Cerebrolysin

Cerebrolysin is a peptide-based drug that exhibits unique neurotrophic and neuroprotective activity. The effects of Cerebrolysin have been investigated and confirmed in various cell culture and animal models of neurodegeneration and ischemia. For example, in ApoE knock-out mice, which suffer from early neuronal degeneration, Cerebrolysin treatment reversed cognitive impairment (Masliah E et al., 1999; Rockenstein E, 2002). Treatment for 4 weeks also reestablished normal MAP2 levels in the frontal cortex, increased the synaptic density and had morphological effects. These results suggest a normalization of neuronal cytoarchitecture compared to controls. In a gerbil model of cerebral ischemia/reperfusion, Cerebrolysin decreased hydroxyl radical formation in the cerebral cortex and hippocamus. A significant number of pyramidal and hippocampal neurons in the CA1 region were saved (Sugita Y et al., 1993).

Stroke therapy
Stroke is the third most common cause of death worldwide. Damage from stroke has frightening proportions. Data from the US show that 157,991 people there were killed by a stroke in 1995; more than 700,000 people per annum suffer a stroke; and about 4.4 million US residents are stroke survivors. The yearly economic burden of stroke was about $51 billion in 1999. The incidence of stroke is rising every year. But stroke is neither unpreventable nor untreatable. Early recognition, treatment in stroke units, and the attempt to treat the patients as early as possible have led to huge improvements in survival and rehabilitation. Unfortunately, stroke patients still wait, on average, for 13 hours before presenting at the emergency department and receiving treatment. Neuroprotective and neurotrophic agents have opened new avenues in stroke treatment and increase the potential for survival and rehabilitation, even for patients who are unlucky enough to present later than the critical window of 3 hours after the event. Next to thrombolysis, protection of vulnerable neurons with neuroprotective agents has become the premier option for the treatment of ischaemic stroke. Cerebrolysin, a neuroprotective and neurotrophic drug containing peptides with unique biological activity, protects the nerve cells from the hazards of the ischemic cascade. Cerebrolysin reduces excitotoxic damage, blocks overactivation of calcium-dependent proteases, and scavenges free oxygen radicals. It increases neuronal viability and survival during and after ischemic events.

Clinical trials with Cerebrolysin demonstrate that it is significantly effective in acute stroke and stroke rehabilitation and improves neurological function, global scores, activities of daily living, and cognitive performance. Trials of Cerebrolysin in stroke encompass more than 1,500 ischaemic stroke patients.

Randomised, double-blind, placebo-controlled clinical trials with Cerebrolysin in stroke Barolin GS et al. (1996) Haffner Z et al. (1999) Herrschaft H et al. (1998) Ladurner G et al. (2000) Muresanu DF (1999) Wege HW et al. (2001) 418 Patients with Acute Ischaemic Stroke and During Early Rehabilitation 48 Patients with Acute Ischaemic Stroke 69 Patients with Acute Ischaemic Stroke 146 Patients with Acute Ischaemic Stroke and During Early Rehabilitation 60 Patients with Acute Ischaemic Stroke 60 Patients with Acute Ischaemic Stroke and During Rehabilitation

Open-label clinical trials with Cerebrolysin in stroke Domzal T et al. (1995) Gusev EI et al. (1994) Volc D et al. (1998) 131 Patients with Acute Ischaemic Stroke 60 Patients with Acute Ischaemic Stroke 331 Patients with Acute Ischaemic Stroke and During Rehabilitation

