Cerebrolysin

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain, which has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2020. To assess the benefits and harms of Cerebrolysin or Cerebrolysin-like agents for treating acute ischaemic stroke. We searched the Cochrane Stroke Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, and LILACS in May 2022 and a number of Russian databases in June 2022. We also searched reference lists, ongoing trials registers, and conference proceedings. Randomised controlled trials (RCTs) comparing Cerebrolysin or Cerebrolysin-like agents started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke. Three review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence. Seven RCTs (1773 participants) met the inclusion criteria of the review. In this update we added one RCT of Cerebrolysin-like agent Cortexin, which contributed 272 participants. We used the same approach for risk of bias assessment that was re-evaluated for the previous update: we added consideration of the public availability of study protocols and reported outcomes to the selective outcome reporting judgement, through identification, examination, and evaluation of study protocols. For the Cerebrolysin studies, we judged the risk of bias for selective outcome reporting to be unclear across all studies; for blinding of participants and personnel to be low in three studies and unclear in the remaining four; and for blinding of outcome assessors to be low in three studies and unclear in four studies. We judged the risk of bias for generation of allocation sequence to be low in one study and unclear in the remaining six studies; for allocation concealment to be low in one study and unclear in six studies; and for incomplete outcome data to be low in three studies and high in the remaining four studies. The manufacturer of Cerebrolysin supported three multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged two studies to be at high risk of other bias and the remaining five studies to be at unclear risk of other bias. We judged the study of Cortexin to be at low risk of bias for incomplete outcome data and at unclear risk of bias for all other domains. All-cause death: Cerebrolysin or Cortexin probably result in little to no difference in all-cause death (risk ratio (RR) 0.96, 95% confidence interval (CI) 0.65 to 1.41; 6 trials, 1689 participants; moderate-certainty evidence). None of the included studies reported on poor functional outcome, defined as death or dependence at the end of the follow-up period, early death (within two weeks of stroke onset), quality of life, or time to restoration of capacity for work. Only one study clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Non-death attrition (secondary outcome): Cerebrolysin or similar peptide mixtures may result in little to no difference in non-death attrition, but the evidence is very uncertain, with a considerable level of heterogeneity (RR 0.72, 95% CI 0.38 to 1.39; 6 trials, 1689 participants; very low-certainty evidence). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.16, 95% CI 0.81 to 1.66; 3 trials, 1335 participants; moderate-certainty evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38; 3 trials, 1335 participants; moderate-certainty evidence) and an increase in the total number of people with non-fatal SAEs (RR 2.39, 95% CI 1.10 to 5.23; 3 trials, 1335 participants; moderate-certainty evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent (RR 2.87, 95% CI 1.24 to 6.69; 2 trials, 1189 participants). Total number of people with adverse events: Cerebrolysin or similar peptide mixtures may result in little to no difference in the total number of people with adverse events (RR 1.03, 95% CI 0.92 to 1.14; 4 trials, 1607 participants; low-certainty evidence). Moderate-certainty evidence indicates that Cerebrolysin or Cerebrolysin-like peptide mixtures derived from cattle brain probably have no beneficial effect on preventing all-cause death in acute ischaemic stroke. Moderate-certainty evidence suggests that Cerebrolysin probably has no beneficial effect on the total number of people with serious adverse events. Moderate-certainty evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use.

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke. In May 2016 we searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian Databases. We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma). Randomised controlled trials (RCTs) comparing cerebrolysin, started within 48 hours of stroke onset and continued for any time, with placebo or no treatment in people with acute ischaemic stroke. Two review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data. We identified six RCTs (1501 participants) that met the inclusion criteria.We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians.None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset).All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence).Serious adverse events (SAEs): there was no significant difference in the total number of SAEs with cerebrolysin (RR 1.16, 95% CI 0.81 to 1.67). This comprised no difference in fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the number of people with non-fatal SAEs (20/667 with cerebrolysin and 8/668 with placebo: RR 2.47, 95% CI 1.09 to 5.58, P = 0.03) (3 trials, 1335 participants, moderate-quality evidence).Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence). The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence of an increase in non-fatal SAEs with cerebrolysin use but not in total SAEs.

Cerebrolysin for vascular dementia.

Although vascular dementia is the second most common cause of dementia globally, evidence-based treatments are still lacking. Cerebrolysin is a porcine brain-derived preparation that is said to have neurotrophic and neuroprotective activity. In many parts of the world Cerebrolysin, given as a series of daily intravenous infusions, is used as a potential intervention for vascular dementia. A previous Cochrane Review on Cerebrolysin in vascular dementia yielded inconsistent results. We wished to update the review to add new studies from the international literature and employ contemporary methods for appraising the strength of the evidence. This is the first update of a review first published in 2013. Primary: to assess the effect of Cerebrolysin on cognitive function, global function, and all-cause mortality in people living with vascular dementia. Secondary: to assess the adverse effects of Cerebrolysin and to assess the effect of Cerebrolysin on quality of life and caregiver burden. We searched ALOIS, MEDLINE, Embase, PsycINFO, CINAHL, ISI Web of Knowledge, LILACS, the Cochrane Library, ClinicalTrials.gov, and the WHO ICTRP on 16 June 2017, 9 May 2018, and 9 May 2019. We expanded the search by adding four Chinese databases, searched from 1 January 2012 to 19 May 2019. We checked bibliographies of relevant papers identified and contacted pharmaceutical companies, trial authors, and experts in the field to identify any additional published or unpublished data. We included all randomised controlled trials of Cerebrolysin used in people living with vascular dementia. We applied no language restriction. Two review authors independently selected trials for inclusion and evaluated their methodological quality. Data were extracted and analysed using mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (95% CI) for continuous outcomes. We reported dichotomous outcomes as risk ratio (RR) with 95% CI. We assessed the strength of the available evidence using the GRADE approach. We identified six randomised controlled trials with a total of 597 participants that were eligible for inclusion in the 2013 review. No new studies were eligible for inclusion in this update. Participants in the included studies, where dementia severity was reported, had mild to moderate severity of vascular dementia (four trials). The included studies tested varying doses and duration of Cerebrolysin treatment. Follow-up ranged from 15 days to three years. Five of included studies were conducted in China (three studies), Russia (one study), and Romania (one study), while relevant information of other study was unclear. Where details of funding were available, all studies were supported by the pharmaceutical industry (three studies). Cognitive function was measured using the Mini-Mental State Examination (MMSE) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+). Combining the MMSE and ADAS-cog+ data (three studies, 420 people), there was a beneficial effect of Cerebrolysin (SMD 0.36, 95% CI 0.13 to 0.58; very low-quality evidence). Global function was measured by Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC+) or Investigator's Clinical Global Impression (CGI). We assessed response rates on these measures (the proportion of participants with a CIBIC+ score of < 3; or at least moderate improvement of the CGI rating at the last visit). There was a beneficial effect of Cerebrolysin (two studies, 379 participants, RR 2.69, 95% CI 1.82 to 3.98; very low-quality evidence). Only one trial described mortality and reported no deaths. Four studies reported adverse events; data from two studies (379 people) were in a format that permitted meta-analysis, and there was no difference in rates of adverse effects (RR 0.91, 95% CI 0.29 to 2.85; very low-quality evidence). No studies reported on quality of life or caregiver burden. Courses of intravenous Cerebrolysin improved cognition and general function in people living with vascular dementia, with no suggestion of adverse effects. However, these data are not definitive. Our analyses were limited by heterogeneity, and the included papers had high risk of bias. If there are benefits of Cerebrolysin, the effects may be too small to be clinically meaningful. There have been no new studies of Cerebrolysin in vascular dementia since the last Cochrane Review. Cerebrolysin continues to be used and promoted as a treatment for vascular dementia, but the supporting evidence base is weak. Adequately powered, methodologically robust trials are needed to properly assess the effects of Cerebrolysin in vascular dementia.

