Animals

With the development of society and the improvement of people’s quality of life, more and more families have pets, among which dogs and cats are the most common. According to the American Pet Products Association (APPA) report, in 2021, 70% of American households had pets [1]. Owning a pet has a positive impact on a person’s mental and physical health [2-4]. There is a tendency among pet owners worldwide to treat dogs and cats as family members. Since dogs and cats have become an important part of human life, taking care of their health is very important.

The most common diseases in dogs and cats

1. Inflammatory bowel disease  is the most common cause of chronic vomiting and diarrhea in dogs and cats [5]. The term “inflammatory bowel disease” refers to a group of diseases characterized by chronic or recurrent inflammation of the gastrointestinal tract (GIT). Inflammatory bowel disease is a multifactorial disease of dogs and cats, characterized by chronic enteropathies that can significantly affect the quality of life. The exact etiology of inflammatory bowel disease is unknown. It is believed that the factors associated with inflammation of the gastrointestinal tract have a genetic and external basis (nutrition, ecology). The state of the local immune system of the mucous membranes of the gastrointestinal organs plays an important role in maintaining the function of the gastrointestinal tract in animals [6-7].

Clinical signs of inflammatory bowel disease may include vomiting, diarrhea, blood in stools, weight loss, and appetite changes. Certain breeds of dogs are considered to be predisposed to chronic bowel disease, including the Soft Coated Wheaten Terrier, Basenji, Boxer, French Bulldog, German Shepherd, Norwegian Lundehund, and Yorkshire Terrier. Although the genetic component of inflammatory bowel disease in cats is less well understood, it has been suggested that Siamese cats and other Oriental breeds are more predisposed to developing IBD [8-9]. Endoscopic examination with biopsy of the gastrointestinal mucosa is necessary to confirm the diagnosis of inflammatory bowel disease and to determine the stage of disease. The most commonly reported endoscopic abnormalities in dogs and cats with inflammatory bowel disease include mucosal laxity, increased granularity, and erosions of the gastrointestinal mucosa. The treatment of inflammatory bowel disease is associated with many difficulties because of the unclear etiology. Since the immune system plays an important role in the pathogenesis of inflammatory bowel diseases, immunoprotection will facilitate progress in the treatment of this group of pathologies.

2. Cancers (tumors)  of various etiologies can occur not only in humans, but also in pets – dogs and cats. Animals can develop various types of cancer, and some of them are curable if diagnosed early and treated effectively [10]. According to some data, about 25% of dogs worldwide develop some type of cancer during their lives. In the case of dogs over 10 years of age, the statistics are even higher – 50% of them develop cancer before the end of their lives. Some studies show that lymphoma is one of the most common types of cancer affecting pets. Lymphoma is more common in cats than in dogs.

Skin cancers are statistically more common than other types of cancer, with mast cell tumors being the most common. About one-third of all cancers in dogs are skin tumors, and 20% of these are mast cell tumors. Overall, 50% of skin cancers can be found on the body of a pet, while about 40% of these are located on the limbs (especially the hind legs), neck, or head. 11% of skin cancers occur in multiple locations on the body at the same time. Cats are less susceptible to skin cancer. Most skin cancers are malignant.

About half of all mammary gland tumors in dogs and over 80% in cats are malignant. Spaying your dog or cat before 12 months of age can significantly reduce the risk of this type of tumor.

Cancers of the mouth and nose are particularly common in cats. This type of cancer usually causes symptoms such as loss of appetite, local pain, and bleeding from the mouth or nose. Some animals may experience swelling of the face or difficulty breathing, depending on the extent of the cancer spread. About 45 in 100,000 cats develop oral cancer, of which 69% are squamous cell carcinomas and 18% are fibrosarcomas.

Bone tumors are most common in large breed dogs over 7 years of age. Of all the types of bone tumors that can develop in cats, osteosarcoma accounts for 70%.

Lymphoma, an enlargement of one or more lymph nodes, is another common cancer that affects both cats and dogs. This disease is more common in cats because it can be caused by the feline leukemia virus. Lymphoma accounts for about 33% of all cancers in cats, with an incidence of 40 to 200 cases per 100,000 cats. The disease affects cats from 4 to 5 months of age to 19 to 20 years of age. In comparison, lymphomas account for only 7 to 24% of all cancers in dogs. Dogs often develop a type of cancer similar to non-Hodgkin lymphoma in humans.

