Reviews on Clinical Pharmacology and Drug Therapy

Zinc is an essential component of more than 10% of the human proteome and serves as a cofactor for nearly 300 metalloenzymes. Interaction with zinc regulates protein activity and influences numerous intracellular processes, whereas removal of zinc from an enzyme results in complete loss of its enzymatic activity. Thus, zinc functions as an intracellular signaling molecule at all levels of signal transduction, affecting multiple metabolic pathways. Reparative regeneration is a cascade mechanism for restoring cells and tissues lost due to pathological processes. Understanding the molecular mechanisms of reparative regeneration is crucial for developing clinical strategies to enhance tissue repair capacity. Zinc plays a key role in reparative regeneration. Modulation of zinc-dependent signaling pathways represents a promising approach in experimental pharmacology. Novel Russian zinc complexes with N-alkenylimidazoles have demonstrated efficacy as pharmacologic agents in correcting a wide range of pathological conditions associated with reparative regeneration. These compounds have shown antihypoxic, antioxidant, wound-healing, anti-inflammatory, antiulcer, and analgesic effects. Their safety and high bioavailability offer broad translational potential. Wound healing is a complex and evolving process involving multiple cell types, including immune cells. These cells secrete cytokines and growth factors that contribute to the amplification of inflammation. This review provides a contemporary overview of zinc-dependent intracellular and systemic processes and highlights possible mechanisms of action of zinc complexes within the molecular and cellular pathways of reparative regeneration.

Pain management, along with the prevention of infectious complications, is among the primary objectives of the perioperative period. In infants and newborns, intense pain triggers a stress response. In similar surgical interventions, the stress response activated by afferent neuronal impulses from the site of injury in newborns is greater in magnitude but shorter compared with that in adults. Effective analgesia with opioids during cardiac surgery has been shown to improve surgical outcomes. Prolonged, high-intensity pain in a newborn with ineffective analgesia leads to the progression of such pathological conditions as hypoxia, metabolic acidosis, impaired liver and kidney function, an increased risk of sepsis, disseminated intravascular coagulation, and higher neonatal mortality. At present, the capabilities of traditional analgesia methods remain limited. In this regard, the main approaches to improving the efficacy of pain management in pediatric practice include various regimens combining non-opioid analgesics, supplemented with opioids if necessary, as well as the development of new effective and safe pharmacologic agents with analgesic activity.

BACKGROUND: Analysis of cardiovascular system variability in the frequency domain allows for the assessment of both neural and non-neural mechanisms of cardiac regulation. This analysis is challenging due to the multiple input and output mechanisms of cardiovascular and respiratory control.

AIM: The work aimed to investigate changes in spectral, phase, and coherence relationships, as well as the transfer function |gain(f)|, between oscillations of left ventricular end-diastolic pressure, specific peripheral vascular resistance, left ventricular stroke volume, and R–R intervals of the electrocardiogram during acute hypoxia at the dominant spectral component corresponding to the respiratory frequency.

METHODS: Effective (n = 17) and ineffective (n = 20) types of adaptation were determined based on the direction of changes in the heart pumping parameters during the transition from normoxia to hypoxia. Effective and ineffective types of adaptation were demonstrated in the same subject during different hypoxic tests, just as the same subjects could demonstrate either only effective or only ineffective adaptation.

RESULTS: Changes in gain(f) and cross-spectral power density in pairs of oscillatory processes were used to assess alterations in cardiac regulation (Frank–Starling mechanism, arterial–cardiac baroreflex, and others). For effective adaptation during hypoxia, a statistically significant (p < 0.05) increase in gain for end-diastolic pressure–stroke volume relationship was observed, whereas spectral power of this parameter did not change, reflecting inability to increase CO through heterometric myogenic autoregulation during hypoxia at rest. Under these conditions, increase in CO occurs mainly due to chronotropic effect. In pairs of oscillatory processes—end-diastolic pressure–specific peripheral resistance or specific peripheral resistance–R–R intervals—cross-spectral power density significantly decreased (p < 0.05) during effective adaptation. Reduction in amplitudes of these oscillatory pairs reflects adequate functioning of arterial–cardiac baroreflex in decreasing specific peripheral resistance during effective adaptation.

CONCLUSION: Quantitative changes in analyzed indices of cardiac pump function under acute hypoxia are determined by alterations in their rhythmic interactions, both among themselves and with oscillations of R–R intervals at dominant respiratory frequency, as well as by displacement of A_QRS (the maximum depolarization vector) in frontal plane. Identified patterns represent effectiveness of adaptation to severe hypoxia.

