Is Echinacea Toxic to Dogs?

With the development of China's social economy, the country's pet culture has also seen a corresponding rise. More and more pets are entering people's daily lives, with pet dogs being the most commonly kept. The health of pets is also attracting more and more attention. Pet dogs are prone to a number of common diseases, among which canine distemper and canine parvovirus are the main infectious diseases that endanger the dog-keeping industry due to their strong infectivity, high incidence and mortality rates. Currently, there are no effective drugs for the treatment of canine distemper and canine parvovirus. Vaccination has achieved some results in preventing these two diseases, but due to the influence of various factors such as the vaccine itself, the immunization process, maternal antibodies and individual differences, the immune protection rate is low, and diseases break out due to immune failure. To prevent unnecessary economic losses, an effective method is to use drugs that enhance the body's resistance or the efficacy of vaccines, such as immune enhancers, to improve the body's immunity and enhance the efficacy of vaccines.

Echinacea, as a natural herbal medicine, is a good immune enhancer with the advantages of being safe and non-toxic. In addition to enhancing the body's immune system, echinacea can also improve the immune effect of vaccines. The combined use of echinacea and vaccines against major infectious diseases in dogs (such as canine distemper vaccine and canine parvovirus vaccine) can increase the antibody titer after immunization, improve the immunity and resistance of pets, and reduce the incidence of diseases in pets. Extending the application of echinacea to pet dogs can fill the current scarcity of domestic clinical immune enhancers for pets and has broad application prospects.

1 Pharmacological activity

The main active ingredients of Echinacea are caffeic acid derivatives, polysaccharides, glycoproteins and alkylamide compounds [1-2]. Echinacea and its active ingredients have a wide range of pharmacological activities, including immunomodulatory activity, anti-inflammatory activity, antibacterial and antiviral activity, and antioxidant capacity [3-5].

1.1 Immunomodulatory activity

Echinacea has significant immunomodulatory ability and can enhance the body's immune function (both nonspecific and specific immunity). Its immunomodulatory effect is closely related to enhancing the function of macrophages and lymphocytes, and stimulating the production of cytokines and antibodies. Immunomodulatory activity is the most important biological activity of Echinacea.

Echinacea can promote the growth and development of immune organs [3]. Hao Zhihui et al. [6] reported that Echinacea extract in the diet can significantly increase the average daily weight gain of broiler chickens, reduce the feed conversion ratio, and increase the thymus and bursa index. Feng Shanyang [7] reported that Echinacea can significantly increase the bursa, thymus and spleen index of chickens, promote the development of immune organs, and thus enhance the body's specific and non-specific immune functions.

Echinacea can regulate the function and proliferation of immune cells. Echinacea can significantly enhance the killing ability of natural killer (NK) cells in broiler chickens, significantly stimulate the proliferation of T lymphocytes, and promote the proliferation of peripheral blood mononuclear cells [8]. Echinacea extract can significantly increase the CD4+ / CD8+ ratio of the T lymphocyte subset in the peripheral blood of Ross 308 broiler chicks immunized against infectious bursal disease virus [9].

Echinacea can improve the immune function and biochemical indicators of blood. Echinacea can not only increase the serum immunoglobulin level and reduce the total cholesterol level in mice, but also increase the red blood cell RBC-C3bR rosette rate (erythrocyte immune function) and interleukin-2 and tumor necrosis factor-α content in broilers, and can also improve the blood routine indicators [10]. Another study reported that Echinacea can increase the total protein and albumin content in chicken plasma and reduce triglyceride levels [11].

Echinacea can enhance humoral immunity. Studies have shown that Echinacea can enhance the immune response of dogs to canine distemper vaccine and canine parvovirus vaccine and increase antibody titers [12-13]. It can significantly increase the antibody titer of IBDV and Newcastle disease vaccine in the peripheral blood of broilers, and can significantly enhance the antibody titer of NDV [14]. Echinacea can significantly increase the antibody levels of swine fever, swine respiratory and reproductive disorders syndrome vaccine and swine erysipelas [15-17].

1.2 Anti-inflammatory activity

The roots and above-ground parts of Echinacea purpurea contain polyunsaturated isobutylamide, which has immunomodulatory properties and can prevent inflammation caused by pathogens. In addition, the cichoric acid and polysaccharide fractions of Echinacea purpurea also have immunomodulatory and anti-inflammatory activities. Cichoric acid can inhibit hyaluronidase and protect collagen III from the effects of free radicals that can cause degradation [1].

