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 products 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.
Pharmacodynamics:
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)
Toxicology:
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.
Pharmacokinetics:
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)
Indications
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).
Skin graftings.
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.
Package sizes
400mg/10ml × 5
Shelf life
60 months