Formula and application of compound infertility agent containing clarithromycin and quinestrol and based on CYP enzyme activity inhibition

Abstract

The invention discloses a formula and application of a compound infertility agent containing clarithromycin and quinestrol and based on CYP enzyme activity inhibition. The clarithromycin composition comprises clarithromycin, quinestrol and baits. The CYP enzyme inhibitor and the endocrine sterilant are combined for use, so that the synergist can effectively inhibit the activity of CYP enzyme in tissues such as livers of rats, the metabolic clearance rate of the sterilant is remarkably reduced, and the oral bioavailability and the system exposure level of the sterilant are improved. Therefore, when the same infertility effect is achieved, the use dosage of the infertility agent can be greatly reduced, so that the cost is saved, and the environmental load is reduced; or under the same dosage, a more thorough and more lasting population sterility effect can be obtained, and the practicability and competitiveness of a pest mouse sterility control technology are greatly improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pest control, and particularly relates to a formula of a compound rodent sterilizing agent containing clarithromycin and quinestrol based on inhibition of CYP enzyme activity and application thereof. BACKGROUND

[0002] The overpopulation of rodents poses a continuous threat to agricultural production, ecological balance and human health. Compared with traditional acute rodenticides, the rodent control technology based on endocrine disruption has the advantages of mild action, strong targeting and environmental friendliness, and is considered as an important development direction for sustainable rodent control. Among them, steroid hormones (such as levonorgestrel and quinestrol) as typical endocrine sterilizing agents can simulate or antagonize endogenous hormones, interfere with the normal reproductive cycle of rodents, and cause infertility, so as to achieve long-term population inhibition from the source.

[0003] However, such sterilizing agents still face significant challenges in practical application. The core problem lies in the high expression of cytochrome P450 enzyme system in rodents, especially in the liver. CYP enzymes are the most important drug metabolism I phase functional enzyme system in organisms, which is responsible for the oxidation metabolism of endogenous and exogenous compounds to facilitate excretion. When rodents ingest steroid hormone sterilizing agents, they will be quickly recognized and catalyzed by CYP enzymes (such as CYP3A and CYP2C subtypes) for metabolism, resulting in hydroxylation, dealkylation and other reactions, which leads to the decomposition and inactivation of the original drug, shortens the biological half-life, and ultimately the effective blood drug concentration reaching the reproductive target organs (such as ovaries and testes) is much lower than the theoretical design level. This "first-pass effect" and systematic accelerated metabolism seriously weaken the actual efficacy of the sterilizing agent, forcing people to increase the dosage, which not only increases the cost, but also brings potential ecological toxicology risks.

[0004] To solve the above problems, researchers have tried various ways, but the effects are not ideal. For example, simply increasing the dose of sterilizing agents is not only uneconomical, but also may cause ecological safety problems due to the intake of non-target organisms; developing new sterilizing agent molecules faces barriers such as long research and development cycle, high cost and strict registration and approval. Therefore, seeking a synergistic strategy that can precisely intervene in the metabolic pathway of rodents and effectively improve the bioavailability of existing endocrine sterilizing agents has become a technical bottleneck that needs to be broken through in the field. SUMMARY

[0005] To achieve the above purpose, the technical scheme adopted by the present application is as follows: a formula of a compound rodent sterilizing agent based on inhibition of CYP enzyme activity, which has strong CYP enzyme inhibition activity, the synergist is used in combination with quinestrol to achieve the reduction and synergistic effect of quinestrol.

[0006] The present inventors creatively turn the research perspective to the specific inhibition of CYP enzymes. By introducing a highly efficient and safe CYP enzyme inhibitor, the key drug metabolism channel in the liver and other tissues of the pest rodents is temporarily "turned off" or "weakened" during the administration period, thereby slowing down the decomposition rate of the steroidal contraceptive and prolonging its action time, achieving the reduction of the contraceptive dosage and the increase of the efficiency. This strategy does not need to change the existing mature contraceptive varieties, and can significantly improve the performance of the rodent control, providing a new technical solution for the green and efficient control of rodent pests.

