Use of dimetridazole in the preparation of a medicament for treating feline diarrhea

Abstract

The present application relates to the field of veterinary medicine, in particular to the application of dimetridazole in the preparation of a medicine for treating cat diarrhea. The present application first discovers the new medical use of the compound dimetridazole, and proposes to use it for preparing a medicine for treating cat diarrhea. Secondly, the present application also provides a dimetridazole chewable tablet preparation for treating cat diarrhea, which has a short healing cycle and good treatment effect. The dimetridazole chewable tablet preparation has high light stability, good dissolution and less side effects. It has been proved by experiments that the dimetridazole chewable tablet preparation has very good curative effect and can greatly shorten the treatment cycle of cat diarrhea.

Description

[0001] This invention is a divisional application of Chinese Patent Application 202211272996.2, filed on October 18, 2022. The original application was entitled "Application of dimetridazole in the preparation of drugs for treating feline diarrhea, a dimetridazole preparation for treating feline diarrhea". Technical Field

[0002] This invention relates to the field of veterinary drugs, and in particular to the use of dimetridazole in the preparation of drugs for treating feline diarrhea. Background Technology

[0003] Demeton-methyl, chemically known as 1,2-dimethyl-5-nitroimidazole, has the molecular formula C5H7N3O2 and a molecular weight of 141.13. Its structural formula is as follows:

[0004]

[0005] The compound is an off-white or slightly yellow powder that is unstable under light and gradually turns black upon exposure to light. It is odorless or essentially odorless and soluble in chloroform, ethanol, dilute alkalis and dilute acids, but insoluble in water and ether.

[0006] The approved indications for dimetridazole are: prevention of swine diarrhea caused by spirochetes, and prevention and treatment of histomoniasis and hexatriginosis in poultry. It is known to be used to treat avian vibriosis hepatitis, necrotic tissue infection, and histomoniasis in turkeys. A search revealed no reports of its use in the preparation of drugs for treating feline diarrhea.

[0007] Trichomoniasis in pigs is a newly discovered protozoan disease in recent years, and it is most commonly seen in piglets as persistent diarrhea, which is one of the important causes of diarrhea in piglets. In order to screen the ideal drug for treating this disease, the article "Observation on the Therapeutic Effect of Different Drugs on Trichomoniasis in Pigs" carried out relevant research. The study treated pigs by adding 1500g of 20% dimetridazole per 1000kg of feed. The results showed that due to drug resistance and the problem of concurrent infection with other intestinal bacteria (such as Escherichia coli and Salmonella) after infection with Trichomoniasis, the use of dimetridazole alone could not completely cure the pigs. Although Trichomoniasis was not detected in fecal examination, some pigs still had diarrhea, and the treatment effect was not ideal. Summary of the Invention

[0008] The primary objective of this invention is to propose a novel application of dimetridazole in the preparation of drugs for treating feline diarrhea;

[0009] A second objective of this invention is to provide a dimetridazole formulation for treating feline diarrhea;

[0010] A third objective of this invention is to provide a method for preparing dimetridazole chewable tablets;

[0011] The fourth objective of this invention is to propose the use of dimetridazole preparations or dimetridazole chewable tablets in the preparation of drugs for treating feline diarrhea.

[0012] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0013] This invention first proposes the application of the compound dimetridazole in the preparation of drugs for treating feline diarrhea.

[0014] The approved indications for dimetridazole are: prevention of swine diarrhea caused by spirochetes, and prevention and treatment of histomoniasis and hexatriginosis in poultry. Clinically, it is mainly used to treat avian vibriosis hepatitis, necrotic tissue, and histomoniasis in turkeys. A search has not yet found any reports on the use of dimetridazole in the preparation of drugs for treating feline diarrhea.

[0015] There are many causes of diarrhea in cats, but most are due to infections caused by protozoa such as amoebae, toxoplasmosis, trichomoniasis, coccidia, and Giardia lamblia, or bacteria such as Salmonella, Campylobacter, Clostridium perfringens, Staphylococcus, and Escherichia coli. The principle behind treating feline diarrhea caused by protozoan infections with the compound dimetridazole is that dimetridazole inhibits the redox reaction of protozoa, causing the nitrogen chain to break. The principle behind treating feline diarrhea caused by anaerobic bacterial infections with dimetridazole is that the iron-sulfur protein in anaerobic bacteria reduces the nitro groups; the reduction product interacts with DNA, causing damage, breakage, and unwinding of the bacterial DNA helix, ultimately leading to bacterial death.