1.3 Antibacterial and antiviral activity

Echinacea purpurea contains chicoric acid and caffeic acid, which have significant antibacterial effects against gram-positive and gram-negative bacteria. The polysaccharides in Echinacea purpurea can exert bacteriostatic and bactericidal effects by mobilizing the body's immune defense function [18]. In addition, Echinacea purpurea can prevent infections caused by Candida albicans [4].

Echinacea stems and leaves and extracts exhibit antiviral activity, and the mechanism of action is related to immune stimulation and anti-hyaluronic acid. Echinacea has a certain inhibitory effect on influenza and herpes viruses, and can also inhibit the activity of hyaluronidase, thereby blocking the binding of viral receptors on the cell surface [19].

1.4 Antioxidant capacity

Echinacea root and its derivatives are a good natural source of antioxidants and can be used to prevent and treat damage caused by free radical induction. Echinacea's cichoric acid and polyphenols have the ability to scavenge and detoxify free radicals in the body, protecting the skin's collagen proteins from free radical damage [5, 20-21].

2 Safety pharmacology

Echinacea has no potential for undesirable adverse effects on the cardiovascular system, respiratory system and central nervous system in animals such as dogs, cats and mice at doses within or above the therapeutic range.

Pang Yunlu et al. [22] studied the effects of Echinacea on heart rate, electrocardiogram, blood pressure and respiration in conscious Beagle dogs. The results showed that oral administration of 0.125–1.25 g/kg Echinacea significantly reduced the heart rate of conscious Beagle dogs, but had no significant effect on the P, T and R waves, Q–T interval, QRS interval, P-R interval and blood pressure and respiration had no significant effect (P > 0.05), which indicates that Echinacea has no significant effect on the respiratory and cardiovascular systems of dogs and is safe and reliable when applied at the effective dose.

Zhang Yingtao et al. [23] reported that after Echinacea purpurea extract equivalent to 5, 10, and 20 g/kg of raw medicine was administered to anesthetized cats via the duodenum, there was no significant effect on blood pressure, electrocardiogram, heart rate, heart rhythm, respiratory rate, or respiratory depth in cats; when Echinacea purpurea was given to mice at 5, 10, or 20 g/kg by gavage once a day for 7 days, there was no significant effect on the mice's spontaneous activity or nervous system.

Zhang Wei et al. [24] observed the effects of different concentrations of Echinacea root powder decoction on the central nervous system, respiratory system and heart rate of healthy Kunming mice for one week by gavage to examine the potential adverse reactions of Echinacea root powder. The results showed that Echinacea root powder had no significant effect on the central nervous system, respiratory system and heart rate of healthy Kunming mice.

3 Toxicological studies

Echinacea and its extracts are relatively low in toxicity and have a wide margin of safety. They are a safe type of Chinese herbal medicine. Echinacea has no carcinogenic, teratogenic or mutagenic effects and no reproductive or genetic toxicity.

EMA reports [25] that Echinacea has low acute toxicity. The LD50 value of fresh pressed Echinacea juice is higher than the recommended maximum dose, for example, higher than the oral dose of 15 g/kg bw in rats, higher than the intravenous dose of 5 g/kg in rats, higher than the oral dose of 30 g/kg bw in mice, and higher than the intravenous dose of 10 g/kg in mice.

The EMA reported the repeated dose toxicity of freshly pressed Echinacea purpurea juice, which was administered at doses of 800, 2400 or 8000 mg/kg bw/day for 4 weeks. Compared with the control group, there were no changes in clinical chemistry indicators or autopsy indicators. The EMA reported that Echinacea is not mutagenic. Regarding the carcinogenicity of Echinacea, the EMA stated that considering that Echinacea is not mutagenic, it is therefore considered unnecessary to conduct carcinogenicity studies.

