Diclofenac sodium, also known as diclofenac, is the third generation of potent non-steroidal anti-inflammatory drugs. In recent years, it has been widely used in animal medicine for antipyretic and analgesic, and has therefore become a clinically "aspirin" in veterinary medicine. Some veterinarians or veterinary pharmacies have also applied this medicine to the treatment of animal diseases such as neuritis, arthritis and fever caused by various inflammations. The effect is remarkable and has been highly evaluated in veterinary clinics. In view of this, in order to effectively promote the scientific application of diclofenac sodium in China's veterinary clinic, and accelerate the research and development of this drug in China, the author consulted relevant research data, and reviewed the latest research progress of the drug for reference.
I. Study on the mechanism of pharmacological action
As a phenylacetic acid derivative, diclofenac sodium is a non-steroidal anti-inflammatory analgesic. It was first developed and used in clinical practice by Ciba-Geigy Pharmaceutical Co., and was launched in 1974. It was synthesized in China in 1985 and has been produced in many domestic pharmaceutical companies. Meevog A reported that the drug is clinically used for anti-inflammatory, analgesic, antipyretic and anti-rheumatic effects, and its anti-inflammatory and antipyretic effects are strong. Because it has the advantages of good curative effect, small side effects and long-term application non-accumulation in similar drugs, it has been applied in more than 120 countries and regions in 1995 and is one of the best-selling drugs in the world.
Prashant M and other research reports that the drug's mechanism of action mainly inhibits the metabolism of arachidonic acid by inhibiting the cyclooxygenase pathway. At the same time, it also promotes the binding of arachidonic acid to triglyceride (triacylglycerol). Reduce the concentration of free arachidonic acid in the cells, thereby indirectly inhibiting the synthesis of leukotrienes.
Second, the study of pharmacodynamics
Diclofenac sodium is more common in China's synthetic process and clinical reports in human medicine. In veterinary clinic, it is mainly used to treat fever and syndromes caused by cold syndrome, and it has been found that the drug has strong resistance. Inflammation, analgesia and antipyretic effects are more effective than aspirin, paracetamol and indomethacin, about 26 to 50 times that of aspirin. In 2001, experts from the Experimental Veterinary Medicine Factory of Shandong Academy of Agricultural Sciences took the lead in the development of medical diclofenac sodium into veterinary diclofenac sodium injection. The dosage form added taurine, which enhanced the clinical efficacy and reduced diclofenac sodium. The toxic side effects broaden the use of diclofenac sodium. The veterinary diclofenac sodium injection has an effective rate of more than 98% in the prevention and treatment of fever, painful diseases, rheumatoid arthritis, muscle damage and the like, and the cure rate is over 95%, in order to solve the febrile fever disease. A class of effective control drugs was provided. After clinical application to more than 370 million pigs, the mortality of pigs was reduced and the economic benefits of farmers were reversed. Foreign experts have studied the use of diclofenac sodium in mammals, and relatively few studies on poultry. In foreign countries, because people pay special attention to animal welfare, Machin, Cheng and Kestin and other scholars have studied the application of diclofenac sodium in broiler leg squats and laying hens. It has been found that diclofenac sodium can improve the walking ability and increase of broiler chickens. Feeding performance of broken hens.
However, it has been found that chickens are sensitive to diclofenac sodium. Intramuscular injections can cause mental dysfunction, and diclofenac sodium is rarely reported in poultry. If the dose is too large, it is easy to cause poisoning.
Third, the study of pharmacokinetics
Diclofenac sodium is rapidly absorbed and completely absorbed, and the plasma half-life is short, and the peak time is fast. Therefore, it takes 3-4 times a day to maintain the drug effect, and the blood drug concentration produces a "peak and valley" phenomenon, and the drug can be reduced with the food. Absorption rate. The drug has a half-life of about 2 hours and a plasma protein binding rate of 99%.
The therapeutic concentration of diclofenac sodium in the blood circulation can be achieved by different routes of administration of the various formulations. Oral, intravenous or intramuscular injection due to first-pass elimination by the liver, low bioavailability, and certain hepatotoxicity and gastrointestinal reactions. Transdermal administration can eliminate its gastrointestinal tract irritation, but absorption is limited by the stratum corneum barrier, and the passive diffusion transdermal rate is small. It is necessary to add a penetration enhancer to promote transdermal delivery of the drug. At the same time, transdermal administration is toxic and easy to administer, but due to the large individual differences in drug concentration, individualized administration should be promoted. Oral sustained-release, controlled-release preparations overcome the above disadvantages to a certain extent and have a long-lasting effect, which can reduce the number of administrations. Diclofenac sodium has a high peak in rectal administration and high bioavailability, and is effective for treating acute symptoms such as post-operative pain.
Fourth, the study of toxicology
Diclofenac sodium is a powerful antipyretic drug. Veterinarians have tried to use it for fever, inflammation, etc. caused by arthritis, neuralgia, and cold syndrome. However, poultry is very sensitive to it and is very toxic to chickens. Some people think that the toxic mechanism is sodium ion, which can cause urate deposition in chickens, mainly as gout-like lesions and high mortality.
