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Actovegin is a Deproteinized Hemoderivative of Calf Blood that is obtained by ultra-filtration. The Deproteinized Hemoderivative of Calf Blood contains only physiological components, anorganic substances socle as electrolytes and essential trace elements and 30% of organic components as amino acids, oligopeptides, nucleosides, intermediary ******** of the carbohydrate and of the fat metabolism, and components of the cellular membranes as glycosphingolipids. One of the physiologic components of Actovegin is inositol phospho-oligosaccharides ( IPOs ). These compounds are thought to possess central and peripheral insulin effects, suggesting that a therapeutic benefit could be obtained in disorders of impaired glucose utilization. The molecular weight of the organic components is below 6000 Dalton.
The active components in Actovegin promote glucose uptake by cerebral and skeletal muscle and other cells and stimulate intrinsic glucose transport by regulating glucose carrier GluT1; Actovegin? activates piruvate-dehydrogenase (PDH) and thereby leads to increased utilization of glucose by cells and formation of energy-rich substances (“insulin-like?effect). (Oberermaier-Kusser et al. 1989 Actovegin also increases uptake and utilization of oxygen by hypoxic tissues and cells (which can be proven by Warburg’s test) via promoting mitochondrial respiratory function and decreases formation of lactate, as a result, it protects hypoxic tissue. (Machicao, 1993; Kununaka et al. 1991)
Acute toxicity: Acute toxicity tests in mice (NMRI mice, male and female mixed) showed that the fifty percent lethal doses (LD50, calculated as dry weight) were as follows:
-intravenous administration: 2.31 g/kg;
-intraperitoneal administration: 2.97 g/kg;
-sucutaneous administration: 5.57 g/kg;
-oral administration: 7.93 g/kg
Subchronic toxicity: Experiments performed in rabbits (Deutsche Riesenschecken rabbits, female) demonstrated that there was no evidence of either macroscopic or microscopic organic pathological changes as compared to normal control animals after infusing 20% Actovegin? intravenously once a day at a dose of 7.0 ml/kg, 7 days a week, for 3 months. Actovegin? has no toxicity on fertility, embryo and fetus; it has no teratogenic, mutagenic, or carcinogenic effects.
Actovegin is a calf-blood derived hemodialysate. Since it is not a single-component drug, conducting a pharmacokinetic study is impossible. However, for its bioavailability, certain pharmacological studies in animals may provide some reference: glucose tolerance studies in rats showed that blood glucose level started to decline as early as at 5 minutes after intravenous administration of Actovegin , and the effect reached its peak at 180 minutes after administration. (Bachmann et al. 1968) improved at 15 minutes after parenteral administration of Actovegin . (Quadbeck et al. 1964)
Disturbances in the cerebral circulation and nutrition (ischemic insultus, cranio-cerebral traumas).
Disturbances of peripheral (arterial, venous) blood flow and sequels resulting from these disturbances (arterial angiopathy, ulcus cruris).
Burns, scalds, erosions.
Wound-healing impairment: torpid wounds, decubitus;
Radiation-induced skin and mucous membrane lesions (prophylaxis and therapy).
Mode of action
Actovegin produces an organ-unrelated increase of the cellular energy metabolism. The activity is confirmed by measurement of the increased uptake and of the elevated utilization of glucose and oxygen. These two effects are coupled and they result in a rise of the ATP-turnover and thus in a greater provision of energy in the cell. In deficiency states with impairment of the normal functions of the energy metabolism (hypoxia, substrate deficiency) and in states of increased energy requirement (reparation, regeneration) Actovegin promotes the energy-dependent processes of the functional metabolism and of the conservation metabolism. An increase of the blood supply is seen as a secondary effect
Effects related to therapeutic indication:
Effects related to glucose transport
-The IPO fraction of Actovegin demonstrated a positive effect on glucose carrier activity( GLUT1) in the plasma membrane
-Actovegin stimulated glucose uptake in cerebral tissues, as well as other isolated animal tissues
Effects related to glucose utillization
-The IPO fraction of Actovegin activated glucose oxidation as well as the PHD complex
-The IPO fraction of Actovegin acts indirectly on the citric acid cycle by causing increased formation of acetyl COA
Effects related to oxygen uptake on energy metabolism
-Actovegin increased the respiratory capacity of mitochondria
-Actovegin improved oxygen uptake in Anesthetized dogs
-Actovegin demonstrated a positive effect on cerebral metabolism of rats under conditions of Hypoxia
Safety of Actovegin
The manufacturer Nycomed Austria GmbH confirms that all measures are in place to guarantee the TSE safety of Actovegin. According to the actual guideline EMEA/410/01 final (issued in February 2001, replacing CPMP/BWP/1230 REV.1) and the Final Opinion of the Scientific Steering Committee on the geographical BSE risk (issued in July 200) the safety of a medicinal product is determined by several important factors:
1. Animals as source of material: the most satisfactory source of materials is from countries which are free of BSE and have appropriate surveillance systems. Materials may be used from countries with a low BSE incidence. The calf blood used as raw material for Actovegin derives from calves born, raised and slaughtered in Australia. Australia is officially categorised as BSE ? and Scrapie free country by the OIE (World Organization for Animal Health) and the SSC (Scientific Steering Committee of the European Union). Surveillance systems are in place.
2. Parts of animal bodies and body fluids used as starting materials: tissues and body fluids are categorised in four categories (from category I = high infectivity like brain to category IV= safest category, no detectable infectivity like blood and milk). Actovegin is manufactured from calf blood, blood is in the safest tissue category IV.
3. Age of animals: the sourcing from young animals is seen as very important safety factor. The blood used as raw material for Actovegin production derives from calves below six months of age. The calves were never fed animal carcasses fodder and are declared fit for human consumption, as all proven by veterinary certificates. Moreover the traceability of every Actovegin batch back to the individual calves as blood donors is ensured. The mother cows (dams) of the calves are also known.
4. A production process should be designed which is thought to remove or inactivate TSE agents. Validation studies are currently not generally required. The manufacturing process of Actovegin is BSE validated, thus proven to be capable of removing hypothetically present TSE agents.
5. A risk analysis was performed according to the PhPMA system showing that Actovegin is absolutely BSE safe. Moreover Actovegin is a natural drug with proven efficacy and also a general favourable safety profile over decades. These benefits cannot be substituted by a chemical drug. In conclusion, Actovegin is BSE safe and fullfills even more safety measures than required by actual guidelines.