Oxiracetam - Educational material

Oxyracetam, chemically known as 4-hydroxy-2-oxopyrrolidine-N-acetamide or ISF-2522, is a cyclic derivative of γ-aminobutyric acid (GABA). It is a water-soluble member of the racetam group, which is known for its greater potency compared to its predecessor, Piracetam. Developed in the 1970s from Piracetam by adding a hydroxyl group, oxyracetam contains a pyrrolidone nucleus, a common feature among the racetams. Its action on AMPA-sensitive glutamate receptors and its ability to increase neurotransmitter release make oxyracetam a favourite among nootropic users to improve memory, learning and overall brain health. Additionally, its mild stimulant properties further contribute to its popularity.

Interestingly, it is administered as a mixture of two forms: (S)-oxiracetam and (R)-oxiracetam, with pharmacological effects mainly attributed to one of these forms. This specificity suggests that the use of only the active form has the potential to increase the efficacy of the drug, simplify its pharmacokinetics and minimise possible drug interactions and side effects. It is worth noting that (S)-oxiracetam has better absorption and a slower elimination rate.

The unique properties of oxyracetam, including its almost odourless and slightly bitter crystalline powder, along with its water solubility, provide users with a variety of ingestion options, whether in powder or capsule form, with or without food. Its ability to cross the blood-brain barrier and concentrate in key areas of the brain, such as the hippocampus, cerebral cortex and striatum, underline its effectiveness in improving clinical outcomes for a range of brain disorders, including neurodegenerative diseases, stroke and cognitive and memory deficits.

Oxyracetam, cognitive performance and dementia

Numerous human studies have shown that oxyracetam acts as a cognitive enhancer and has significant benefits for people with dementia. In a study involving 65 participants at different stages of dementia, such as Alzheimer's disease (AD), multiple-infarct dementia (MID) or mixed forms, the effect of oxyracetam was evaluated compared to placebo over a 12-week period. Results showed that oxyracetam 800 mg twice daily showed significant improvements in cognitive function and quality of life compared to placebo. Subjects reported improvements in memory, associative thinking and skills
problem-solving, which were particularly evident in tasks such as controlled association, recall of short stories and performance on Raven's progressive matrices [1]. Furthermore, although two participants dropped out of the study due to side effects, the majority of participants found the treatment manageable and few experienced mild side effects such as dry mouth and dizziness [1]. Another study of patients with MID and primary degenerative dementia (PDD) showed significant improvements in verbal fluency and a significant positive effect on non-cognitive symptoms such as depression and mood lability among patients with PDD, as measured by the Relatives' Assessment of Global Symptomatology-Elderly (RAGS-E) scale [2].

In addition, a large study tested oxyracetam in the treatment of different types of dementia, including the type that worsens over time, the type caused by strokes and a mixture of both. Administering a dose of 800 mg twice a day for 12 weeks showed that oxyracetam helped improve brain function more than placebo. This means that patients were able to think better and perform daily tasks more easily. Furthermore, oxyracetam was safe to use; people had only minor side effects, such as several patients in both the oxyracetam and placebo groups experiencing minor problems. There were no serious problems or changes in health control, making oxyracetam a safe option for dementia [3]. Another study comparing selegiline and oxyracetam in 40 patients with mild to moderate dementia found positive results with the administration of oxyracetam. Together with selegiline, oxyracetam improved memory and cognitive performance with minimal side effects. This study suggests that oxyracetam in combination with selegiline may be a better option for some patients with dementia [5].

Furthermore, the study tested the efficacy of nicergoline and oxyracetam in patients experiencing cognitive dysfunction after stroke. Nicergoline, which improves blood circulation and is traditionally used to treat cognitive dysfunction, was combined with oxyracetam, known for its cognitive-enhancing properties. Over a one-month period, 120 patients were treated with nicergoline alone or a combination of both drugs. The Montreal Cognitive Assessment Scale (MoCA) was used to assess cognitive performance before and after treatment. Those in the combination therapy group showed significantly better cognitive improvement than those in the nicergoline-only group, achieving an impressive cognitive improvement success rate of 93.3%. This study highlights the potential of combining these two drugs to significantly improve cognitive rehabilitation after stroke [6]. Furthermore, researchers investigated the cognitive and behavioural effects of oxyracetam in patients with senile dementia of the Alzheimer's type (SDAT) and multi-infarct dementia (MID). A double-blind, placebo-controlled study involving 60 patients who were given 800 mg of oxyracetam or placebo twice daily for an initial 90 days was conducted. Significant improvements in cognitive function were noted in the oxyracetam group, as evidenced by better scores on several neuropsychological tests. After the initial trial phase, most patients continued treatment with oxyracetam in an open-label follow-up study for one year. These results confirmed cognitive benefits and additional improvements in memory function. The treatment was well tolerated and no significant adverse effects were reported [7].