Safety of Cerebrolysin
No safety concerns for Cerebrolysin were noted in clinical trials. Adverse events (AEs) were rare and equally frequent in Cerebrolysin-treated groups or control groups. Most common AEs included vertigo, agitation and feeling hot. All AEs were mild and transient. There were no changes in the vital signs of the patients nor in any of the lab parameters. An important fact: Cerebrolysin can be used safely in patients with acute haemorrhagic stroke (Shi Y et al., 1990). This allows the critical period to the start of treatment to be shortened, because Cerebrolysin can be given immediately, without waiting for brain imaging results. For further information please go to "Clinical safety". Safety of Cerebrolysin is assured through many years of clinical application, information from post-

marketing surveillance studies, and safety data from randomized, controlled clinical trials. Reported events from all sources indicate that adverse reactions due to the drug generally are mild in intensity and transient. There is no evidence for systemic toxicity. Data from double-blind, placebo-controlled clinical trials clearly demonstrate an incidence rate of adverse events under Cerebrolysin treatment similar to that of placebo-treated patients.

Following table gives an overview of all adverse events reported in clinical trials, summarized by body systems according to COSTART: Body as a whole Cardiovascular system Digestive system Endocrine system Hemic and lymphatic system Injection site reaction Metabolic and nutritional disorders Musculoskeletal system Nervous system Respiratory system Skin and appendages Special senses Urogenital system 74 98 73 1 6 4 11 3 213 38 15 5 5 546 Of these 546 reported adverse events, the most frequent were: Headache Vertigo Nausea 41 31 24

Increased sweating Agitation Fever Hypertension Hallucinations Hypotension Confusion Flu syndrome

21 20 18 18 14 11 10 10

These data were derived from 8,057 patients, corresponding to an incidence rate of 6.77 events per 100 patients.

The folowing table gives an overview of all adverse events reported from ongoing post-marketing surveillance studies, summarized by body systems according to COSTART: Body as a whole Headache Fever Asthenia Cardiovascular system Vasodilation Tachycardia Hypertension Phlebitis Digestive system Nausea/vomit/malaise Diarrhea Nervous system Vertigo Agitation 39 15 11 5 3 2 16 10 4 1 1 7 4 2 1

Nervousness Confusion Hostility Skin and appendages Allergic cutaneous reaction Pruritus 3

7 3 3

2 1 70

These data derived from 2,986 patients corresponding to an incidence rate of 2.34 events per 100 patients.

The accumulated evidence demonstrates that Cerebrolysin is safe and well tolerated.

Therapeutic indications

Organic, metabolic and neurodegenerative disorders of the brain, especially senile dementia of Alzheimer's type Post-apoplectic complications Craniocerebral trauma; post operative trauma, cerebral contusion or concussion

Contraindications Hypersensitivity to one of the components of the drug Epilepsy Severe renal impairment

Special warnings and special precautions for use Special care is indicated in cases of:

allergic diathesis

epileptic conditions and grand mal convulsions; Cerebrolysin treatment may result in an increase in the frequency of seizures although there are no indications that Cerebrolysin causes renal stress, the product should not be administered in the presence of existing severe renal insufficiency

Interaction with other medicaments and other forms of interaction On the basis of Cerebrolysin's pharmacological profile, special attention should be given to possible additive effects when used in conjunction with anti-depressants or MAO-inhibitors. In such cases it is recommended that the dose of the anti-depressant is lowered. Cerebrolysin should not be mixed with balanced aminoacid solutions in an infusion. Pregnancy and lactation Animal studies did not show any indication of reproductive toxicity. However, no data is available for humans. Therefore, during pregnancy and lactation, Cerebrolysin should only be used after careful risk/benefit considerations. Effects of the ability to drive and use machines Clinical tests of Cerebrolysin have shown no effects on ability to drive a car or operate machinery.

