Possibilities of using amantadines in the setting of the novel coronavirus infection in patients with Parkinson's disease

The novel coronavirus infection pandemic prompted not only the development of vaccines, but also the study of the effectiveness of already known drugs with antiviral activity. These drugs include adamantanes.Objective: to assess possible mechanisms of antiviral action of amantadine and memantine.Patients and methods. The study included 75 patients with Parkinson's disease (PD): 49 (65.3%) women and 26 (34.7%) men. The age of the patients ranged from 37 to 88 years (mean age: 65±7 years). The duration of the disease varied from 1 to 25 years (mean 12±7 years). Among the monitored PD patients, 22 (29.3%) had a novel coronavirus infection. Of 22 patients with coronavirus infection, 8 (36.4%) patients received adamantanes (four – amantadine sulfate, three – amantadine hydrochloride, one – memantine) in the complex therapy of PD for at least 3 months. On average, the duration of adamantane administration was 8±5 months.Results and discussion. PD patients who received adamantanes were less likely to develop COVID-19 than those who did not take adamantanes (p<0.05). At the same time, there were no significant differences in gender, age, duration of the disease and concomitant pathology in the com pared groups (p>0.05). Among patients who received adamantanes, the disease proceeded more easily, the number of cases of pneumonia was 3 times less (odds ratio 3; 95% confidence interval 0.44–20.3). In this group, no lethal outcomes were recorded, however, due to the small sample of patients, the differences between the groups were not statistically significant (÷2=1.99; p>0.05).Conclusion. The results of a retrospective study showed that the use of amantadine and memantine in patients with PD may have an effect on reducing morbidity and mortality in the novel coronavirus infection. This is consistent with published clinical observations suggesting a possible protective effect of amantadine and memantine against coronavirus infection.

The possibilities of pharmacological correction of ademol oxidative stress in rates with traumatic brain injury

Annotation. An important measure of intensive care in patients with traumatic brain injury (TBI) is the use of pharmacotherapeutic agents with antioxidant properties. The aim of this study was to evaluate the effect of ademol compared with amantadine sulfate and 0.9% NaCl solution on the course of oxidative stress in the brain of TBI rats. The experiments were performed on 28 white male rats weighing 160-190 g. The experimental TBI model of severe severity was caused by the action of a carbon dioxide flow under pressure created using a gas balloon pneumatic gun. The therapeutic effect of ademol on model TBI was evaluated with a 2 mg/kg dose. The pseudoperated animals and control group received a 0.9% solution of NaCl and amantadine sulfate at a dose of 2 ml/kg and 5 mg/kg i/v. Data were processed using StatPlus 2009. We used the parametric criterion of t-Student, non-parametric criterion of W. White, paired criterion Ť. Wilcoxon, Fisher's angular transformation at p <0,05. In the course of the experiment, it was found that treatment of rats with TBI ademol leads to a decrease in the activity of lipid peroxidation and oxidative degradation of proteins (p<0.05) and promotes the normalization of the activity of antioxidant enzymes in cells of traumatically damaged brain (p<0.05). The use of ademol compared to amantadine sulfate and 0.9% NaCl solution was accompanied by a more significant decrease in the activity of lipid peroxidation and oxidative degradation of proteins and an improvement in the level of antioxidant enzymes in damaged brain of animals with TBI (p<0.05).

Practical aspects of prescribing antiparkinsonian drugs. The place of amantadines in the management of Parkinson’s disease

Treatment of Parkinson’s disease (PD) includes the administration of dopaminergic and occasionally non-dopaminergic drugs, in mono- or in combination therapy. One of the key drug used to treat Parkinson’s disease is levodopa considered a gold standard. In addition levodopa can also be used as a challenge test to confirm the accuracy of diagnosis of PD known as the “Levodopa challenge test”. However many non levodopa class of drugs are also used and consist of dopamine agonists (ADRs), MAO-B and COMT inhibitors, as well as drugs working on glutamate such as a group of drug with NMDA receptor inhibitor activity (amantadines). The successful treatment of PD therefore depends on the correct choice of drugs to initiate treatment and sustainance of such therapy. The main parameters for personolised treatment include the patient’s age, severity and pattern of motor deficit, the state of cognitive function and lifestyle. Levodopa, although the most effective, is almost invariably associated with motor fluctuations and dyskinesias. Before prescribing levodopa, in addition to MAO-B inhibitors and ADRs, amantadines can be used as a monotherapy. Once replacement of therapy is required, then it is necessary to use a coefficient to calculate an equivalent dose of levodopa known as the levodopa equivalent dose. Progression of PD is inevitable inspite of adequate symptomatic therapy and at the advanced stage of PD approaches for the management of motor complications of levodopa need to be considered. For motor fluctuations these strategies require a change in the dosage regimen of levodopa (daily dose and frequency of intake), as well as the addition of an adjunct drug – ADRs, MAO-B inhibitor or COMT inhibitor. When dyskinesias arise, the management depends on correct identification of the type of dyskiensias. The commonest type of dyskinesia is peak dose dyskinesias related to peak plasma levodopa levels after intake. Amantadine provides a quick and long-lasting antidyskinetic effect which has been confirmed in open label as well as double-blind placebo-controlled studies. Compared to аmantadine chloride, amantadine sulfate has more stable pharmacokinetic parameters and a better safety profile. In addition, parenteral administration of amantadine sulfate can be utilized for severely ill patients with akinetic crisis in PD. Amantadine also has a broad spectrum effect and these may include improvement of fatigue and apathy. Some data also suggest that the use of amantadine in patients may increase life expectancy, improve survival and reduce the risk of dementia.