In addition, the study assessed the potential of oxyracetam to counteract scopolamine-induced amnesia in healthy volunteers. The double-blind crossover study involved the administration of different doses of oxyracetam or placebo before inducing cognitive impairment with scopolamine. The study carefully measured effects on cognitive performance in several domains, including verbal memory and attention. Interestingly, oxyracetam, particularly at a dose of 1,600 mg, showed a significant ability to improve cognitive function impaired by scopolamine. This study confirmed the efficacy of oxyracetam in enhancing cognitive performance [8]. Furthermore, in a study involving 140 patients with hypertensive cerebral haemorrhage, researchers investigated the efficacy of combining nerve growth factor (NGF) with oxyracetam compared to the use of oxyracetam alone. Patients were randomly assigned to receive the combination treatment or oxyracetam alone for one month. Clinical outcomes were assessed using various scales, including the National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS), focusing on neurological outcomes, muscle strength and inflammatory markers. The results showed that the combination therapy led to more significant improvements in cognitive function, reduced inflammation and higher survival rates compared to the control group. This study revealed the potential of NGF and oxyracetam in providing a synergistic effect to improve recovery from hypertensive cerebral haemorrhage [9].

In a clinical trial involving 96 people with dementia, patients received 1,600 mg of oxyracetam daily or placebo for 26 weeks. Results showed significant improvements in cognitive function and reaction time in the oxyracetam group compared to the placebo group. Patients themselves expressed a preference for oxyracetam and the treatment was well tolerated with no reported side effects. It is noteworthy that oxyracetam was exceptionally well tolerated with no serious adverse effects. These results suggest that oxyracetam improves information processing in the brain, making it a promising option for the treatment of cognitive impairment in dementia [12]. Similarly, another study showed significant improvements in cognitive function and reaction time in the oxyracetam group throughout the study period. In contrast, the placebo group showed a decline in cognitive function after twelve months. Oxyracetam was well tolerated and patients preferred the treatment to placebo and no adverse effects were reported. This study suggests that oxyracetam maintains its cognitive-enhancing effects in the long term, offering potential benefits for people with dementia [13]. Furthermore, in a comparative study of older people showing signs of mental deterioration, oxyracetam showed superior efficacy to piracetam in improving cognitive function. Patients treated with oxyracetam showed significant improvements in clinical indices, such as the Geriatric Depression Scale (GDS), and neurophysiological measures, including P300 wave latency and amplitude. This study highlights the potential of oxyracetam to significantly enhance cognitive abilities, focusing on critical brain functions such as attention and memory, suggesting that oxyracetam may be particularly useful in helping older people with memory and attention problems [16].

In addition, in a crossover study, 12 healthy volunteers who had taken 5 mg of diazepam were then injected intravenously with 1 g of oxyracetam or saline solution. Electroencephalogram (EEG) measurements were taken before and after the injection to assess brain activity. The results showed an increase in alpha wave activity, associated with relaxed alertness, and a decrease in delta wave activity, associated with deep sleep, particularly in frontotemporal brain areas. These findings suggest that oxyracetam may improve cognitive function in people taking benzodiazepines, without interfering with the sedative effects of the drugs [14]. In addition, a detailed study involved 40 outpatients with mild to moderate dementia to assess the efficacy of oxyracetam in improving cognitive function. For 90 days, participants received 800 mg of oxyracetam twice daily or placebo. Results showed significant improvements in various cognitive tests such as the MMSE (Mini-Mental State Examination) and the Auditory Continuous Performance Test for those taking oxyracetam. This study provides evidence that oxyracetam may be a valuable treatment for dementia, improving patients' attention and neuropsychological function without side effects, suggesting that a dose of 1,600 mg daily is both safe and beneficial [15].

Oxyracetam for organic brain syndrome (OBS)

The study looked at how oxyracetam could help people with organic brain syndrome (OBS), a condition in which brain function is reduced due to various diseases. In this study, 43 patients received oxyracetam or placebo for eight weeks. Improvements in thinking, concentration and other mental abilities were observed in those taking oxyracetam. This suggests that oxyracetam may be a helpful drug to improve the quality of life of OBS sufferers by improving their brain function [4]. In a clinical trial involving 40 patients with organic brain syndrome, a condition characterised by memory loss and cognitive difficulties. The researchers evaluated the effects of oxyracetam on various symptoms. Patients were divided into groups receiving oxyracetam or placebo, and treatment lasted for four weeks. Interestingly, patients treated with oxyracetam began to show improvements in symptoms such as memory, anxiety and fatigue within the first week, with continued progression throughout the study. These findings highlight the potential of oxyracetam as a beneficial and well-tolerated option for treating symptoms of organic brain syndrome [11].