[0016] Trials of drugs using dimetridazole as the active ingredient to treat feline diarrhea have shown that dimetridazole is highly effective in treating feline diarrhea. For example, with a dose of 40 mg / kg twice daily, the cure rate exceeded 50% on the first day of administration, reaching 55.6%, and by the sixth day of administration, all cats were cured, with a cure rate as high as 100%.

[0017] Preferably, the cat diarrhea is caused by protozoa.

[0018] As a further preferred option, the protozoan is Trichomonas fetus.

[0019] Compared to other protozoa that cause diarrhea in cats, *Trichomonas fetus* has certain unique characteristics. For a long time after its discovery in cats, due to limitations in detection technology, *Trichomonas fetus* was often confused with *Trichomonas vaginalis* or even *Giardia lamblia*, leading to misdiagnosis and mistreatment in clinical practice. It wasn't until 2001 that *Trichomonas fetus* was first identified using molecular biology methods as the pathogen of feline trichomoniasis, causing chronic intestinal diarrhea in cats. Its morphological characteristics include three anterior flagella and one posterior flagella, along with a wavy membrane extending along the body. The axon of *Trichomonas fetus* is a rigid rod-shaped tissue that penetrates the trophozoite and protrudes from the posterior end, with a length of approximately 10–25 micrometers and a width of approximately 3–15 micrometers.

[0020] In addition to the diseases mentioned above, the clinical indications for dimetridazole also include avian trichomoniasis, bovine trichomonas disease, and swine trichomonas disease. It should be noted that avian trichomoniasis differs significantly from feline fetal trichomonas. Avian trichomoniasis is oval or elliptical in shape, measuring (5–19) × (2–9) micrometers. Compared to the three anterior flagella of feline fetal trichomonas, avian trichomoniasis has four free flagella originating from the anterior end of the parasite. Furthermore, although cats, cattle, and pigs are all mammals, the genotypes, hosts, target organs, diseases caused, drug sensitivity, and mechanisms of action of these three types of trichomoniasis differ considerably, making conversion between them challenging.

[0021] (1) Different genotypes of Trichomonas vaginalis. A series of studies have been conducted on the identification of feline, bovine, and porcine Trichomonas vaginalis isolates. Through DNA sequencing, studies have found a single nucleotide polymorphism in the transcriptional spacer region of feline and bovine fetal Trichomonas vaginalis. In addition, there are certain differences in 10 gene loci, including protein-coding genes such as cysteine ​​protease, malate dehydrogenase 1, and ITS sequence. Current research shows that there are also significant genetic differences between porcine and feline fetal Trichomonas vaginalis.

[0022] (2) The target organs and diseases caused by Trichomonas vaginalis are different. In bovine fetal trichomonas disease, the bovine reproductive system is the target organ of Trichomonas vaginalis, which can cause inflammation of the bovine reproductive system, infertility and early abortion. In swine trichomonas vaginalis, it colonizes the hollow organs of domestic pigs, including the stomach, cecum and colon, and mainly causes intractable diarrhea in piglets. In feline fetal trichomonas vaginalis colonizes the distal ileum and colon, which can cause lymphoplasmacytic and neutrophilic colitis, as well as chronic foul-smelling diarrhea.

