Research About Yinning Tablets On Acute Toxicity And Long-term Toxicity, A Clinical Relative Factors Study Of Hyperthyroid Liver Damage

BackgroundHyperthyroidism is general term for a group of diseases that several etiologies caused thyroxine excessive which leaded to the system such as nerve, cardiovascular, digestion excitability increased and metabolic hyperfunction. Hyperthyroidism’s common symptom is the more eaten, the easier hungry, weight loss, debility, cardiopalmus, tachycardia, fatigue, impatience, excitable, etc. The thyroid gland is often diffuse, symmetric mild to moderate swelling. Lots of diffuse thyroid enlargement patients usually have different degree of exophthalmos, severe patients easily into thyroid crisis without adequate treatment and with infection, operation of various stress. The etiology of hyperthyroidism is complicated, and the exact pathogenesis is unclear too. Chinese medicine theory considered that the simple goiter is hyperthyroid many areas. It is generally acknowledged that the causes of this diseases is ferrite Yinkui, kidney Yin deficiency, Yin deficiency an Yang excess of the patient, with the addition of gentle disposition disorders, therefor it became born hyperactivity of fire due to Yin deficiency, Qi-Yin deficiency, block phlegm, and so on. The lesion location of hyperthyroidism involved liver, kidney, lung, spleen, heart, mainly in liver and kidney. Hyperthyroidism often involving many systems and organs, in which common and often easily overlooked is the liver damage. The incidence of hyperthyroidism hepatic damage up to37%-76.7%. A considerable number of patients with hyperthyroidism accompanies hepatic damage, causing abnormal liver function, hepatomegaly, jaundice, etc.It mostly used anti-thyroid medication, radioactive iodine and operation, and so on in modern medicine, but cannot correct the disorder of immune function and have some limitations and side effects. Western medicine antithyroid drug therapy is effective, but the treatment is long, after stopping the high recurrence rate of50to80%. Goiter, exophthalmos and other symptoms is not easy to control, and side effects is severe. Patients with allergic reactions(such as pruritus, rash, fever, about1%～5%), bone marrow effects(leukopenia, thrombocytopenia, anemia,1%), and hepatic, joint pain, edema, alopecia, etc. Operation treatment have indications and contraindications, and easy to injury of the parathyroid and laryngeal nerve. Over the past10years Chinese medicine treatment of hyperthyroidism has been encouraging progress. Syndrome differentiation, treatment means flexible and diverse, curative effect, especially due to neutropenia or liver damage cannot tolerate the treatment of Western medicine, Chinese medicine treatment have unique advantages and characteristics.Yinning tablets are a result of on-chip Guangzhou Hospital of the South side of clinical experience. It is based on theory of TCM (traditional Chinese medicine) and through the modern technology, screened hundreds of Chinese herbal medicine from pharmacology, pathological science perspective. Yinning tablets were composed of nine traditional Chinese medicines such as astragalus, Kunming mountain hitom, turtle shell, angelica, rehmanniae and liquorice. All of these medicines altogether had nourishing yin, softening hardness, detoxifying and resolving efforts. The clinical observation suggests that Yinning tablets had a better clinical effect on Yin-deficiency, phlegm-damp and blood stasis hyperthyroidism. It can effectively eliminate hyperthyroidism symptoms, fast repair the normal function of each system, improved their immune function, in order to cure this disease. And the preliminary experiments showed that Yinning tablets can protect the liver and avoid of anti-thyroid drugs caused liver damage. It filled the treatment drug blank of treat hyperthyroidism and protected liver at the same time.This research will combine multidisciplinary research methods and techniques such as toxicology, pharmacology, animal experimental method and biodemography. Research about Yinning Tablets on acute toxicity and long-term toxicity. A clinical relative factors study of hyperthyroid liver damage by a retrospective analysis of hyperthyroidism cases.PurposeDepending on acute toxicity and long-term toxicity, this passage research about target organ and tissue action of Yinning Tables; to evaluate using safety by analysis clinic index as blood, biological chemistry and pathological technology; in order to reveal hazards degree and mechanism of toxic action; and finally to ensure safety range of Yinning Tablets in clinic usage. A clinical relative factors study of hyperthyroid liver damage, it will provide the basis for prevention and treatment of hyperthyroidism.Methods1. Research about Yinning Tablets on acute toxicitythe40KM mice were randomly divided into two groups according to weight and number, including administration group (32g·kg-1) and blank group, each mouse been administrated for two times in24hours,the time cell is6h. In the time cell and the next14days, observe the general symptom, such as appearance, behavior, excretion, death and intoxication(symptom, degree, intoxication, persistence, reversible), record the weight and food consumption, finally execute the mice, gross anatomy and macroscopic observe the pathological