CN108403679B - Application of L-thyroxine sodium in preparation of medicine for treating renal injury caused by depleted uranium - Google Patents
Application of L-thyroxine sodium in preparation of medicine for treating renal injury caused by depleted uranium Download PDFInfo
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- General Health & Medical Sciences (AREA)
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- Public Health (AREA)
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Abstract
The invention relates to application of L-thyroxine sodium in preparation of a medicine for treating renal injury caused by Depleted Uranium (DU), which can effectively treat thyroid and renal injury caused by DU, is beneficial to reducing medication under the condition of simultaneously suffering from the two injuries, and provides a new way for treating the thyroid and renal injuries. The application also has the effect of safe use.
Description
Technical Field
The invention relates to application of L-thyroxine sodium, in particular to application of L-thyroxine sodium in preparation of a medicine for treating renal injury caused by depleted uranium.
Background
Depleted Uranium (DU) is a substance composed primarily of uranium-238, and because of its good penetration and inexpensive raw materials, it is widely used in nuclear power plants, counterweights, radiation protection, and military activities (e.g., as armor materials and ammunition components). During the production and experiment of DU, there may be irregular operation to release it into the environment, enter the body through respiratory tract, digestive tract or skin, and cause damage to the body.
DU emits high-linear energy-transfer α and β particles, which are both radiotoxic and heavy metal toxic, and their biological effects are related to various factors, such as exposure dose, duration, and exposure route. Because of radioactivity, the traditional Chinese medicine composition can cause acute or chronic functional damage to an organism, wherein the influence on the thyroid function and the renal function is particularly obvious; the injury to renal function caused by DU is called DU nephrotoxicity. For the treatment of DU nephrotoxicity, currently, the drug excretion-promoting treatment methods are mainly used, such as excretion-promoting treatment with sodium bicarbonate, catechol compounds, hydroxypyridones compounds, etc., however, these methods have the following problems: sodium bicarbonate can cause disturbance of the aqueous electrolyte; the catechol compound is greatly influenced by pH and has low gastrointestinal absorption rate; the hydroxypyridones have high renal toxicity, so that a safe and effective DU detoxification drug is not available at present.
The effective component L-thyroxine sodium in Youmetone is a thyroid hormone, is white or brown crystalline powder, is insoluble in water and ethanol, has water solubility of 0.15 g/L (25 deg.C), pH of 8.3-9.5, and is soluble in mineral acid, alkali hydroxide, sodium bicarbonate, etc. Synthetic L-thyroxine sodium contained in r-metolac, which is identical to thyroxine naturally secreted by the thyroid gland, is converted into triiodothyronine (T3) in peripheral organs, like endogenous hormones, and then exerts its specific action by binding to the T3 receptor. Replacement therapy for hypothyroidism in general; non-toxic treatment of goiter (normotothyroidism); preventing recurrence of goiter after goiter resection; the antithyroid drug is used for the adjuvant treatment of hyperthyroidism; post-operative inhibition therapy of thyroid cancer; thyroid inhibition test, etc.
Disclosure of Invention
The invention aims to provide application of L-thyroxine sodium in preparation of a medicine for treating DU-induced thyroid or/and kidney injury, which can effectively treat the DU-induced thyroid and kidney injury, is beneficial to reducing medication under the condition of simultaneously suffering from two injuries, provides a new way for treating the thyroid and kidney injury, and has the effect of safe use.
The technical scheme of the invention is as follows: the application of L-thyroxine sodium in preparing medicine for treating thyroid and/or renal injury; thyroid and/or kidney injury treated with this application is caused by DU.
The dosage of the L-thyroxine sodium is 20-80 mg/kg/day.
The L-thyroxine sodium (Youmele) is provided by Merck KGaA, Darmstadt, and the specification is 100 mg/tablet, wherein the content of the L-thyroxine sodium is 50 ug/tablet. Human body test data show that the application of levothyroxine in different periods of pregnancy has no toxic effect on fetuses, causes no deformity, does not damage fertility, has no mutagenesis information so far, and has no any sign that thyroid hormone can cause genome change to damage offspring. Therefore, the nail polish is safe and effective.
The cellular experiments of the applicant show that the L-thyroxine sodium has the treatment effect on the cells damaged by DU when the L-thyroxine sodium is 125-875 nmol/L, wherein the treatment effect is the best at 625 nmol/L; animal experiments show that the L-thyroxine sodium can effectively treat thyroid and kidney injuries of rats caused by DU.
Drawings
FIG. 1 shows the results of an experiment for treating DU-injured cells with L-thyroxine sodium;
FIG. 2 is the experimental result of Free triiodothyronine (FT 3) in animal model of L-thyroxine sodium treatment of DU injury;
FIG. 3 is the experimental result of Free Thyroxine (FT 4) of the animal model for treating DU injury by L-Thyroxine sodium;
FIG. 4 is the result of the triiodothyronine (T3) experiment in animal model of the L-thyroxine sodium treatment of DU injury;
FIG. 5 shows the results of Thyroxine (T4) experiments in animal models of L-Thyroxine sodium treatment of DU-injured cells;
FIG. 6 shows the results of the blood Urea Nitrogen (UREA) experiment of the animal model for treating DU injury with L-thyroxine sodium;
FIG. 7 shows the results of serum Creatinine (CREA) experiments in animal models of DU-induced injury treated with L-thyroxine sodium.