Oxyracetam and psychiatric disorders

A study involving 60 elderly patients with organic mental disorders compared the therapeutic effects of oxyracetam with those of piracetam. Increasing doses to 2400 mg daily, the researchers observed significant improvements in both subjective and objective measures of key symptoms over time. Oxyracetam was notably superior to piracetam in improving memory function, while piracetam was more effective in reducing symptoms associated with paranoid thoughts and agitation. Both drugs were well tolerated, suggesting that nootropics such as oxyracetam may represent a new therapeutic option for more targeted treatment of CNS disorders [17]. Another study compared the efficacy and safety of oxyracetam and donepezil in the treatment of mild to moderate Alzheimer's disease. Together with donepezil, oxyracetam also showed significant improvements in most parameters in both groups. Improvements in MMSE were similar between therapies. Overall, oxyracetam and donepezil showed comparable benefits and safety profiles in the treatment of Alzheimer's disease [18].

Oxyracetam and recovery after stroke

The study, conducted at the Fifth People's Hospital in Wuhu between March 2019 and July 2020, involved 120 early-stage stroke patients with hemiplegia (post-stroke patients who could not move one side of their body well). The researchers compared the effect of oxyracetam alone with that of oxyracetam in combination with a Traditional Chinese Medicine (TCM) rehabilitation programme for the treatment of haemiplegia. Of the 120 patients, half received oxyracetam alone and the other half received it together with TCM treatments for one month. Interestingly, the results of the study showed that the group receiving the oxyracetam combination had better improvement in motor and neurological function, less brain swelling and greater satisfaction with the treatment compared to those who received oxyracetam alone. This suggests that oxyracetam in combination with TCM may offer a more effective recovery strategy for patients with haemiplegia in the early stages of stroke [19]. Furthermore, a study conducted at the Fourth Hospital of Hebei Medical University between January 2013 and September 2017 analysed the effects of cerebellar nucleus electrical stimulation (FNS), oxyracetam and nimodipine on patients with post-stroke cognitive impairment (PSCI-ND). The study involving 96 patients showed that while FNS showed the most significant improvement in cognitive functions such as visuospatial and executive abilities, oxyracetam also had a positive effect on cognitive improvement, with both therapies being safe and effective [20].
In addition, a study involving 162 patients with MI from March 2018 to December 2020 was treated with clopidogrel and oxyracetam. Together with personalised symptomatic nursing care, the combined administration of clopidogrel and oxyracetam significantly improved patient outcomes compared with routine nursing care. The group with personalised care showed better improvement in daily activities, neurological function, shorter hospital stay and higher patient satisfaction. This study highlights the benefits of personalised care together with medication for people recovering from stroke [21]. One study also analysed the combined administration of oxyracetam by injection with Salivae Miltiorrhizae liguspyragine hydrochloride and glucose by injection for stroke (cerebral infarction). The researchers observed a marked improvement in the patients' cognitive function and daily living abilities. This suggests that this combination may facilitate recovery by increasing cerebral blood flow and reducing inflammatory cytokines [22].
Furthermore, in recovery from acute haemorrhage, the combined use of oxyracetam with Ginkgo Biloba extract showed significant neuroprotective effects. The combination therapy improved neurological function and reduced cerebral oedema, which may be attributed to synergistic effects on the reduction of oxidative stress and modulation of inflammatory markers [23] [24]. In addition, combined butylphthalide and oxyracetam therapy in
cognitive impairment after stroke has investigated synergistic benefits on cognitive recovery and cerebral blood flow. Butylphthalide is known for its neuroprotective effects, potentially by modulating mitochondrial function and reducing oxidative stress, while oxyracetam improves cognition by affecting neurotransmitter systems. This combination was found to significantly improve cognitive function, suggesting that their molecular actions may effectively reduce inflammation and increase cerebral blood flow, thus offering a promising therapeutic approach to post-stroke rehabilitation [26].
In an animal study, researchers investigated the effect of S-oxyracetam on blood-brain barrier (BBB) dysfunction after ischaemic stroke in rats. Rats treated with S-oxyracetam showed reduced brain damage and stroke-induced inflammation. It also preserved the integrity of the BBB, reduced leakage and improved levels of tight junction protein, essential for BBB function. Furthermore, S-oxiracetam enhanced the brain's protective mechanisms, suggesting its potential as a protective agent against stroke-induced BBB dysfunction [32].