Zhao Dan et al. [26] studied the teratogenic effects of Echinacea powder on rats to evaluate the reproductive toxicity of Echinacea. Sexually mature SD rats of both sexes were caged and mated. Pregnant rats were randomly divided into three dose groups of high (1 g/kg), medium (0.5 g/kg), and low (0.05 g/kg) dose groups, a negative control group, and a positive control group. The test article was administered orally to the rats from gestation day 7 to 16 to observe the growth and development of the mother rats and their fetuses. The results showed that the weight gain of pregnant rats in each dose group of the test article, the weight of live fetuses, body length and tail length were significantly higher than those of the positive control group (P<0.01), while the number of absorbed fetuses, the number of stillbirths and the malformation rate were significantly lower than those of the positive control group. There were no significant differences in all indicators between each dose group of the test article and the negative control group. The results show that Echinacea purpurea powder has no maternal toxicity, embryotoxicity or teratogenicity in rats.

Xu Peiyu et al. [27] studied the toxicity and teratogenicity of Echinacea purpurea extract in pregnant rats and rat fetuses. The study set up three dose groups based on the recommended human dose, which were 833.3, 1666.6 and 3333.3 mg/kg, respectively equivalent to 25, 50 and 100 times the recommended human dose, and a negative control group and a positive control group. The test subjects were administered orally at 7–16 days of pregnancy, and the relevant indicators of pregnant rats and fetuses were examined. The results showed that the weight gain of pregnant rats in each dose group was normal, and there was no significant effect on the average weight, length and tail length of live fetuses per litter. No external or visceral abnormalities were found, and there was no significant reduction in weight gain in pregnant rats in each dose group. Studies have shown that Echinacea has no maternal toxicity or embryotoxicity, and it is not teratogenic.

Zhao Dan et al. [28] evaluated the potential mutagenicity of Echinacea extract by conducting the Kunming mouse typhoid Salmonella reverse mutation test on Echinacea extract. The experiment used an echinacea extract suspension to perform the Ames test. The plate infiltration method was used to count the number of revertant colonies in TA97, TA98, TA100, and TA102 standard test strains after incubation at 37 °C for 48 h at four different concentrations. The results showed that neither +S9 nor –S9 caused a significant increase in the number of revertant colonies in any of the dose groups, and the Ames test result was negative. This indicates that Echinacea purpurea extract does not cause an increase in the number of revertant mutations in Salmonella typhimurium and has no genotoxicity.

Yu Meng et al. [29] studied the genotoxicity of Echinacea purpurea extract. The conventional methods of the bone marrow cell micronucleus test, mouse sperm deformity test and Ames test were used in the experiment. The results showed that there was no statistically significant difference between each dose group of the Echinacea extract and the negative control group (P>0.05), and there was a statistically significant difference compared with the negative control group (P<0.01). It can be concluded that Echinacea extract has no reproductive genotoxicity in mice and is not mutagenic to Salmonella typhimurium.

4 Clinical application

Echinacea can enhance the antibody titer of dogs against canine distemper vaccine, canine parvovirus vaccine and rabies vaccine, and has a positive effect on the immune system of dogs. It is safe and has no side effects, and can be used clinically as an immune enhancer to enhance the immune effects of dogs against canine distemper vaccine and canine parvovirus vaccine.

Yu Yinxiong [12] studied the clinical application of echinacea root powder in dogs. The test dogs were randomly divided into 4 groups: a low, medium and high dose group and a blank control group. After 7 days of observation, the drugs were administered continuously for 21 days, and then discontinued for 7 days. The test period was 28 days in total. On the 7th, 14th, 21st and 28th days of the test, blood was collected from the radial vein of the forelimb and the serum was separated. to detect the antibody levels of canine distemper virus (CDV) and canine parvovirus (CPV) in the serum, and to measure the levels of interleukin (IL-2, IL-6, IFN-α, and LYS). The results showed that Echinacea root powder can increase the IL-2 content in the peripheral serum of immunized dogs, reduce the IL-6 content, and increase the LYS content, and can maintain a certain concentration level for a certain period of time.

Guan et al. [13] studied the immune enhancing effect of Echinacea root preparations on canine distemper virus (CDV) and canine parvovirus vaccine (CPV). Twenty-five healthy poodle puppies were randomly divided into five test groups, with five puppies in each group. All test dogs were vaccinated with live attenuated vaccines, and side effects were observed for three consecutive days. Groups 1 to 4 were given oral doses of 0.1 g/kg, 0.2 g/kg, 0.4 g/kg or 0.8 g/kg of the Echinacea preparation daily, while group 5 served as a control group. After 21 days of administration of the Echinacea preparation, the dogs were observed for a further 7 days. The titer of serum antibodies to CPV and CDV was measured using enzyme-linked immunosorbent assay (ELISA) on days 7, 14, 21 and 28 of the study, and the results were analyzed using one-way analysis of variance. The results showed that the antibody titer increased significantly after oral administration of Echinacea preparations, and was positively correlated with the dose. Dogs in group 4 (0.8 g/kg) had significantly higher antibody titers against canine distemper virus and canine parvovirus at all time points. The study showed that Echinacea can be used as an immune enhancer to increase the efficacy of canine distemper vaccine and canine parvovirus vaccine.