Undesirable effects

In rare cases the desired effects of activation have also been associated with agitation (aggression, confusion, insomnia). In one study rare cases of hyperventilation, hypertonia, hypotonia, tiredness, tremor, depression, apathy, dizziness and symptoms of influenza (eg. cold, cough, infections of the respiratory tract) were reported. Single cases of grand mal attack and convulsions have been reported with Cerebrolysin. In rare cases, gastro-intestinal disturbances, such as loss of appetite, dyspepsia, diarrhea, constipation, vomiting and nausea, have been observed. If injected too quickly, feelings of heat or sweatiness, dizziness, and, in isolated instances, palpitations or arrhythmias may result. Injection site reactions, such as erubescence, pruritus and burning have been reported. In very rare cases, hypersensitivity or allergic reactions such as skin reactions, local

vessel reactions, headache, neck pain, limb pain, fever, lower backache, dyspnoea, chills and shock like state have been observed. As Cerebrolysin is used in the elderly, the above-mentioned undesirable effects are typical of this patient population and may be observed without drug use. Overdose There are no known instances of health related negative effects due to overdose or intoxication.

Dementia
Introduction Demen?ia is the fourth most common cause of death in G7 countries and will be so worldwide soon. The human and economic costs are enormous. Demen?ia is estimated to cost 100 billion dollars per year in the US, and the incidence is rising every year. However, if onset could be delayed on average for only one year, in the US there would be ~210,000 fewer persons afflicted with this disease after 10 years. This would result in annual savings of nearly 10 billion US dollars. Currently, therapy of demen?ia is focused on symptomatic treatment. Neurotrophic agents open new avenues in demen? ia treatment and may be able to modify the underlying disease. Cerebrolysin, a unique neurotrophic and neuroprotective drug containing biologically active peptides, can slow down the progressive global and cognitive decline of demen?tia patients. Data from recent clinical trials show that Cerebrolysin has a stabilising effect in patients with demen?ia, and demonstrate that it is significantly efficacious in cognitive function, global scores, and activities of daily living. Cerebrolysin induces longterm benefits, with sustained improvements for at least three months after withdrawal. Trials of Cerebrolysin in demen?ia encompass more than 2,500 patients. Safety data show that Cerebrolysin is well tolerated.

Randomised, double-blind, placebo-controlled clinical trials with Cerebrolysin in demen?ia

Bae CY et al. (2000) Panisset M et al. (2000) Ruether E et al. (2001) Ruether E et al. (1994) Ruether E et al. (2000) Xiao S et al. (2000) Vereshchagin NV et al. (1991) Xiao S et al. (1999)

58 Patients with AD 192 Patients with AD 149 Patients with AD 120 Patients with AD Follow-Up of Above1994 Clinical Trial 157 Patients with AD 60 Patients with VD 148 Patients with VD

Open-label clinical trials with Cerebrolysin in demen?ia Gavrilova SI et al. (1998) 55 Patients with AD Iakhno NN et al. (1996) 20 Patients with VD Rainer M et al. (2000, 1997) 1.006 Patients with AD Takahashi M et al. (1993) 22 Patients either with AD or with VD

s in Patients with Alzheimer's Disease

The neurotrophic drug Cerebrolysin leads to statistically and clinically significant improvements in cognitive performance, global function, and activities of daily living of patients with demen?ia. Patients on Cerebrolysin experience symptomatic improvement after only one month of treatment, which can be reinforced with a second treatment course. Beyond its symptomatic benefit, Cerebrolysin demonstrates a stabilizing effect on the pathological process and patients show sustained treatment benefit even after drug withdrawal. The safety profile of Cerebrolysin is excellent with only rare and benign side-effects. Cerebrolysin is safe and effective in dementia.