[0023] Furthermore, the article "Observation on the therapeutic effects of different drugs on trichomonas vaginalis in pigs" mentions that using dimetridazole alone to treat diarrhea in pigs cannot completely cure the disease due to drug resistance issues and the problem of secondary infection with other intestinal bacteria after infection with trichomonas vaginalis. Some pigs still have diarrhea. According to the literature (Andersen, LA et al. (2018) Prevalence of enteropathogens in cats with and without diarrhea in four different management models for unowned cats in the southeast United States. Vet J 236:49–55.), 39% of cats with diarrhea symptoms are associated with Trichomonas infection. Currently, rominidazole is reported to be the only effective drug for treating feline fetal Trichomonas, with a treatment cycle of more than two weeks. However, due to the significant toxicity of rominidazole, which can cause neurotoxicity (Plumb's Veterinary Drug Handbook (2008) p. 807), lethargy, vomiting, etc., and has strong teratogenicity, it is listed as a prohibited drug. Therefore, there is a strong need to develop a safe and effective drug for feline fetal Trichomonas. The present invention uses dimetridazole to treat diarrhea caused by feline fetal Trichomonas with unexpected results.

[0024] This invention utilizes dimetridazole to treat diarrhea caused by feline trichomonas fetus. By controlling the dosage, the problem of drug resistance is solved, achieving a short-term, one-time eradication of the trichomonas with excellent results. Specifically, an efficacy study of dimetridazole in treating feline diarrhea caused by feline trichomonas fetus showed that after one week of treatment, the stools of all nine affected cats returned to normal, and all feline trichomonas fetus tests were negative, resulting in a 100% effective rate and a 100% cure rate.

[0025] This invention provides a dimetridazole formulation for treating feline diarrhea, with dimetridazole as the active ingredient and also containing other pharmaceutically acceptable excipients.

[0026] Preferably, the pharmaceutically acceptable excipients include one or more of the following: fillers, sweeteners, lubricants, flow aids, colorants, and palatability enhancers.

[0027] As a further preferred option, the formulation is a chewable tablet.

[0028] The existing dimetridazole drugs are dimetridazole premixes, but they have the following disadvantages:

[0029] (1) The existing method of using dimetridazole premix is ​​to stir a certain amount of premix into the diet or dissolve it in drinking water. Due to the poor stability and blackening of dimetridazole products, its actual utilization rate for treatment is not high, and it is not easy to store and use, which easily leads to waste.

[0030] (2) Existing dimetridazole premixes are bitter and have poor palatability, which will reduce animal feed intake and ultimately lead to insufficient drug intake, thus affecting the clinical efficacy of the drug.

[0031] (3) Existing dimetridazole premix has a certain degree of irritation to the respiratory mucosa and obvious side effects;

[0032] (4) Existing dimetridazole premixes are easily affected by various acids, bases and enzymes during the absorption process in the body, which leads to a decrease in efficacy.

[0033] This invention provides a dimetridazole chewable tablet for treating feline diarrhea. By modifying the dosage form and adding colorants, the light contact area and light transmittance of the formulation are reduced, significantly improving the drug's light stability. In comparison, the maximum single impurity of existing dimetridazole premixes after 30 days of light exposure is approximately 37 times that of the dimetridazole chewable tablet of this invention under the same light conditions, while the total impurity is approximately 7.4 times higher. This demonstrates that the light stability of the dimetridazole chewable tablet of this invention is significantly superior to that of the dimetridazole premix, making it easier to store. Furthermore, the dimetridazole chewable tablet provided by this invention corrects the bitterness of dimetridazole by adding sweeteners and palatability enhances its taste and palatability, leading to higher cat obedience and thus higher drug utilization. Compared to dimetridazole premixes, the dosage is easier to control, reducing waste. Furthermore, the dimetridazole chewable tablets of the present invention can be directly absorbed through the sublingual capillaries after chewing, resulting in rapid absorption, high bioavailability, and minimal side effects. They do not pass through the gastrointestinal tract or enterohepatic circulation, do not burden the gastrointestinal tract, do not damage the liver, and do not have a first-pass effect, resulting in high blood drug concentrations.

[0034] As a further preferred embodiment, the mass fractions of each component of the dimetridazole preparation are: dimetridazole 25-35, filler 35-55, sweetener 5-25, lubricant 1-3, gliding agent 1-3, colorant 2-5, and palatability enhancer 2-10.

[0035] As a further preferred option, the filler includes one or more of direct-pressed lactose, microcrystalline cellulose, pregelatinized starch, mannitol, sorbitol and xylitol.

[0036] As a further preferred option, the sweetener includes one or more of aspartame, sucralose, sodium saccharin, and sorbitol.

