Thymalin Research & Studies

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.

The immunomodulatory activity of peptide drugs i.e. tinrostim (dosage form) prepared of squid optical ganglia and pharmacopoeia thymain was studied. Tinrostim showed a stimulating effect on the humoral and cellular nimmune responses when administered parenterally in experimental animals, as well as on the phagocytic activity of neutrophils, comparable to the effect of thymalin. It was demonstrated that both the peptide drugs increased the production of pro-(TNFa, IL-1) and antiinflammatory (IL- 10) cytokines in the culture of intact cells of peripheral blood in vitro. It is essential that when tinrostim was used in 10-fold different doses (0.005 mg / kg and 0.05 mg /kg) in mice, the effect of the lower dose was comparable to the effect of the higher dose.

The review presents the interference between thymus and pineal gland during their involution. The research data of thymus peptides influence on pineal gland and pineal peptides on thymus are summarized. Analysis of these data showed that pineal peptides (Epithalamin, Epitalon) had more effective geroprotective effect on thymus involution in comparison with geroprotective effect of thymic peptides (Thymalin, Thymogen) on involution of pineal gland. The key mechanisms of pineal peptides effect on thymus dystrophy is immunoendocrine cooperation, which is realized as transcription's activation of various proteins.

The interference between thymus and pineal gland during their involution is considered in this review. The research data about influence of thymus peptides on pineal gland and pineal peptides on thymus is summarized. Analysis of these data showed that pineal peptides (epithalamin, epitalon) had more effective geroprotective effect on thymus involution in comparison with geroprotective effect of thymic peptides (thymalin, thymogen) on involution of pineal gland. The key mechanisms of pineal peptides effect on thymus dystrophy is immunoendocrine cooperation, which is realized as transcription's activation of various proteins.

Immunomodulatory molecule L-Glu-L-Trp was isolated from natural calf thymic peptide complex Thymalin by reverse-phase high performance liquid chromatography. On the basis of the synthesized dipeptide a pharmaceutical was designed containing this compound, which later receives the brand name Thymogen. The agent activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced changes in intracellular composition of cyclic nucleotides, and activated neutrophilic chemotaxis and phagocytosis. The effect of dipeptide on survival, life span and spontaneous tumor development was studied in female rats. Seventy-six, five-month-old outbred female rats were randomly subdivided into two groups and were subcutaneously injected with 0.2 ml of normal saline (controls, 32 rats) or with 5 micrograms/rat of the dipeptide L-Glu-L-Trp, dissolved in 0.2 ml of saline (44 rats), 5 times per week for 12 months. Animals were monitored up to their natural death and all the tumors discovered were studied microscopically. Mean life span of rats in both groups was similar but that of 10% maximum survived control rats constituted 949 +/- 16.1 days, whereas in the dipeptide-treated rats this value was 1048 +/- 21.1 days (P < 0.001). Six out of 44 rats treated with the drug survived over the maximum life span of control rats (965 days). The aging rate indicated as alpha in the Gompertz equation, was 0.0071 days-1 in controls and 0.0041 days-1 in rats exposed to L-Glu-L-Trp. Total tumor incidence was 1.5 times lower (P < 0.01), malignant tumor incidence 1.7 times lower (P < 0.01), and hematopoietic malignancies (leukemias and lymphomas) 3.4 times lower (P < 0.02) in rats exposed to the dipeptide in comparison with controls. Thus, treatment with L-Glu-L-Trp delayed aging rate and decreased spontaneous tumor incidence in rats.

Four-day monitoring using standard methods of studying free group behavior of animals in an "open field" (Opto-Varimex, USA) showed that all the peptide immunomodulators under study possessed a neuromodulating effect comparable with that of known drugs. They change the character of the circadian rhythms of the animals' motor activity and the dynamics of extinction of the orientation-investigation reaction. In comparison with the control the activity of the drugs under study was distributed as follows: ethymizol > cerebrolysin > thymalin > nootropil > thymogen > T-activin > cortexin > dibazol.