Cerebrolysin is a nootropic drug which contains low molecular biologically active neruropeptides, which penetrate through blood-brain barrier and act directly on the nerve cells. The drug possesses a multimodal organo-specific effect on the brain, provides metabolic regulation, neuroprotection, functional neuro-modulation, and neurotrophic activity as well. Metabolic regulation: Cerebrolysin improves the efficiency of aerobic energy metabolism in the brain, improves the intracellular protein synthesis in the developing and aging brain. Neuroprotective effect: Cerebrolysin protects neurons (brain nerve cells) from the damaging effects of lactic acidosis, prevents the formation of free radicals, increases survival and prevents neuronal death during hypoxia and ischemia, reduces the damaging neurotoxic effect of certain amino acids (glutamate). Neurotrophic activity: Cerebrolysin is the only peptide containing nootropic drug with proven neurotrophic activity similar to the action of a neuronal growth factor (NGF). Functional neuromodulation: the medication possesses a positive effects in patients with cognitive impairment, for concentration improvement and memory problems. Which are Cerebrolysin Pharmacokinetics characteristics? Cerebrolysin has a complex composition which contains a mixture of biologically active oligopeptides which exert poly-functional action. Finally this does not allow to carry a Pharmacokinetic analysis of individual components. When the medication is prescribed? Cerebrolysin is prescribed in the following conditions:
Complex

therapy of endogenous depression (in combination with psychotherapy and antidepressants) Post-apopletic complications Chronic cerebrovascular disorders Brain and spinal cord injuries (craniocerebral trauma, post operative trauma, concussion, cerebral contusion,) Alzheimer disease Ischemic stokes (treatment the complications) Mental retardation Senile dementia How the medication is used? The drug is used parenterally. The dose of duration of treatment depends on the disease you treat and severity of the disease, patients. The medication is used as intra-venous and intra-muscular injections which should be made only by a medical staff. If you need the recommended doses of the medicine consult our customer support. Any medication information available on the website or provided by our customer support is for informational purposes only. Which side effects are possible with Cerebrolysin?

In excessively rapid injections: in cases rare the medication may cause feeling the heat, sweating, dizziness, tachycardia or fibrillation.
Digestive system: loss of appetite, indigestion, diarrhea, constipation, nausea and vomiting. Central nervous system and peripheral nervous system: rarely - excitement, vaggressive

behavior, confusion, insomnia, seizures, convulsions. Allergic reactions: hypersensitivity reactions, headache, pain in the neck, legs, lower back, shortness of breath, chills and collaptoid state. Local reactions: hyperemia of the skin, itching and burning at the injection site. According to the results of clinical studies there were reported the following Cerebrolysin side effects: Cardiovascular system: hypertension, hypotension. Central nervous system and peripheral nervous system: fatigue, tremor, depression, apathy, dizziness. Other: hyperventilation, influenza-like symptoms (cough, runny nose, respiratory tract infections). Note that some Cerebrolysin side effects (agitation, hypertension, hypotension, lethargy, tremors, depression, apathy, dizziness, headache, shortness of breath, diarrhea, nausea) were identified during clinical trials and occurred equally in patients, receiving Cerebrolysin , and patients taking placebo. Which are Cerebrolysin contraindications?
Acute kidney insufficiency Epileptic status Known hypersensitivity to any

of the drug ingredients

The medication should be used with caution in I trimester of pregnancy and during breastfeeding. The application of medicines during pregnancy and breastfeeding is possible only in case when the estimated benefit for mother overweighs potentional risk for the fetus. There were no conducted clinical studies which could determine negative effects of Cerebrolysin for the fetus. The medication is contraindicated in patients with acute renal failure. Cerebrolysin cautions In excessively rapid implementation of injections a patient may develop fever, sweating, dizziness. Therefore, the drug should be administered slowly. The medication can be used along with the following standard solutions for infusion: 0.9% sodium chloride, Ringer's solution, 5% solution of dextrose (glucose). The medication can simultaneously be used Cerebrolysin with vitamins and drugs, improving blood circulation. However these drugs should not be mixed in one syringe with Cerebrolysin . You should use only the clear solution of the medication . Clinical trials have shown that Cerebrolysin does not affect the ability to drive vehicles and use machinery. Cerebrolysin overdose

There are no reported any cases of overdose side effects caused by this medication. Do not exceed the recommended dose. How the medication can interact with other medicines? Cerebrolysin may enhance the effects of antidepressants and MAO inhibitors in concomitant use. The drug is not compatible with lipid containing solution and solutions which change pH. The medication should not be mixed with aminoacids solution. How the medication should be stored? The preparation should be stored out of reach of children, protected from light place at temperature not more than 25C. Expiration date is 5 years (for vials) and 4 years (for flasks).