[0037] As a further preferred option, the lubricant includes one or more of magnesium stearate, talc, and polyethylene glycol 6000.

[0038] As a further preferred embodiment, the flow aid comprises colloidal silica.

[0039] As a further preferred embodiment, the colorant includes one or more of Sunset Yellow, Tartrazine, Amaranth, Carmine, Fruit Green, Indigo, β-carotene, and Grape Violet.

[0040] As a further preferred option, the palatability enhancer includes one or more of beef flavoring, chicken flavoring, fish flavoring, and shrimp flavoring.

[0041] A method for preparing dimetridazole chewable tablets for treating feline diarrhea includes the following steps:

[0042] (S.1) Mix dimetridazole, filler, sweetener, lubricant, gliding agent, colorant and palatability enhancer thoroughly to obtain a mixed powder;

[0043] (S.2) The mixed powder is compressed into tablets to obtain dimetridazole chewable tablets.

[0044] As a further preferred embodiment, (S.1) includes the following steps:

[0045] a. Sift the filler and colorant together and mix thoroughly;

[0046] b. Sift the mixture obtained in step a together with dimetridazole and the palatability enhancer, and mix thoroughly.

[0047] c. Sift the mixture obtained in step b together with the sweetener, lubricant, and gliding agent, mix them evenly, and obtain a mixed powder.

[0048] The aforementioned dimetridazole preparation or dimetridazole chewable tablets are used in the preparation of drugs for treating feline diarrhea.

[0049] Verification has shown that the dimetridazole chewable tablets of the present invention have a good therapeutic effect on feline diarrhea. For example, when the dosage is 40mg / kg and administered twice daily, the cure rate reaches 55.6% on the first day of administration, and all cats are cured by the sixth day of administration, with a cure rate as high as 100%.

[0050] As a further preferred embodiment, the cat diarrhea is cat diarrhea caused by protozoa.

[0051] As a further preferred option, the protozoan is Trichomonas fetus.

[0052] Diarrhea in cats caused by Trichomonas fetus is difficult to diagnose, persistent, prone to recurrence, and highly contagious, posing a certain threat to the health of cats. Currently, the most effective drug used in veterinary clinical practice is ronidazole, but its shortest treatment period is as long as two weeks, and due to the significant toxicity of ronidazole, it has considerable side effects.

[0053] Verification showed that the dimetridazole chewable tablets of the present invention were effective in treating diarrhea caused by feline fetal trichomonas. After one week of treatment, no persistent soft stools or bloody stools were observed in the nine affected cats, and their stools all returned to normal. Furthermore, all fetal trichomonas tests in the affected cats were negative, with a drug efficacy rate of 100% and a cure rate of 100%. This significantly shortened the treatment period for feline diarrhea, and no obvious side effects were observed throughout the entire treatment process.

[0054] Compared with the prior art, the present invention has the following advantages:

[0055] (1) This invention has discovered new medical uses for the known compound 1,2-dimethyl-5-nitroimidazole, opening up a new application field with good pharmaceutical prospects;

[0056] (2) The dimetridazole chewable tablets of the present invention have a very significant effect in treating feline diarrhea, with strong pharmacological effects, high cure rate, and short treatment cycle;

[0057] (3) The dimetridazole chewable tablet provided by the present invention reduces the light contact area by changing the dosage form and adding coloring agent, which greatly improves the light stability of the drug, facilitates storage, and ensures high drug safety.

[0058] (4) The present invention provides a demetronidazole chewable tablet that corrects the bitterness of demetronidazole by adding sweeteners, palatability enhancers, etc. The chewable tablet has a good taste and good palatability, cats have high obedience, and the drug utilization rate is higher. Compared with demetronidazole premix, the feeding dosage is easier to control and less likely to cause waste.

[0059] (5) The dimetridazole chewable tablets of the present invention can be directly absorbed by the sublingual capillaries after chewing. The absorption speed is fast and the bioavailability is high. Since it does not pass through the gastrointestinal tract and liver circulation, the side effects are small, it will not burden the gastrointestinal tract, will not damage the liver, and will not have the first-pass effect. The blood concentration of the drug in the body is high.

