Our pets – dogs and cats. Let’s keep them in good health with peptide bioregulators

Kozhevnikova E.O., Linkova N.S., Saburova I.Y., Pinaev R.N.

Relevance. As society progresses and the general quality of life improves, more and more families are opting to adopt pets, with dogs and cats being the most prevalent. According to a report by the American Pet Products Association (APPA), by 2021, 70% of American families were pet owners [1]. The owning of a pet positively impacts human mental and physical health [2-4]. Considering dogs and cats as family members has become a global trend. Since dogs and cats have increasingly become important to human life, ensuring their health is a significant matter.

Diseases most commonly found in dogs and cats

1. 1. Inflammatory bowel disease is the most prevalent cause of chronic vomiting and diarrhea in canines and felines [5]. The term «inflammatory bowel disease» is used to describe a group of conditions characterized by persistent or recurrent inflammation of parts of the gastrointestinal (GI) tract in dogs and cats. Inflammatory bowel disease (IBD) is a multifactorial disease characterized by chronic enteropathies that can significantly affect the quality of life. The exact etiology of the irritated bowel system is unknown. The factors associated with gastrointestinal (GI) inflammation are believed to originate from both genetic and external causes, such as nutrition and ecology. The state of the local immune system of the mucous membranes of the GI organs plays an essential role in the maintenance of GI functions in animals [6-7].

   The clinical manifestations of inflammatory bowel disease encompass a wide spectrum of symptoms, including vomiting, diarrhea, blood in the stool, weight loss, and appetite disturbances. A number of breeds of dogs have been identified as being predisposed to chronic intestinal disease, including the Soft Coated Wheaten Terrier, Basenji, Boxers, French Bulldogs, German Shepherd Dog, Norwegian Puffin Dog, and Yorkshire Terrier. While The genetic underpinning of inflammatory bowel disease in cats are not yet fully elucidated, studies have proposed that Siamese and other Oriental breeds may exhibit a heightened susceptibility to developing IBD [8-9]. An endoscopic investigation accompanied by mucosal biopsy of the GI tract is imperative for substantiating a diagnosis of IBD and ascertaining its stage. The most prevalent endoscopic abnormalities observed in dogs and cats with IBD encompass mucosal friability, augmented granularity and erosions of the GI mucosa. The management of IBD poses significant challenge due to the ambiguous etiology underlying the condition. Given the pivotal role of the immune system in the pathogenesis of inflammatory bowel diseases, the development of immunoprotective strategies holds considerable promise for enhancing the efficacy of treatment modalities for this group of pathologies.

2. 2. Neoplasms (tumors) of different etiologies can occur not only in humans, but also in pets — dogs and cats. Animals can develop a variety of cancers. Some of these neoplasms are curable if diagnosed early and treated effectively [10]. According to some reports, approximately 25% of dogs worldwide will develop a form of cancer during their lifetime, with this statistic being even higher for dogs over 10 years of age. In this category, 50% of dogs will develop cancer before the end of their life [2]. Some studies show that lymphoma is one of the most common types of neoplasms that affect pets. Lymphoma manifests at a higher frequency in cats than in dogs.

   Skin cancer has been found to be statistically more prevalent than other forms of cancer, with mast cell tumors ranking first in terms of incidence. Skin tumors account for approximately one-third of all cancers in dogs, with 20% of these being mast cell tumors. Overall, 50% of skin tumors are found on a pet’s body, while about 40% of them are localized on the limbs (particularly the hind limbs), neck, or head. 11% of skin tumors manifest in multiple areas of the body concurrently. Cats exhibit a reduced susceptibility to skin cell cancers, with the majority of skin tumors manifesting as malignant.

   It is estimated that approximately 50% of mammary tumors in dogs and more than 80% in cats are malignant. Neutering can significantly reduce the risk of developing this type of cancer in dogs and cats.

   Oral and nasal cancers are particularly prevalent in cats, often manifesting through symptoms such as lack of appetite, localized pain, and bleeding from the mouth or nose. In advanced cases, animals may also exhibit signs of swelling of the muzzle or difficulty breathing, depending on the extent of the cancer. The prevalence of oral malignancies among cats is approximately 45 cases per 100,000, with squamous cell carcinomas accounting for 69% of cases and fibrosarcomas constituting 18%.