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from porcine brain that has potential neuroprotective properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. This is an update of a review first published in 2010 and last updated in 2017. To assess the benefits and harms of Cerebrolysin for treating acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian databases in October 2019. We also searched reference lists, ongoing trials registers, and conference proceedings. Randomised controlled trials (RCTs) comparing Cerebrolysin, started within 48 hours of stroke onset and continued for any length of time, with placebo or no treatment in people with acute ischaemic stroke. Two review authors independently applied the inclusion criteria, assessed trial quality and risk of bias, extracted data, and applied GRADE criteria to the evidence. Seven RCTs (1601 participants) met the inclusion criteria of the review. In this update we re-evaluated risk of bias through identification, examination, and evaluation of study protocols and judged it to be low, unclear, or high across studies: unclear for all domains in one study, and unclear for selective outcome reporting across all studies; low for blinding of participants and personnel in four studies and unclear in the remaining three; low for blinding of outcome assessors in three studies and unclear in four studies. We judged risk of bias to be low in two studies and unclear in the remaining five studies for generation of allocation sequence; low in one study and unclear in six studies for allocation concealment; and low in one study, unclear in one study, and high in the remaining five studies for incomplete outcome data. The manufacturer of Cerebrolysin supported four multicentre studies, either totally, or by providing Cerebrolysin and placebo, randomisation codes, research grants, or statisticians. We judged three studies to be at high risk of other bias and the remaining four studies to be at unclear risk of other bias. All-cause death: we extracted data from six trials (1517 participants). Cerebrolysin probably results in little to no difference in all-cause death: risk ratio (RR) 0.90, 95% confidence interval (CI) 0.61 to 1.32 (6&#xa0;trials, 1517 participants, moderate-quality evidence). None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset), or time to restoration of capacity for work and quality of life. Only one trial clearly reported on the cause of death: cerebral infarct (four in the Cerebrolysin and two in the placebo group), heart failure (two in the Cerebrolysin and one in the placebo group), pulmonary embolism (two in the placebo group), and pneumonia (one in the placebo group). Serious adverse events (SAEs): Cerebrolysin probably results in little to no difference in the total number of people with SAEs (RR 1.15, 95% CI 0.81 to 1.65, 4 RCTs, 1435 participants, moderate-quality evidence). This comprised fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the total number of people with non-fatal SAEs (RR 2.15, 95% CI 1.01 to 4.55, P = 0.047, 4 trials, 1435 participants, moderate-quality evidence). In the subgroup of dosing schedule 30 mL for 10 days (cumulative dose 300 mL), the increase was more prominent: RR 2.86, 95% CI 1.23 to 6.66, P = 0.01 (2 trials, 1189 participants). Total number of people with adverse events: four trials reported on this outcome. Cerebrolysin may result in little to no difference in the total number of people with adverse events: RR 0.97, 95% CI 0.85 to 1.10, P = 0.90, 4 trials, 1435 participants, low-quality evidence. Non-death attrition: evidence from six trials involving 1517 participants suggests that Cerebrolysin results in little to no difference in non-death attrition, with 96 out of 764 Cerebrolysin-treated participants and 117 out of 753 placebo-treated participants being lost to follow-up for reasons other than death (very low-quality evidence). Moderate-quality evidence indicates that Cerebrolysin probably has little or no beneficial effect on preventing all-cause death in acute ischaemic stroke, or on the total number of people with serious adverse events. Moderate-quality evidence also indicates a potential increase in non-fatal serious adverse events with Cerebrolysin use.

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, China, and other Asian and post-Soviet countries. To assess the benefits and risks of Cerebrolysin for treating acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (October 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (November 2014), MEDLINE (1966 to November 2014), EMBASE (1974 to November 2014), Web of Science Core Collection, with Science Citation Index (1940 to November 2014), LILACS (1982 to December 2014), OpenGrey (1980 to December 2014), and a number of Russian Databases (1998 to December 2014). We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of Cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma). Randomised controlled trials comparing Cerebrolysin started within 48 hours of stroke onset and continued for at least two weeks with placebo or no treatment in people with acute ischaemic stroke. Two review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data. We included one trial involving 146 participants. We evaluated risk of bias and judged it to be high for generation of allocation sequence, low for allocation concealment, high for incomplete outcome data (attrition bias), unclear for blinding, high for selective reporting and high for other sources of bias. The manufacturer of Cerebrolysin, pharmaceutical company Ebewe, provided Cerebrolysin and the placebo, as well as the randomisation codes. There was no difference in the number of deaths (6/78 in Cerebrolysin group versus 6/68 in placebo group; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.29 to 2.58) or in the total number of adverse events (16.4% versus 10.3%; RR 1.62, 95% CI 0.69 to 3.82) between the treatment and control groups. Routine administration of Cerebrolysin to people with acute ischaemic stroke cannot be supported by the available evidence from RCTs.

Current neuroprotective agents in stroke.

What is expected from neuroprotection is to inhibit neuronal death and halt or decelerate the neuronal loss to lower the mortality rates, decrease disability, and improve the quality of life following an acute ischemic stroke. Several agents were described as neuroprotective up to date; however, there is still debate which to use in the neurorehabilitation of stroke patients, in terms of both efficacy and also safety. In this review, we discuss the agents, citicoline, cerebrolysin and MLC901 (NeuroAiD II), the three agents which have started to be used frequently in neurorehabilitation clinics recently in the light of the current literature.

Cerebrolysin: a review of its use in dementia.

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks' duration in patients with Alzheimer's disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer's disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

Spotlight on cerebrolysin in dementia.

Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks' duration in patients with Alzheimer's disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer's disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

[Cerebrolysin peptides as mood stabilizers].

To establish the molecular mechanisms of the mood stabilizing (normothymic) action of the neuroprotector Cerebrolysin. Mass-spectrometric analysis of the peptide composition of cerebrolysin followed by a complex bioinformatics analysis was utilized. Cerebrolysin contains considerable amounts of Leu- and Met-enkephalins, partial analogues of enkephalins, peptide fragments of beta-lipotropin. These peptides stimulate the endorphinergic system thus contributing to normothymic action and an increase in the levels of the brain-derived neurotrophic factor (BDNF). Specific inhibition of kinases ABL1, PINK1, CDK5 and arginine N-methyltransferase PRMT5 by the peptides of cerebrolysin has a multidirectional effect on the dopaminergic system, also helping to stabilize mood. Cerebrolysin peptides do not directly affect neither the serotonergic, adrenergic, nor GABAergic systems. The normothymic effect of Cerebrolysin is due to the stabilization of endorphinergic and dopaminergic neurotransmission.