[0060] (6) The preparation method of the dimetridazole chewable tablets for treating feline diarrhea of ​​the present invention is simple, easy to operate, and does not require complicated equipment and preparation steps. Detailed Implementation

[0061] The present invention will be further described below with reference to specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0062] The standardized preparation method for dimetridazole chewable tablets described in the following examples is as follows:

[0063] (S.1) Pass the dimetridazole, coloring agent and palatability attractant through a 100-mesh sieve respectively, and set aside;

[0064] (S.2) Weigh the prescribed amount of filler and colorant together and pass them through a 30-mesh sieve, then mix them thoroughly;

[0065] (S.3) The mixture obtained in (S.2) is combined with the prescribed amount of dimetridazole and palatability enhancer and passed through a 30-mesh sieve and mixed evenly;

[0066] (S.4) The mixture obtained in (S.3) is combined with the prescribed amounts of sweetener, lubricant and gliding agent and passed through a 30-mesh sieve. The mixture is then thoroughly mixed to obtain a mixed powder.

[0067] (S.5) The mixed powder is compressed into tablets to obtain dimetridazole chewable tablets, each of which weighs 200 mg. Example 1

[0068] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0069] Demeton-methyl: 30 parts; direct-pressure lactose: 52 parts; sorbitol: 10 parts; magnesium stearate: 2 parts; sunset yellow: 1 part; beef flavoring: 5 parts. Example 2

[0070] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0071] Demeton-methyl: 30 parts; Direct-pressed lactose: 32 parts; Sorbitol: 15 parts; Magnesium stearate: 1 part; Colloidal silica: 1 part; Fruit green: 3 parts; Fish flavoring: 18 parts. Example 3

[0072] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0073] Demeton-methyl: 35 parts; Pregelatinized starch: 35 parts; Aspartame: 9 parts; Talc: 3 parts; Colloidal silica: 3 parts; Carmine: 5 parts; Shrimp flavoring: 10 parts. Example 4

[0074] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0075] Demeton-methyl: 25 parts; Mannitol: 55 parts; Sucralose: 5 parts; Talc: 1 part; Colloidal silica: 2 parts; Amaranth: 2 parts; Chicken flavoring: 10 parts. Example 5

[0076] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0077] Demeton-methyl: 30 parts; xylitol: 40 parts; sodium saccharin: 19 parts; polyethylene glycol 6000: 2 parts; colloidal silica: 1 part; indigo: 3 parts; chicken flavor: 5 parts. Example 6

[0078] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0079] Demeton-methyl: 28 parts; Sorbitol: 45 parts; Sucralose: 15 parts; Polyethylene glycol 6000: 3 parts; Colloidal silica: 3 parts; β-carotene: 4 parts; Shrimp flavoring: 2 parts. Example 7

[0080] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0081] Demeton-methyl: 32 parts; Microcrystalline cellulose: 37 parts; Aspartame: 25 parts; Talc: 1 part; Colloidal silica: 1 part; Tartrazine: 2 parts; Fish flavoring: 2 parts. Example 8

[0082] A type of dimetridazole chewable tablet, the components and their mass fractions are as follows:

[0083] Demeton-methyl: 30 parts; Direct-pressed lactose: 34 parts; Sorbitol: 16 parts; Magnesium stearate: 1 part; Colloidal silica: 1 part; Grape purple: 3 parts; Chicken flavor: 15 parts.

[0084] To test the light stability, dissolution, and therapeutic effect of the dimetridazole chewable tablets prepared according to this invention, the following verification experiments were conducted:

[0085] Verification Experiment 1: Light Stability Test

[0086] (1) Test sample: Dimetridazole chewable tablets prepared in Example 2;

[0087] (2) Comparative sample: Dimetridazole premix (manufacturer: Hefei Zhonglong Shenli Animal Pharmaceutical Co., Ltd.; approval number: Veterinary Drug No. 120151143);

[0088] (3) Determination method: High performance liquid chromatography (HPLC) as specified in Section IV, General Chapter 0512 of the 2020 edition of the Chinese Pharmacopoeia, as follows:

[0089] a. Solution preparation

[0090] Preparation of test solutions: Take appropriate amounts of the test sample and control sample and place them in different brown volumetric flasks. Dissolve and dilute with methanol to prepare test solution and control solution containing approximately 0.5 mg of sample per ml.