   Bone tumors manifest more frequently in large breeds of dogs that have reached seven years oа age or more. Among the various types of bone tumors that may develop in felines. Osteosarcoma is responsible for 70% of cases.

   Lymphoma, characterized by the swelling of one or more lymph nodes, is a a prevalent cancerous condition affecting both cats and dogs. Its prevalence is particularly notable in cats, as it can be triggered by the feline leukemia virus. Lymphoma constitutes approximately 33% of all tumors observed in cats. with an incidence ranging from 40 to 200 cases per 100,000 pets. The diseases manifests in cats between 4 and 5 months of age and persists until they reach 19 to 20 years of age. In comparison, only 7 to 24% of all cancers in dogs are lymphomas. Dogs often develop a form of cancer similar to non-Hodgkin’s lymphoma in humans.

3. 3. Kidney disease is common in cats and dogs and can occur over a long period of time (chronic kidney disease) or suddenly (acute kidney injury). In the case of acute kidney disease, immediate treatment initiation is of paramount importance. Chronic kidney disease frequently arises from degenerative renal changes, and its diagnosis in the early stages can be challenging. Chronic kidney disease affects approximately 3% of cats and 2% of dogs [11]. Nephron damage associated with chronic kidney diseases is usually irreversible and can be progressive. Chronic kidney disease is a major cause of morbidity and mortality, especially in older dogs and cats. In small dogs and cats, kidney disease occurs at an average age of 12-14 years. On large dogs, chronic kidney disease can diagnosed as early as 7 years of age. Given the limited utilization of renal replacement therapy (dialysis and transplantation) in veterinary medicine, the treatment paradigm for chronic kidney disease in canines and felines emphasizes early detection and the administration of renoprotective agents, which aim to decelerate the progressive loss of nephrons.

4. 4. Musсuloskeletal disorders are frequently observed in small pets, with the most prevalent conditions including osteoarthritis, discopathy, discospondylosis, osteodystrophy, hip dysplasia, osteochondrodysplasia, and trauma. These diseases typically manifest in older animals, though breed-specific predispositions exist as well. Canines and felines with elongated bodies and shortened legs (including dachshunds, bassets, corgis, peckingeses, skye terriers, Dandie Dinmont Terriers, munchkins and dwarf cats), as well as dogs with markedly curles or absent tails (such as English bulldogs, pugs and basenjis) are predisposed to intervertebral disc displacement. Labaradors, Rottweilers, Chow-сhows and Sharpeis are vulnerable to developing osteoarthritis. In small breeds of dogs, including Spitz, Pekingese, Dwarf Poodle, Tsverkshnautser, Yorkshire terrier and French Bulldog, the most prevalent health concern is Lagg-Calva-Perthes disease, which is characterized by necrosis of the head and neck of the femur. Scottish lop-eared cats are predisposed to osteochondrodysplasia. The genetic mutation that results in lop-earedness when two lop-eared cats are bred together has been shown to result in a high degree of certainty of osteochondrodysplasia in Scottish cats, particularly when the breeding protocol is not adhered to. Additionally, osteochondrodysplasia is a prevalent concern in breeds such as the Bengal cat and Maine Coon, as well as in fast-growing puppies of large and giant breeds, including the Alaskan Malamute, Bernese Mountain Dog, German Shepherd, and Mastiff. The genetic mutation that results in lop-earedness when two lop-eared cats are bred together has been shown to result in a high degree of certainty of osteochondrodysplasia in Scottish cats, particularly when the breeding protocol is not adhered to. Additionally, osteochondrodysplasia is a prevalent concern in breeds such as the Bengal cat and Maine Coon, as well as in fast-growing puppies of large and giant breeds, including the Alaskan Malamute, Bernese Mountain Dog, German Shepherd, and Mastiff. Joint injuries in dogs and cats can result from unfortunate jumps, falls, and bumps, leading to bone fractures, dislocations, sprains, and ligament tears.

