Reviews on Clinical Pharmacology and Drug Therapy

Neurodegenerative diseases are characterized by progressive loss of specific types of nerve cells, accompanied by atrophy of corresponding regions of the spinal cord or brain, which clinically manifests as severe neurological and cognitive impairments. These diseases can present at any age and may be associated with genetic predisposition, as well as inflammatory and autoimmune processes. Neurodegenerative diseases are a common cause of disability and mortality among affected patients. Thus, the development of new effective domestic drugs for the treatment of neuropathology is a significant objective for the healthcare system of the Russian Federation. The majority of these are biosimilar drugs reproducing pharmacological substances of foreign (donepezil+memantine, ANB-4, GNR-093) and Russian (interferon beta-b) origin. However, original pharmaceutical substances have also been developed. Three of these, ANB-4, divosilimumab, and sampheginterferon beta-a, are classified as next-in-class drugs. This review article analyzes original and biosimilar organic and genetically engineered pharmaceutical drugs developed in Russia for the treatment of neurodegenerative diseases, which have either been registered in recent years or are currently undergoing clinical trials in the Russian Federation. The development of effective and safe Russian pharmaceutical agents for the treatment of neuropathology may increase the accessibility of therapy for a larger number of patients, significantly improve their health and quality of life, as well as reduce the burden on the healthcare system.

It is reported that according to WHO report (2020), more than 229 million people in 87 countries have malaria despite the use of antimalarial drugs. Moreover, modern combination therapy cannot exclude this disease either. The fact is that malaria pathogens, as well as pathogens of other infectious diseases, gradually acquire resistance to anti-infective drugs. And such resistance of parasites to antimalarial drugs increases with increasing duration of use of these drugs in the community. In other words, antimalarial drugs used in the treatment and prevention of malaria are not only factors in the treatment and prevention of malaria, but gradually acquire the role of factors affecting the “natural” selection of pathogens. It is with the help of applied antimalarial drugs that parasites gradually adapt to existence in the organism of malaria patients, trying to survive despite the availability of drugs. It is shown that the intensity of mutations of malaria pathogens in their population, parasite load, choice of antimalarial drugs, accounting and control of antimalarial activity of the drugs used, the effectiveness and safety of the drugs used, their single and course doses, the effectiveness of individual course antimalarial therapy and control of drug-parasite interaction are the main factors in the effectiveness of treatment and prevention of malaria, as well as the factors of drug resistance of parasites. The review reiterates the importance of knowledge of the basic metabolism and life cycle of both parasite and host in understanding the mechanism of drug action and drug resistance in parasites. This knowledge is very important for the selection of new drug targets for the search and development of new antimalarial drugs. It is reported that fever, diurnal rhythm of body temperature, and therapeutic hyperthermia are not only factors in preventing infection, keeping patients healthy, and the course of malaria, but also factors in the mechanism of action of antimalarial drugs, the efficacy of drug therapy for infection, and the resistance of malaria pathogens to antimalarial drugs.

Background: Long-term antithyroid therapy used to treat autoimmune hyperthyroidism can potentially induce thyroid hormone deficiency. Therefore, the development of thyrotropin receptor regulators which can inhibit thyrotropin activation through orthosteric agonists (thyrotropin, antithyroid autoantibodies) and stimulate its basal activity is crucial. Allosteric thyrotropin regulators with the activity of agonists and negative allosteric modulators has been demonstrated to have this effect.

Aim: To compare the effects of TPY4, a thieno[2,3-d]pyrimidine derivative, and 612-627-Lys(Palm)Ala, a peptide derivative of the third cytoplasmic loop of thyropropin receptor, on the basal and thyropropin-stimulated activity of adenylate cyclase in thyroid membranes and on the basal and thyrotropin-releasing hormone-stimulated levels of thyroid hormones in male rats.

Methods: The activity of adenylate cyclase in plasma membranes of thyroid cells purified from rat thyroids was measured by radioisotope assay using [α-³²P]-adenosine triphosphate, radiolabeled sodium adenosine triphosphate, as a substrate. The effect of pharmaceutical agents on basal and thyrotropin-releasing hormone-stimulated levels of thyroid hormone was evaluated by injecting 612–627-Lys(Palm)Ala peptide (at 750 μg/kg) and TPY4 (at 15 mg/kg) to rats. Blood levels of free thyroxine, total triiodothyronine, and thyrotropin were determined by enzyme immunoassay.

Results: Micromolar levels (10^–9 M) of TPY4 and 612–627-Lys(Palm)Ala increased the basal activity of adenylate cyclase and decreased thyrotropin stimulation in plasma membranes of thyroid cells. TPY4 demonstrated superior inhibitory activity on thyropropin, whereas the peptide induced a more significant stimulatory response in adenylate cyclase. When administered to rats, both compounds increased the synthesis of free thyroxine and total triiodothyronine, albeit to varying levels. However, they also inhibited the synthesis by thyrotropin-releasing hormone-induced thyroid axis activation (at 100 μg/rat). These compounds did not demonstrate a substantial effect on blood levels of thyrotropin-releasing hormone-stimulated thyropropin, suggesting that they are targeted to thyrotropin-releasing hormone in thyrocytes.