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries. To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke. In May 2016 we searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian Databases. We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma). Randomised controlled trials (RCTs) comparing cerebrolysin, started within 48 hours of stroke onset and continued for any time, with placebo or no treatment in people with acute ischaemic stroke. Two review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data. We identified six RCTs (1501 participants) that met the inclusion criteria.We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians.None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset).All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence).Serious adverse events: two trials reported on this outcome, with 90% confidence cerebrolysin increased the risks of serious adverse events by at least one third compared to placebo: 62/589 in cerebrolysin group versus 46/600 in placebo group; RR 1.37 90% CI 1.01 to 1.86 (2 trials, 1189 participants, moderate-quality evidence).Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence). The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence suggesting that serious adverse events may be more common with cerebrolysin use in acute ischaemic stroke.

Alzheimer's disease: cerebrolysin and nanotechnology as a therapeutic strategy.

Cerebrolysin for vascular dementia.

Vascular dementia is a common disorder without definitive treatments. Cerebrolysin seems to be a promising intervention based on its potential neurotrophic and pro-cognitive effects, but studies of its efficacy have yielded inconsistent results. To assess the efficacy and safety of Cerebrolysin for vascular dementia. We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 4 November 2012 using the terms: Cerebrolysin, Cere, FPF1070, FPF-1070. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. All randomized controlled trials of Cerebrolysin for treating vascular dementia without language restriction. Two authors independently selected trials and evaluated the methodological quality, then extracted and analysed data from the included trials. Six randomized controlled trials with a total of 597 participants were eligible. The meta-analyses revealed a beneficial effect of Cerebrolysin on general cognitive function measured by mini-mental state examination (MMSE) (weighted mean difference (WMD) 1.10; 95% confidence interval (CI) 0.37 to 1.82) or Alzheimer's Disease Assessment Scale Cognitive Subpart, extended version (ADAS-cog+) (WMD -4.01; 95% CI -5.36 to -2.66). It also improved patients' global clinical function evaluated by the response rates (relative risk (RR) 2.71, 95% CI 1.83 to 4.00). Only non-serious adverse events were observed in the included trials, and there was no significant difference in occurrence of non-serious side effects between groups (RR 0.97, 95% CI 0.49 to 1.94). Cerebrolysin may have positive effects on cognitive function and global function in elderly patients with vascular dementia of mild to moderate severity, but there is still insufficient evidence to recommend Cerebrolysin as a routine treatment for vascular dementia due to the limited number of included trials, wide variety of treatment durations and short-term follow-up in most of the trials.

Cerebrolysin for acute ischaemic stroke.

Cerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue which has proposed neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia and China. To assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (February 2009), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2009), MEDLINE (1966 to February 2009), EMBASE (1974 to February 2009), LILACS (1982 to February 2009), Science Citation Index (1940 to February 2009), SIGLE Archive (1980 to March 2005), and a number of relevant Russian Databases (1988 to February 2009). We also searched reference lists, ongoing trials registers and conference proceedings. Randomised controlled trials comparing cerebrolysin with placebo or no treatment in patients with acute ischaemic stroke. Three review authors independently applied the inclusion criteria, assessed trial quality and extracted the data. We included one trial involving 146 participants. There was no difference in death (6/78 in the cerebrolysin group versus 6/68 in the placebo group; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.29 to 2.58) or in the total number of adverse events (16.4% versus 10.3%; RR 1.62, 95% CI 0.69 to 3.82) between the treatment and control groups. There is not enough evidence to evaluate the effect of cerebrolysin on survival and dependency in people with acute ischaemic stroke. High-quality and large-scale randomised controlled trials may help to gain a better understanding of the potential value of cerebrolysin in acute ischaemic stroke.

[Cognitive impairment in post-traumatic stress disorder].

Post-traumatic stress disorder (PTSD) is a common mental health disorder, with an incidence of up to 12.5% among primary care patients. Most often, PTSD is detected in combat veterans, victims of terrorist attacks and terror, but it can also be a consequence of traumatic brain injury and medical interventions. Impaired cognitive functioning is a key feature of PTSD, including attention deficits and reduced processing speed, executive dysfunction, and impairments in verbal learning and memory. Cognitive impairments in PTSD are significantly persistent and are largely similar in nature to neuropsychological impairments in neurodegenerative pathology. Possible pathogenetic mechanisms underlying PTSD are the development of neuroinflammation, oxidative stress and decreased production of neurotrophic factors. One of the promising areas of treatment is the use of Cerebrolysin, which has powerful neurotrophic and anti-inflammatory activity.

Efficacy analysis of neuroprotective drugs in patients with acute ischemic stroke based on network meta-analysis.

This network meta-analysis aims to explore the efficacy and safety of neuroprotective agents in patients with ischemic stroke and attempts to identify which drug is the most effective in improving outcomes for patients with acute ischemic stroke (AIS) through a ranking method. We comprehensively searched the PubMed, Medline, Embase, Web of Science, and Cochrane library databases from their establishment to 30 June 2024. Data were extracted from the studies identified, and their quality was assessed using the Cochrane risk-of-bias tool or the Newcastle-Ottawa Scale (NOS). The outcome measures were for a favorable prognosis, based on the modified Rankin Scale score (mRS) or National Institutes of Health Stroker Scale (NIHSS) score, mortality, and adverse effect with different drug regimens. We utilized Stata version 16.0 and Review Manager (RevMan) version 5.3.0 for statistical analysis. A total of 35 studies were included: 25 randomized control trials, eight retrospective studies, and two prospective studies. The total sample size was 18,423 cases and included nine interventions: citicoline, edaravone (EDV), edaravone dexborneol, cinepazide maleate, cerebrolysin, minocycline, ginkgolide, ginkgo diterpene lactone meglumine (GDLM), and conventional (CON) treatment. Our analysis revealed that, except for edaravone dexborneol, the ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM treatment schemes reduced the mortality of patients with AIS compared with CON. Each drug regimen significantly improved the neural function of these patients compared with CON, which from highest to lowest was citicoline + vinpocetine, GDLM, citicoline, edaravone dexborneol, cinepazide maleate, ginkgolide, EDV, and CON. Moreover, we also found that, except for citicoline, the ginkgolide, EDV, edaravone dexborneol, GDLM, and cinepazide maleate treatment schemes had a high total treatment effective rate in these patients, the order from highest to lowest being ginkgolide, EDV, edaravone dexborneol, GDLM, cinepazide maleate, CON, and citicoline. In terms of the ineffective rate, we found that, compared with CON, the edaravone dexborneol, EDV, citicoline, GDLM, ginkgolide, and cinepazide maleate treatment schemes all had a lower ineffective rate. Finally, our analysis revealed that, except for cinepazide maleate and ginkgolide, the EDV, minocycline, edaravone dexborneol, GDLM, citicoline, and cerebrolysin schemes all had a higher rate of adverse effect on patients compared to CON. Based on the impact of the adverse effect with different surgical interventions, we further analyzed the effect of these drug treatments by the total treatment effective rate combined with adverse effect, revealing that EDV, ginkgolide, and edaravone dexborneol were the safest and most effective treatments. In patients with AIS, ginkgolide, EDV, cinepazide maleate, citicoline, cerebrolysin, minocycline, and GDLM were associated with a reduction in mortality rate. Moreover, ginkgolide, EDV, edaravone dexborneol, and GDLM treatment schemes revealed not only a high total treatment effective rate but also a low rate of treatment inefficacy. When considering the combination of the total treatment effective rate with adverse effect, EDV, ginkgolide, and edaravone dexborneol were revealed as the safest and most effective.