   Hip dysplasia is the most prominent health disorder afflicting large breeds of dogs. This hereditary condition manifests during the periods of active growth on canines, with particular susceptibility noted in breeds such as Central Asian Shepherds, German Shepherds and Labradors [13]. The risk of developing hip dysplasia is exacerbated by improper nutrition, characterized by the consumption of poor-quality dry food, a diet consisting exclusively of meat, and an imbalanced calcium and phosphorus ratio in diet. The progression of the disease leads to cartilage degeneration and destruction, resulting in joint regeneration and significant pain response in the dog. Hip joints are predominantly affected, followed by elbow joints, primarily due to the physical demands imposed on dogs, such as climbing stairs, jumping and running [14].

   The clinical signs of hip dysplasia manifest gradually and may vary depending on the animal’s breed. They are most visible between 4 and 9 months of age and include decreased activity, reluctance to rise, unwillingness to climb stairs, and a general sense of fatigue. Joint pain is often palpable, and the animal may exhibit a «wobbly gait». As the disease progresses, animal attempt to evade pain by sparing the affected limb, which can result in atrophy of the pelvic limb muscles [15]. In contrast to cats, which exhibit a lower prevalence of joint dysplasia due to their greater mobility and lower body mass, X-ray examination is a diagnostic modality employed in veterinary medicine for joint dysplasia in animals [16-18].

Peptide bioregulators for prevention and treatment of various diseases in dogs and cats

Peptide and non-peptide bioregulators represent a novel approach to maintaining and enhancing health. They regulate numerous physiological processes in the human body, rendering them suitable for both therapeutic and preventive applications. Given the prevalence of similarities in the pathogenesis of diseases in humans and animals, and the tendency for bioregulators to undergo preclinical studies in animals, they can be considered promising pharmaceutical agents in veterinary medicine.

1. Peptide bioregulators for the prevention and therapy of inflammatory bowel disease in dogs and cats

The application of peptide gastroprotectors Chonluten and Stamakort can be an effective strategy for the prevention and treatment of gastrointestinal disorders in canines and felines.

Chonluten — is an EDG tripeptide (Glu-Asp-Gly, glutamic acid, asparagic acid, glycine) exhibiting a protective effect on the GI tract in experimental studies on small laboratory animals. Chonluten is a dietary supplement available for administration in cats and dogs in the form of drops applied under the tongue. Its potential applications include the following: prevention and supportive therapy for gastrointestinal diseases, such as gastritis and peptic ulcer disease; the healing of gastric mucosa defects; the prevention of gastric cancer, heartburn and other digestive disorders.

An experiment was conducted to determine the efficacy of Chonluten in healing gastric ulcers in rats. The study involved 32 male rats of the Sprague-Dawley line, which were randomly divided into three groups: 1 — intact rats; 2 — modelling of gastric ulcer and administration of saline solution, and 3 — modelling of gastric ulcer and administration of Chonluten subcutaneously at a dosage of 0.5 µg/0.5 ml, 4 — simulation of a gastric ulcer, followed by the administration of an antibiotic solution. Specifically, Klacid was administered intramuscularly at a dose of 10 mg per 1 ml of physiological solution on a daily basis for a period of five days, commencing from the onset of the ulcer. The ulcer was modeled by injecting cystamine-HCI into the rat stomach. A 24-31 mm² ulcer manifested at the border between the antral and fundal parts of the stomach 12 hours after the administration of cystamine-HCl. Concurrently with the initial cystamine-HCl injection, Helicobacter pylori culture was introduced into the rat stomach. Following the application of Chonluten for 21 days after ulcer appearance, complete healing (epithelization) was observed. During the process of gastric ulcer formation, a 3-6-fold increase in the synthesis of signaling molecules, including cNOS, iNOS, HSP70, and NFkB -p65, has been observed in the epitheliocytes. cNOS and iNOS represent constitutive and inducible forms of NO synthase, respectively. Nitric oxide (NO) is a molecule that plays a critical role in the regulation of various physiological processes, including the inflammatory response, vasoconstriction and dilation, and immune response. HSP70 is a stress-protective heat protein that is synthesized in response to the release of free radicals, thereby neutralizing their potentially damaging effects on cells.NFkB-p65 is a transcription factor that activates the inflammatory response. Chonluten exhibits significant efficacy in normalizing the synthesis of these signaling molecules in the gastric epithelium. Furthermore, during the process of ulcer formation in gastric epitheliocytes, there is an increase in the mRNA expression of genes associated with proinflammatory cytokines (TNFa) and enzymes of the antioxidant system (SOD, Cox-2) by 3.7, 5, and 2 times, respectively. Chonluten reduces the mRNA expression of TNFa, SOD, and Cox-2 genes to a normal level, thereby restoring their expression to a healthy state. Therefore, Chonluten regulates the expression of cytokine genes and enzymes of the antioxidant system, thereby facilitating its reparative effect on gastric ulcers [19-20].