Oxyracetam and autism spectrum disorders: Based on an animal study

In an animal study, a rat model of autism spectrum disorder (ASD) showed potential benefits from combining oxyracetam with zinc. Oxyracetam is known for its effects on improving synaptic transmission and plasticity, possibly through modulation of glutamatergic and cholinergic systems. In combination with zinc, an important modulator of neurotransmitter systems and neurodevelopmental processes, treatment led to improvements in behavioural and biochemical markers of ASD. These potential results point to a molecular approach targeting neurotransmitter balance, reduction of inflammation and oxidative stress, offering a new perspective on the management of ASD [25].

Oxyracetam for brain function

During a clinical trial, researchers investigated the potential effects of oxyracetam and Yangxue Qingnao granules on improving brain function. They found that patients taking both drugs showed significantly better improvements in brain function and blood flow compared to those taking only oxyracetam. It appears that combining these therapies may be a good way to help people with these types of brain problems [27]. Additionally, a study on the combined use of Qingkailing injection with oxyracetam showed positive results in the treatment of patients with vascular dementia. The results were promising, showing significant improvements in thinking, blood flow and daily activities in people receiving both therapies. This suggests that this combination may be a new treatment for vascular dementia, addressing both the symptoms and some of the causes [28]. Similarly, the combined use of oxyracetam with GM1 (a substance that promotes nerve cell repair) has shown promising results. Simultaneous use led to faster and more significant improvements in brain function, as measured by lower levels of S100 protein and neuron-specific enolase, markers indicative of brain damage. Furthermore, the combined treatment effectively reduced inflammation, a common problem after brain injury. This suggests that oxyracetam and GM1 together may offer a better strategy for treating the brain after severe injury by reducing markers of brain damage and suppressing inflammation, with minimal side effects [29].

Oxyracetam and recovery after brain injury

Researchers investigated the efficacy of oxyracetam in early traumatic brain injury (TBI), a condition with limited specific treatments. They tested oxyracetam on cell models and mice with TBI, treating the mice with oxyracetam for five days. The results showed that oxyracetam increased levels of protective enzymes and reduced markers of inflammation and cell death in cell models. In mice, it reduced brain damage, swelling and brain cell death. In addition, it reduced inflammatory markers and improved cognitive function, suggesting that oxyracetam may help reduce brain inflammation and cognitive issues after TBI [30]. Similarly, another study found that rats treated with oxyracetam showed significantly better neurological and cognitive performance in learning and memory tests compared to untreated rats. These findings indicate that oxyracetam may reduce neuronal damage and improve cognitive function after TBI [33]. Furthermore, in the study, oxyracetam delivered via nanotechnology (TiO2 nanorods) was administered to injured rats. Oxyracetam showed a significant improvement in motor and memory functions. Interestingly, it improved cerebral blood flow and reduced brain damage more effectively, highlighting the potential of nanotechnology-enhanced oxyracetam in the treatment of concussion head injury [31].

Possible effects of oxyracetam: Based on animal studies

It is important to know that Alzheimer's disease leads to harmful changes in the brain, including over-activation of microglia, cells that protect the brain but can cause damage under certain conditions. Oxyracetam, a drug that improves brain function, was tested for its potential to calm these microglia and reduce their damaging production under laboratory conditions. Researchers found that oxyracetam could prevent microglia from overreacting to toxins associated with Alzheimer's disease, thereby reducing their harmful effects. It also helped to maintain healthier communication between brain cells, particularly by controlling inflammation and oxidative stress [34]. Together with the other mechanisms discussed above, the study showed that oxyracetam effectively counteracted the adverse effects of NMDA receptor blockers by preventing the expected decline in acetylcholine, a key neurotransmitter for brain function. This action highlights the potential of oxyracetam in preserving memory and learning ability by ensuring the smooth functioning of cholinergic and glutamatergic neurotransmission, important pathways for cognitive processes [35]. In this way, oxyracetam maintains healthy levels of acetylcholine in the brain by potentially acting against NMDA receptor blockers. Additionally, in conditions such as neonatal hypoxic-ischaemic brain injury, where the brain suffers from reduced oxygen and blood flow, inflammation greatly exacerbates the damage. Oxyracetam showed promise in reducing brain damage in newborn mice by converting damaging microglia activity into a protective form. This change not only reduced inflammation, but also improved brain clearance processes through increased phagocytosis and autophagy, key to removing damaged cells and debris. Oxyracetam activated specific cellular pathways that encourage protective behaviour by microglia [36].

Dosage of oxyracetam

Oxyracetam has been tested at different doses for cognitive and memory improvement in various disease states.

