Gryb, Titov, Chmyr, and Khlibeychuk: Experience of Using Amantadine Sulfate (PK-Merz) in Patients with Ischemic Stroke



Problem statement and analysis of the recent research

In 2011, the General Assembly of the United Nations recognized stroke as one of the most important non-communicable diseases resulting in disability and death worldwide. At the same time, the priority directions in the fight against stroke were determined. Currently, among patients with past stroke approximately 18-20% go back to work. By 2025, the incidence of stroke will have reduced by 25% due to conducting universal information and prevention campaign regarding the reduction in the distribution of risk factors being able to modify among the world’s population

In our country, the indicators of mortality and disability are significantly higher than in Western European countries and the USA. This situation is caused by the disadvantages of organizing prevention training programs and emergency medical care in case of stroke as well as by the extreme complexity of rehabilitation without correct understanding of a multidisciplinary approach to the problem.

Over recent decades, recanalization and reperfusion the predictive instrument of which is intravenous thrombolysis within the therapeutic window extended to 4.5 hours, have been the main therapeutic strategies in the acute phase of ischemic stroke

In case of acute occlusion of the middle cerebral artery, in patients having contraindications to intravenous rt-PA treatment in particular, intra-arterial thrombolysis may be performed within 6 hours of stroke onset (level of evidence B) if patients are treated in a specialized stroke center.

Combined interventions (intravenous thrombolysis in combination with ultrasound, laser, anticoagulants, neuroprotectors, hypothermia, etc.) attract increasingly more attention due to a powerful potential of the recovery of perfusion as well as brain protection from ischemic injury. Unfortunately, there is no evidence base which could confirm the safety and efficacy of combined revascularization in ischemic cerebrovascular events. There is a lack of reliable evidence of greater efficacy of mechanical means in comparison with pharmacological thrombolysis in ischemic stroke.

If the therapeutic window closed or the patient has any contraindications to thrombolysis, according to unified protocol the use of aspirin (160-325 mg a day) or triflusal (600 mg a day) within 48 hours is recommended. It should be noted that when using triflusal bleeding occurs more rarely [8]. Early aspirin use is proven to be rather effective in acute ischemic stroke and increases the number of patients who recovered by 13 persons per 1,000 patients who underwent treatment of stroke. Moreover, additionally in 10 per 1,000 patients a complete recovery of lost neurological functions was observed.

The aforementioned beneficial influences are registered on the background of the increase in the risk of symptomatic intracranial hemorrhage (additionally in 2 per 1,000 patients).

When using one of the antiplatelet drugs, the doctor is able only to prevent further adhesion and aggregation cascade performing early secondary stroke prevention which includes statins.

One more therapeutic strategy used by a neurologist is neuroprotection (cerebroprotection) having sufficient scientific justification; moreover, today the need for neuroprotective agents is greater than ever.

Under normal conditions, neurons use the large amount of energy for functioning of ionic pumps the most important of which is the sodium-potassium pump. It provides the stable concentration of ions inside and outside the cell that is necessary for neuronal excitation, namely, depolarization and repolarization. In ischemia, anoxic depolarization occurs [14] resulting in cytotoxic edema which within 4-6 hours due to the damage to the blood–brain barrier (BBB) is accompanied by vasogenic edema which reaches its peak one the 2nd-4th days. Depolarization results in the release of the large amount of glutamate, namely an excitatory neurotransmitter which is quite common in the CNS by presynaptic neuron endings. Neuroglia which absorbs its excess amount is damaged as well, therefore, glutamate exitotoxicity occurs, namely, mediator is found attached to NMDA and AMPA receptors thereby provoking an increase in calcium levels which, in turn, activates a range of enzymes and chain reaction begins, namely oxidative stress, inflammation, cell death. Most cells die within the first hours due to necrosis, however, hereafter within a few days or even weeks the infarct area may increase due to other mechanisms, apoptosis in the penumbral area in particular. There are several ways how to activate apoptosis. They are divided into internal activation (due to an increase in the concentration of intracellular calcium, free radicals and glutamate) and external activation associated with the activation of cell death receptors. Timely and mixed blocking of molecular mechanisms being the basis for these pathological processes can reduce brain damage, the severity of manifestations and complications of the disease. This is the goal of neuroprotection.

Therefore, potential targets of interventions include the effects of excitatory amino acids, such as glutamate, transmembrane calcium fluxes, activation of cell proteases, apoptosis, effects of free radicals, inflammation as well as the restoration of the membrane and neurotransmitter systems. More than 1,000 substances were studied in experimental ischemic stroke and in many cases the promising results were obtained.