However, studies on the toxicity of diclofenac sodium in animal toxicity have so far been reported in very small amounts. In foreign countries, Oaks et al. studied the toxic effects of vultures on diclofenac sodium. It was found that vultures suffered from visceral gout after they were fed with diclofenac sodium poisoned poultry. In addition, Reddy et al. studied the toxicity of diclofenac sodium and nimesulide in chickens under experimental conditions. In China, Shuqiang et al first reported the toxicity test of diclofenac sodium on chickens in 2001. Liu Qihong et al reported in 2006 the toxicity test of chicken oral diclofenac sodium on chickens. Zhao Zengcheng reported the poisoning of diclofenac sodium in broilers in 2007. In the diagnosis and treatment, Fu Zhifa et al reported in 2008 the diagnosis and treatment of poisoning caused by oral administration of sodium diclofenacate in chickens. Qi Yufeng also reported in 2011 that fur animals were treated with drugs containing sodium diclofenac to cause poisoning. Diagnosis and treatment. Regarding the toxicity of diclofenac sodium in poultry, Irtaza Hussain et al. studied the toxic effects of diclofenac on chicks, pigeons, quails and starlings.
In the teratogenic study on animals, the dose of the mice was 5,000 times that of humans, and the rats and rabbits were used up to 2500 times. No teratogenic effects were found, although these amounts had reached toxicity to the mother and the fetus. The toxicity of the mother to diclofenac sodium is dystocia, prolonged pregnancy, and decreased fetal weight, growth and survival rate. It can be seen that diclofenac sodium can penetrate the placental barrier of rats and mice.
V. Research on clinical application
Because China is a large country for animal husbandry, the number of chickens, ducks, geese and oysters is huge. In view of the good anti-inflammatory, analgesic and antipyretic effects of diclofenac sodium, the drug is of great significance in the prevention and control of mammalian and avian diseases. Therefore, from the veterinary clinical, pathological anatomy, histopathology and serum biochemistry, the pathogenic mechanism is explored, and the pharmacological mechanism, toxicity and safety range of diclofenac sodium can be comprehensively studied, which can not only fill the diclofenac sodium in poultry research in China. The blank can also fill the gap in the international study on the toxicity of diclofenac sodium to other poultry, which has important practical significance and high economic value.
In the study, Irtaza Hussain et al. pointed out that in all experimental animals, chicks had the most serious clinical symptoms, followed by pigeons and Japanese cockroaches, and the youngest brother had the mildest clinical symptoms. Serum urea levels did not change significantly in chicks, but decreased significantly on pigeons and significantly increased on baboons and starlings. Diclofenac sodium oral doses of 10 mg and 20 mg per kilogram of chicks had visceral gout, while the same dose did not observe gout in Japanese cockroaches and starlings. Anatomical findings showed that the kidneys and liver of all the experimental animals were swollen, and histological examination showed tubular necrosis, hepatic steatosis and hepatocyte necrosis. Diclofenac sodium oral doses of 10 mg and 20 mg per kilogram of chicks and pigeons have urate crystals and substantial lesions in the liver and kidneys.
In view of China's largest poultry farming country in the world, various diseases of poultry are prevalent and occur in different degrees each year. In the prevention and control of diseases, drug prevention and treatment still occupy the main aspects. Therefore, studying the toxic effects of diclofenac sodium on poultry is helpful to guide veterinary drug manufacturers to correctly organize formulas and guide farmers to use drugs correctly. It is also conducive to promoting the application of diclofenac sodium in veterinary clinics in China, and has prevention and control of diseases in poultry industry in China. Significance.
Sixth, the study of avian adverse reactions
The adverse reactions of diclofenac sodium to poultry are mainly manifested in toxic effects and urate deposition. In veterinary clinics, chickens are very sensitive to diclofenac sodium. If a little overdose can cause chicken poisoning or even death, some experts have reported this.
How diclofenac sodium causes chicken urate deposition, the mechanism of action is currently unclear. However, the two methods are more likely. One is that diclofenac sodium interferes with the metabolism of sputum and increases the production of uric acid. Second, it damages the kidney, resulting in decreased renal urate clearance and reduced excretion. The exact mechanism of action requires further research. In view of the fact that the only excretion pathway for uric acid in chickens is the kidney, renal function damage affects the clearance of urate in the renal tubules, which inevitably leads to difficulty in excretion of urate and deposits on the surface of organs and tissues. Uric acid exists in two forms in the body: one in protein-bound form, combined with a stable concentration of uric acid; the other is in free form, and when the amount of uric acid produced by metabolism in the body is too high, the concentration of free uric acid is greatly increased. At the same time, the solubility of uric acid is very low.
Closed study and other studies found that: uric acid is discharged in the form of soluble urate, diclofenac sodium is mainly distributed in the liver, kidney, spleen, etc., the highest concentration in the blood, due to the low solubility of diclofenac sodium urate, making it The above-mentioned organs and tissues are deposited in large amounts, and uric acid poisoning occurs due to urate excretion disorder. In the research experiment, Liu Qihong et al found that diclofenac sodium and ammonium chloride share water, and the death of chickens increases under the same conditions. The author has repeatedly encountered cases of chicken urate deposition caused by diclofenac sodium, but not in pigs and other mammals. See this situation. The reason is that due to the lack of arginase in poultry, the final metabolite of strontium is uric acid, not urea in mammals.
Seven, summary
As a strong non-steroidal anti-inflammatory analgesic drug, veterinary diclofenac sodium has good anti-inflammatory and analgesic effects in veterinary clinic. In order to promote the scientific application of the drug in China's veterinary clinic, we will increase the investment in the drug, speed up the research and development of new dosage forms, ensure the safe measurement range of the drug, and provide a healthy development and disease prevention and treatment for the poultry industry in China. continue trying.
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