Efficacy of ademol in experimental cranial injury on the effect of oxidative stress

Objective. To evaluate the effectiveness and safety of ademol for oxidative stress in the brain of rats with traumatic brain injury (TBI). Materials and methods. In 260 male-rats weighing 160-180 g, the preclinical efficacy of ademol was studied against the background of the actual developed TBI model. Several groups of animals were formed: pseudo-operated (TBI + 0.9 % NaCl intravenously), control pathology (TBI + 0.9 % NaCl intravenously), TBI + ademol 2 mg/kg intravenously, comparison drug (TBI + amantadine sulfate). The experimental model was induced by the action of a stream of carbon dioxide under pressure using a gas-balloon air pistol “Baikal MR-654K”, evaluated only severe trauma (the air pistol hole is close to the center of the trepanation hole in rats). Ademol (Ademol-Darnytsia, Ukraine) was administered in several doses to determine the conditionally effective dose, and the reference drug amantadine sulfate (PC-Merz, Switzerland) was administered slowly with infusomate for 2 h after 12 h for 8 days, 60 min after injury. Biochemical processes in traumatically damaged brain (in homogenates and postnuclear supernatant) were studied on the 8th day, oxidative stress parameters were evaluated by the content of malonic dialdehyde (MDA) by reaction with thiobarbituric acid, carbonyl groups of proteins (CGP) – by reaction with dinitrophenylhydrazine, activity of antioxidant enzymes – by reaction with superoxide dismutase (SOD), glutathione peroxidase (GPO) and catalase. Statistical processing was performed according to StatPlus programs, by parametric and nonparametric criteria, the differences were considered significant at p<0.05. Results and discussion. Hyperactivation of free radical oxidation of biomembrane lipids is registered in the brain structures of injured rats. In the group of pseudooperated animals, the median content of the secondary metabolite of lipoperoxidation MDA in the brain was 13.2 (95 % confidence interval (CI) 12.8-14.2) μmol/g of dry tissue. In the control pathology group, the MDA index is 2.28 times (p<0.05) higher than in pseudooperated animals, the median is 30.8 (95 % CI 28.6-33.3) μmol/g of dry tissue. The use of the studied drugs reduces the activation of lipid peroxidation processes in brain tissues. Ademol had the most active influence. In the group of animals treated with this drug, the content of MDA in the brain was lower by 58.3 % (p<0.05) than in the control pathology group, the median was 14.6 (95 % CI 12.6-15.5) μmol/g of dry tissue. Amantadine sulfate was inferior to ademol: the content of MDA in the brain was lower by 48.4 % (p<0.05), the median was 16.1 (95 % CI 14.9-16.7) μmol/g of dry tissue. The development of TBI was associated with the activation of oxidative modification of CGP. In pseudooperated animals, the median content of CGP in the brain was 4.73 (95 % CI 4.29-5.01) μmol/g of dry tissue, the level of CGP is 1.77 times higher (p<0.05) in control pathology group. The active preventive drug was ademol: the content of CGP in the brain decreased by 40.1 % (p<0,05) than in animals of the control pathology group, the median was 4.90 (95 % CI 4.62-5.54) μmol/g of dry cloth. Amantadine was slightly inferior to ademol in this effect: the content of CGP in the brain was lower by 39.1 % (p<0.05), against control pathology, the median was 4.99 (95 % CI 4.65-5.59) μmol/g of dry cloth. Oxidative stress occurred against the background of decreasing the rate of inactivation of the superoxide anion radical: the median activity with the participation of SOD in the brains of pseudooperated animals was 2.68 (95 % CI 2.23-3.05) um. od/mg protein; there was also a decrease in the activity of SOD in the brain by 51.7 % (p<0.05) in the control pathology group, the median activity of the enzyme was 1.31 (95 % CI 0.97-1.57) um. od/mg protein. Pharmacotherapy prevented a drop in the reaction rate of SOD: on the background of ademol, it was 105 % higher than the control pathology group, the median of its activity was 2.69 (95 % CI 2.17-3.16) um. od/mg protein. Amantadine sulfate was slightly inferior to ademol: the activity of SOD in the brain was less by 101 %, the median of its activity was 2.53 (95 % CI 2.09-3.11) um. od/mg of protein. TBI is also accompanied by inhibition of hydrogen peroxide inactivation by the enzymes GPO and catalase: a decrease in brain tissues activity of GPO by 55.3 % and catalase by 53.0 %. When corrected with ademol, the activity of GPO in brain was higher by 70.9 %, as well as the activity of catalase – by 89.5 % (ranged from 6.39 to 7.45 μcatal/mg protein), against levels in the control pathology group. Amantadine sulfate contributed to an increase in the activity of GPO by 44.5 % (from 55.5 to 61.2 μmol/min per 1 mg of protein), an increase in catalase – by 79.0 % (from 6.21 to 6.75 μcatal/mg of protein) than indicators in the control pathology group. Conclusions. The use of ademol in rats with TBI contributes to the probable restraint of oxidative stress: reducing the prooxidative effect of trauma and activation of antioxidant enzymes.