Detailed Description
Materials and instruments
(1) Materials:
youmele (Merck KGaA, supplied by Darmstadt);
rat alveolar type II epithelial cells (RLE-6 TN) (Shanghai Ganning Biotech Co., Ltd.);
1640 medium (gibco);
cell Counting Kit-8(CCK-8) reagent (Dongli chemical technology (Shanghai) Co., Ltd.);
DMSO (import), fetal bovine serum (gibco), DU, ultrapure water (made in Perl water system).
(2) The instrument comprises the following steps:
constant temperature incubator (Labserv CO-150 type, Thermo Fisher Scientific);
super clean bench (suzhou jiabao purification engineering equipment limited);
low speed automatic balance centrifuges (LDZ 5-2, Beijing King Liji centrifuge Co., Ltd.);
microplate reader (Milli-Q Integral 5), 96-well plate.
(3) The preparation method of the medicine comprises the following steps:
the Youmele tablet is prepared into powder, a proper amount of L-thyroxine sodium is weighed, the L-thyroxine sodium suspension is suspended by ultrapure water, the L-thyroxine sodium suspension is absorbed, DMSO is added in a ratio of 1:1 to dissolve the L-thyroxine sodium suspension (sodium bicarbonate is not used for directly dissolving Youmele, carbonate has a discharge promoting effect on DU, and the problem that the solution PH is too high, so that cells are damaged and experiments are interfered is avoided). The L-thyroxine sodium solution was diluted 1000-fold with medium to give a final solution of 0.02 ug/UL.
Second, the embodiment
Example 1 cell experiments
(1) The experimental method comprises the following steps: RLE-6TN cells are inoculated in a 96-well plate, 5000 cells/well are placed in a constant-temperature incubator to be cultured for 24 hours, 125, 250, 375, 500, 625, 750, 875 and 1000 nmol/L of L-thyroxine sodium solution is added into a plurality of groups of wells, and a normal control group and a control group are simultaneously set up, so that 10 groups are total. And putting the mixture into a constant-temperature incubator for incubation for 1h, adding 500 umol DU into each hole except a normal control group, culturing for 24h, adding CCK-8, and detecting the OD value at 450 nm by using an enzyme-labeling instrument after culturing for 2 h.
(2) Results
And (3) detecting data:
experimental results of treating DU-injured cells by L-thyroxine sodium
| NC | |
125 | 250 | 375 | 500 | 625 | 750 | 875 | 1000 | |
| 1.931 | 0.517 | 0.869 | 0.707 | 1.028 | 0.955 | 1.010 | 1.074 | 0.794 | 0.537 | |
| 1.484 | 0.523 | 0.533 | 0.738 | 1.124 | 0.823 | 1.006 | 1.075 | 0.540 | 0.624 | |
| 1.917 | 0.522 | 0.567 | 0.800 | 0.907 | 1.226 | 1.288 | 0.831 | 0.772 | 0.418 | |
| 1.811 | 0.460 | 0.566 | 0.685 | 0.845 | 1.362 | 1.414 | 1.133 | 0.767 | 0.517 | |
| 1.853 | 0.501 | 0.656 | 0.767 | 0.702 | 0.991 | 1.235 | 1.036 | 0.732 | 0.506 | |
| Mean value of | 1.799 | 0.505 | 0.656 | 0.740 | 0.925 | 1.071 | 1.180 | 1.028 | 0.718 | 0.521 |
| Standard deviation of | 0.183 | 0.026 | 0.151 | 0.046 | 0.188 | 0.218 | 0.205 | 0.134 | 0.119 | 0.074 |
As a result: when depleted uranium is added, cell viability drops significantly. After the treatment of the eumet, the cell survival rate is obviously increased compared with that of a control group. However, the more the nail polish is not used, the higher the cell survival rate is, and when the drug amount reaches a certain degree, the cell survival rate is not influenced positively, and even the survival rate is possibly lower. From the above data, it was found that the cell survival rate was the highest when the amount of the added Youmetone was 625 nmol/L. See fig. 1.
And (4) conclusion: both low and high doses of the drug have a therapeutic effect on DU-damaged cells, but too high a dose may cause the damage to be exacerbated.
Example 2 animal experiments
(1) Materials: sprague Dawley male rats, body weight 200 + -20 g, Youmetone (Merck KGaA, supplied by Darmstadt), DU, ultrapure water.
(2) The instrument comprises the following steps: syringe, stomach filling needle
(3) The preparation method of the medicine comprises the following steps: making the Youmetone into powder, weighing an appropriate amount, suspending Youmetone with ultrapure water, sucking the suspension, when in use, suspending the solution uniformly, sucking an appropriate amount (calculated by the content of L-thyroxine sodium), adding into ultrapure water, mixing uniformly, and administrating by intragastric administration.
