed that the myocardial cells of the model control group were hypertrophied by HE staining, the nuclei were deeply stained, and the cell spacing became larger; ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg/kg group In the ISO+NADPH 4mg/kg group, the decrease of myocardial cell hypertrophy was more obvious with the increase of NADPH dose; this indicates that NADPH can alleviate the pathological changes of ISO-induced mouse cardiomyocyte hypertrophy.

As shown in Fig. 2(c), the heart HWI and LVWI of the model control group increased significantly after ISO treatment for 2 weeks; compared with the model control group, the positive control group, ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg/kg Heart HWI and LVWI were significantly lower in the group and ISO+NADPH 4 mg/kg group; this indicates that NADPH can effectively alleviate ISO-induced cardiac hypertrophy in mice.

The QRS complex reflects the changes in potential and time during the depolarization of the left and right ventricles. In the left ventricular hypertrophy, the QRS complex voltage increased in the electrocardiogram and the wave group time prolonged. The effect of NADPH on ISO-induced changes in electrocardiogram in mice is shown in Figures 3(a) and 3(b).

As can be seen from Figures 3(a) and 3(b), the QRS amplitude of the model control group was significantly higher than that of the normal control group, indicating that the left ventricular hypertrophy occurred in the mice; the positive control group, ISO+NADPH 1 mg/kg group, ISO+NADPH 2 mg The QRS wave voltage of the mice in the /kg group and the ISO+NADPH 4 mg/kg group decreased; this indicates that NADPH has ameliorating effect on cardiac hypertrophy.

The effects of NADPH on cardiac function in mice are shown in Table 1 and Figure 4.

Table 1 Effect of NADPH on cardiac function in mice

As can be seen from Table 1 and Figure 4, (1) systolic left ventricular diameter (LVIDs), diastolic left ventricular diameter (LVIDd), and left ventricular end systolic volume (LV Vols) in the model control group compared with the normal control group. The left ventricular end-diastolic volume (LV Vold) was significantly increased, while the ejection fraction (EF) and left ventricular short-axis shortening rate (FS) were significantly reduced; this indicates that the model control group developed left ventricular hypertrophy and heart. Reduced function; (2) The above indicators of positive control group, ISO+NADPH 1mg/kg group, ISO+NADPH 2mg/kg group and ISO+NADPH 4mg/kg group have improved to some extent, especially ISO+NADPH 2mg/kg The EF and FS of the group of mice showed an increasing trend; this indicates that NADPH has a mitigating effect on ISO-induced cardiac hypertrophy and cardiac dysfunction.

Na+-K+-ATPase relies on ATP to allow Na ⁺ efflux and K ⁺ influx to maintain Na ⁺ and K ⁺ levels inside and outside the cell; Ca ²⁺ -Mg ²⁺ -ATPase relies on ATP to pump intracellular Ca ²⁺ to The sarcoplasmic reticulum or extracellular to maintain intracellular calcium homeostasis. The effect of NADPH on ATPase content in myocardial tissue of mice is shown in Figure 5.

As can be seen from Fig. 5, compared with the model control group, Na ⁺ -K ⁺ -ATPase in the myocardial tissue of the ISO+NADPH 1 mg/kg group, the ISO+NADPH 2 mg/kg group, and the ISO+NADPH 4 mg/kg group, Both Ca ²⁺ -Mg ²⁺ -ATPase and total ATPase activity were significantly increased.

(4) Experimental conclusion

(1) NADPH can alleviate the pathological changes of myocardial hypertrophy in mice and alleviate cardiac hypertrophy; (2) NADPH can increase Na ⁺ -K ⁺ -ATPase and Ca ²⁺ -Mg ² in myocardial tissue of mice ⁺ -ATPase and total ATPase activity to maintain intracellular ionic homeostasis.

Experimental Example 3 Effect of NADPH on blood pressure in normal rats

(1) Experimental materials

SD rats (male, weight 250-300 g) were provided by the Experimental Animal Center of Suzhou University Medical College;

Non-invasive blood pressure detection system (Kent Scientific, CODA20496).

(2) Experimental method

The blood pressure of non-invasive tail artery was measured in rats. The blood pressure of awake rats was measured by volumetric pressure recording sensor. The rats were kept for 2 days. The blood pressure of the rats was measured by non-invasive blood pressure detection system. The experimental environment was quiet and constant, and the adaptive training started 3 days later. Formal experiment. Divided into two groups: saline group; NADPH 10mg/kg group. Two rats were tested in each experiment. The baseline blood pressure was measured first. After the basal blood pressure was stable, one intravenous saline was injected at 2 mL/kg, and the other intravenously was administered with 0.5% NADPH 2 mL/kg. The intravenous drug was recorded for 30 min, 60 min. Blood pressure after 90 min and 120 min.

(3) Experimental results

The effect of NADPH on blood pressure in normal rats is shown in Figure 6.

It can be seen from Fig. 6 that after 30 minutes, 60 minutes, 90 minutes, and 120 minutes of NADPH administration, the systolic blood pressure, diastolic blood pressure, mean blood pressure, and pulse pressure difference of normal rats were not significantly different from those before administration, and at each time point. There was no significant difference in the saline group (P>0.05).

(4) Experimental conclusion

NADPH had no significant effect on blood pressure in normal rats.

It is apparent that the above-described embodiments are merely illustrative of the examples, and are not intended to limit the embodiments. Other variations or modifications of the various forms may be made by those skilled in the art in light of the above description. There is no need and no way to exhaust all of the implementations. Obvious changes or variations resulting therefrom are still within the scope of the invention.

Claims

The application of NADPH in the preparation of a medicament for treating cardiac hypertrophy.
The use of NADPH in the preparation of a medicament for the treatment of heart failure.
The use according to claim 1 or 2, wherein the medicament comprises a pharmaceutically effective amount of NADPH and a pharmaceutically acceptable carrier.
The use according to claim 3, characterized in that the carrier is selected from the usual pharmaceutical excipients, or physiological saline, or distilled water.
The use according to any one of claims 1 to 4, wherein the drug is NADPH, and a conventional excipient is added according to a conventional process to prepare a clinically acceptable tablet, capsule, powder, mixture, pill, granule. A syrup, a syrup, a plaster, a suppository, an aerosol, an ointment or an injection.
The use according to any one of claims 1 to 5, wherein the administration mode of the drug is selected from the group consisting of oral administration, injection administration, sublingual administration, rectal administration, transdermal administration, and spraying. At least one of inhalation.