1. Cognitive and memory impairment: In a multicentre study involving patients with types of dementia such as primary degenerative dementia, multi-infarct dementia or mixed dementia, a dose of 800 mg twice daily for 12 weeks showed significant improvements in memory and cognitive function [1]. Similarly, the same dose of 800 mg twice daily was used to increase verbal fluency and address non-cognitive symptoms in patients with multi-infarct dementia (MID) and primary degenerative dementia (PDD), showing significant benefits in verbal communication and mood issues [2, 3].
2.  In the case of organic brain syndrome (OBS): A slightly higher dose of 1600 mg per day, divided into two doses over eight weeks, led to noticeable improvements in cognitive function and attention [4].
3. In the case of dementia: A study comparing oxyracetam with selegiline in the treatment of senile and senile dementia highlighted the tolerability and safety of oxyracetam, with patients receiving two doses of 800 mg tablets daily [5]. In a long-term study in patients with dementia, administration of oxyracetam 800 mg twice daily provided cognitive benefits and was safe [7].
4. Amnesia: In a study evaluating the potential of oxyracetam to combat scopolamine-induced amnesia in volunteers, acute oral doses (800, 1600, 2400 mg) were administered, with the 1600 mg dose being particularly effective in improving cognitive performance [8].
5. It is worth noting that in a phase I study investigating the pharmacokinetics of (S)-oxiracetam in healthy volunteers doses ranging from 400 mg to 2,000 mg in single dose studies and from 400 mg to 1,600 mg in multiple dose studies have been evaluated, demonstrating a favourable safety profile and pharmacokinetic properties of the drug [10]. These different types of studies recommend varying doses of oxyracetam and its potential as a beneficial cognitive enhancer and treatment option for various cognitive disorders.
   Accordingly, recommended doses of oxyracetam range from 400 mg to 1,600 mg daily, depending on the treatment of various neurological conditions.

Understanding the pharmacokinetics of (S)-Oxiracetam: Based on human studies

In a study with healthy Chinese volunteers, the researchers investigated the pharmacokinetic properties of (S)-oxiracetam, the key active nootropic enantiomer of oxiracetam, the researchers reported in a detailed study with volunteers. This was a comprehensive Phase I study, characterised by double-blind, controlled and dose escalation. The dose administered ranged from 400 mg to 2,000 mg for SAD and from 400 mg to 1,600 mg for MAD, with both single (SAD) and multiple (MAD) doses.

Oxyracetam excretion: The study showed that (S)-oxiracetam was mainly excreted unchanged in urine (55.03%) and faeces (36.16%), with no evidence of chiral transformation. 

Levels of (S)-oxiracetam in the body increased in a predictable manner from doses of 400 mg to 1,600 mg, with little change noted when the dose was increased to 2,000 mg. Time to reach the systemic circulation: The drug was rapidly absorbed, reaching peak blood concentrations within approximately 45 to 60 minutes after ingestion and remained in the body for an average of approximately 6.12 to 6.60 hours. After or before a meal: Eating before taking the drug did not change the overall level of (S)-oxiracetam to which the body was exposed, although it took longer for the drug to reach its maximum blood concentration - approximately 3 hours. With repeated administration, (S)-oxiracetam blood concentrations stabilised on the fifth day, with a slight increase detected after one week of daily dosing. All adverse effects reported during the study were mild to moderate and were not related to the amount of drug administered. Overall, (S)-oxiracetam was found to have a good safety profile and effective pharmacokinetic properties, indicating that it is well tolerated and warranting further investigation into its potential benefits as a treatment [10].

Conclusions

Oxyracetam, a derivative of the nootropic Piracetam, is used to improve cognitive performance and quality of life in patients with dementia. Developed in the 1970s, it has shown greater efficacy than its predecessor due to its action on AMPA-sensitive glutamate receptors, oxidative stress, inflammation and its ability to increase neurotransmitter release. Oxyracetam significantly improved verbal fluency and cognitive function in patients with multimorbid dementia and primary degenerative dementia, making it valuable for improving verbal communication and emotional stability among affected individuals. In a study in which oxyracetam was administered at a dose of 800 mg twice daily for 12 weeks, patients showed marked improvements in memory, associative thinking and problem-solving skills, which positively affected their quality of life and cognitive function. In addition, the drug was effective in reducing non-cognitive symptoms associated with dementia, particularly in patients with PDD, who showed significant improvements in emotional stability and mental functioning. The solubility and mild stimulant properties of oxyracetam also contribute to its widespread use among those seeking cognitive improvement. Furthermore, animal studies have shown the positive effects of oxyracetam in the treatment of traumatic brain injury. In particular, the combination of oxyracetam with other therapies such as nerve growth factor or nicergoline,
significantly improved outcomes in patients with cognitive impairment after stroke, suggesting synergistic benefits. In several studies, oxyracetam was well tolerated with few side effects.

