Nootropics are medicines restoring cognitive functions (memory, attention, decision-making ability, etc.) affected by damaging influences such as ischemia, respiratory hypoxia, trauma, various toxic effects.
The modern nootropic drugs range includes a fairly broad spectrum of medicines. Their parent compound is piracetam – a drug that emerged in the mid-1960s and has been considered to be a modern nootropic up to this day.
Most nootropics have a central antihypoxic effect and a complex polyvalent action mechanism. Thus, in the description of the action mechanism of pyracetam and its numerous analogues (aniracetam) its effect on the GABAergic system is indicated as a key component, however characterized as ambiguous. In addition the drug stimulates acetylcholine release, increases dopamine and norepinephrine synthesis in the brain.
In accordance with the nootropics ability to affect various parts of the cerebral component of pathogenesis a number of researchers proposed the concept of the nootropic drugs “clinical activity spectrum”. It is stated that unlike the antiasthenic, vegetostabilizing and adaptogenic action peculiar virtually for all the representatives of this drugs group the remaining effects including actually noo- and mnemotropic are not characteristic for all of them (see in Appendix Figure 1).
The basic indications for the nootropic drugs prescription are cerebroasthenic disorders and encephalopathies of various origin (eg, at persistent or dynamic cerebral circulation disorders, organic CNS lesions of traumatic origin, mental retardation, etc.). Herewith the drugs with express stimulating characteristics are mainly used for asthenic reactions and the drugs with a noticeable tranquilizing effect – for organic disorders with hypersthenic presentations.
In most cases the nootropic drugs are well tolerated and have virtually no contraindications. Rather rarely the application of nootropics with a stimulating effect may cause hyperstimulation with anxiety, irritability and insomnia.
The development of compounds with nootropic activity has been in progress up to the present. One of the new drugs of this group is Noopept – the original dipeptide offering nootropic and neuroprotective properties. According to the chemical structure Noopept represents an ethylic ester of N-phenyl-acetyl-L-prolyl-glycine:
Piracetam has chemical structure of 2-oxo-1-pyrrolidine acetamide:
When administered orally Noopept is absorbed in the digestive tract and enters the systemic blood circulation unchanged; the relative bioavailability of the drug dosage form for rabbits amounts to 99.7%. Six Noopept metabolites are formed in the body – three phenyl-containing and three desphenyl. The main metabolites active is cyclo-prolylglycine, identical to the endogenous cyclic dipeptide with nootropic activity.
The drug chronic toxicity study for the experimental animals at the doses exceeding the average nootropic dose by 2 to 20 times showed that Noopept has no damaging effect on the internal organs, does not lead to significant behavioral reactions distortions, changes in hematological and biochemical values for all the experimental animals.
The drug has no immunotoxic, teratogenic effects, manifests no mutagenic properties, does not affect the next generation postnatal development and the animals’ reproductive function adversely.
The maximum antiamnesic effect is determined for the doses of 0.5-0.8 mg/kg. The action duration is 4-6 hours after a single dosing. At its increase to 1.2 mg/kg the effect fades out (“domical” dependence). For the model nootropic pyracetam the maximum effect was detected at a dose of 500 mg/kg, at the dose increase to 800-1000 mg/kg the effect also fades out.
Noopept nootropic effect is selective. Within a wide range of doses (0.1-200 mg/kg) the drug manifests no stimulating or sedative effect, does not distort the movements coordination, has no myorelaxant action. Continuous Noopept administration at a dose of 10 mg/kg does not lead to its neurotropic activity spectrum change, there is no cumulative effect, tolerance development or new drug action components manifestation. At the drug cessation minor activation phenomena were noticed, with no signs of “rebound” anxiety development typical for some nootropics.
The wide range of nootropic and neuroprotective activities of Noopept was the basis for the clinical studies conducting on its administration for adults with impaired memory, attention and other intellectual and mnestic functions after traumatic brain injury and chronic cerebrovascular insufficiency.
The study purpose: to evaluate the safety and therapeutic efficacy of the drug of Noopept in comparison with pyracetam for the patients with mild cognitive impairment at organic brain diseases of vascular and traumatic origin.
- To study the effectiveness of Noopept in comparison with piracetam for the patients with organic brain disease of vascular origin.
- To study the effectiveness of Noopept in comparison with piracetam for the patients with organic brain disease of traumatic origin.
- To specify the possible adverse effects of Noopept.