[Cerebrolysin for acute ischemic stroke].

The review discusses existing evidence of benefits and risks of cerebrolysin--a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue with proposed neuroprotective and neurotrophic properties, for acute ischemic stroke. The review presents results of systematic search and analysis of randomised clinical trials comparing cerebrolysin with placebo in patients with acute ischemic stroke. Only one trial was selected as meeting quality criteria. No difference in death and adverse events between cerebrolysin and placebo was established. The authors conclude about insufficiency of evidence to evaluate the effect of cerebrolysin on survival and dependency in people with acute ischemic stroke.

Neuroprotective action of Cortexin, Cerebrolysin and Actovegin in acute or chronic brain ischemia in rats.

This study was the first to compare the neuroprotective activity of Cerebrolysin&#xae;, Actovegin&#xae; and Cortexin&#xae; in rodent models of acute and chronic brain ischemia. The neuroprotective action was evaluated in animals with acute (middle cerebral artery occlusion) or chronic (common carotid artery stenosis) brain ischemia models in male rats. Cortexin&#xae; (1 or 3 mg/kg/day), Cerebrolysin&#xae; (538 or 1614 mg/kg/day) and Actovegin&#xae; (200 mg/kg/day) were administered for 10 days. To assess the neurological and motor impairments, open field test, adhesive removal test, rotarod performance test and Morris water maze test were performed. Brain damage was assessed macro- and microscopically, and antioxidant system activity was measured in brain homogenates. In separate experiments in vitro binding of Cortexin&#xae; to a wide panel of receptors was assessed, and blood-brain barrier permeability of Cortexin&#xae; was assessed in mice in vivo. Cortexin&#xae; or Cerebrolysin&#xae; and, to a lesser extent, Actovegin&#xae; improved the recovery of neurological functions, reduced the severity of sensorimotor and cognitive impairments in rats. Cortexin&#xae; reduced the size of necrosis of brain tissue in acute ischemia, improved functioning of the antioxidant system and prevented the development of severe neurodegenerative changes in chronic ischemia model. Radioactively labeled Cortexin&#xae; crossed the blood-brain barrier in mice in vivo with concentrations equal to 6-8% of concentrations found in whole blood. During in vitro binding assay Cortexin&#xae; (10 &#x3bc;g/ml) demonstrated high or moderate binding to AMPA-receptors (80.1%), kainate receptors (73.5%), mGluR1 (49.0%), GABAA1 (44.0%) and mGluR5 (39.7%), which means that effects observed in vivo could be related on the glutamatergic and GABAergic actions of Cortexin&#xae;. Thus, Cortexin, 1 or 3 mg/kg, or Cerebrolysin&#xae;, 538 or 1614 mg/kg, were effective in models acute and chronic brain ischemia in rats. Cortexin&#xae; contains compounds acting on AMPA, kainate, mGluR1, GABAA1 and mGluR5 receptors in vitro, and readily crosses the blood-brain barrier in mice.

Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson's disease.

Parkinson's disease (PD) is affecting >10 million people worldwide for which no suitable cure has been developed so far. Roughly, about two people per thousand populations are affected with PD like symptoms especially over the age of 50. About 1% of the populations above 60 years suffer from PD-like disease. The prevalence of the disease is increasing over the years, and future projections by 2020 could be 12-14 millions people affected by the disease. Thus, exploration of suitable therapeutic measures is the need of the hour to enhance quality of the life of PD patients. PD induced brain pathology includes loss of dopaminergic neurons in the substantia niagra that could later extends to other cortical regions causing loss of voluntary motor control. Deposition of &#x3b1;-synuclein in the brain further leads to neurodegeneration. However, the exact cause of PD is still unknown. It appears that breakdown of the blood-brain barrier (BBB) and leakage of serum component into the brain could lead to neurodegeneration in PD. Thus, novel treatment strategies that are able to restore BBB breakdown and enhance neuronal plasticity and neuroregeneration in PD could be effective in future therapy. With the advancement of nanotechnology, it is worthwhile to understand the role of nanodelivery of selected agents in PD to enhance neuroprotection. In this review new role of BBB, brain edema, and neuropathology in PD is discussed. In addition, superior neuroprotection induced by nanowired delivery of a multimodal drug cerebrolysin in PD is summarized based on our own investigations.

Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide.

Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (&#x391;&#x3b2;P) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.

Cerebrolysin in Patients with TBI: Systematic Review and Meta-Analysis.

TBI (traumatic brain injury) is one of the most common causes of deaths and failure to return to society according to the latest statistics. Cerebrolysin is a drug approved for use in patients diagnosed with TBI. It is a mixture of neuropeptides derived from purified porcine brain proteins and multiple experimental studies have proven its neuroprotective and neurorestorative properties both in vitro and in vivo. In our meta-analysis, we analyze the latest clinical study reports on the use of Cerebrolysin in patients with TBI. The authors searched the databases: Pub Med, Cinahl, Web Of Science, and Embase from database inception until 11th July 2022. Ten clinical studies were eligible and included in the final analysis, including both retrospective and prospective studies of 8749 patients. Treatment with Cerebrolysin was associated with a statistically significant change in GCS and GOS. Mortality of any cause and the length of stay was not affected by the treatment. Our findings support and confirm the beneficial effects of Cerebrolysin treatment on the clinical outcome of patients after TBI. Further multi-center studies to optimize dosing and time of administration should be conducted.

Life-Threatening Anaphylaxis due to Cerebrolysin&#xae;.

In this case report, we describe a well-documented, severe anaphylactic reaction after intravenous administration of cerebrolysin, a neurotrophic agent derived from highly purified porcine brain tissue, consisting of peptides and free amino acids. Cerebrolysin has been in use for decades, in various neurological diseases, but especially stroke and traumatic brain injury, with the aim of enhancing cognitive performance. After administration of cerebrolysin to an 85-year-old male patient suffering from subacute stroke, he developed a fulminant anaphylactic reaction. Following institutional standards, vital functions were quickly restored. The anaphylactic reaction was clearly confirmed by laboratory tests. To date, only rare cases of anaphylaxis due to cerebrolysin have been published in the literature. The current report is intended to raise awareness for the possibility of such a reaction, given the widespread use of cerebrolysin in several indications in mostly critical patients. The case shows how a completely unexpected life-threatening situation can be successfully treated by targeted measures, if the situation is recognized quickly. In light of this event, we consider pathophysiology of allergic reactions and treatment guidelines.