[0091] Preparation of control solutions: Accurately measure 0.5 ml of the test sample solution and the control sample solution, respectively, and place them in different 100 ml volumetric flasks. Dilute with methanol to the mark and shake well to obtain the test sample control solution and the control sample control solution.

[0092] Preparation of system suitability solution: Take an appropriate amount of demetronidazole system suitability reference standard (containing impurity 1), dissolve and dilute it with methanol to prepare a solution containing 0.5 mg demetronidazole and 2.5 μg impurity 1 per 1 ml.

[0093] b. Chromatographic conditions

[0094] Octadecylsilane-bonded silica gel was used as the packing material; water-methanol (80:20) was used as the mobile phase; the flow rate was 1.0 ml / min; the detection wavelength was 310 nm; and the column temperature was 30 °C.

[0095] c. Determination method

[0096] Accurately measure 10 μL each of the test sample solution and the reference sample solution, and inject them into the liquid chromatograph. Record the chromatograms up to twice the retention time of the main component peak. Perform the same method on the control sample. To minimize error, if the chromatogram of the test sample solution contains a peak with the same retention time as impurity 1 in the system suitability solution, its peak area must not exceed the peak area of ​​dimetridazole in its own reference solution; the peak areas of other unknown impurities must not exceed the peak area of ​​dimetridazole in its own reference solution.

[0097] (4) Place the same test sample and the control sample under a light intensity of 4500±500Lx for 10 days and 30 days, and use the above determination method to detect the content of related substances again.

[0098] (5) The contents of relevant substances were calculated by peak area using the external standard method as follows:

[0099]

[0100] (6) The above test results show that when the storage condition is 0 days, the impurity 1, maximum single impurity, and total impurity of the test sample are all less than those of the control sample, indicating that the dimetridazole chewable tablets of the present invention are slightly better than the existing dimetridazole premix. After 10 days of light treatment, the impurity content of the control sample changed significantly, especially the maximum single impurity content, which reached 24 times that of the initial test and the total impurity content reached 3.8 times that of the initial test. After 30 days, the maximum single impurity reached about 37 times that of the initial test and the total impurity reached about 7.9 times that of the initial test. It can be seen that the light stability of the control sample dimetridazole premix is ​​poor and it is difficult to store for a long time. However, after 10 days and 30 days of light treatment, the impurity content of the test sample changed very little. In terms of the maximum single impurity, after 30 days of light treatment, its content is about 1 / 37 of the maximum single impurity of the dimetridazole premix under the same light conditions. It can be seen that the light stability of the dimetridazole chewable tablets of the present invention is significantly better than that of the dimetridazole premix and it is easier to store.

[0101] Verification Test 2: Dissolution Test

[0102] (1) Test sample: 12 tablets of dimetridazole chewable tablets prepared in Example 1 were taken;

[0103] (2) Dissolution test method: The method is as follows: Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0931, Method I. The dissolution medium is pH 1.0 hydrochloric acid solution, volume 900 ml, rotation speed 50 r / min. After 30 minutes, take 10 ml of solution, filter it, and take the filtrate as the dissolution stock solution. Accurately measure 2 ml of the dissolution stock solution, put it in a 10 ml brown volumetric flask, add dissolution medium to dilute and make up to volume, shake well, and the test solution is obtained. Take the above test solution and measure its absorbance at 275 nm and 439 nm with a UV-Vis spectrophotometer. Calculate the dissolution rate using the dual-wavelength equal absorption difference method.

[0104] (3) The dissolution results are as follows:

[0105]

[0106] (4) The above test results show that the average dissolution rate of the dimetridazole chewable tablets prepared in Example 1 of the present invention is as high as 96.9% in 30 min, which far exceeds the tablet dissolution standard, and the dissolution is good with high bioavailability.