Manufacturer Distributor Contents

Indications

Ever Neuro Pharma Globo Asiatico

Brain-derived peptide Organic, metabolic and neurodegenerative disorders of the brain especially senile dementia of Alzheimer's type; postapoplectic complications; craniocerebral trauma; postoperative trauma, cerebral contusion or concussion. Single doses of up to 50 mL can be administered, but a course of therapy is the preferred option. A recommended optimum course of therapy comprises daily application over a total of 10-20 days. Recommended Dose: Adults: Organic Brain Disorders, Metabolic Disorders and Neurodegenerative Diseases (Dementia): 5-30 mL daily. Postapoplectic Complications and Craniocerebral Trauma: 10-50 mL daily. Children: 1-2 mL daily. The effectiveness of therapy can be increased by repeated courses, until no further benefit results. After the initial course, the frequency of doses may be reduced to 2 or 3 times/week. A treatment-free period, equal in length to the therapy course, should be allowed between successive therapy courses. Administration: Doses of up to 5 mL IM and up to 10 mL undiluted IV may be given. Doses between 10 mL up to a maximum of 50 mL are recommended only as a slow IV infusion after dilution with the suggested standard infusion solutions. The duration of the infusion should be between 15 and 60 min. There are no known instances of health-related negative effects due to overdose or intoxication. Hypersensitivity to one of the components of Cerebrolysin. Epilepsy. Severe renal impairment. Although there are no data indicating that Cerebrolysin causes renal stress, Cerebrolysin should not be administered in the presence of existing severe renal failure. Allergic diathesis. Cerebrolysin treatment may result in an increase in the frequency of seizures; epileptic conditions and grand mal convulsions. Effects on the Ability to Drive or Operate Machinery: Clinical tests of Cerebrolysin have shown no effects on the ability to drive a car or operate machinery. Use in pregnancy & lactation: Animal studies did not show any indication of

Dosage

Overdosage

Contraindications

Special Precautions

reproductive toxicity. However, no data are available for humans. Therefore, during pregnancy and lactation, Cerebrolysin should only be used after careful risk/benefit considerations. Use in the elderly: As Cerebrolysin is used in the elderly, and the undesirable effects as follows, are typical of this patient population, they may also be observed without drug use.
Adverse Drug Reactions

In rare cases, the desired activating effects have also been associated with agitation (aggression, confusion, insomnia). In 1 study, rare cases of hyperventilation, hypertension, hypotension, tiredness, tremor, depression, apathy, dizziness and symptoms of influenza (eg, cold, cough, respiratory tract infections) were reported. Single cases of grand mal attacks and convulsions have been reported after administration of Cerebrolysin. In rare cases, gastrointestinal disturbances eg, loss of appetite, dyspepsia, diarrhea, constipation, vomiting and nausea, have been observed. If injected too quickly, feelings of heat or sweating, dizziness, and in isolated instances, palpitations or arrhythmias may result. Injection site reactions eg, erythema, pruritus and burning have been reported. In very rare cases, hypersensitivity or allergic reactions eg, skin and local inflammatory reactions, headache, neck and limb pain, fever, low back pain, dyspnea, chills and shock-like state have been observed.
Click to view ADR Monitoring Website