[0007] The present application first provides the use of clarithromycin as a reduction-in-dosage and increase-in-efficiency agent of quinestrol in rodent control.

[0008] The present application also provides a compound rodent contraceptive formula based on the inhibition of CYP enzyme activity, characterized in that it comprises clarithromycin, quinestrol and food bait.

[0009] Preferably, the mass percentage of each component is as follows: clarithromycin 0.0001%-1.0%; quinestrol 0.001%-1.0%; and the rest is food bait.

[0010] Preferably, the food bait is made of one or any combination of rice, rice, wheat, corn, soybean, peanut raw materials or their products.

[0011] Preferably, the formula further comprises one or more of edible oil, edible sugar and milk powder, and in hot and humid areas, edible sugar and milk powder can be replaced by saccharin and creamer, so that the rodenticide is not easy to ferment or attract insects. Further preferably, the content of edible oil is 0.1%-1% of the total weight of the finished product; the content of edible sugar is 0.1%-5%; and the content of milk powder is 0.1%-5%.

[0012] The present application also provides the use of the above formula in rodent control.

[0013] The present application has the following advantages:

[0014] By using the CYP enzyme inhibitor in combination with the endocrine contraceptive, the synergist can effectively inhibit the CYP enzyme activity in the liver and other tissues of the pest rodents, significantly reduce the metabolic clearance rate of the contraceptive, and improve the oral bioavailability and systemic exposure level. This makes it possible to significantly reduce the dosage of the contraceptive while achieving the same sterilization effect, thereby saving costs and reducing environmental load; or under the same dosage, a more thorough and longer-lasting population sterilization effect can be achieved, greatly improving the practicality and competitiveness of the rodent sterilization control technology. DETAILED DESCRIPTION

[0015] The following examples are further illustrations of the present application and are not intended to limit the present application.

[0016] Example 1:

[0017] Select the bait combination according to the dominant rat species in different areas to increase palatability and attractiveness. Take rice as an example to prepare two examples of compound rodenticide with moderate Chinese medicine:

[0018] 1. Take 1000 grams of rice and put it in a container. Take 0.5 grams of clarithromycin, 0.1 grams of ethinyl estradiol, 10 grams of edible oil, and 10 grams of sugar and dissolve them in 500 milliliters of hot water containing 0.5% Tween 80. Pour it into the container containing 1000 grams of rice, mix well, soak for 24 hours, and stir frequently during the soaking period. Dry at room temperature and it is ready for use. This concentration of rodenticide is suitable for fixed-point mass release, with 50-500 grams per release point depending on the rat density.

[0019] 2. Take 1000 grams of rice and put it in a container. Take 1.0 grams of clarithromycin, 1.0 grams of ethinyl estradiol, 10 grams of edible oil, and 10 grams of sugar and dissolve them in 500 milliliters of hot water containing 1.0% Tween 80. Pour it into the container containing 1000 grams of rice, mix well, soak for 24 hours, and stir frequently during the soaking period. Dry at room temperature and it is ready for use. This concentration of rodenticide is more suitable for multiple-point scattering in rat activity sites, with 20-100 grams per pile.

Claims

1. Use of clarithromycin as a reducing synergist of quinestrol in rat extermination.

2. A formula of a compound sterilant for killing mice based on inhibiting CYP enzyme activity, characterized in that: The bait comprises clarithromycin, quinestrol and food.

3. The formulation of claim 2, wherein, The mass percentage of each component is as follows: clarithromycin 0.0001%-1.0%; quinestrol 0.001%-1.0%; and the rest is food.

4. The formulation of claim 2 or 3, wherein, The food is made of one or any combination of rice, paddy, wheat, corn, soybean, peanut raw material or products thereof.

5. The formulation of claim 2, wherein, The formula further comprises one or several of edible oil, sugar and milk powder, and in hot and humid areas, sugar and milk powder can be replaced by saccharin and creamer.

6. The formulation of claim 5, wherein, The edible oil content is 0.1%-1% of the total weight of the finished product, the sugar content is 0.1%-5%, and the milk powder content is 0.1%-5%.

7. Use of the formula of any one of claims 2-6 in rat extermination.