Niu Xiaofei et al. [30] studied the effect of echinacea on the immunogenicity of the canine distemper vaccine. The experiment randomly divided healthy dogs into two groups, the test group and the control group, with eight dogs in each group. Based on the results of the antibody level test, all dogs were vaccinated against canine distemper at 45 days of age. The test group was given 20 ml of Echinacea extract orally every day from 45 to 60 days of age, while the control group was given the same dose of saline. Blood was taken from the forelimbs of the test dogs at 45, 60 and 75 days of age, centrifuged and the serum prepared.

The serum microneutralization test was used to determine the antibody titer of canine distemper virus (CDV) in the serum. The results of the study showed that at 45 days of age, the puppies had a low maternal antibody titer, which was at the critical point of effective protection. At this time, they were vaccinated against canine distemper, and by 60 days of age, the puppies were once again in a state of effective antibody protection. The antibody titer of the experimental group was significantly higher than that of the control group. At 75 days of age, the antibody titer decreased, but it was still within the range of effective protection, and the antibody titer of the experimental group was still significantly higher than that of the control group. The study showed that the antibody titer of the experimental group fed with Echinacea purpurea extract was significantly higher than that of the control group fed normally, and Echinacea purpurea had a strengthening effect on the vaccine immunity of dogs.

Torkan et al. [31] studied the effect of oral Echinacea extract on the immune system of dogs. Fourteen healthy dogs were randomly divided into two treatment groups. The first group was given 5% Echinacea extract twice a day for two months, and the second group was given drinking water as a control. On days 0, 30 and 60, blood was taken from the test dogs for hematological and immunological tests. The blood tests included packed cell volume, hemoglobin, red blood cell count, white blood cell count, neutrophil count, lymphocytes, monocytes, eosinophils, basophils and B cells. Blood samples were also used to test for IgM and macrophage phagocytic percentage. The results showed that the blood of the dogs in the Echinacea group had significantly higher packed cell volume, haemoglobin, red blood cell count, white blood cell count, neutrophil count, lymphocyte count, phagocytic percentage and IgM levels. At the same time, it was observed in the experiment that Echinacea has a positive effect on the immune system. The red blood cell pressure, hemoglobin, phagocytic percentage and IgM of animals in the Echinacea group changed significantly over time. The study showed that Echinacea extract has immunostimulatory activity in dogs.

Sgorlon et al. [32] studied the effect of adding four nutrients, including Echinacea, to the diet of dogs. The study used 74 dogs for the experiment, with 24 healthy dogs as controls. The dogs in the test group were fed four nutrients, including Echinacea, for 60 consecutive days, with 14 dogs in the Echinacea test group. The test dogs were weighed and blood plasma samples were collected at the beginning (day 0) and end (day 60) of the experiment. The effect of the Echinacea supplement group was reflected in significantly lower levels of tumor necrosis factor (TNF) and nuclear factor (NFKB1) in the plasma, and an increase in plasma zinc concentration. The results of the study showed that Echinacea, as a nutritional supplement, can regulate the immune response of the animal body and improve the health status of the animal body.

5 Conclusion

The immune-enhancing effect of Echinacea in animal health care is gradually being recognized. In China, Echinacea powder and Echinacea oral liquid have been approved for use in improving the immune effect of the Newcastle disease vaccine in chickens, Echinacea root powder has been approved for use in enhancing the immune effect of the porcine reproductive and respiratory syndrome vaccine and the Newcastle disease vaccine in chickens, and Echinacea granules have been approved for use in enhancing the immune response of the swine fever vaccine and the Newcastle disease vaccine in chickens. Currently, no related Echinacea products have been approved for use in dogs in China. Therefore, the development of Echinacea for use in dogs to enhance their immune response to vaccines has broad market application prospects.

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