Disclaimer

This article is written to educate and raise awareness of the substance discussed. It is important to note that the substance discussed is a substance and not a specific product. The information contained in the text is based on available scientific studies and is not intended as medical advice or to promote self-medication. The reader is advised to consult a qualified health professional for all health and treatment decisions.

Links

1. Bottini G, Vallar G, Cappa S, Monza GC, Scarpini E, Baron P, Cheldi A, Scarlato G. Oxiracetam in dementia: a double-blind, placebo-controlled study. Acta Neurol Scand. 1992 Sep;86(3):237-41. doi: 10.1111/j.1600-0404.1992.tb05077.x. PMID: 1414239. https://www.wellesu.com/10.1111/j.1600-0404.1992.tb05077.x
2. Dysken MW, Katz R, Stallone F, Kuskowski M. Oxiracetam in the treatment of multi-infarct dementia and primary degenerative dementia. J Neuropsychiatry Clin Neurosci. 1989 Summer;1(3):249-52. doi: 10.1176/jnp.1.3.249. PMID: 2521069. https://www.wellesu.com/10.1176/jnp.1.3.249
3. Maina G, Fiori L, Torta R, Fagiani MB, Ravizza L, Bonavita E, Ghiazza B, Teruzzi F, Zagnoni PG, Ferrario E, et al. Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double-blind, placebo-controlled study. Neuropsychobiology. 1989;21(3):141-5. doi: 10.1159/000118567. PMID: 2693996. https://pubmed.ncbi.nlm.nih.gov/2693996/
4. Moglia A, Sinforiani E, Zandrini C, Gualtieri S, Corsico R, Arrigo A. Activity of oxiracetam in patients with organic brain syndrome: a neuropsychological study. Clin Neuropharmacol. 1986;9 Suppl 3:S73-8. PMID: 3594459. https://pubmed.ncbi.nlm.nih.gov/3594459/
5. Falsaperla A, Monici Preti PA, Oliani C. Selegiline versus oxiracetam in patients with Alzheimer-type dementia. Clin Ther. 1990 Sep-Oct;12(5):376-84 PMID: 2125242. https://pubmed.ncbi.nlm.nih.gov/2125242/
6. Wang B, Zhong L, Qiao P, Ma Z. Clinical efficacy and safety of nicergoline combined with oxiracetam in the treatment of vascular cognitive impairment. Pak J Pharm Sci. 2020 Jan;33(1(Special)):417-422. PMID: 32173636. https://pubmed.ncbi.nlm.nih.gov/32173636/
7. Villardita C, Grioli S, Lomeo C, Cattaneo C, Parini J. Clinical studies with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia of mild to moderate degree. Neuropsychobiology. 1992;25(1):24-8. doi: 10.1159/000118805. PMID: 1603291. https://pubmed.ncbi.nlm.nih.gov/1603291/
8. Preda L, Alberoni M, Bressi S, Cattaneo C, Parini J, Canal N, Franceschi M. Effects of acute doses of oxiracetam in the scopolamine model of human amnesia. Psychopharmacology (Berl). 1993;110(4):421-6. doi: 10.1007/BF02244648. PMID: 7870912. https://pubmed.ncbi.nlm.nih.gov/7870912/
9. Sun, Y., Xu, B., & Zhang, Q. (2018). Nerve growth factor in combination with Oxiracetam in the treatment of Hypertensive Cerebral Hemorrhage. Pakistan journal of medical sciences, 34(1), 73-77. https://doi.org/10.12669/pjms.341.13395 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857033/
10. Zhang T, Tao Y, Pu J, Zhu M, Wan L, Tang C. Safety, tolerability, and pharmacokinetics of oral (S)-oxiracetam in Chinese healthy volunteers: A randomized, double-blind, controlled phase I study. Eur J Pharm Sci. 2024 Jan 1;192:106621. doi: 10.1016/j.ejps.2023.106621. Epub 2023 Oct 28. PMID: 37898393. https://pubmed.ncbi.nlm.nih.gov/37898393/
11. Saletu B, Linzmayer L, Grünberger J, Pietschmann H. Double-blind, placebo-controlled, clinical, psychometric and neurophysiological investigations with oxiracetam in the organic brain syndrome of late life. Neuropsychobiology. 1985;13(1-2):44-52. doi: 10.1159/000118161. PMID: 3897895. https://pubmed.ncbi.nlm.nih.gov/3897895/
12. Rozzini R, Zanetti O, Bianchetti A. Effectiveness of oxiracetam therapy in the treatment of cognitive deficiencies secondary to primary degenerative dementia. Acta Neurol (Napoli). 1992 Apr;14(2):117-26. PMID: 1414555. https://pubmed.ncbi.nlm.nih.gov/1414555/