However, currently, none of these substances demonstrated the absolute effectiveness, i.e. the ability to significantly improve clinically relevant outcomes of treatment [10].

According to a meta-analysis of clinical trials, citicoline and neurotrophic factors, peptides derived from the brain of a pig and granulocyte-colony stimulating factor in particular, are the most promising agents; they are safe and their effectiveness continues to be studied in large clinical trials.

Thus, the search for an effective agent continues and remains a high priority. Amantadine sulfate which has been used for several decades to treat acute influenza A, Parkinson’s disease, and acute or chronic drug-induced dyskinesia can be considered as one of such agents [1, 4, 15]. The mechanisms of action of the aforementioned substance detected in vivo and in vitro have been described: the blockade of NMDA receptors and sodium channels, agonism to dopamine receptors, increased noradrenaline synthesis as well as anticholinergic effects [12]. Hammond FM. et al. (2014) provided evidence that allow us to consider amantadine as an agent in first-line treatment of aggression and irritability in patients who suffered from traumatic brain injury [13].

However, as an antagonist of glutamate receptors amantadine is able to realize its action at the level of the excitotoxicity cascade [15].

The objective of the research was to compare the efficacy of conventional therapy with treatment regimen using amantadine sulfate (PK-Merz) in patients with acute ischemic stroke.

Materials and methods

The study included 40 patients (24 males, 16 females) admitted to the department of vascular neurology of the Ivano-Frankivsk Regional Clinical Hospital during the period February-October 2014 8.5 (2-14) hours after stroke onset. The average age was 64 (43-78) years. 7 patients who were hospitalized within the therapeutic window had contraindications to thrombolysis, namely, high levels of blood pressure and/or the APTT, administration of direct anticoagulants within the last 48 hours, use of indirect anticoagulants, recent internal bleeding as well as spinal trauma in the preceding 3 months. 13 (32.5%) patients developed atherothrombotic stroke; 9 (22.5%) patients were diagnosed with cardioembolic stroke; in 12 (30%) patients several causes were observed; 6 (15%) patients developed cryptogenic stroke.

After the acutest phase, i.e. on the 4th day after stroke onset (the acute phase) all patients were randomly assigned into 2 groups. Group I included 17 patients receiving conventional treatment. Group II included 23 patients receiving PK-Merz 500.0 (200 mg amantadine sulfate) intravenously once a day for 5 days with the subsequent transition to the pill form of the drug at a dose of 100 mg twice a day (for 2 months) in addition to conventional therapy. Conventional therapy included undifferentiated treatment aimed at preventing and treating respiratory failure, eliminating vascular disorders as well as at preventing and fighting against brain edema, normalizing water and electrolyte balance and acid-alkali balance, correcting disorders of blood osmolarity, eliminating hyperthermia and other autonomic disturbances. All patients received differential treatment:

  1. Acetylsalicylic acid at a dose of 200-300 mg a day or triflusal at a dose of 600 mg a day;

  2. Rosuvastatin at a dose of 20 mg a day or atorvastatin at a dose of 40 mg a day;

  3. ACE inhibitor (the dosage was chosen individually);

  4. Peptide drug derived from the brain of a pig at a dose of 20.0 ml intravenously and citicoline at a dose of 1,000 mg intravenously.

Physical therapy and massage therapy were used. Patients with aphasia were consulted by a speech pathologist who worked with them every day during their hospital stay.

At the time of randomization stroke severity according to the NIH Stroke Scale (NIHSS) was 13 (9-17) points.

The exclusion criteria were: the NIHSS score ≥ 18, oncopathology, mental disorders, kidney failure with creatinine clearance less than 50 ml/min and the QT interval – not more than 420 µs.

The patients’ functional state was evaluated using the NIH Stroke Scale and the modified Rankin Scale; the degree of inhibition of brain function was evaluated by the bispectral index (BIS) defined using the BIS monitor (model А-2000XP, Aspect Medical Systems, USA) that processes the data of continuous electroencephalography in real-time environment and calculates the numerical value of the BIS. The BIS index provides the measurement of the effect of general anaesthesia and brain sedation, i.e. it allows us to monitor the depth of anaesthesia during surgery which is a common practice. The BIS index=100 means that patient is conscious; the BIS index=0 means that brain activity is absent.