Drug Interactions

On the basis of Cerebrolysin's pharmacological profile, special attention should be given to possible additive effects when used in conjunction with antidepressants or MAO inhibitors. In such cases, it is recommended that the dose of the antidepressant is lowered. Incompatibilities: Cerebrolysin should not be mixed with balanced amino acid solutions in an infusion. Cerebrolysin is incompatible with solutions which change the pH (5-8) and with lipid-containing solutions. The compatibility over 24 hrs at room temperature in the presence of light has been tested with the following standard infusion solutions: 0.9% sodium chloride solution (NaCl 9 mg/mL), Ringer's solution (Na+153.98 mmol/L, Ca+2 2.74 mmol/L, K+ 4.02 mmol/L, Cl- 163.48 mmol/L), glucose 5%. Vitamins and cardiovascular drugs may be given concomitantly with Cerebrolysin but the drugs should not be mixed with Cerebrolysin in the syringe. View more drug interactions with Cerebrolysin Instructions for Use & Handling: For single use only. Use only clear, amber solutions. Remove the solution from the vials/ampules immediately before use. When Cerebrolysin is administered via a long-term IV catheter, the catheter

Caution For Usage

has to be rinsed before and after the application with physiological sodium chloride solution.
Storage

Cerebrolysin must be stored at room temperature not exceeding 25C and protected from light. Do not freeze. Shelf-Life: 5 years. Each 1-mL infusion contains porcine brain-derived peptide preparation 215.2 mg in aqueous solution. Cerebrolysin also contains sodium hydroxide and water for injection as excipients. Pharmacology: Pharmacodynamics: The peptide fraction stimulates cell differentiation, bolsters nerve cell function and induces mechanisms of protection and repair. In animal experiments, Cerebrolysin directly influences neuronal and synaptic plasticity, thus improving learning. This has been shown in young, adult and aged animals with reduced cognitive abilities. In models of cerebral ischemia, Cerebrolysin reduced infarct volume, inhibited edema formation, stabilized microcirculation, doubled the survival rate, and normalized lesion-related neurological failure and learning deficits. Positive results were also obtained using models of Alzheimer's disease. In addition to its direct effects on neurons, Cerebrolysin appears to significantly increase the number of glucose transport molecules in the blood-brain barrier, thereby balancing out the critical energy deficit associated with this disease. Quantitative electroencephalography (EEG) studies of healthy volunteers and patients suffering from vascular dementia have shown dose-dependent acute effects of elevated neuronal activity (increase in and frequencies) after 4 weeks of treatment. Regardless of the cause of the disease, be it neurodegenerative dementia of Alzheimer's type or vascular dementia, Cerebrolysin therapy results in improvements in the objective cognitive abilities and in the activities of daily living. After only 2 weeks, there are improvements in the clinical global impression, which increase with continuation of the therapy. Also independent of the type of dementia, approximately 60-70% of patients respond positively to Cerebrolysin therapy. In the case of senile dementia of Alzheimer's type, the improved clinical state of the patient is maintained after the end of active treatment. In particular, the activities of daily living are improved and stabilized over the long-term, which in general leads to a reduced need for patient care and supervision. On the basis of its neurotrophic (nerve growth factor-like) activity, Cerebrolysin can achieve a significant reduction, or in some cases even the cessation of progression, of neurodegenerative processes. Pharmacokinetics: The peptide fraction consists of short biological peptides similar or identical to those produced endogenously. Direct measurement of pharmacokinetic properties has not been performed successfully. Indirect pharmacokinetic data have been established on the basis of Cerebrolysin's pharmacodynamic profile. The neurotrophic activity of Cerebrolysin can be