[Therapy prospects for post-stroke aphasia].

Stroke remains a leading cause of disability worldwide. Cognitive impairment is a major consequence, with post-stroke aphasia developing in approximately 30% of patients after a first stroke. Speech impairments substantially reduce quality of life, complicate rehabilitation, and hinder reintegration into daily activities. Patients with aphasia exhibit greater cognitive deficits and an increased risk of vascular dementia, regardless of stroke type. Speech therapy is a primary treatment modality. Neuroplasticity is central to post-stroke recovery, and agents that stimulate neuroplasticity represent a promising therapeutic direction. Cerebrolysin, a pleiotropic drug composed of peptides with neurotrophic properties and free amino acids, can activate neuroplasticity. Recent findings from the Efficacy and Safety of Cerebrolysin in the Treatment of Aphasia After Acute Ischemic Stroke study (ESCAS) demonstrate that combined speech therapy and Cerebrolysin use accelerates recovery of speech functions, suggesting its value as an adjunct in stroke rehabilitation.

Cerebrolysin: a multi-target drug for recovery after stroke.

Cerebrolysin is a neuropeptide preparation with neurotrophic effects and promotes recovery after brain injury. Its preclinical profile promises wide applications due to its multi-target effects. Currently, Cerebrolysin is used for treatment of cerebral ischemia and neurodegeneration. Areas covered: In stroke, earlier clinical trials with Cerebrolysin were performed mostly in mildly affected stroke populations, which usually have a favorable prognosis. Due to this selection, a floor or ceiling effect of recovery measures in the mild cases may have prevented to show a clear benefit between treatment groups. In contrast, subgroup analyses of more severely affected patients reveal a strikingly positive effect for enhanced recovery. Based on the findings from several studies, it became evident that the effect size of Cerebrolysin was increasing with stroke severity. Other controlled studies showed that Cerebrolysin can be safely used in combination with thrombolysis. More recently, Cerebrolysin has been tested not only for neuroprotection but also for its neurorecovery potential and also showed efficacy in patients with moderate to severe strokes. Expert commentary: Cerebrolysin shows a benefit mostly in moderate to severe ischemic stroke patients and an overall significant&#xa0;effect for functional recovery when combined with neurorehabilitation versus neurorehabilitation alone. This gives lead to the planning of a more rigorous study design in the future.

Cerebrolysin improves sciatic nerve dysfunction in a mouse model of diabetic peripheral neuropathy.

To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

[Cerebrolysin in the treatment of cognitive impairment].

Cognitive impairment is one of the most important problems of modern health care. Currently, according to WHO, more than 55 million people worldwide are living with dementia. Dementia is one of the leading causes of disability and addiction among older people worldwide. Even more significant is the number of patients with mild cognitive impairment who have an increased risk of progression to dementia compared to people of the same age without cognitive impairment. The number of patients with cognitive impairment has also increased due to the consequences of COVID-19. It is necessary to use drugs that not only improve cognitive functions, but also slow down their progression. One of these drugs is cerebrolysin, the effectiveness of which has been confirmed in various types of cognitive impairment. Cerebrolysin, being a preparation from the brain of a pig, belongs to the group of biological drugs. In the production of Cerebrolysin very strict measures are taken to comply with the technology, which ensures the quality and identity of the product from batch to batch. The experience of many years of clinical use of Cerebrolysin testifies not only to its high efficiency, but also to its safety. It should be taken into account that similar substances can be developed in relation to biological products - biosimilars or biosimilars, which can be considered comparable only in case of equivalent pharmacokinetic parameters, efficacy and safety.

Is Cerebrolysin Useful in Psychiatry Disorders?

Background/Objectives: Cerebrolysin is a well-known mixture of peptides that has been used for many years, primarily in patients with neurological disorders. Thanks to its unique properties, this substance supports endogenous repair mechanisms and protects the brain from damaging factors. Cerebrolysin is most widely used in Eastern European countries. However, data on the potential use of cerebrolysin in mental disorders are difficult to find in the literature. This review focuses on the potential use of cerebrolysin in psychiatry, and two independent researchers searched three full-text medical article databases to compile it. Methods: To conduct this scoping review, two independent researchers searched three full-text article databases, Embase, Scopus, and Web of Science, by entering the following phrases: "cerebrolysin psychiatry", "cerebrolysin depression", "cerebrolysin mood", "cerebrolysin bipolar", "cerebrolysin schizophrenia", and "cerebrolysin addiction". Results: The results show that this specific substance could have a relatively small application in psychiatry. Conclusions: The limited amount of available research on the use of cerebrolysin suggests that it may have some significance in supporting the treatment of depression and autism spectrum disorders and alleviating adverse effects during treatment with neuroleptics.

Nanowired delivery of antibodies to tau and neuronal nitric oxide synthase together with cerebrolysin attenuates traumatic brain injury induced exacerbation of brain pathology in Parkinson's disease.

Concussive head injury (CHI) is one of the major risk factors for developing Parkinson's disease in later life of military personnel affecting lifetime functional and cognitive disturbances. Till date no suitable therapies are available to attenuate CHI or PD induced brain pathology. Thus, further exploration of novel therapeutic agents are highly warranted using nanomedicine in enhancing the quality of life of veterans or service members of US military. Since PD or CHI induces oxidative stress and perturbs neurotrophic factors regulation associated with phosphorylated tau (p-tau) deposition, a possibility exists that nanodelivery of agents that could enhance neurotrophic factors balance and attenuate oxidative stress could be neuroprotective in nature. In this review, nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies to neuronal nitric oxide synthase (nNOS) with p-tau antibodies was examined in PD following CHI in model experiments. Our results suggest that combined administration of nanowired antibodies to nNOS and p-tau together with cerebrolysin significantly attenuated CHI induced exacerbation of PD brain pathology. This combined treatment also has beneficial effects in CHI or PD alone, not reported earlier.

Role and Impact of Cerebrolysin for Ischemic Stroke Care.

Stroke is still a significant health problem that affects millions of people worldwide, as it is the second-leading cause of death and the third-leading cause of disability. Many changes have occurred in the treatment of acute ischemic stroke. Although the innovative concepts of neuroprotection and neurorecovery have been vigorously investigated in a substantial number of clinical studies in the past, only a few trials managed to increase the number of promising outcomes with regard to the multidimensional construct of brain protection and rehabilitation. In terms of pharmacological therapies with proven benefits in the post-ischemic process, drugs with neurorestorative properties are thought to be effective in both the acute and chronic phases of stroke. One significant example is Cerebrolysin, a combination of amino acids and peptides that mimic the biological functions of neurotrophic factors, which has been shown to improve outcomes after ischemic stroke, while preserving a promising safety profile. The purpose of this paper is to offer an overview on the role and impact of Cerebrolysin for ischemic stroke care, by touching on various aspects, from its complex, multimodal and pleiotropic mechanism of action, to its efficacy and safety, as well as cost effectiveness.