The BIS index defined during observation and treatment provided us with the information regarding the degree of inhibition of brain function in dynamics.

The study was carried out on the 4th, 10th, 14th days and 2 months after stroke.

To objectively justify the degree of the reliability of the results statistical methods of data analysis using an advanced analytics software package STATISTICA (StatSoft, Inc.) and Microsoft Excel spreadsheets were applied. There were used non-parametric methods of analysis: the arithmetic mean (M), the standard error of the mean (m) and significance value (p) of testing of statistical hypothesis were calculated. When analyzing the BIS index the arithmetic mean (M) and the standard deviation (σ) were calculated. Statistical significance of the difference in the average values of studied characteristics was determined using the Mann-Whitney U test. The comparison of categorical characteristics was performed using the cross-tabulation analysis and Pearson’s chi-squared test (χ2).

Results and Discussion

Therapeutic effects on brain tissue in the ischemic penumbral region are effective within 3 to 24 hours. Therefore, the use of PK-Merz has to be the most effective in the acutest phase of stroke, i.e. until the 3rd day after stroke onset. Clinical and biochemical studies [3] showed that the increase in glutamate levels in cerebral ischemia is biphasic: immediately after vascular occlusion and after reperfusion (in 2-4 hours). Clinical trials showed that the intensity of the second peak of the increase in glutamate levels correlates better with infarct size and namely in the second period (the first hours and the first day after stroke) the correction of the glutamatergic system may be the most effective.

Research papers focusing on the demonstration of positive impact of amantadine sulfate since the first day after stroke have already been published [6, 7]. Nevertheless, we considered the requirements of local protocol and started treatment since the 4th day after stroke, in the early recovery period.

The positive dynamics of the functional state according to the NIHSS was observed in both groups of patients (Fig. 1), the average NIHSS score on the 4th day after stroke was 12.04±0.57. A noticeable difference between the indicators of the scale in both groups was observed on the 10th day after stroke onset: Group I - 10.41±0.59; Group ІІ - 7.96±0.74 (р=0.052). 2 months after the observation complete recovery of functions was observed in 7 patients receiving PK-Merz while in Group I the same result was achieved in 4 patients only. In Group II there were 14 patients with the NIHSS score of less than 5 while in Group I there were 3 patients with the NIHSS score of less than 5. According to the NIHSS the functional state of patients receiving basic therapy was 5.53±0.69, while in Group ІІ it was 2.49±0.78 (р=0.009).

Fig. 1.

Dynamics of indicators of the NIHSS scale when treating patients with ischemic stroke

gmj-23-gmj.2016.3.30-g1.jpg

Note

*

- statistically significant difference between the indicators of patients of Group I and Group II on the 4th, 10th, 14th days and 2 months after stroke, p<0.05

When specifying the indicators of the NIHSS components in dynamics the most significant changes were observed in the parameters of the assessment of consciousness and aphasia (Table 1).

The main criterion for the efficiency of treating a patient with stroke is a rapid positive dynamics of the level of consciousness, and further recovery of neurological deficit. A week after treatment, marked recovery of consciousness in patients receiving PK-Merz as well asmarked improvement in language abilities in aphasic patients was observed compared to the control group (p>0.05).

Table 1 presents the parameters of the assessment of the NIHSS components characterizing the level of consciousness, motor function of the arm and leg and the degree of aphasia: 1A. The level of consciousness; 1B. The level of consciousness: a question; 1C. The level of consciousness: commands; 4. Arm weakness; 5. Leg weakness; 9. Language.

Table 1

Dynamics of the indicators of the NIHSS scale when treating patients with ischemic stroke, points (M±m)

the 4th day the 10th day the 14th day 2 months
Subscales/group after stroke
1A. The level of consciousness
Group І 1.03±0.09 0.81±0.11 0.12±0.04 0.00±0
Group ІІ 0.98±0.07 0.42±0.07* 0.00±0* 0.00±0
1B. The level of consciousness: a question
Group І 1.12±0.16 0.72±0.11 0.34±0.05 0.24±0.05
Group ІІ 1.09±0.14 0.56±0.08 0.23±0.04 0.17±0.04
1C. The level of consciousness: commands
Group І 1.13±0.09 0.51±0.05 0.24±0.08 0.00±0
Group ІІ 1.17±0.06 0.11±0.03* 0.00±0* 0.00±0
4. Arm weakness
Group І 2.72±0.06 2.59±0.06 2.42±0.05 2.12±0.05
Group ІІ 2.78±0.04 2.43±0.05 2.22±0.04* 1.91±0.04*
5. Leg weakness
Group І 2.79±0.05 2.33±0.05 2.19±0.04 1.86±0.04
Group ІІ 2.91±0.04 2.28±0.04 1.94±0.04* 1.33±0.03*
9. Language
Group І 0.94±0.05 0.82±0.04 0.79±0.03 0.69±0.03
Group ІІ 1.31±0.03* 1.00±0.03* 0.68±0.03* 0.57±0.03*

Note.