Description

Mechanism of Action

detected in blood plasma up to 24 hr after a single application. Furthermore, components of Cerebrolysin can cross the blood-brain barrier. Preclinical in vivo experiments revealed identical pharmacodynamic actions on the central nervous system following intra-cerebroventricular or peripheral application. Thus, indirect evidence for the passage of components of Cerebrolysin across the blood-brain barrier has been established. Toxicology: Preclinical Safety Data: Acute Toxicity/Median Lethal Dose (LD50): The LD50 of a male rat, female rat and male/female dog are 68, 74 and >52.2 mL/kg body weight IV, respectively. Chronic Toxicity: Rat: Above 5 mL/kg body weight/day for 26 weeks: Moderate changes in blood counts. Dog: The highest applied dose of 9 mL/kg body weight/day for 28 days (corresponding to approximately 10 times the human therapeutic dose) and the highest applied dose of 4.5 mL/kg body weight/day (corresponding to approximately 5 times the human therapeutic dose) for 26 weeks showed no substance-related systemic intolerability. Reproductive Toxicity: Intravenous administration of Cerebrolysin at doses toxic to the mother, or of the highest possible volume, showed no evidence of teratogenic effects in any phase of reproduction in rats or rabbits, no influence on fertility, breeding capacity, posterity, and no embryotoxic or fetotoxic effects. Sensitizing Potential: Larger molecular weight peptides with antigenic potential are excluded from the infusion solution during the manufacturing and quality control processes. No influence on the immune system has been detected during testing. Tests revealed that Cerebrolysin does not result in the formation of antibodies or in cutaneous anaphylaxis. Cerebrolysin shows no histamine-stimulating potential and no hemagglutinating effects. Carcinogenicity: None of the studies of chronic toxicity or clinical experience have given any indication of carcinogenic effects. Mutagenicity: Cerebrolysin has shown no genotoxic or mutagenic potential, in vitro or in vivo.
MIMS Class Nootropics & Neurotonics/Neurotrophics

ATC Classification C04A - PERIPHERAL VASODILATORS ; Used as peripheral vasodilators.

Poison Schedule Presentation/Packing

Rx Infusion 215.2 mg/mL x 10 mL.

Important information. Read carefully Cerebrolysin 1ml, 5ml and 10 ml ampoules / 30ml, 50ml vials For the modern, safe and effective treatment of disturbed cerebral functions Composition Cerebrolysin is a peptide preparation. The solution, ready for injection or infusion, is free of proteins, lipids and antigenic properties. 1ml of Cerebrolysin concentrate as active ingredient in aqueous solution. Route of administration Solution for intramuscular and intravenous injection or intravenous infusion. Pharmacodynamics The efficacy of Cerebrolysin is proven in numerous animal experiments and clinical trials. Cerebrolysin is a brain-specific peptidergic nootropic drug able to affect the central nervous system in a multimodal way. This multimodal action of Cerebrolysin expresses itself as : 1) regulation and improvement of the neuronal metabolism which prevents lactacidoses in hypoxic or ischaemic episodes, 2) modulation of the synaptic plasticity which corresponds to an improvement of behaviour and learning capacity, and 3) a completely unique neurotrophic effect , including neuronal differentiation, guaranteeing full neuronal function and protection against different types of ischaemic and neurotoxin lesions . In Controlled clinical trials Cerebrolysin treatment leads to an improvement in the cognitive performance and mood of patients suffering from Alzheimers disease. Therefore, the amount of care needed by these sufferers decreases. In these patients marked improvement is observed in 61.7% of the Cerebrolysin - treated group (as assessed by the Clinical Global Impressions scale CGI ). Another clinical trial in patients with vascular dementia demonstrates enhancement of memory performance in the group receiving Cerebrolysin treatment. An improvement in the global clinical picture is also noticed in this illness. A further study involving patients from nine different disease entities established the effectiveness of Cerebrolysin through the use of 11 psychological tests subjected to a variance analysis. After stroke and craniocerebral truma treatment wit Cerebrolysin leads to an accelerated recovery. Literature on Cerebrolysin is available upon request. Pharmacokinetics cerebrolysin passes through the blood-brain barrier . Up to eight hours after iv administration of Cerebrolysin neurotophic activity can be detected in the human long-lasting effects even after a single iv administarion. Toxicological properties Cerebrolysin is generally well tolerated and possesses an extremely high margin of safety. In human therapeutic dosages this produces almost no toxic symptoms. The toxicological data are listed below. Acute toxicity: after a single iv administration of Cerebrolysin the following LD50 values were observed (14 days observation period) :male rats68ml/kg