The influence of amino acids, their mixtures, and peptides on the immune response, phagocytosis in vitro, and in CBA mice, and broiler chickens, as well as on in vitro ability of listed preparations to protect animals' splenocytes from toxic action of benzene and aflatoxin B1 were studied. It was shown that amino acids (Asp, Glu, Val, Trp), amino acid mixtures (cerebrolysine, levamine, aviamine), and the dipeptides GluTrp and LysAsp stimulate the immune response to SRBC at subcutaneous and peroral application. The peptides thymopentin, thymosin alpha-1, and peptide mixtures (thymosin fraction 5, thymalin) stimulate the immune response only at the site of subcutaneous injections. Lys, Tyr, and bursin (LysHisGly-amide), regardless of the mode of application, do not change, but Arg inhibits the immune response. None of the preparations studied change the immune response to Viantigen. Levamine, cerebrolysine, and aviamine are immunoreactive only at low doses (6.5 x 10(2)-6.5 x 10(-8) mg/kg). At a dose of 65 mg/kg these preparations lose immunostimulating properties. Amino acids (6.5 x 10(-2) mg/kg), which stimulate, rather than influence or inhibit the immune response, enhance phagocytosis of S. aureus by granulocytes, regardless of mode of application. Levamine and cerebrolysine in the range of doses of 6.5 x 10(-2)-6.5 x 10(-6) mg/kg do not influence phagocytosis; at a dose of 65 mg/kg, phagocytosis is enhanced. Aviamine stimulates phagocytosis as well at low and at high doses. The ability of preparations to protect in vitro at a low concentration (1.3 x 10(-3) mg/ml) murine or chickens' splenocytes from toxic action of benzene and aflatoxin B1 (at 1:1000 dilution) does not correlate with their action on the immune response and phagocytosis. The protective actions revealed by the following preparations include: (a) stimulating the immune response and phagocytosis (Glu, Asp, Trp, amino acid mixture aviamine, the dipeptides LysAsp, GluTrp, the peptide mixtures thymalin, thymosin fraction 5); (b) enhancing the immune response but not influencing phagocytosis (Met, levamine, cerebrolysine); (c) influencing neither the immune response nor phagocytosis (Gly, Ile). At the same time those preparations (Lys, Arg) that stimulate phagocytosis but influence the immune response in a different way (Lys does not influence; Arg suppresses the response) are inert as antitoxic agents. Antitoxic properties of amino acid preparations levamine, cerebrolysine, and aviamine retain as well in the assays at a rather large (1.3 mg/ml) concentration like their phagocytosis-stimulating properties.

Kept under medical surveillance were 120 patients with duodenal ulcer running an uncomplicated course. All patients and 30 healthy donors were studied for the status of the immunity T-system by spontaneous E-rosette formation (E-RFC) and availability of theophylline-resistant (TPP-RFC) and theophylline-sensitive (TPS-RFC) lymphocytes. With B-system being studied by FAC-rosette formation. All patients with duodenal ulcer displayed a decline in the content of E-RFC, TFP-RFC, TFS-RFC as compared to the indices in controls. Inclusion into the combined therapy of thymalin and dalargin was noted to be associated with a positive dynamics in the rise of T-lymphocytes, their subpopulations to the level in controls, percentage of TFS-RFC. Indices for TFS-RFC did not differ from control ones either before or after the treatment.

Natural thymic peptides have been isolated from calf thymus by mild acid extraction. Pharmaceutical containing natural peptides (Thymalin) was put into practice as immunocorrector. One of the immunomodulatory molecules (L-Glu-L-Trp) has been isolated from Thymalin by reversed-phase high performance liquid chromatography. Pharmaceutical containing this agent (Thymogen) was designed on the base of synthesized dipeptide. A novel immunomodulatory dipeptide was synthesized and termed Vilon. Both natural and synthetic pharmaceuticals activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced the changes in intracellular composition of cyclic nucleotides and cytokine [interleukin (IL-2), interferon (IFN)] excretion of blood lymphocytes. Synthetic dipeptides activated neutrophil chemotaxis and phagocytosis. They had no influence on antioxidant response in thymocytes in comparison with natural peptides. Thymalin and Thymogen were used in persons with chronic pathology and immune dysfunction. The results indicate that thymic peptides participate in the regulating mechanisms of inflammatory processes as cytokine antagonists and show the difference between natural and synthetic products. It is important for the drugs designed to prevent immune dysfunction development.