3. Kidney disease  is common in dogs and cats and can be long-term (chronic kidney disease) or acute (acute kidney injury). In cases of acute kidney injury, prompt treatment is essential. Chronic kidney disease is often the result of degenerative changes in the kidneys and is difficult to diagnose in the early stages. Chronic kidney disease affects approximately 3% of cats and 2% of dogs [11]. Nephron damage associated with chronic kidney disease is usually irreversible and can be progressive. Chronic kidney disease is a leading cause of morbidity and mortality, especially in older dogs and cats. In small dogs and cats, kidney disease manifests at an average age of 12–14 years. In large dogs, chronic kidney disease can be diagnosed as early as 7 years of age. Because renal replacement therapy (dialysis and transplantation) is not commonly used in veterinary medicine, treatment of chronic kidney disease in dogs and cats focuses on early detection and the use of renoprotective drugs to slow the progressive loss of nephrons.

4. Musculoskeletal diseases  are also common in small pets [12]. The most common of these include osteoarthritis, discopathy, discospondylosis, osteodystrophy, hip dysplasia, osteochondrodysplasia, and trauma. These diseases most often occur in older animals. However, there is also a breed susceptible to musculoskeletal diseases. Dogs and cats with long bodies and short legs (dachshunds, basset hounds, corgis, Pekingese, Skye terriers, Dandie Dinmont terriers, munchkins, minskins, and dwarf cats), as well as dogs with tightly curled tails or no tails (English bulldogs, pugs, Basenjis) are at high risk of intervertebral disc displacement. Labradors, rottweilers, chow chows, and shar peis are susceptible to osteoarthritis. In small breeds of dogs – Spitz, Pekingese, Miniature Poodles, Miniature Schnauzers, Yorkshire Terriers, French Bulldogs – the most common disease is Lugg-Calvy-Perthes disease, characterized by necrosis of the head and neck of the femur. Scottish Fold cats are susceptible to osteochondrodysplasia. A mutation causing lop-eared ears in the case of a cross between two lop-eared cats gives an almost 100% guarantee of osteochondrodysplasia in Scottish cats. The risk is especially high in the case of improper breeding of this breed. Bengal and Maine Coon cats, as well as rapidly growing puppies of large and giant breeds (Alaskan Malamutes, Bernese Mountain Dogs, Great Danes, German Shepherds, mastiffs) are also at high risk of osteochondrodysplasia. Joint injuries in dogs and cats include broken bones, dislocations, sprains, and torn ligaments that occur during accidental jumps, falls, and blows.

Hip dysplasia is the most common disease in large breed dogs. It is a hereditary disease that manifests itself during the period of active growth of the animal. Central Asian Shepherd Dogs, German Shepherd Dogs and Labradors are particularly susceptible to this pathology [13]. The risk of hip dysplasia increases with poor nutrition: low-quality dry food, feeding only meat and an incorrect calcium to phosphorus ratio in the diet. As a result of the disease, cartilage deformation and destruction, joint destruction occur, and the dog experiences a significant pain reaction. Dysplasia most often affects the hip joints, less often the elbow joints [14]. This is primarily due to the physical activity that dogs perform: climbing stairs, jumping, running, etc.

Clinical symptoms of hip dysplasia develop gradually and may vary depending on the breed of the animal. They are most visible at the age of 4-9 months. Animals lie down more often, are reluctant to stand up, do not want to climb stairs, tire quickly, feel joint pain on palpation, and a “wobbly gait” appears. As the disease progresses, the animal tries to avoid pain by protecting the limb, which causes atrophy of the pelvic limb muscles [15]. In cats, joint dysplasia is much less common due to their greater mobility and lower weight. X-ray examination is performed to diagnose joint dysplasia in animals [16-18].

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

Peptide and non-peptide bioregulators are an innovative tool for maintaining and improving health. They control many physiological processes in the human body, so they can be used for therapeutic and prophylactic purposes. Given that the pathogenesis of diseases in humans and animals is largely similar, and bioregulators usually undergo preclinical studies on animals, they can be considered promising drugs in veterinary medicine.

1. Peptide bioregulators in the prevention and treatment of inflammatory bowel diseases in dogs and cats

For the prevention and treatment of dogs and cats, it is recommended to use peptide gastroprotectors Honluten and Stamacort.