13. Rozzini R, Zanetti O, Bianchetti A. Treatment of cognitive impairment secondary to degenerative dementia. Effectiveness of oxiracetam therapy. Acta Neurol (Napoli). 1993 Feb;15(1):44-52 PMID: 8456595. https://pubmed.ncbi.nlm.nih.gov/8456595/
14. Giaquinto S, Nolfe G, Vitali S. EEG changes induced by oxiracetam on diazepam-medicated volunteers. Clin Neuropharmacol. 1986;9 Suppl 3:S79-84. PMID: 3594460. https://pubmed.ncbi.nlm.nih.gov/3594460/
15. Villardita C, Parini J, Grioli S, Quattropani M, Lomeo C, Scapagnini U. Clinical and neuropsychological study with oxiracetam versus placebo in patients with mild to moderate dementia. J Neural Transm Suppl. 1987;24:293-8 PMID: 3479527. https://pubmed.ncbi.nlm.nih.gov/3479527/
16. Gallai V, Mazzotta G, Del Gatto F, Montesi S, Mazzetti A, Dominici P, Della Monica A. A clinical and neurophysiological trial on nootropic drugs in patients with mental decline. Acta Neurol (Napoli). 1991 Feb;13(1):1-12. PMID: 1867125. https://pubmed.ncbi.nlm.nih.gov/1867125/
17. Itil, T.M., Menon, G.N., Bozak, M. and Songar, A., 1982. The effects of oxiracetam (ISF 2522) in patients with organic brain syndrome (a double-blind controlled study with piracetam). Drug Development Research, 2(5), pp.447-461. https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/abs/10.1002/ddr.430020506
18. NI Jian-liang, WANG Shui-hong, YANG Hua, CHEN Song, WEI Li-juan. A randomized double-blind control study on oxiracetam and donepezil in treating Alzheimer disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2008, 13(11): 1291-1294. https://manu41.magtech.com.cn/Jweb_clyl/EN/abstract/abstract11338.shtml
19. Zhang, X. and Mao, H., 2022. Clinical effectiveness of a combination of oxiracetam and traditional Chinese medicine rehabilitation program in the treatment of early stroke patients with hemiplegia. Tropical Journal of Pharmaceutical Research, 21(7), pp.1565-1569. https://www.ajol.info/index.php/tjpr/article/view/230114
20. MI, X., SHI, J., LIU, H., WANG, J., CUI, P. and HAN, Y., 2019. Clinical Effects of Electrical Stimulation, Oxiracetam and Nimodipine on the Cognitive Function of Patients with Post-stroke Cognitive Impairment-with No Dementia. Chinese General Practice, 22(11), p.1293. https://www.chinagp.net/EN/10.12114/j.issn.1007-9572.2018.00.269
21. Gao, M., Du, J. and Lei, F., 2022. Study on the Nursing Efficacy of Clopidogrel Combined With Oxiracetam in the Treatment of Patients with Cerebral Infarction. Indian Journal of Pharmaceutical Sciences, 84. https://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=0250474X&AN=171374811&h=yawDds77d%2BUlA15TpdAdq1AU5rjMekm3oWsbbmTqVC9AafJOCFDilive7MRcazxQyH5ILRcOMB4Wy%2FqUOcMYvg%3D%3D&crl=c
22. Lu JianGuo, L.J., Zhang ZhenLi, Z.Z., Wang Jin, W.J. and Li WenZhong, L.W., 2018. clinical study on Salivae Miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection combined with oxiracetam in treatment of cerebral infarction. https://www.cabidigitallibrary.org/doi/full/10.5555/20193007913
23. Jin-hai, M.A. and Tao, W.A.N.G., 2019. Therapeutic effect of oxiracetam combined with Ginkgo biloba extract on acute cerebral hemorrhage and its effect on serum inflammatory factors. Chinese Journal of Contemporary Neurology & Neurosurgery, 19(8). https://search.ebscohost.com/login.aspx?direct=true&profile=ehost&scope=site&authtype=crawler&jrnl=16726731&AN=138424919&h=myifPhf5eJaKKENt3WSK%2BTNmXp%2BNkgl8Cy%2FABI%2FgI8maQngDCyuocx8T5uyXW2e3CJoEJSSjsksNcVIauyuN3g%3D%3D&crl=c
24. Li, X.X., Liu, S.H., Zhuang, S.J., Guo, S.F. and Pang, S.L., 2020. Effects of oxiracetam combined with ginkgo biloba extract in the treatment of acute intracerebral hemorrhage: A clinical study. Brain and Behavior, 10(8), p.e01661. https://onlinelibrary.wiley.com/doi/full/10.1002/brb3.1661