The clinical study was carried out on the basis ин State Scientific Center of Social And Forensic Psychiatry, Russia.
The study covered 50 patients: 35 with organic emotionally labile (asthenic) disorder and 15 with postconcussion syndrome.
Study entry criteria
- Mild cognitive disorders developed due to chronic cerebrovascular insufficiency and at remote stages after a brain injury with cognitive and dysmnesic disorders.
- Evaluation of the cognitive function decline according to the Mini Mental Status Exam (MMSE).
- Age of patients with post-traumatic CNS disorders of 18 to 60 years and with diseases of vascular origin of over 50 years.
- No administration of drugs with psychotropic activity for at least a week before the study commencement.
- Negative pregnancy test.
- Patients’ informed consent of to participate in the tests.
- Psycho-organic disorders at primary degenerative cerebral diseases.
- Manifestations of moderate and severe dementia, including personality regression, the judgment level significant reduction, gross memory disorders, impressive and expressive speech, writing and calculation, distortions in daily activities requiring some supervision, generally preventing the drug main therapeutic effect identification on the basis of the patients’ self-report.
- The state of psychomotor agitation, the presence of delusional and hallucinatory symptoms, delirious disorders, confusion manifestations, as well as depressive disorders of moderate to severe manifestation degree.
- The presence of coexisting somatic and neurological diseases in the exacerbation phase or requiring continuous concomitant drug treatment.
- Signs of chronic alcohol addiction, drug and substance addiction.
- Pregnancy, nursing period.
- The drug individual intolerance.
- Patient’s repeated inclusion in the study.
- Patient’s involvement in other studies.
The study was conducted for the patients with post-traumatic CNS disorders aged 18 to 60 and with diseases of vascular origin aged over 50 receiving Noopept or piracetam.
For the conduction of a randomised, comparative clinical study (phase III) the patients participating in the study were divided into the following groups (see in Appendix Tables 1 and 2):
- Major group I – patients with emotionally labile/asthenic disorder receiving Noopept (20 people).
- Comparison group I – patients with emotionally labile/asthenic disorder receiving piracetam (15 people).
- Major group II – patients with postconcussion syndrome receiving Noopept (10 people).
- Comparison group II – patients with postconcussion syndrome receiving piracetam (5 people).
The following methods were used for the patients’ examination before and during the study (see in Appendix Table 3):
- Symptom severity rate scale, compiled on the basis of the “Unified system of the clinical and pharmacological effects of psychotropic drugs for the patients with borderline disorders assessment”, allowing to obtain objective quantitative data on the therapeutic dynamics of psychopathological symptoms and the drugs psychotropic effects characteristics.
- Mini Mental Status Exam (MMSE) consisting of an array of neuropsychological tests, assessing the cognitive functions: attention, memorization, gnosis, speech, praxis, calculation by points.
- Brief Cognitive Rating Scale (BCRS), allowing to assess the severity of cognitive disorders separate components.
- Cognitive Capacity Screening Examination (CCSE) consisting of an array of tests assessing cognitive functions: orientation, memory, calculation, the ability to come to conclusions, to group objects.
- The clinical global impression scale (CGI) allowing to asses numerically the drug therapeutic effectiveness, its tolerability and safety according to the changes in the indications of “disease severity”, the “general improvement” degree, the “therapeutic effect”, and the presence and severity of adverse effects during the treatment.
- Clinical blood tests, urine tests, biochemical analyzes (AST, ALT).
- Electrocardiography, pregnancy test.
The duration of the patients’ participation in the study corresponded to the periods of the patients’ screening and treatment with Noopept or piracetam and amounted to 63 days.
The study stages
- The patients’ inclusion in the study: screening with mandatory previous therapy cancellation (duration: 7 days).
- Noopept or piracetam treatment course (duration: 56 days).
The conditions for the study interruption for individual patients
- The patient’s refusal to continue the participation in the study.
- Adverse effects incompatible with further administration of Noopept or piracetam.
At the end of the introductory period the patients meeting the requirements for inclusion in the study were prescribed with:
- In the study group – Noopept at a daily dose of 20 mg divided into two doses, the treatment course of 56 days. The second dose was taken before 6 p.m.
- In the comparison group – piracetam at a daily dose of 1200 mg divided into three doses, the treatment course of 56 days. The third dose was taken before 6 p.m.
Noopept or piracetam was prescribed in the form of single-substance therapy. The dose changes, the new drugs prescription or cancellation of any of them were recorded in the individual registration card.