Honluten   is a tripeptide EDG (Glu-Asp-Gly, glutamic acid, aspartic acid, glycine). In experimental studies on small laboratory animals, this peptide showed a protective effect on the gastrointestinal tract. Honluten is a biologically active dietary supplement that can be used in cats and dogs in the form of drops under the tongue. Honluten  ^®  can be recommended for the prevention and maintenance therapy of gastrointestinal diseases: gastritis and gastric ulcers, in the treatment of gastric mucosa damage, in the prevention of stomach cancer, heartburn and other digestive disorders.

The experiment showed that Honluten treats gastric ulcers in rats. The study was conducted on 32 male Sprague-Dawley rats. All animals were randomly divided into groups: 1 – intact rats, 2 – modeling a gastric ulcer and administration of physiological saline, 3 – modeling a gastric ulcer and administration of Honluten subcutaneously at a dose of 0.5 µg / 0.5 ml of physiological saline daily for 5 days from the onset of the ulcer, 4 – modeling a gastric ulcer and administration of the antibiotic Klacid intramuscularly at a dose of 10 mg / 1 ml of physiological saline daily for 5 days from the onset of the ulcer. The ulcer model was obtained by introducing cystamine-HCl into the rat stomach. An ulcer with an area of ​​24-31 mm2 appeared at the border of the pyloric part and the fundus of the stomach 12 hours after the administration of cystamine-HCl. Simultaneously with the first administration of cystamine-HCl to the rat stomach, a Helicobacter Pylori culture was introduced. Under the influence of Chonluten, on the 21st day after the ulceration, its complete healing (epithelialization) was observed. During the formation of a gastric ulcer, the synthesis of signaling molecules cNOS, iNOS, HSP70, NFkB-p65 in epithelial cells increases 3-6-fold. cNOS and iNOS are constitutive and inducible forms of NO synthase, enzymes involved in the formation of nitric oxide. Nitric oxide is involved in the regulation of the inflammatory response, narrowing and dilating of blood vessels and the immune response. HSP70 is a heat shock protein that protects against stress. Its synthesis increases in response to the release of free radicals to eliminate their harmful effect on cells. NFkB-p65 is a transcription factor that activates the inflammatory response. Honluten effectively normalizes the synthesis of these signaling molecules in the gastric epithelium. In addition, when an ulcer is formed in the gastric epithelial cells, the mRNA expression of the proinflammatory cytokine TNFα genes and the antioxidant enzymes SOD, Cox-2 increases 3.7, 5, and 2 times, respectively. Honluten reduces the mRNA expression of the TNFα, SOD, Cox-2 genes to normal levels. Honluten thus normalizes the expression of the cytokine genes and antioxidant enzymes. This is the basis of its reparative effect in gastric ulcers [19-20].

Stamacort  is a polypeptide complex obtained by extraction from the gastric mucosa of young animals. Stamacort, like Honluten, is a biologically active dietary supplement and can be used in dogs and cats in the form of drops. Stamacort contains peptides with a molecular weight of 75 to 1850 Da. Stamacort is recommended for humans for the prevention and maintenance treatment of gastrointestinal diseases: gastritis and gastric ulcer, treatment of gastric mucosa lesions, gastric polyps, prevention of stomach cancer, heartburn, belching, feeling of heaviness in the stomach and other digestive disorders.

The effect of Stamacort on the formation of gastric erosions was studied in the acute immobilization stress model in rats. Erosions in the gastric mucosa were observed in 137 rats with acute immobilization stress (AIS). All animals were divided into groups: 1 – control (intramuscular administration of physiological solution for 5 days after AIS), 2 – administration of Stamacort at a dose of 15 μg/kg intramuscularly for 5 days after AIS, 3 – administration of Stamacort at a dose of 15 μg/kg intramuscularly for 3 days before and 3 days after AIS. The third group was created to study the prophylactic protective effect of Stamacort on the digestive system. In both regimens, Stamacort reduced the formation of erosions in rats with AIS by 1.4 times. Stamacort also activated the immune system in rats in the AIS state. This was expressed by the normalization of the number of plasma cells and mast cells in the gastric mucosa [21].

Since inflammatory bowel diseases in dogs and cats may be associated with immune system dysfunction, the peptide bioregulators Vladonix and Kristagen may be effective in this case.

