Psychopharmacology & biological narcology

BACKGROUND: Previously, we published a hypothesis regarding the possible role of adenosine and vagal afferents in the mechanism of the antiparkinsonian action of N-decyltropine (IEM-1556). It lies in the ability of IEM-1556 to stimulate gastric vagal afferents as a key link in the this mechanism.

AIM: This study is to compare the antiparkinsonian activity of IEM-1556 with the reference antiparkinsonian agent (levodopa) during their chronic oral administration in a prophylactic regimen to rats with rotenone-induced parkinsonism.

METHODS: The antiparkinsonian effect of IEM-1556 (3 and 10 mg/kg), as well as the reference agent levodopa (10 and 20 mg/kg), in rats with rotenone-induced parkinsonism was assessed based on the elimination of catalepsy and oligokinesia.

RESULTS: Oral administration of N-decyltropine (IEM-1556) at a dose of 10 mg/kg significantly exceeds the antiparkinsonian activity of levodopa at a dose of 20 mg/kg, being three times more effective in reducing the number of rats with severe oligokinesia. Additionally, unlike levodopa, IEM-1556 completely eliminates severe catalepsy in rats with rotenone-induced parkinsonism. IEM-1556 appears to be a safer agent compared with levodopa, as it prevents rat mortality throughout the experiment, whereas levodopa increases mortality by the end of the study. Preliminary anesthesia of the gastric mucosa with 1% lidocaine almost completely abolishes the antiparkinsonian activity of IEM-1556 at a dose of 10 mg/kg, while not affecting the antiparkinsonian activity of levodopa at a dose of 20 mg/kg.

CONCLUSIONS: This suggests that stimulation of vagal afferents in the stomach may underlie the antiparkinsonian effect of IEM-1556 but not levodopa. IEM-1556 may be considered a potential alternative to levodopa in patients with parkinsonism resistant to levodopa therapy.Oral administration of N-decyltropine (IEM-1556) at a dose of 10 mg/kg significantly exceeds the antiparkinsonian activity of levodopa at a dose of 20 mg/kg, being three times more effective in reducing the number of rats with severe oligokinesia. Additionally, unlike levodopa, IEM-1556 completely eliminates severe catalepsy in rats with rotenone-induced parkinsonism. IEM-1556 appears to be a safer agent compared with levodopa, as it prevents rat mortality throughout the experiment, whereas levodopa increases mortality by the end of the study. Preliminary anesthesia of the gastric mucosa with 1% lidocaine almost completely abolishes the antiparkinsonian activity of IEM-1556 at a dose of 10 mg/kg, while not affecting the antiparkinsonian activity of levodopa at a dose of 20 mg/kg. This suggests that stimulation of vagal afferents in the stomach may underlie the antiparkinsonian effect of IEM-1556 but not levodopa. IEM-1556 may be considered a potential alternative to levodopa in patients with parkinsonism resistant to levodopa therapy.

In cerebrovascular insufficiency, neuroprotective pharmacotherapy is usually carried out in 2 strategic directions: blockade of pathophysiological reactions of ischemic cascades and increase in the tolerance of brain neurons to ischemia/hypoxia. This approach to pharmacotherapy of patients with ischemic brain damage is the key to effective neuroprotection. Pharmacological blockade of ischemia-induced pathophysiological reactions is achieved by using drugs that affect pathogenetic targets in the dynamics of the ischemic process, which allows blocking the development of neurotoxic effects and reducing the likelihood of functional and structural changes in neurons. The work discusses the prospects for pharmacotherapy of cerebrovascular insufficiency through activation of endogenous adaptation mechanisms. The author’s own research and other sources data on the efficacy and safety of various pharmacotherapeutic agents are analyzed. The neuroprotective effects of these agents are based on activating physiological mechanisms of cellular adaptation to ischemia/hypoxia. A pharmacotherapeutic rationale is given for selecting and evaluating the pharmacodynamics of agents aimed at stimulating physiological mechanisms of neuroprotection (including neurotrophic and neuroplasticity processes). Neuroprotective pharmacotherapy for both acute cerebrovascular accidents and chronic cerebrovascular insufficiency should be combined and aimed not only at blocking pathological reactions of the ischemic cascade but also at activating endogenous adaptation mechanisms. The selection of pharmacological agents for implementing pharmacological neuroprotection by activating physiological adaptation mechanisms depends on the neuroprotection period and the intended pharmacological targets.