Cerebrolysin in Alzheimer's disease.

Cerebrolysin is a neuropeptide preparation mimicking the action of endogenous neurotrophic factors. Positive effects of Cerebrolysin on &#x3b2;-amyloid- and tau-related pathologies, neuroinflammation, neurotrophic factors, oxidative stress, excitotoxicity, neurotransmission, brain metabolism, neuroplasticity, neuronal apoptosis and degeneration, neurogenesis and cognition were demonstrated in experimental conditions. These pleiotropic effects of Cerebrolysin on Alzheimer's disease-related pathogenic events are consistent with a neurotrophic-like mode of action, and seems to involve the activation of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 &#x3b2; intracellular signaling pathway. The clinical efficacy of Cerebrolysin in Alzheimer's disease was evaluated in several randomized, double-blind, clinical trials, showing consistent benefits on global clinical function and cognition, improvements in behavior at high doses, and minor effects on daily living activities in patients with mild to moderate Alzheimer's disease, as well as in subgroups of moderate to moderately severe patients. In addition, the clinical benefits of Cerebrolysin were largely maintained for several months after ending treatment, a finding that supports its discontinuous administration. Cerebrolysin was generally well tolerated and did not induce significant adverse events in Alzheimer's patients. Although long-term studies are needed, the data available suggest that Cerebrolysin is effective as monotherapy and constitutes a promising option for combined therapy in Alzheimer's disease.

Sleep deprivation enhances amyloid beta peptide, p-tau and serotonin in the brain: Neuroprotective effects of nanowired delivery of cerebrolysin with monoclonal antibodies to amyloid beta peptide, p-tau and serotonin.

Sleep deprivation is quite frequent in military during combat, intelligence gathering or peacekeeping operations. Even one night of sleep deprivation leads to accumulation of amyloid beta peptide burden that would lead to precipitation of Alzheimer's disease over the years. Thus, efforts are needed to slow down or neutralize accumulation of amyloid beta peptide (A&#x3b2;P) and associated Alzheimer's disease brain pathology including phosphorylated tau (p-tau) within the brain fluid environment. Sleep deprivation also alters serotonin (5-hydroxytryptamine) metabolism in the brain microenvironment and impair upregulation of several neurotrophic factors. Thus, blockade or neutralization of A&#x3b2;P, p-tau and serotonin in sleep deprivation may attenuate brain pathology. In this investigation this hypothesis is examined using nanodelivery of cerebrolysin- a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies against A&#x3b2;P, p-tau and serotonin (5-hydroxytryptamine, 5-HT). Our observations suggest that sleep deprivation induced pathophysiology is significantly reduced following nanodelivery of cerebrolysin together with monoclonal antibodies to A&#x3b2;P, p-tau and 5-HT, not reported earlier.

Cost-effectiveness of Cerebrolysin as an add-on treatment for neurorecovery after traumatic brain injury.

Traumatic brain injuries (TBIs) are a leading cause of death and long-term disability worldwide, with incidence and injury mechanisms varying by age group and region. Impairment of functional status, diagnoses of anxiety and depression are encountered post-TBI. Studies have shown that Cerebrolysin can have positive effects among TBI survivors. We conducted a cost-effectiveness analysis (CEA) among patients with moderate TBI, using data from the CAPTAIN II trial. This exercise was carried out on a three-month timeline from the provider's perspective. Two models were incorporated in the CEA: control (placebo group) and treatment (Cerebrolysin group). Our analysis showed that Cerebrolysin had a high probability of being cost-effective, based on Glasgow Outcome Scale Extended (GOSE) (in over 80% of patients with moderate TBI), Hospital Anxiety and Depression Scale (HADS) Depression and Anxiety scores (for the former two, in over 95% of patients with moderate TBI), when assuming a lasting effect (12 months) of the CAPTAIN trial intervention protocol. A model-based approach is needed to account for potential sources of bias beyond the 90-day observation period of this clinical trial. Furthermore, economic evaluations incorporating patients diagnosed with all TBI severities are needed.

Cerebroprotection in acute ischemic stroke: Perspectives on combining cerebrolysin with recanalization therapy.

This article provides perspectives on the use of Cerebrolysin as an adjunct treatment to reperfusion therapy in acute ischemic stroke (AIS). In the evolving landscape of AIS reperfusion therapy, we hypothesize that adjunctive cerebroprotective therapy, such as Cerebrolysin, is likely to further improve patient outcomes. Beyond its established neurorecovery benefits, recent data indicate that Cerebrolysin also offers protection to the neurovascular unit and the blood-brain barrier. This paper introduces the CErebrolysin in RECanalization And Perfusion (CERECAP) program, a collaborative initiative of independent academic investigations exploring the favorable trends of Cerebrolysin in reperfusion. The CERECAP program has generated compelling data demonstrating Cerebrolysin's alignment with current AIS reperfusion therapy concepts, particularly its role in early intervention targeting multiple pathways. We review these studies and discuss the critical need to clearly define the patient population that benefit most from adjunctive Cerebrolysin therapy in AIS.

Modulation of neurotrophic factors in the treatment of dementia, stroke and TBI: Effects of Cerebrolysin.

Neurotrophic factors (NTFs) are involved in the pathophysiology of neurological disorders such as dementia, stroke and traumatic brain injury (TBI), and constitute molecular targets of high interest for the therapy of these pathologies. In this review we provide an overview of current knowledge of the definition, discovery and mode of action of five NTFs, nerve growth factor, insulin-like growth factor 1, brain derived NTF, vascular endothelial growth factor&#xa0;and tumor necrosis factor alpha; as well as on their contribution to brain pathology and potential therapeutic use in dementia, stroke and TBI. Within the concept of NTFs in the treatment of these pathologies, we also review the neuropeptide preparation Cerebrolysin, which has been shown to resemble the activities of NTFs and to modulate the expression level of endogenous NTFs. Cerebrolysin has demonstrated beneficial treatment capabilities in vitro and in clinical studies, which are discussed within the context of the biochemistry of NTFs. The review focuses on the interactions of different NTFs, rather than addressing a single NTF, by outlining their signaling network and by reviewing their effect on clinical outcome in prevalent brain pathologies. The effects of the interactions of these NTFs and Cerebrolysin on neuroplasticity, neurogenesis, angiogenesis and inflammation, and their relevance for the treatment of dementia, stroke and TBI are summarized.

Cerebrolysin for stroke, neurodegeneration, and traumatic brain injury: review of the literature and outcomes.

Cerebrolysin therapy has the potential to significantly aid in the treatment of a wide variety of debilitating neurological diseases including ischemic strokes, neurodegenerative disorders, and traumatic brain injuries. Although Cerebrolysin is not approved for use in the USA, it is used clinically in over 50 countries worldwide. In this review, we focus on outlining the role that Cerebrolysin has in stimulating the molecular signaling pathways that are critical for neurological regeneration and support. An extensive evaluation of these signaling pathways reveals that Cerebrolysin has the potential to intervene in a diverse array of pathophysiological causes of neurological diseases. In the clinical setting, Cerebrolysin is generally safe for human use and has provided functional improvement when used as an adjunct treatment. However, our literature review revealed inconsistent results, as several clinical studies suggested that Cerebrolysin treatment has minor clinical relevance and did not have significant advantages over a placebo. In conclusion, we found that Cerebrolysin therapy can potentially play a major role in the treatment of many neurological diseases. Nevertheless, there remains much to be elucidated about the efficacy of this treatment for specific neurological conditions, and more robust clinical data is needed to reach a consensus and properly define the therapeutic role of Cerebrolysin.