Conclusion: Structurally different allosteric ligands of thyrotropin receptor, i.e., thieno[2,3-d]pyrimidine derivative TPY4 and peptide 612–627-Lys(Palm)Ala, were found to have a similar spectrum of pharmacological activity, functioning as thyrotropin receptor agonists and negative allosteric modulators. Their inhibitory effect on thyrotropin receptor hyperactivation while maintaining euthyroidism offers a promising avenue for the development of novel pharmaceutical agents for the treatment of autoimmune hyperthyroidism.

Background: Luteinizing hormone and human chorionic gonadotropin are widely used in medicine for the treatment of reproductive disorders. However, these hormones are associated with numerous adverse effects. Therefore, low-molecular-weight allosteric luteinizing hormone receptor agonists are currently being developed, with the most active compounds being thieno[2,3-d]pyrimidine derivatives.

Aim: To investigate the stimulatory effects of the synthetic compound TP03 on the activity of membrane adenylate cyclase in vitro and on testicular and ovarian steroidogenesis in vivo as compared to those of Org43553, considered the gold standard among low-molecular-weight luteinizing hormone receptor agonists.

Methods: The effects of TP03 and Org43553 (10^–8–10^–3 M) on the basal and human chorionic gonadotropin-stimulated (10–9 M) adenylate cyclase activity in membrane fractions isolated from rat testes and ovaries were evaluated in vitro using [α-³²P]-adenosine triphosphate. Furthermore, the in vivo experiments investigated the effects of TP03 and Org43553 (two intraperitoneal doses, 10 and 20 mg/kg) on blood testosterone levels of male rats and blood progesterone levels of immature female rats previously stimulated with Follimag®, and the effects of co-administration of TP03 or Org43553 (10 mg/kg, intraperitoneal) with human chorionic gonadotropin (10 IU/rat, subcutaneous) on testosterone levels of male rats. Testosterone and progesterone levels were determined by enzyme immunoassay.

Results: TP03 proved comparable to Org43553 in its ability to stimulate adenylate cyclase in testicular and ovarian membranes of rats. When administered to male rats, TP03 demonstrated a dose-dependent stimulation of testosterone synthesis. Similarly, TP03 increased progesterone levels in immature female rats, showing comparable efficacy to Org43553. The co-administration of low doses of TP03 and human chorionic gonadotropin to male rats has been observed to produce an additive effect on testosterone levels, with this effect being more significant than that observed with a combination of Org43553 and human chorionic gonadotropin.

Conclusion: TP03, developed by the authors, has been shown to have a comparable ability to stimulate testicular and ovarian steroidogenesis as Org43553. Furthermore, it has been demonstrated to have an additive effect in combination with human chorionic gonadotropin, suggesting its potential for enhancing the effectiveness of gonadotropin therapy.

Background: The regulation of extracellular dopamine levels in the nucleus accumbens is a critical component of the brain reward system. The development of fast-scan cyclic voltammetry facilitated the measurement of variations in dopamine release over time, correlating with behavioral responses. However, the available data on extracellular dopamine levels in response to self-stimulation are somewhat conflicting.

Aim: To analyze the patterns of dopamine release in the nucleus accumbens that occur in response to the ventral tegmental self-stimulation, as measured by fast-scan cyclic voltammetry.

Methods: Electrodes were implanted into male Wistar rats to induce self-stimulation and monitor extracellular dopamine levels. The release of dopamine was measured telemetrically, while rats were allowed to move freely. Dopamine levels were measured by monitoring its extracellular concentrations in the nucleus accumbens in vivo using fast-scan cyclic voltammetry. The ventral tegmental irritation was maintained on a fixed-ratio one schedule using a rectangular pulse train with a 38° head elevation.

Results: The first head elevation, and consequently the activation of reward stimulation, induced an increase in the signal of fast-scan cyclic voltammetry, which decreased over time. The release of dopamine in response to self-stimulation demonstrated a consistent increase compared to the baseline levels prior to the initiation of the reaction training. A definitive correlation between the amplitude/time of dopamine release and the intensity of the self-stimulation response was not observed. The maximum dopamine concentration in response to the electrical stimulus increased and remained at a higher level for at least 20 subsequent head elevations. However, the hallmarks of exploratory behavior persisted, despite variations in dopamine levels. The release of dopamine in the initial five minutes of the experiment gradually decreased every two minutes. Following a period of prolonged self-stimulation, the release of dopamine decreased at an interval of 0.5 min.

Conclusion: The study findings are consistent with the hypothesis of fluctuations in the emotional continuum that activates the brain reward mechanisms. Dopamine levels have been demonstrated to reflect the regulatory mechanisms underlying approach and avoidance behaviors in response to self-stimulation and may result from the synthesis of an antedating reward (motivational excitement) followed satisfaction after motor activity.