* - statistically significant difference between the indicators in Group I and Group II, p<0.05

Due to rapid recovery of consciousness and hemodynamic stabilization in patients of Group II lost functions were restored quite promptly: it was noted when assessing the dynamics of the total NIHSS score as well. Moreover, in group of patients receiving PK-Merz the proportion of aphasic patients was higher at the start of treatment (p<0.05) and significant improvement was observed 2 months after the observation: the subscale “language” differed significantly from that in patients receiving basic therapy only (р<0.05).

The BIS index is a parameter which provides direct measurement of the effect of general anaesthesia and brain sedation [2, 9], and due to the possibility of continuous electroencephalography recording it allows us to monitor the level of consciousness and its dynamics during various therapeutic options. Fig. 2 and Fig. 3 present the positive dynamics with obvious changes in the BIS indices on the 4th and 10th day after stroke: Group I - 74.00±11.16 and 86.53±8.92 (р<0.001), Group ІІ - 77.86±13.14 and 94.50±8.98 (р<0.001), respectively indicating the efficacy of both methods of treatment.

Fig. 2.

Dynamics of the BIS index in patients of Group I on the 4th and 10th day after stroke, M±σ, р<0.001

gmj-23-gmj.2016.3.30-g2.jpg
Fig. 3.

Dynamics of the BIS index in patients of Group II on the 4th and 10th day after stroke, M±σ, р<0.001

gmj-23-gmj.2016.3.30-g3.jpg

However, on the 10th day after stroke onset the level of consciousness in patients of Group II significantly differed from that in patients of Group I (Fig. 4): 94.58±8.92 vs. 86.53±8.92 (р<0.001). It is to be recalled that the BIS=10 serves as the indicator of clear consciousness, i.e. on the 10th day after stroke most patients of Group II were fully conscious.

Fig. 4.

Comparison of the BIS index in patients of Group I and Group II on the 10th day after stroke, M±σ, р<0.021

gmj-23-gmj.2016.3.30-g4.jpg

It should be noted that the use of NMDA receptor blockers as neuroprotective therapy is not a new treatment option in neurology. No study involving the administration of selfotel (CGS19755), aptiganel (Cerestat), dextrorphan, dextromethorphan, СP-101.606, magnesium sulfate, memantine, remacemide, МК-801, NPS1506 [11] produced the positive results. However, considering the positive results of recent studies [1, 4, 5, 6, 7, 12, 13, 15], that corresponds to case-control study (level of evidence D) one should believe that a large-scale study considering modern knowledge and concepts of stroke development will be carried out.

Thus, due to the blockade of NMDA receptors, which contributes to the reduction in the intensity of the glutamate cascade preserving the penumbral area as well as due to the increase in dopamine concentration both by increasing the release and blocking the re-uptake in presynaptic nerve cells, the use of amantadine sulfate is a pathogenetically justified means of neuroprotection in the acute phase of ischemic stroke. Its use contributes to rapid recovery of consciousness, significant regression of neurological deficit resulting in disability reduction.

Conclusions

The use of amantadine sulfate (PK-Merz) when treating patients with ischemic stroke conventionally is pathogenetically justified being indicated as neuroprotective (cerebroprotective) therapy.

In the acute phase of ischemic stroke it is recommended to administer 200 ml of PK-Merz 500.0 intravenously within 3 hours (for 5 days) with the subsequent transition to the pill form of the drug at a dose of 100 mg twice a day for 2 months.

Prospects for further research

The study was carried out 3 days after stroke, i.e. after the acutest phase of ischemic stroke considering all the approved unified and local protocols of treating stroke. In our opinion, in the future, it will be reasonable to use the aforementioned preparation since the first day after stroke under conditions of randomized trials considering its safety and positive results.

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Copyright (c) 2017 Viktoria Anatoliivna Gryb, Ivan Ivanovych Titov, Galyna Stepanivna Chmyr, Galyna Ivanivna Khlibeychuk

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