(4) The experimental method comprises the following steps: 30 Sprague Dawley male rats (body weight 200 + -20 g) were randomly divided into 5 groups and 6 groups, namely, normal group (NC), control group (C), 20 ug/kg treatment group, 40 ug/kg treatment group and 80 ug/kg treatment group. The NC group is normally raised without any treatment; group C, intraperitoneal injection of DU 5 mg/kg is carried out, and treatment is not carried out; 20 ug/kg of the group, 20 ug/kg of Youmeile (calculated according to L-thyroxine sodium) per day, and DU 5 mg/kg is injected into the abdominal cavity after 1.5h of first intragastric administration; 40 ug/kg treatment group, 40 ug/kg stomach-filling Youmele every day, 1.5h stomach-filling for the first time, and injecting DU 5 mg/kg in abdominal cavity; 80 ug/kg, 80 ug/kg of Youmeile per day, and DU 5 mg/kg is injected into the abdominal cavity after the first intragastric administration for 1.5 h. DU was injected only once. The 20 ug/kg treatment group, 40 ug/kg treatment group and 80 ug/kg treatment group were continuously perfused for 4 days, and serum was collected on day 5 to detect the values of Free triiodothyronine (FT 3) (unit: pmol/L), Free Thyroxine (FT 4) (unit: pmol/L), triiodothyronine (T3) (unit: nmol/L), Thyroxine (T4) (unit: nmol/L), blood Urea Nitrogen (Urea Nitrogen, UREA) (unit: mmol/L) and blood Creatinine (Creatinine, CREA) (unit: μmol/L).
(5) Results
And (3) detecting data:
mean value of serum detection for each group
| FT3 | FT4 | T3 | T4 | UREA | CREA | |
| NC | 3.99 | 13.97 | 1.50 | 52.16 | 7.57 | 24.67 |
| C | 1.54 | 9.84 | 0.78 | 29.38 | 33.98 | 190.92 |
| 20ug/kg | 1.54 | 10.88 | 0.73 | 34.46 | 34.35 | 210.86 |
| 40ug/kg | 1.90 | 13.28 | 0.75 | 39.86 | 30.12 | 169.48 |
| 80ug/kg | 1.54 | 15.51 | 0.78 | 44.76 | 27.52 | 164.14 |
As a result: after DU injection, damage is caused to thyroid and kidney, FT3, T3, FT4 and T4 are reduced, and UREA and CREA are increased. After 4 days of continuous treatment of the eumet hance, FT3 and T3 do not rise obviously, the expression levels of FT4 and T4 are obviously increased compared with the control group, and the treatment effect is in direct proportion (in a certain range) to the drug amount, which indicates that the treatment effect of the eumet hance on the thyroid injury caused by DU is good. The kidney of the rat is also severely damaged by DU injection, the increase of creatinine and urea is abnormal and obvious, and the creatinine and urea are reduced to a certain extent compared with the control group after 4 days of continuous treatment by the Youmele, which indicates that the Youmele also has a certain treatment effect on the kidney damage caused by the DU. See fig. 2-7.
And (4) conclusion: the Youmeile can effectively treat the thyroid and kidney injuries of the rats caused by DU.
Claims (2)
1. Application of L-thyroxine sodium in preparing medicine for treating renal injury caused by depleted uranium is provided.
2. Use according to claim 1, characterized in that: the dosage of the L-thyroxine sodium is 20-80 mg/kg/day.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727473A (en) * | 2011-04-08 | 2012-10-17 | 复旦大学 | Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102727473A (en) * | 2011-04-08 | 2012-10-17 | 复旦大学 | Pharmaceutical usage of N,N'-1,2-ethanediylbis[N-[(2,3-dihydroxyphenyl) methyl]]-glycine and derivatives thereof |
Non-Patent Citations (5)
| Title |
|---|
| L-thyroxine-induced hyperthyroidism affects elements and zinc in rats;Baltaci AK et al.;《Bratisl Lek Listy》;20131231;第114卷;125-128 * |
| Metallothionein deficiency aggravates depleted uranium-induced nephrotoxicity;Yuhui Hao，et al;《Toxicology and Applied Pharmacology》;20150703;第287卷;306-315 * |
| Thyroid hormones modulate zinc transport acitivity of rat intestinal and renal brush-border membrane;Rajendra Pradsa,et al.;《American Journal of Physiology》;19991231;第276卷;E774-782 * |
| Zinc Protects Human Kidney Cells from Depleted Uranium-induced Apoptosis;Yuhui Hao et al.;《Basic&Clinical Pharmacology&Toxicology》;20141231;第114卷;271-280 * |
| 铀的急性肾毒性及其救治方法研究进展;郝玉徽等;《中华放射医学与防护杂志》;20130430;第33卷(第2期);207-211 * |
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