The cause of biological death in warm-blooded animals and humans is hypoxic brain cell damage. Consequently, oxygen gas is the leading antihypoxant in emergency medical care for all critical conditions. The most common method of oxygen administration is mechanical ventilation. However, in cases of asphyxia caused by airway obstruction with thick sputum, mucus, pus, and/or blood, inhaled oxygen does not reach the alveoli and is not absorbed into the bloodstream. In such situations, traditional mechanical ventilation becomes ineffective and fails to prevent biological death due to hypoxic brain cell damage. At the beginning of the 21st century, as an alternative to gaseous oxygen, mechanical ventilation, and extracorporeal membrane oxygenation, the development of intrapulmonary oxygen-producing antihypoxants through physicochemical repurposing of hydrogen peroxide was initiated in Russia. Professor P.D. Shabanov served as the mind behind and coordinator of the development of new-generation antihypoxants. A new group of antihypoxants — warm alkaline hydrogen peroxide solutions — was discovered. The most effective oxygen-producing antihypoxants, when applied locally via the intrapulmonary route, generate significant volumes of medical oxygen gas through catalase-mediated decomposition of hydrogen peroxide into water and molecular oxygen. The local intrapulmonary, endotracheal, and endobronchial pharmacodynamics and pharmacokinetics of warm alkaline hydrogen peroxide solutions are inseparable from interactions with catalase present in sputum, mucus, serous fluids, purulent masses, and blood that obstruct the airways during asphyxia and/or severe acute respiratory obstruction. The new generation of antihypoxants has demonstrated high therapeutic potential as powerful medical oxygen gas generators when administered intrapulmonarily, endobronchially, or endotracheally during acute severe suffocation caused by airway blockage with colloidal liquids containing catalase. It is hypothesized that intrapulmonary oxygen-producing antihypoxants could be considered therapeutic agents for emergency blood oxygen saturation through the lungs when mechanical ventilation is ineffective and extracorporeal membrane oxygenation is not feasible.

Irina S. Zavodskaya was the Corresponding Member of the Russian Academy of Medical Sciences, Doctor of Medical Sciences, Professor, and a prominent Soviet and Russian pharmacologist. She headed the Department of Pharmacology at the Institute of Experimental Medicine following the footsteps of her mentor Sergey V. Anichkov, a distinguished Soviet pharmacologist, a key figure in Russian pharmacology, Hero of Socialist Labor, Lenin and State Prize laureate, and Academician of the USSR Academy of Medical Sciences.

I.S. Zavodskaya conducted original studies on various aspects of visceral pathology induced by stressors. A novel approach to studying the mechanisms of neurogenic organ damage — from the pharmacological perspective — was pioneered by the scientific school of Academician S.V. Anichkov.

I.S. Zavodskaya supervised 24 dissertations. The results of her research have been published in numerous works (over 500 scientific publications) and are widely recognized both in Russia and over the world. She wrote six monographs, two of them were translated into English and published in Oxford.

I.S. Zavodskaya’s scientific and public contributions were recognized with state awards, including the Order of the Badge of Honor (2002) and the Medal “For Valorous Labor.” Her scientific achievements also gained international recognition: she was awarded the N.P. Kravkov Commemorative Medal (Russia), the Medal of the Mario Negri Institute (Italy), and the Honorary Badge of the Bulgarian Academy of Sciences.

Irina S. Zavodskaya made a significant contribution to the advancement of fundamental research in Russian pharmacology for the benefit of human health.