changes of organs.2. Research about Yinning Tablets on long-term toxicityThe48SD rats were randomly divided into four groups, including three administration of different dose (0.6,3,6) g·kg-1and one blank group for control. Above dose equivalent to10,50and100times of clinical daily dose. The long-term toxicity of Yinning tablets in rats was investigated during30d administration time. Rats free feeding and drinking water. When kill the rats, Hematology, blood biochemistry, weights and tissue index, and the pathological change in major organs were investigated. Observe the general symptom every day, such as food intake, behavior, excreta. Record the weight and food consumption each week and timely adjust the dosage according to weight change. Thirtieth days24hours after dosing, anesthetized rats with3%solution of sodium pentobarbital. From the Abdominal aorta blood, determine the hematology index such as RBC, WBC, HGB, PLT, LY. Determine the blood biochemical index such as AST, AST, BIL, TP from the blood serum. Calculate the organ coefficients and routine pathological examination.3. A clinical relative factors study of hyperthyroid liver damageA retrospective analysis of hyperthyroidism cases of our hospital from2008to2010. According to diagnostic standard of liver damage, divide the patients into two groups, including simple hyperthyroidism group and hyperthyroid liver damage group. Diagnostic standard of liver damage as follows:(1) Definitive diagnosis of thyrotoxicosis from clinical symptoms, signs and thyroid function tests.(2) Liver function tests have the following one or more:①Elevated ALT and AST;②Elevated AKP;③Elevated γ-GT;④Elevated TB or DB;⑤TP or ALB drop;⑥Enlargement of the liver.(3)Exclude other causes of liver damage and hepatomegaly.(4) After the control of hyperthyroidism, liver function and hepatomegaly to return to normal. To determine age, sex, duration of disease, liver function and thyroid levels of patients, to analyze the clinical factor of hyperthyroid liver damage.Results1. Yinning tablets on mice acute toxicityMice in each group spirit and autonomic activity in good condition, skin hair clean, excretion of normal, also there were no other toxicity symptom during the dosing interval and14day observation period. Gross anatomy observation by naked eye, the heart, liver, spleen, lung, kidney and other organ abnormalities were found. According to Yinning tablets suspension concentration (0.4g·mL-1) and the mice maximum gastric perfusion volume (40mL·kg-1), to reach the MTD is32g·kg-1, equivalent to534times of daily clinical dosage. Yinning tablets on mouse body weight and food intake were not affected. Gross anatomy of the mouse, observe the organs with the naked eye, the heart, liver, spleen, lung, kidney are no exception.2. Yinning tablets on rat long-term toxicityDuring the administration, rat appearance signs, activity, food intake and excretion are normal of each dose group, and without a death. Yinning tablets on rat body weight, food consumption, organ coefficients were without effect. There was significant difference of minority of Hematology and blood biochemical indexes between the drug group the blank control group. Finally, kill the rats, observe the heart, liver, spleen, lung, kidney and other organs with naked eye, shape, size, color is normal, there was no congestion, swelling, necrosis and other anomalies. Fixed the organs with10%formaldehyde for48h, make pathological section, under light microscope, there are no exception of heart, liver, spleen, lung, kidney and other organs between different dosage groups and the blank control group. 3. A clinical relative factors study of hyperthyroid liver damageThe incidence of liver damage accompanied with hyperthyroid was58.0%; liver damage was not correlated with gender of hyperthyroidism patient (P=0.995); liver damage was not correlated with age of hyperthyroidism patient (P=0.994); the difference was significantly of ALT, AST, TB, DB, IB, TP, ALB, G between the liver damage group and normal group; the difference was not significantly of A/G; the difference was significantly of T3, T4between two groups.Conclusion1. Acute toxicity experiment:acute toxicity was light of Yinning tablets on mice, it does not affect the appearance of symptoms, behavioral activity in mice. So we can not measure the LD50, but the MTD is32g·kg-1. We can conclude that Yinning tablets safe in clinic.2. Long-term toxicity experiment:Lavaged with Yinning tablets (0.6g·kg-1、3g·kg-、6g·kg-1) for30days,the observation of long-term toxicity shows high, medium and low doses of Yinning tablets groups comparing with control group in subjects of general physical condition of rats, as:behavior, food intake, weight, blood, blood biochemical indexes,organ coefficients, an shape of important organs and microscopy examation of pathological section witch had not obviously pathology change and significant difference. But in some part of indicator of hematology index and blood biochemical, medical group have significance difference to compare with control group. The results shows that under the dosage of6g·kg-1for30days, the rats dose not appearance toxicity function.3. Patients with hyperthyroidism are susceptible to liver damage. The seriousness of liver damage is significantly correlated with thyroid hormone level and so on rather than age and gender.