BACKGROUND: The search for new agents for the pharmacological management of gambling addiction remains an urgent task in contemporary psychoneuropharmacology. A GluA1 AMPA receptor antagonist (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist), IEM-1460, has previously been proposed as a potential therapeutic option for addiction. Glutamatergic inputs are known to modulate the activity of the mesolimbic dopamine system. It can be hypothesized that the antiaddictive effect of IEM-1460 is mediated through the interaction between glutamatergic and dopaminergic systems.

AIM: The work aimed to investigate the effect of GluA1 AMPA receptor blockade on impulsive behavior in a gambling addiction model, its role in modulating extracellular dopamine levels in the nucleus accumbens, and its effects on ion currents in isolated neurons.

METHODS: Experiments were conducted in vivo in Wistar rats and in vitro in isolated Danio rerio neurons. The effect of IEM-1460 (1, 3, and 10 mg/kg, intraperitoneally) on impulsive behavior in a gambling addiction model using a three-arm maze, and on dopamine release in the nucleus accumbens in response to electrical stimulation of the ventral tegmental area, was assessed using intravital fast-scan cyclic voltammetry. In isolated Danio rerio neurons, the effect of IEM-1460 on ion currents induced by the AMPA receptor agonist kainic acid was evaluated using the patch-clamp technique.

RESULTS: IEM-1460 at 1 mg/kg administered intraperitoneally most effectively reduced impulsive behavior in the gambling addiction model and increased dopamine release in the nucleus accumbens in response to electrical stimulation of the ventral tegmental area. In vitro, IEM-1460 produced a pronounced blocking effect on AMPA glutamate receptors.

CONCLUSION: Selective blockade of GluA1-AMPA receptors with IEM-1460 reduced impulsive behavior in the gambling addiction model and increased extracellular dopamine levels in the nucleus accumbens, as measured by fast-scan cyclic voltammetry.

BACKGROUND: At present, studying the mechanisms that potentiate or prevent posttraumatic stress disorder is of particular relevance, as it may help identify new therapeutic approaches. Arginine vasopressin is known to be involved in the modulation of stress and pain responses. However, the effects of this peptide on pain sensitivity and related biochemical mechanisms in a posttraumatic stress disorder model have not been studied.

AIM: The work aimed to evaluate the effects of the synthetic vasopressin analog 1-deamino-8-D-arginine vasopressin (DDAVP) on pain sensitivity, serum corticosterone concentration, brain-derived neurotrophic factor (BDNF) levels, and monoamine content in the parietal cortex and spinal cord in rats during the acute period after vital stress.

METHODS: The study included 41 male Wistar rats. All animals were divided into four groups: five intact rats (control), 12 rats receiving DDAVP, 12 rats exposed to vital stress induced by a single experience of witnessing the death of a partner caused by a predator (tiger python), and 12 rats receiving DDAVP on days 1–5 after vital stress. DDAVP was administered intranasally at a single dose of 2 μg and a cumulative dose of 10 μg. BDNF levels in the parietal cortex and spinal cord, as well as serum corticosterone concentration, were determined using enzyme-linked immunosorbent assay. Levels of norepinephrine (NE), serotonin (5-HT), dopamine (DA), and their metabolites in the brain were measured by high-performance liquid chromatography.

RESULTS: DDAVP administration produced an analgesic effect, accompanied by increased BDNF and NE levels and decreased homovanillic acid (HVA) levels in the sensorimotor cortex. In the spinal cord, DDAVP increased BDNF levels and reduced NE, 5-HT, and 3,4-dihydroxyphenylacetic acid (DOPAC) content. On day 5 after vital stress, rats demonstrated reduced pain sensitivity along with elevated blood corticosterone levels; in the sensorimotor cortex, NE levels increased and HVA levels decreased; in the spinal cord, NE and DOPAC levels decreased. In stressed rats, DDAVP increased pain sensitivity, elevated blood corticosterone levels, increased BDNF, NE, and DA levels in the parietal cortex, and reduced NE, DA, and DOPAC levels in the spinal cord.

CONCLUSION: The analgesic effect of DDAVP was associated with elevated BDNF levels and altered NE and DA metabolism in the sensorimotor cortex and spinal cord, as well as with changes in 5-HT content in the spinal cord. On day 5 after vital stress, rats developed analgesia, which involved glucocorticoid mechanisms and NE and DA signaling at both cortical and spinal cord levels. DDAVP administration during the acute period after vital stress induced hyperalgesia in rats, correlating with increased BDNF levels in the sensorimotor cortex and the involvement of noradrenergic and dopaminergic systems at cortical and spinal cord levels.