Vladonix  is ​​a complex of immunomodulatory peptides isolated from bovine thymus, belonging to the cytomedin group and produced in the form of a dietary supplement (capsules and sublingual drops). Dipeptides EW (alpha-glutamyl-tryptophan) and KE (lysyl-glutamic acid) are active substances of the Vladonix preparation (they are part of it). Kristagen is a tripeptide EDP (glutamyl-asparagyl-proline), an immunomodulator, produced in the form of a dietary supplement (capsules and sublingual drops), which is also an active substance of the Vladonix preparation.

Vladonix affects all cells of the immune system, regulates the number and ratio of T and B lymphocytes and their subpopulations, stimulates the immune response of cells, enhances phagocytosis, activates the processes of regeneration and hematopoiesis in case of their inhibition, improves cellular metabolism, normalizes blood clotting. The effects of short peptides EDP (  Kristagen  ), KE, EW shown in in vivo and in vitro studies are similar to the immunomodulatory effects of the thymus polypeptide complex. At the same time, dipeptides KE and EW regulate the immunity of T lymphocytes to a greater extent, and Kristagen has a more pronounced effect on B lymphocytes. The main features of these short peptides include: natural origin, high specificity, safety, efficacy in microdoses and availability in production.

The molecular mechanism of action of Vladonix is ​​due to the ability of its short peptides to regulate gene expression and the synthesis of immunogenic proteins. The EW dipeptide changes the expression of mitochondrial genes and genes regulating the synthesis of proteins related to the cell defense system. The KE dipeptide changed the expression of genes responsible for cell division, cell structure, metabolism, the IL-2 cytokine gene and the SIRT6 histone deacetylase gene (anti-aging protein) [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 (EDP tripeptide) changed the expression of genes regulating the synthesis of proteins responsible for adaptive processes in the cell [23-24].

Scheme of the use of peptide bioregulators in the complex treatment of inflammatory bowel diseases in dogs and cats.

The dosage of the peptide bioregulators listed below is selected based on the body weight of the animal (dog or cat)*. If necessary, the dose and frequency of administration can be increased. Preclinical studies of peptide bioregulators have shown that they are non-toxic. In an acute toxicity experiment (single peptide administration) conducted on animals, exceeding the therapeutic dose by 5000 times proved to be safe. In subacute toxicity studies (peptide administration for 3 months) and chronic toxicity studies (peptide administration for 6 months), exceeding the therapeutic dose by 300-3000 times did not cause 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 soft food for animals. It is important to ensure that the animal has eaten all the food and has received the required dose of peptide. The course of treatment lasts from one to six months, depending on the stage of the disease. To maintain the effect and prevent relapses, it is recommended to repeat the course of treatment after 1-3 months.

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

Note 2.  Peptide bioregulators in capsules for dogs and cats can also be used. 1 capsule contains 0.1 mg of the active peptide substance, i.e. 100 mcg. The dosage of peptide bioregulators in capsules given below is selected depending on the body weight of the animal (dog or cat):

• up to 10 kg – 1 capsule every other day or once 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 oncological diseases in humans and animals are in most cases associated with immune system dysfunction, the use of peptide bioregulators Vladonix and Kristagen will increase the activity of T and B bonds of the immune system and the resistance of the animal’s body to the progression of tumor growth. Previous studies on small laboratory animals and cell cultures have shown that peptide immunoprotectors and Honluten can slow down the growth of various types of cancer cells: Burkitt’s lymphoma, Zaidel’s hepatoma, etc. [25-27].

A unique peptide bioregulator that normalizes the functions of the neuroimmunoendocrine system, has an oncostatic effect and extends life in various animal species in the experiment by 42% is a complex of pineal polypeptides – a biologically active dietary supplement Endoluten [27-29]. Endoluten in the form of drops (lingual form) can be used in animals.

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

Pielotax  is a complex of polypeptides obtained from the renal parenchyma of young animals. Pielotax acts selectively on kidney cells, normalizes their metabolism and functions, and regulates the urinary system. Pielotax is available as a biologically active dietary supplement and can be used in dogs and cats in the form of sublingual drops (lingual form). In a clinical study in middle-aged patients suffering from gouty nephropathy, high efficacy of the drug Pielotax was demonstrated [30]. In 78% of cases, Pielotax caused an improvement in well-being, normalized sleep, reduced frequency and intensity of joint pain, and improved laboratory parameters of blood and urine. Pielotax activates the metabolism of kidney tissue and improves secretory function. Pielotax increases the synthesis of the renal cell division protein (Ki67) by 2.2 times and reduces the synthesis of the apoptosis protein p53 (cell death) in these cells by 20%. In this way, Pielotax stimulates cell renewal in kidney tissue [31].