[0107] Verification Experiment 3: Examination of the therapeutic effect on feline diarrhea

[0108] (1) Selection of test subjects: 54 cats with diarrhea were clinically enrolled and divided into 6 groups, each numbered 1-10, 11-20, 21-29, 30-38, 39-46, and 47-54 respectively. The treatment drugs for the first to fourth groups were dimetridazole chewable tablets prepared in Example 1. The fifth and sixth groups were positive control groups, which were given enrofloxacin tablets and metronidazole tablets respectively.

[0109] (2) Specific administration parameters: Group 1, dosage 30 mg / kg, once daily; Group 2, dosage 40 mg / kg, once daily; Group 3, dosage 30 mg / kg, twice daily; Group 4, dosage 40 mg / kg, twice daily; Group 5, dosage of enrofloxacin 5 mg / kg, twice daily; Group 6, dosage of metronidazole 15 mg / kg, once daily.

[0110] (3) Clinical efficacy observation: After one week of continuous administration, the diarrhea status of the cats was observed, and a cat diarrhea observation table was prepared. "√" indicates that the stool has returned to normal, "×" indicates that the stool has not returned to normal and diarrhea continues, and "√a" indicates that the stool has not returned to normal and has turned into soft stool. D0 represents the first day of administration, D1 represents the second day of administration, D2 represents the third day of administration, and so on. The clinical efficacy observation results are as follows:

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117] (4) Data Summary: Summarize the above experimental data table and calculate the cure rate of the relevant drugs. The cure rate calculation formula is: Drug cure rate = Number of cats in this group whose stool returned to normal / Total number of cats in this group. The summary cure rate table is as follows:

[0118]

[0119] (5) The above experimental results show that: when the dimetridazole chewable tablets prepared in Example 1 of this invention are used to treat feline diarrhea, the experimental results show that after one week of treatment, the vast majority of cats are cured. Among them, at a dosage of 40 mg / kg twice a day, the average cure rate of cats on the first day of administration (D0) reaches 55.6%, and on the sixth day of administration (D5), the stools of all 9 cats in the group have returned to normal, with a cure rate as high as 100%. However, in the group that uses enrofloxacin and metronidazole to treat feline diarrhea, after one week of administration, only 7 cats have stools that become soft, with a cure rate of 0%.

[0120] Verification Experiment 4: Evaluation of the efficacy of treatment for feline diarrhea caused by Trichomonas fetus.

[0121] (1) Selection of test subjects: A total of 9 cats with diarrhea caused by fetal trichomoniasis were included in the clinical group and numbered 1 to 9;

[0122] (2) Specific administration parameters: The dimetridazole chewable tablets prepared in Example 1 were administered at a dose of 20 mg / kg once a day for one week, and the diarrhea was observed.

[0123] (3) Clinical efficacy observation: The diarrhea status of the affected cats was observed, and an efficacy assessment form for feline diarrhea caused by Trichomonas fetus was created. "√" indicates that the stool has returned to normal, and "×" indicates that the stool has not returned to normal and diarrhea persists. After one week of treatment, fecal tests for Trichomonas fetus were performed on the affected cats. "Negative" indicates no detection, and "positive" indicates that the cat is persistently infected with Trichomonas fetus. The experimental results are as follows:

[0124]

[0125] (4) The above experimental results show that after one week of treatment with dimetridazole chewable tablets, the stool of all 9 affected cats returned to normal, and the fetal trichomonas test of the affected cats was negative. The drug efficacy rate was 100% and the cure rate was 100%. Specifically, the efficacy rate was 55.6% on day 3 (D2), 66.7% on day 4 (D3), 88.9% on day 5 (D4), and reached 100% on day 7 (D6). Compared with ronidazole, the current first-line drug for treating feline diarrhea caused by fetal trichomonas, the treatment cycle was shortened by half, and no obvious side effects were found during the entire treatment process, making it safe and reliable.

Claims

1. The application of the compound dimetridazole in the preparation of drugs for treating feline diarrhea, characterized in that, The cat diarrhea is caused by a protozoan, namely Trichomonas fetus; Trichomonas fetus colonizes the distal ileum and colon and causes lymphoplasmacytic and neutrophilic colitis.

2. The application according to claim 1, characterized in that, The fetal trichomonas caused chronic foul-smelling diarrhea.

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