Stamakort is a polypeptide complex extracted form the gastric mucosa of young animals. It is a dietary supplement that can be used in cats and dogs in the form of drops. Stamakort contains peptides with molecular weights ranging from 15 to 1850 Da. Its use in humans is recommended for the prophylaxis and supportive therapy of gastrointestinal diseases, including gastritis, peptic ulcer disease, healing of gastric mucosal defects, polyps in the stomach, prevention of gastric cancer, heartburn, belching, heaviness in the stomach and other digestive disorders.

An investigation was conducted to determine the effect of Stamakort on the formation of gastric erosions in a model of acute immobilization stress in rats. A total of 137 rats were subjected to acute immobilization stress (AIS), resulting in the appearance of erosions in the gastric mucosa. The subjects were divided into three groups: 1) a control group that received intramuscular injections of a physiological solution for five days after AIS, 2) a group that received intramuscular injections of Stamakort at a dosage of 15 µg/kg for five days after AIS, and 3) a group that received intramuscular injections of Stamakort at a dosage of 15 µg/kg for three days before and three days after AIS. The third group was established to study the preventive (prophylactic) gastroprotective effect of Stamakort.

In both application regimens, Stamakort demonstrated a 1.4-fold reduction in the incidence of erosions in rats during AIS. Additionally, Stamakort induced immune system activation in rats with OIS, as evidenced by the normalization of plasma and mast cell numbers in the gastric mucosa [21].

Given the potential association between inflammatory bowel disease in dogs and cats and immune system dysfunction, the peptide bioregulators Vladonix and Crystagen may prove efficacious in such cases.

Vladonix is a complex of immunomodulating peptides isolated from bovine thymus, which belongs to the group of cytomedicins. It is produced in the form of dietary supplements, including capsules and sublingual drops. The active beginnings of Vladonix include dipeptides EW (alpha-glutamyl-tryptophan) and KE (lysyl-glutamic acid). Crystagen, a tripeptide EDP (glutamyl-aspartate-proline), is another immunomodulator that is available in the form of dietary supplements (capsules and sublingual drops) and is as well an active ingredient in Vladonix.

Vladonix exerts a multifaceted influence on the immune system, regulating the number and ratio of T- and B-lymphocytes and their subpopulations. It stimulates reactions of cellular immunity, enhances phagocytosis, activates the processes of regeneration and hematopoiesis in cases of their inhibition, improves cellular metabolism, and normalizes blood coagulation. The effects of the short peptides EDP (Crystagen), KE, and EW, as revealed in both in vivo and in vitro studies, bear a resemblance to the immunomodulatory effect of thymus polypeptide complex. The dipeptides KE and EW exhibit a heightened capacity to regulate T-cell immunity, while Crystagen exerts a more pronounced effect on B-cells. The salient characteristics of these short peptides encompass their natural origin, high specificity, safety, efficacy in microdoses, and the availability of their production.

The molecular mechanism of action of Vladonix is attributable to the capacity of its constituent short peptides to modulate gene expression and the synthesis of immunogenesis proteins. Dipeptide EW altered the expression of mitochondrial genes and genes regulating the synthesis of proteins associated with the cell’s defense systems. The KE dipeptide modifies the expression of genes associated with cell division, cell structure, metabolism, the IL-2 gene, and the histone deacetylase SIRT6 gene, which plays a role in anti-aging processes [22]. According to molecular modeling and physicochemical studies, the EW dipeptide binds to the DNA sequence cytosine-guanine-cytosine-guanine, and the KE dipeptide binds to the sequence thymine-cytosine-guanine-adenine. Crystagen (tripeptide EDP) altered the expression of genes regulating the synthesis of proteins responsible for adaptive processes in the cell [23-24].