body weight , female rats 74ml/kg body weight ; dogs, male and female >52.2ml/kg body weight. Chronic toxicity (multiple doses over six months) rats received up to 12.5ml/kg body weight daily for 26 weeks. Only moderate changes in the blood count were observed, dogs ; the highest administrated doses were 9ml/kg body weight daily for 28 days (about 10 times the human therapeutic dosage) and 4.5ml/kg body weight daily for 26 weeks (about five times the human therapeutic dosage): no systemic substance-dependent intolerance reactions were observed . Reproductive toxicity: Cerebrolysin was injected iv to the dams at the highest possible volumes: in no case was an alteration of the gestagenic period observed, in rabbits. Neither embryotoxic nor teratogenic effects nor impairments of embryonic or neonatal developments were found; no influence on the progeny (F1 and F2 generations) was evident. Influence on the fertility and reproductive performance of the parent anilmals potential, effect or carcinogenicity in toxicological tests, neither in vitro nor in vivo. Indications disturbances of concentration and memory degenerative dementias, including Alzheimers disease vascular demenatias, eg multi-infarct dementia mixed forms of dementia (degenerative and vascular contribution) sequels of stroke (ischaemic and haemorrhagic) posttraumatic or postoperative complaints, eg following cerebral contusion, concussion, or neurosurgical operation. Contraindications hypersensitivity to one of the components of the drug status epilepticus or grand mal conulsions; an increase in the seizure frequency may be seen in these cases status epilepticus or grand mal conulsions; an increase in the seizure frequency may be seen in these cases severe impairments of renal function Slide effects Cerebrolysin is generally well tolerated. If injected too fast it may cause a moderate heat sensation. In extremely rare cases a hypersensitivity reaction manifested itself as chills, headaches or as slight increase in body temperature the cause of which is probably the hyperresponiveness of the patient. In no case to date has the undesirable effect persisted or proved threatening to the patient. Warning and precautionary measures Patients with severe renal impairment must be excluded from a Cerebrolysin therapy. Animal experimental data did not show any evidence to teratogenic effects. There is no clinical experience with Cerebrolysin in women. Therefore, unless the potential benefits outweigh any potential risk. Cerebrolysin should not be administered during preguancy and the lactation period. Interactions The concomitant administration of Cerebrolysin with antidepressive drugs or MAO inhibitors can lead to cumulative effects. In these cases a dose reduction of the antidepressive drug is advisable. Dasage and administration Cerebrolysin is available in 1ml, 5ml and 10ml ampoules and vials of 30ml and 50ml. Up to 5ml per intramuscular administration, for administration over 5mlan intravenous injection or infusion is advised. Cerebrolysin can also be

given diluted in a standard iv solution (eg physiological saline solution, flingers solution, glucose 5%, dextran 40) infused slowly over approximately 20 to 60 minutes, Once daily application of Cerebrolysin for a minimum of 10 to 20 days are recommended. This constitutes a course of therapy. In mild cases 1-5ml, in severe cases 10-30ml should be applied. The length of the therapy and the individual doses on the age of the patient as well as on the disease. Usually a treatment period of three to four weeks is recommended. Therapy courses can be repeated several times in accordance with the clinical picture of the patient until no further improvement can be observed. Therapy-free intervals should be maintained between courses. In severe cases it is advisable not to interrupt treatment abruptly but to continue with one injection every other day for a period of four weeks. From the above mentioned clinical trials the following daily dosage guits can be deducted dementias 3-50ml daily, in postapplectic deficits and brain injuries 10-50ml daily. Presentation and packs Original packs with 10 ampoules of 1ml Original packs with 5 ampoules of 5ml Original packs with 5 ampoules of 10ml Original packs with 5 vials of 30ml Original packs with 5 vials of 50ml Storage Keep in a safe place out the reach of children. Store at room temperature not over 25C, away from light.