Ovagen  is a hepatoprotector whose efficacy as a nephroprotectant in the aging process and kidney pathologies of various origins has been experimentally confirmed. The molecular mechanisms of the protective effect of Ovagen on aging kidney cells have been studied. It has been established that Ovagen activates cell growth by reducing the expression of the “aging” and apoptosis proteins p16, p21, p53 and increasing the expression of the “youth” protein Sirtuin-6 [32]. The efficacy of Ovagen and Pielotax has been demonstrated in a model of cisplatin-induced renal failure in animals [33]. Pielotax and Ovagen normalize diuresis, urinary creatinine concentration and its excretion, glomerular filtration rate, absolute sodium ion reabsorption, reduce urinary protein concentration and its excretion, and sodium and potassium ion concentration in urine.

Ovagen demonstrates nephroprotective activity in experimental models of post-gentamicin nephropathy and ischemia-reperfusion-induced renal injury in rats. The nephroprotective activity of Ovagen is demonstrated by preventing the development of oliguria and azotemia, reducing proteinuria and sodium excretion, antioxidant activity, and normalizing the energy supply of renal cells [34].

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

Sigumir  is a polypeptide complex obtained by extraction from the cartilage and bone tissue of young animals. Sigumir is a biologically active dietary supplement that can be used in dogs and cats in the form of a sublingual solution. Sigumir contains peptides with a molecular weight of 75 to 10,000 Da. Sigumir is recommended for humans for the prevention and treatment of diseases of the musculoskeletal system: osteoarthritis, rheumatism, osteochondrosis, osteoporosis, gout, etc. The Institute of Toxicology of the Federal Medical and Biological Agency of Russia conducted an analysis of the composition of the cartilage polypeptide complex. Using matrix-activated laser desorption/ionization and ultra-performance liquid chromatography combined with mass spectrometry, indicated that AED was charged ( Kartalax  ) has biological activity similar to Sigumir [35]. The tripeptide AED (alanine-glutamine-asparagine) is also produced as a biologically active dietary supplement in sublingual form.

In two experimental models of post-traumatic fractures in old rabbits, the repair effect of a polypeptide complex extracted from cartilage and bone tissue on bone tissue was demonstrated. In the study group, a polypeptide complex of cartilage and bone tissue was administered daily for 5 days to the bone defect site at a dose of 0.7 mg/kg dissolved in 2 ml of physiological solution. In the control group, healing occurred naturally. On day 28 after the administration of the polypeptide complex, the formation of a fully developed femur was observed. At that time, the bone defect was still under control. In the second experiment, a Teflon fistula was introduced into the femur of rabbits under general anesthesia and attached to the femur. This experimental design allows for the assessment of the migration of bone marrow elements into the resulting empty space. The group of experimental animals was injected into the lumen of the fistula with a polypeptide complex of cartilage and bone tissue at a dose of 0.7 mg in 1 ml of physiological solution from day 1 to 7 of the experiment. Under the influence of the polypeptide complex, bone tissue formation was observed in the 3rd week of the experiment. In the case of the control (administration of physiological solution), this effect was achieved later, only at the end of the 4th week of the study [36].

In another experiment, the development of posttraumatic osteoarthritis in rats was modeled. For this purpose, animals were injured in the area of ​​the internal femoral condyle. On the fifth day, degenerative-dystrophic changes in the cartilage tissue of the articular surface, characteristic of osteoarthritis, were observed in the rats. Animals from the experimental groups were administered intramuscularly a polypeptide complex of cartilage and bone tissue in doses of 0.02 mg or 0.2 mg in 0.4 ml of physiological solution once a day for 10 days. Rats from the control group were administered 0.4 ml of physiological saline solution according to the same schedule. On the 28th day of the experiment, the structure of cartilage tissue was restored under the influence of the polypeptide complex of cartilage and bone tissue [36].

Since musculoskeletal disorders in dogs and cats are often accompanied by an inflammatory response and pain syndrome, the immunomodulating peptide bioregulators Vladonix and Kristagen will help inhibit inflammation and relieve pain syndrome, increasing the effectiveness of treatment.

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