The dosage of the lingual peptide bioregulators is here and below selected based on the weight of the animal. If necessary, the dosage and frequency of administration can be increased. In preclinical studies, peptide bioregulators have been shown to be non-toxic. In acute toxicity tests (single administration of the peptide) in animals, a dose 5000 times higher than the therapeutic dose was safe. In subacute (peptide administration for 3 months) and chronic (peptide administration for 6 months) toxicity studies, exceeding the therapeutic dose by 300-3000 times did not cause any side effects.

• up to 5 kg — 2-5 drops 1-2 times a day
• from 5 kg to 10 kg — 5 −10 drops 1-2 times a day
• from 11 to 25 kg — 10-20 drops 1-2 times a day
• from 26 to 60 kg — 10-20 drops 2-3 times a day
• over 60 kg — 15-30 drops 1-3 times a day

All peptide bioregulators can be added to the animal’s soft food. It is important to make sure that the animal has completely eaten the food and received the required dosage of peptide. The course of administration varies from 1 to 6 months, depending on the severity of the condition. To maintain the achieved effect and prevent recurrence of the disease, it is recommended to repeat the administration after 1-3 months.

* Note 1. 1 ml (20 drops) of a lingual bioregulator contains 0.1 mg (100 µg) peptide as an active ingredient in the form of lyophilizate (dry powder). Two drops of a lingual bioregulator contain 10 mcg of active ingredient. For animals in preclinical studies, the effective active dose was defined as 10 µg per 1 kg body weight (i.e., 2 drops of the drug per 1 kg body weight).

Note 2. Peptide bioregulators in capsule form can also be administered to animals. Each capsule contains 0.1 milligrams of the active peptide substance, equivalent to 100 micrograms. The dosage of peptide bioregulators in capsules is here and below determined by the animal’s weight:

• up to 10 kg — 1 capsule every other day or every three days
• from 11 to 25 kg — 1-2 capsules once a day
• from 26 to 60 kg — 1-2 capsules 1-2 times a day
• over 60 kg — 1-3 capsules 1-3 times a day

2. Application of peptide bioregulators in the complex treatment of oncological diseases in dogs and cats

Since cancer in humans and animals in most cases is associated with impaired functions of the immune system, the use of peptide bioregulators Vladonix and Crystagen will increase the activity of T and B-cells of the immune system and the resistance of the animal organism to the progression of tumor growth. Previous studies in small laboratory animals and in cell cultures demonstrated that peptide immunoprotectants and Chonluten can retard the growth and development of various types of cancer cells, including Berkitts’s lymphoma, Seidel’s hepatoma, and other types of cancer [25-27].

A unique peptide bioregulator normalizing the functions of the neuroimmunoendocrine system, exhibit an oncostatic effect, and increase life expectancy in different animal species by 42% in experimental models is the polypeptide complex of epiphysis, a dietary supplement Endoluten [27-29]. Endoluten, administered in the form of drops (lingual form), is suitable for use in animals.

The continuous use of peptide bioregulators in combination with standard therapy will prevent tumor growth and maintain remission.

3. Application of peptide bioregulators in the complex treatment of kidney diseases in dogs and cats

Pielotax is a complex of polypeptides derived from the kidney parenchyma of young animals. It has a selective effect on kidney cells, normalizing their metabolism and functions, and regulating the urinary system. Pielotax is available in the form of a dietary supplement and can be used in dogs and cats in the form of sublingual drops.

A clinical trial conducted on middle-aged patients diagnosed with gouty nephropathy demonstrated the efficacy of Pielotax, revealing improvements in well-being, sleep normalization, reduced joint pain intensity, and enhanced laboratory parameters in blood and urine tests in 78% of cases [30]. The study further observed the activation of kidney tissue metabolism and the strengthening of their secretory function under the influence of Pielotax. It has been observed that Pielotax increases the synthesis of renal cell division protein (Ki67) by 2.2 times and reduces the synthesis of apoptosis protein p53 (cell death) in these cells by 20%. Therefore, Pielotax increases the synthesis of renal cell division protein [31].