Comparing the biological activity and composition of Cerebrolysin with other peptide preparations.

Neurological disorders, ranging from acute forms such as stroke and traumatic brain injury to neurodegenerative diseases like dementia, are the leading cause of disability-adjusted life years (DALYs) worldwide. A promising approach to address these conditions and promote nervous system regeneration is the use of the neuropeptide preparation Cerebrolysin, which has been shown to be effective in both clinical and preclinical studies. Despite claims of similar clinical efficacy and safety by several peptide preparations, concerns regarding their generic composition and efficacy have been previously raised. Based on these reports, we analyzed the peptide composition and neurotrophic activity of several peptide preparations allegedly similar to Cerebrolysin and approved in some countries for treating neurological diseases. Our results demonstrate that these preparations lack relevant biological activity and that the peptide composition is significantly different from Cerebrolysin. peptide.

Cerebrolysin induces hair repigmentation associated to MART-1/Melan-A reactivation.

Hair graying, a prototypical sign of human aging, is a progressive loss of pigmentation from growing hair shafts caused by disease and as a side effect of medications. Cerebrolysin is a neuropeptide preparation that mimics the effect of endogenous neurotrophic factors. Cerebrolysin has been widely used in neurologic conditions, such as cerebral stroke, Alzheimer's disease, and dementia, among others. Cerebrolysin treatment has achieved to regain or maintain the cognitive ability of affected patients; however, up to date, there are no reports about the reactivation of hair pigmentation. We describe a previously not described effect occurring on patients receiving Cerebrolysin treatment for neurologic diseases and whether this effect is associated in reactivation of melanocytes and melanin expression. Here, we report five patients (mean age, 70.6&#xa0;years), who also had age-related hair graying and scalp hair repigmentation during Cerebrolysin treatment. Macroscopic analysis revealed hair repigmentation consisted in diffuse darkening of the scalp hair. Impregnation and immunostaining analysis were performed on scalp biopsies taken before and after Cerebrolysin treatment; the results showed greater melanin and melanocyte marker MART-1/Melan-A staining following Cerebrolysin treatment. We present, to our knowledge, the first report on hair repigmentation is a previously not described effect occurring following Cerebrolysin treatment.

C-REGS2-A multinational, high-quality comparative effectiveness study of Cerebrolysin in moderate acute ischemic stroke.

The main objective of the Cerebrolysin REGistry Study in Stroke 2 (C-REGS2) was to systematically record the routine clinical use of Cerebrolysin in patients with moderate ischemic stroke (IS) following the principles of a prospective controlled effectiveness study (CES) to compare its effectiveness in terms of functional recovery to patients treated with standard therapy alone. C-REGS2 used an open-label, prospective controlled comparative effectiveness design aligning with the Target Trial Emulation Framework (TTEF) and the GRACE principles for high-quality observational studies based on the principles of high-quality comparative effectiveness research (HQCER) to capture treatment effects in clinical practice. The study was conducted in 16 countries worldwide between April 2018 and April 2024. Moderate IS was defined as baseline NIH Stroke Scale (NIHSS) score 8-15. Treatment modalities and concomitant medications were according to local standards. The methodology included rigorous pre-specified analysis and tight risk-based centralized monitoring, to ensure minimal enrollment bias, maximize data quality and overall reliability of trial results. The compared patient groups were standardized using a restricted cohort design and non-parametric multilevel stratification following the Good Research for Comparative Effectiveness (GRACE) principles. The primary endpoint was ordinal analysis of the modified Rankin Scale (mRS) at 90&#x2009;days after stroke onset. Secondary endpoints were the ordinal NIH Stroke Scale (NIHSS) at day 21 and 90 after stroke onset, the ordinal mRS at 21&#x2009;days after IS, the proportion of patients with excellent recovery (mRS 0-1) as well as the proportion of patients with functional independence (mRS 0-2) at 90&#x2009;days after stroke onset and the ordinal analysis of Montreal Cognitive Assessment (MoCA) scale at 90&#x2009;days after IS. Out of 1865 enrolled patients, the target population (TP) comprised 1769 patients (1021 Cerebrolysin-treated and 748 controls). The median NIHSS at baseline was 10.0. Median Cerebrolysin dose was 30 ml, median treatment duration was 10&#x2009;days. Cerebrolysin was superior to standard therapy in the primary endpoint independently to prior thrombolysis (MW 0.6157; confidence interval (CI) 0.5910-0.6404; P&#x2009;<&#x2009;0.0001) as well as in all secondary endpoints: mRS at day 21 (MW 0.6065, 95% CI 0.5811-0.6319, P&#x2009;<&#x2009;0.0001), NIHSS at day 21 (MW 0.5792; 95% CI 0.5576-0.6008; P&#x2009;<&#x2009;0.0001) and NIHSS at day 90 (MW 0.5781; CI 0.5561-0.6002; P&#x2009;<&#x2009;0.0001). Additional pre-specified secondary endpoints (proportion of patients with excellent recovery and functional independence) showed moderate superiority for Cerebrolysin. The ordinal MoCA showed superiority for Cerebrolysin in the TP (MW 0.5530; CI 0.5282-0.5778; P&#x2009;<&#x2009;0.0001) with more pronounced effects in the subgroup with cognitive impairments at baseline (Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE)&#x2009;&#x2a7e;&#x2009;3.3). No differences in safety measures were recorded. The study is notable for its robust data integrity, with valid entries of 90.9% for the primary 90&#x2009;day mRS assessment with multilevel case mix standardization and an overall dropout rate to the final visit of only 5.7%. The results of the C-REGS2 study showed the effectiveness and safety of Cerebrolysin treatment for moderate acute IS in real-world clinical practice.

Speech Therapy Combined With Cerebrolysin in Enhancing Nonfluent Aphasia Recovery After Acute Ischemic Stroke: ESCAS Randomized Pilot Study.