Original immunological studies allowed the authors to design a combined treatment of laryngeal papillomatosis (LP) with administration of immunomodulators and cytostatics. Surgery was performed on demand. Thymic hormone preparation (T-activin, thymalin, thymogen) and prospidin served as immunomodulators and cytostatic, respectively. To create lymphotropism, prospidin was delivered by means of electrophoresis following subcutaneous introduction of 8--16 U lidase. Sensitivity of patients to thymalin was tested in vitro by thymalin-induced changes in the number of CD2--DR+ lymphocytes. Adjuvant modalities were age-adjusted dibasol as inductor of interferon genesis and adaptogens (eleutherococcal fluid extract, B and C vitamins). Such treatment was given to 39 children. Remission duration increased 1.6--2.6-fold, 6 of 7 children with primary LP achieved persistent remission. Positive changes in immunological indices occurred in 84% of children. The above treatment outcomes support the efficacy of the method in childhood LP.

To evaluate the possible antiviral activity of a number of peptide bioregulators, an acute influenza infection was induced in developing chick embryos and mice. Four peptide preparations were used: two medicinal peptide preparations of the thymus (thymalin and thymogen) and peptide preparations obtained from the tracheal mucosa (PTM) and lung parenchyma (PLP) of calves according to the technology used for obtaining thymalin. For control, remantadin (for type A virus) and adapromin (for type B virus) were used as antiviral remedies. In experiments on mice, the preparations were introduced 24 hours and 1 hour before and 24, 48 and 72 hours after intranasal challenge. The effectiveness of the preparations was evaluated by the death rate of the animals. In case of type A virus the effectiveness of the preparations was distributed as follows: remantadin > thymogen > thymalin > > PTM. In case of type B virus, adapromin and PTM were found to produce a similar effect, while the preparations of the thymus and PLP had no influence on the death rate of the animals. In experiments on developing chick embryos, none of the peptide preparations under study had any influence on the infection caused by the viruses of both hypes. The results obtained in this investigation are indicative of the absence of direct antiviral activity in the tested peptide preparations. At the same time thymalin, thymogen and PTM significantly enhance the immunological resistance of the body to virus infection, different activity spectra of PTM and the thymus being indicative of the specific nature of their action.

The content of medium-weight molecular peptides (MMP), lipid peroxidation (LPO) activity, the profile of blood thyroid hormones, and radioactive iodine absorption by the thyroid were determined in 104 patients with light, moderate and grave diffuse toxic goiter (DTG). The content of MMP in the blood correlated with the gravity of DTG and thus may serve an additional test for its determination. Depending on the treatment 66 patients with DTG of medium gravity were distributed into 5 groups: group I included patients given mercazolyl, group II patients on lithium carbonate, group III patients who received mercazolyl and thymalin, group IV patients on mercazolyl and piracetam, and group V included patients given mercazolyl, thymalin and piracetam. A study was made of the blood content of MMP and LPO activity before therapy and after euthyroidism attainment. The treatment with the use of mercazolyl, thymalin and piracetam was found to produce a beneficial effect on the parameters under study and the clinical course of DTG.

It is established that the effect of thymus-derived species is connected with the cyclic nucleotide system. The action of thymus-derived immunocorrectors (thymalin, thymagen, vilosen) on catabolic processes of cyclic nucleotides has been observed under conditions of anaphylaxy and sensibilization. They show that sensibilization of the animal is bound up with a decrease of the cAMP/cGMP ratio. Anaphylaxis induces levelling of the cAMP/cGMP ratio up to the reference level. So, activity of enzymes of cyclic nucleotide catabolism grows due to the influence of thymogen, thymalin and vilosen in lymphocytes of sensibilized guinea pigs and tends to an increase in lymphocytes of anaphylaxis-treated animals.