The compared drugs effectiveness was assessed according to CGI, cognitive functions, MMSE, cognition scale, symptoms severity evaluation, mental status.
The safety assessment was carried out taking into account the undesirable adverse effects and the laboratory indicators deviations, taking into account their severity degree, gravity, duration and possible connection with Noopept or piracetam therapy.
No significant differences between the groups of patients were identified.
The study results
All the patients completed their participation in the study. No cases of early termination due to the refusal to continue the therapy, its lack of effectiveness or the adverse effects appearance have been recorded.
For the patients with organic emotionally labile (asthenic) disorder who received Noopept as a result of the treatment statistically significant improvement was achieved for the criteria of “orientation”, “attention”. For the criteria of “memorization” and “speech, gnosis, praxis” no noticeable improvement was recorded as a result of the treatment. For the patients with postconcussion syndrome a significant improvement in attention rates was noticed. No significant dynamics of the criteria of “memorisation”, “speech, gnosis, praxis” was revealed in this group of patients either. The efficacy of Noopept concerning the stated symptomatology exceeded that of piracetam (see in Appendix Tables 4 and 5).
The range of symptoms whose positive dynamics was statistically significant differed slightly for the two condition types at Noopept prescription. According to these criteria at the psychopathological symptoms gravity rating scale (anxiety, increased irritability, affective lability, low mood, increased exhaustion, apathy, psychomotor agitation, psychomotor retardation, insomnia, general adaptation assessment) Noopept efficacy became reliable by the end of the treatment course. The remaining symptoms were identified as low-informative to identify the effectiveness (see in Appendix Table 6).
The dynamics of somatoneurological signs according to the psychopathological symptoms gravity rating scale at Noopept prescription for the patients with organic emotionally labile disorder and postconcussion syndrome differed. For the patients with an organic emotionally labile disorder a positive effect was observed concerning the following criteria: “muscle hypotension”, “sweating”, “vasomotors lability”, “orthostatic disorders”, “hyperesthesia”. The drug effect for the criteria of “headaches” was not revealed, the remaining signs were less informative. For the patients with postconcussion syndrome the drug effect for the criteria of “muscle hypotension”, “headaches”, “orthostatic disorders”, “hyperesthesia” was not observed. The remaining signs were less informative.
Cognitive abilities distinctively improved at Noopept prescription. Thus out of 20 patients with an organic emotionally labile disorder and postconcussion syndrome improvement varying degrees was noticed for all the 20 and 10 patients respectively (see in Appendix Figures 1 and 2) by the end of the treatment with Noopept.
Reliable positive dynamics (somewhat less distinct at postconcussion syndrome) evidencing the effectiveness of Noopept was noticed for all the criteria of the “Brief cognition assessment scale” (see in Appendix Tables 7 and 8).
Generally the effectiveness of Noopept and piracetam for the patients with an organic emotionally labile disorder (Mann-Whitney test, a comparison of two samples) according to the mini mental status exam, symptom severity scale (psychopathological and somatoneurological signs), brief cognition scale, general clinical impression scale did not differ significantly. Concerning most of the above parameters the therapeutic effect of Noopept appeared to be higher.
The number of adverse events at Noopept therapy was by 2.5 times lower (at the absolute patients number higher by 1.5 times ) (see in Appendix Table 9).
Compared to piracetam the risk of adverse events (AE) development for the patients reduced by 12% to 62% at Noopept administration (see in Appendix Table 10).
The results of the conducted clinical study showed that Noopept is an effective drug for the treatment of patients with an organic emotionally labile disorder and postconcussion syndrome. At the administration of Noopept compared to piracetam the risk of adverse events developments is reduced by 12% to 62% with 95% reliability.
Noopept is recommended for the treatment of patients with an organic emotionally labile disorder and postconcussion syndrome. The safety and good tolerability of the drug allow to recommend it as the main drug for the studied conditions therapy.