Stroke-induced aphasia significantly impacts communication and quality of life. Despite the standard treatment being speech and language therapy, outcomes vary, highlighting the need for additional therapies. Cerebrolysin, a neuroprotective and neurotrophic agent, has shown potential in stroke management. This study addresses the notable gap in research about the combined use of Cerebrolysin and speech therapy, evaluating their synergistic potential in the treatment of aphasia. The ESCAS trial (The Efficacy and Safety of Cerebrolysin in the Treatment of Aphasia After Acute Ischemic Stroke), a prospective, randomized-controlled, double-blinded study was conducted in 2 Romanian stroke centers. Participants included those with left middle cerebral artery territory ischemic stroke and nonfluent aphasia, enrolled 3 to 5 days poststroke. Inclusion criteria were right-handedness and Romanian as the mother tongue. Participants received Cerebrolysin or a placebo combined with speech and language therapy in 10-day cycles over 3 intervals, and evaluations were done at baseline, 30, 60, and 90 days respectively. The main outcome measure was Western Aphasia Battery for language function. Changes at days 30, 60, and 90 compared with baseline were quantified, and the effect estimand used was the difference in means between groups. Secondary outcome measurements were the National Institutes of Health Stroke Scale for neurological deficit, the modified Rankin Scale for global disability, and the Barthel Index for activities of daily living. Out of 132 enrolled patients, 123 were included in the intention-to-treat analysis, and 120 in the per-protocol analysis. Overall, both groups showed improvement at subsequent visits compared with the baseline for Western Aphasia Battery and the National Institutes of Health Stroke Scale. The Cerebrolysin group showed greater improvements in Western Aphasia Battery (visit 4 mean increase of 35.579&#xb1;16.316 [95% CI, 31.289-39.869] points; P<0.001) compared with the placebo group (20.774&#xb1;12.486 [95% CI, 17.603-23.945] points; P<0.001), a difference in means of 14.805 (95% CI, 9.521-20.089) points (P<0.001). The Cerebrolysin group also showed significant improvements (higher decreases) in National Institutes of Health Stroke Scale scores compared with the placebo group (2.085 [95% CI, 1.076-3.094] points; P<0.001). Safety analysis raised no concerns (number of patients with adverse events P=0.105, number of adverse events per patient P=0.134). Additionally, the Cerebrolysin group showed greater improvements in functional independence (Barthel Index) and a trend toward reduced disability (modified Rankin Scale) compared with the placebo group. Cerebrolysin combined with speech and language therapy offers promising potential for enhancing recovery in poststroke nonfluent aphasia. Significant improvements were observed in language and neurological deficits, underscoring the importance of adjunctive therapies in nonfluent aphasia rehabilitation. Further research with larger cohorts is needed to fully establish the efficacy of this combination therapy. URL: https://www.isrctn.com; Unique identifier: ISRCTN54581790.

Efficacy of Cerebrolysin Treatment as an Add-On Therapy to Mechanical Thrombectomy in Patients with Acute Ischemic Stroke Due to Large Vessel Occlusion in Anterior Circulation: Results of a 3-Month Follow-up of a Prospective, Open Label, Single-Center Study.

This study hypothesized that Cerebrolysin, a multimodal neuroprotective agent, enhances the efficacy and safety of mechanical thrombectomy (MT) in both acute ischemic stroke (AIS) and recovery stroke phases in selected patients with good collateral status (CTA-CS 2-3) and effective recanalization (mTICI 2b-3). A single-center, prospective, open-label, single-arm study with blinded outcome assessment of 50 consecutive patients with moderate-to-severe AIS treated with MT&#x2009;&#x2264;&#x2009;6&#xa0;h of stroke onset followed by Cerebrolysin (30&#xa0;ml iv within 8&#xa0;h of onset and continued to day 21, first cycle) and in a recovery phase (between 69-90&#xa0;days, second cycle) compared to 50 historical controls matched by propensity scores. Key outcomes included functional independence (mRS 0-2 at 90&#xa0;days), safety endpoints, and neurological recovery (NIHSS at 24&#xa0;h and 7&#xa0;day post MT). Patients receiving Cerebrolysin achieved higher rates of mRS 0-2 at 90&#xa0;days (68% vs. 44%, p&#x2009;=&#x2009;0.016, OR 2.7, 95% CI 1.2-6.1; NNT: 4.2), had reduced risk of secondary ICH (14% vs. 40%, p&#x2009;=&#x2009;0.02; RR 0.37, 95% CI 0.14-0.95), and had lower NIHSS on day 7 (median [IQR]: 3 [4] vs. 6 [9], p&#x2009;=&#x2009;0.01). There was a significant difference in Barthel Index scores between the Cerebrolysin group and the control group at 30&#xa0;days (median [IQR]: 77 [32] vs. 63 [50], p&#x2009;=&#x2009;0.03) and at 3&#xa0;months (86 [22] vs. 75 [29], p&#x2009;=&#x2009;0.01) primarily driven by the increase in the mobility and transfer components. Multivariate analysis identified Cerebrolysin as an independent predictor of favorable outcomes at 3&#xa0;months (OR 7.5, 95% CI 1.8-30.9), particularly in patients with diabetes (interaction OR 9.6, 95% CI 1.01-92). The overall mortality rates at 30 and 90&#xa0;days were similar in both groups (2% vs 6% and 8% vs 12%, p&#x2009;>&#x2009;0.1). Cerebrolysin improved functional outcomes at 90&#xa0;days, accelerated neurological recovery, and reduced complications post-MT in patients with small ischemic core, good collateral circulation, and effective recanalization at baseline. These findings warrant further randomized trials to validate its efficacy and explore its long-term benefits.Registration: URL: https://www.clinicaltrials.gov ; unique identifier: NCT04904341.

Cerebrolysin after moderate to severe traumatic brain injury: prospective meta-analysis of the CAPTAIN trial series.

This prospective meta-analysis summarizes results from the CAPTAIN trial series, evaluating the effects of Cerebrolysin for moderate-severe traumatic brain injury, as an add-on to usual care. The study included two phase IIIb/IV prospective, randomized, double-blind, placebo-controlled clinical trials. Eligible patients with a Glasgow Coma Score (GCS) between 6 and 12 received study medication (50&#xa0;mL of Cerebrolysin or physiological saline solution per day for ten days, followed by two additional treatment cycles with 10&#xa0;mL per day for 10&#xa0;days) in addition to usual care. The meta-analysis comprises the primary ensembles of efficacy criteria for 90, 30, and 10&#xa0;days after TBI with a priori ordered hypotheses based on multivariate, directional tests. A total 185 patients underwent meta-analysis (mean admission GCS&#x2009;=&#x2009;10.3, mean age&#x2009;=&#x2009;45.3, and mean Baseline Prognostic Risk Score&#x2009;=&#x2009;2.8). The primary endpoint, a multidimensional ensemble of functional and neuropsychological outcome scales indicated a "small-to-medium" sized effect in favor of Cerebrolysin, statistically significant at Day&#xa0;30 and at Day&#xa0;90 (Day 30: MWcombined&#x2009;=&#x2009;0.60, 95%CI 0.52 to 0.66, p&#x2009;=&#x2009;0.0156; SMD&#x2009;=&#x2009;0.31; OR&#x2009;=&#x2009;1.69; Day 90: MWcombined&#x2009;=&#x2009;0.60, 95%CI 0.52 to 0.68, p&#x2009;=&#x2009;0.0146; SMD&#x2009;=&#x2009;0.34, OR&#x2009;=&#x2009;1.77). Treatment groups showed comparable safety and tolerability profiles. The meta-analysis of the CAPTAIN trials confirms the safety and efficacy of Cerebrolysin after moderate-severe TBI, opening a new horizon for neurorecovery in this field. Integration of Cerebrolysin into existing guidelines should be considered after careful review of internationally applicable criteria.