25. Paudel, R., Raj, K., Gupta, Y. et al.Oxiracetam and Zinc Ameliorates Autism-Like Symptoms in Propionic Acid Model of Rats. Neurotox Res 37, 815-826 (2020). https://doi.org/10.1007/s12640-020-00169-1 https://link.springer.com/article/10.1007/s12640-020-00169-1#
26. Jiang, W., Yu, X. D., & Deng, Y. (2023). Effect of Butylphthalide combined with Oxiracetam on cognitive function, Intellectual recovery and serum inflammatory factors in patients with cognitive impairment after cerebral infarction. Pakistan journal of medical sciences, 39(2), 485-490. https://doi.org/10.12669/pjms.39.2.6901 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10025735/
27. Wang Zhen, W.Z., Bi XueChao, B.X., Cui HuiJuan, C.H., Sun DaBao, S.D., Du JinMing, D.J., Liu BaoPing, L.B., Guo Jian, G.J., Li WenYing, L.W. and Cui Song, C.S., 2016. Clinical observation of Yangxue Qingnao Granules combined with Oxiracetam in treatment of vascular cognitive impairment. https://www.cabidigitallibrary.org/doi/full/10.5555/20163295980
28. You XiaoHan, Y.X., Yang Miao, Y.M., Liu YanLong, L.Y., Qian LaYan, Q.L., Liu Lei, L.L., Ming XiaGuang, M.X. and Ma Long, M.L., 2018. Clinical study of Qingkailing Injection combined with oxiracetam in treatment of vascular dementia. https://www.cabidigitallibrary.org/doi/full/10.5555/20183288558
29. Guo, Y., Wang, X., Lian, L. and Pan, S., 2023. Co administration of oxiracetam and monosialotetrahexosylganglioside for the treatment of patients with craniocerebral injury, and their effect on serum S100 proteins and neuron specific enolase. Tropical Journal of Pharmaceutical Research, 22(1), pp.159-165. https://www.ajol.info/index.php/tjpr/article/view/241853
30. Youn, D.H., Han, S.W., Kim, JT. et al.Oxiracetam alleviates anti-inflammatory activity and ameliorates cognitive impairment in the early phase of traumatic brain injury. Acta Neurochir 165, 2201-2210 (2023). https://doi.org/10.1007/s00701-023-05674-8 https://link.springer.com/article/10.1007/s00701-023-05674-8#
31. Niu, F., Sharma, A., Wang, Z., Feng, L., Muresanu, D.F., Sahib, S., Tian, Z.R., Lafuente, J.V., Buzoianu, A.D., Nozari, A. and Menon, P.K., 2021. Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury. Progress in Brain Research, 265, pp.139-230. https://www.sciencedirect.com/science/article/abs/pii/S0079612321001503
32. Huang, L., Shang, E., Fan, W., Li, X., Li, B., He, S., Fu, Y., Zhang, Y., Li, Y. and Fang, W., 2017. s-oxiracetam protects against ischemic stroke via alleviating blood brain barrier dysfunction in rats. European Journal of Pharmaceutical Sciences, 109, pp.40-47. https://www.sciencedirect.com/science/article/abs/pii/S0928098717304281
33. Li, J.W., Yang, D.J., Chen, X.Y. and Liang, H.Q., 2013. protective effect of oxiracetam on traumatic brain injury in rats. Zhongguo Ying Yong Sheng li xue za zhi= Zhongguo Yingyong Shenglixue Zazhi= Chinese Journal of Applied Physiology, 29(4), pp.298-300. https://europepmc.org/article/med/24175546
34. Zhang, H., Jia, L. and Jia, J., 2020. oxiracetam offers neuroprotection by reducing amyloid β-induced microglial activation and inflammation in Alzheimer's disease. Frontiers in Neurology, 11, p.548699. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.00623/full
35. Belfiore P, Ponzio F, Biagetti R, Berettera C, Magnani M, Pozzi O. Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7. Neurosci Lett. 1992 Aug 31;143(1-2):127-30. doi: 10.1016/0304-3940(92)90248-6. PMID: 1436656. https://pubmed.ncbi.nlm.nih.gov/1436656/
36. Wang, D., Wei, Y., Tian, J. et al.Oxiracetam Mediates Neuroprotection Through the Regulation of Microglia Under Hypoxia-Ischemia Neonatal Brain Injury in Mice. Mol Neurobiol 58, 3918-3937 (2021). https://doi.org/10.1007/s12035-021-02376-z https://link.springer.com/article/10.1007/s12035-021-02376-z#