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|Table 1. Emotionally labile (asthenic) disorder|
|Noopept (n=20)||Piracetam (n=15)||Groups difference (Fisher’s exact test)|
|Age (years)||56.3||59.8||p ˃ 0.05|
|Sex||M (9) F (11)||M (4) F (11)||–|
|Disease duration (years)||3.5||4.9||p ˃ 0.05|
|Table 2. Postconcussion syndrome|
|Noopept (n=10)||Piracetam (n=5)||Groups difference (Fisher’s exact test)|
|Age (years)||44.9||39.6||p ˃ 0.05|
|Sex||M (4) F (6)||M (1) F (4)||–|
|Disease duration (years)||2.4||2.0||p ˃ 0.05|
|Table 3. The patients’ examination methods|
|Screening and randomization||3||7||14||21||28||42||56|
|Symptom severity rate scale||X||X||X||X||X||X||X||X|
|Cognitive Capacity Screening Examination (CCSE)||X||X||X||X||X||X||X||X|
|Brief Cognitive Rating Scale (BCRS)||X||X||X||X||X||X||X||X|
|Clinical global impression scale (CGI)||X||X||X||X||X||X||X|
|Blood, urine tests||X||X|
|Biochemical blood analyzes (AST, ALT)||X||X|
|Adverse effects evaluation||X||X||X||X||X||X||X|
|Table 4. Results of Mini Mental Status Exam (MMSE) at the screening and by the end of the study for the patients receiving Noopept and piracetam|
|Organic emotionally labile (asthenic) disorder|
|Orientation||105||˂ 0.001||45||˂ 0.01|
|Attention||153||˂ 0.001||120||˂ 0.001|
|Here and elsewhere: W – Wilcoxon’s test result|
|Table 5. Criteria of the Symptom severity rate scale (psychopathological symptoms) for the patients receiving Noopept at the screening (1) and by the end of the study (2)|
|Criteria||Noopept (1)||Noopept (2)|
|Organic emotionally labile (asthenic) disorder|
|Anxiety||210||˂ 0.001||105||˂ 0.001|
|Increased irritability||210||˂ 0.001||120||˂ 0.001|
|Affective lability||171||˂ 0.001||120||˂ 0.001|
|Low mood||210||˂ 0.001||120||˂ 0.001|
|Increased exhaustion||210||˂ 0.001||105||˂ 0.001|
|Apathy, indifference||153||˂ 0.001||105||˂ 0.001|
|Psychomotor agitation||55||˂ 0.01||–|
|Psychomotor retardation||36||˂ 0.02||–|
|Insomnia||153||˂ 0.001||91||˂ 0.001|
|General adaptation assessment||153||˂ 0.001||120||˂ 0.001|
|Increased irritability||55||˂ 0.01||–||–|
|Affective lability||55||˂ 0.01||–||–|
|Low mood||55||˂ 0.01||–||–|
|Increased exhaustion||36||˂ 0.05||–||–|
|Apathy, indifference||45||˂ 0.01||–||–|
|Psychomotor retardation||36||˂ 0.05||–||–|
|General adaptation assessment||55||˂ 0.01||–||–|
|Table 6. Criteria of the Symptom severity rate scale (somatoneurological signs) for the patients receiving Noopept at the screening (1) and by the end of the study (2)|
|Criteria||Noopept (1)||Noopept (2)|
|Organic emotionally labile (asthenic) disorder|
|Muscle hypotension||45||˂ 0.01||55||˂ 0.01|
|Vasomotors lability||36||˂ 0.02||–||–|
|Orthostatic disorders||28||˂ 0.016||–||–|
|Table 7. cognitive rating scale results for the patients receiving Noopept at the screening and by the end of the study|
|Organic emotionally labile (asthenic) disorder|
|Ability to concentrate and calculate||190||˂ 0.001|
|Short-time memory for current events||190||˂ 0.001|
|Long-time memory for the past||219||˂ 0.001|
|Activity and self-care||190||˂ 0.001|
|Ability to concentrate and calculate||45||˂ 0.01|
|Short-time memory for current events||55||˂ 0.01|
|Long-time memory for the past||55||˂ 0.01|
|Activity and self-care||55||˂ 0.01|
|Table 8. Comparative evaluation of the patients according to the “Brief cognitive rating scale”|
|therapy beginning||therapy end||therapy beginning||therapy end|
|Organic emotionally labile (asthenic) disorder – condition gravity|
|Organic emotionally labile (asthenic) disorder – improvement|
|Postconcussion syndrome – condition gravity|
|Postconcussion syndrome – improvement|
|Table 9. Recorded adverse effects at the studied drugs administration|
|Table 10. Adverse events development role|
|Noopept (n=30)||Piracetam (n=20)||Degree difference||SE||CI 95%|
|Number of patients with adverse events||4-0.13||10-0.5||0,37||0,13||0,12-0,62|