Ovagen, a hepatoprotective agent, has demonstrated efficacy as a nephroprotective agent in experimental models of aging and renal pathology of various etiologies. The molecular mechanisms underlying Ovagen’s nephroprotective action in aging kidney cells have been investigated, revealing its capacity to stimulate cell growth and reduce the expression of «aging» and apoptosis proteins, such as p16, p21, and p53, while concurrently increasing the expression of the «youth» protein Sirtuin-6 [32].

The efficacy of Ovagen and Pielotax has been demonstrated in an animal model of cisplatin-induced renal failure [33]. Pielotax and Ovagen normalize diuresis, urinary creatinine concentration and its excretion, glomerular filtration rate, absolute reabsorption of sodium ions, decreased urinary protein concentration and its excretion, and the concentration of sodium and potassium ions in urine.

In experimental models of gentamicin nephropathy and ischemia-reperfusion renal injury in rats, Ovagen has been demonstrated to exhibit a nephroprotective effect, which is characterized by the prevention of oliguria and azotemia, a reduction in proteinuria and sodium excretion, an antioxidant effect, and the normalization of energy supply to renal cells [34].

4. Application of peptide bioregulators in the complex treatment of musculoskeletal diseases in dogs and cats

Sigumir is a polypeptide complex extracted from cartilage and bone tissue of young animals. Sigumir is a dietary supplement that can be administered to dogs and cats as a solution under the tongue. Sigumir contains peptides with molecular weights ranging from 75 to 10,000 Da. Sigumir in humans is recommended for prophylaxis and supportive therapy in diseases of the musculoskeletal system, including arthrosis and arthritis, rheumatism, osteochondrosis, osteoporosis, gout and others. The Institute of Toxicology of FMBA of Russia analyzed the composition of the polypeptide complex of cartilage. The tripeptide AED (Cartalax), which is similar in biological activity to Sigumir, was found in it by the methods of matrix-activated laser desorption/ionization and ultra-performance liquid chromatography-mass spectrometry [35]. The tripeptide AED (alanine-glutamine-asparagine) is also produced as a dietary supplement in sublingual form.

The reparative effect of the polypeptide complex from cartilage and bone tissues on bone tissues was demonstrated in two experimental models of traumatic fracture in aged rabbits. In the study group, the polypeptide complex from cartilage and bone tissues at a dose of 0.7 mg/kg dissolved in 2 ml of physiological solution was applied daily to the site of the bone defect for 5 days. In the animals of the control group, healing proceeded naturally. On the 28th day after application of the polypeptide complex, the formation of a complete femur was observed. In the control group, the bone defect persisted at this time. In the second experiment, injections were made into the femur of anesthetized rabbits through a Teflon fistula that was fixed to the femur. This experimental design allows us to evaluate the migration of medullary elements into the created void space. From the 1st to the 7th day of the experiment, the polypeptide complex of cartilage and bone tissues was injected into the lumen of the fistula at a dose of 0.7 mg in 1 ml of physiological solution. Under the influence of the polypeptide complex, bone tissue formation was observed in the 3rd week of the experiment. In the control (administration of saline solution), this effect was achieved later, only at the end of the 4th week of the study [36].

In another experiment, the development of post-traumatic osteoarthritis in rats was modeled. The animals were traumatized in the area of the medial femoral condyle. On day 5, the rats developed degenerative-dystrophic changes in the cartilage tissue of the articular surface, characteristic of osteoarthritis. Animals of experimental groups received intramuscularly polypeptide complex of cartilage and bone tissues in doses of 0.02 mg or 0.2 mg in 0.4 ml physiological solution once a day for 10 days. The rats of the control group were injected with 0.4 ml physiological solution according to the same scheme. On the 28th day of the experiment, under the influence of the polypeptide complex of cartilage and bone tissues, the cartilage tissue structure was restored [36].

Since diseases of the locomotor system in dogs and cats are often accompanied by inflammatory reaction and pain syndrome, immunomodulatory peptide bioregulators Vladonix and Crystagen will help to control inflammation and relieve pain syndrome, thus increasing the effectiveness of treatment.

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The review and practical recommendations were prepared by the team
of Peptides authors: Ekaterina
Kozhevnikova, Natalia Linkova, Irina Saburova, and Roman Pinaev.