Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-06-22
2003-06-17
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S053000, C514S169000, C514S027000, C424S195110, C536S004100
Reexamination Certificate
active
06579853
ABSTRACT:
TECHNICAL FIELD
The present invention relates to ginsenoside Rb
1
or its salt useful as cell-protective (cytoprotective) agents. More particularly, the present invention pertains to pharmaceutical compositions comprising ginsenoside Rb
1
or its salt for inhibiting apoptosis or apoptosis-like cell death or pharmaceutical compositions comprising ginsenoside Rb
1
or its salt for promoting the expression of a cell death-inhibitory or antiapoptotic gene product Bcl-x
L
. More further particularly, the present invention pertains to pharmaceutical compositions comprising ginsenoside Rb
1
or its salt for intravenous administration.
BACKGROUND ART
Originally, methods for treatment of cerebral apoplexy (cerebral vascular diseases) are different among cerebral infarction, cerebral embolism, cerebral hemorrhage, transient ischemic attack and subarachnoid hemorrhage, and strictly, no effective countermeasure can be taken unless a cerebral CT inspection is performed. For example, thrombolytic agents can be used only for the treatment of cerebral infarction and cerebral embolism and are regarded as a contraindication for the treatment of cerebral hemorrhage. However, cerebral apoplexy is a serious disease resulting in a permanent disorder of higher functional activities or threatening the survival of patients, if no treatment is performed for protecting nerve cells or neurons at risk in the lesion site as early as possible. Consequently the treatment should be initiated without a moment's delay. Even the period of time for the CT inspection of brain is, to put it strongly, a factor to make the possibility of recovery smaller for the patients with cerebral apoplexy. Surely, the treatment of acute cerebral apoplexy is a struggle against not only cerebral apoplectic lesion but also a time after its onset. Quite unfortunately, at present, whatever the disease type of cerebral apoplexy (cerebral infarction, cerebral hemorrhage, cerebral embolism, subarachnoidal hemorrhage and transient ischemic attack) is, it is the actual condition that few drugs showing a potent effect, if administered immediately after the onset of cerebral apoplexy, are known.
Ginsenoside Rb
1
is a compound having the following chemical structure:
Ginsenoside Rb
1
is a known compound with references, for example, by Shibata et al. (Shibata et al., Economic and medicinal plant research, World Scientific, Philadelphia, pp. 217-284, 1985).
Intraperitoneal administraction of ginsenoside Rb
1
has been reported to show a tranquilizing action on the brain (Yoshimura H. et al., Eur. J. Pharmacol., 146, 291-197, 1988), but no mechanism of the action has been elucidated. In the central nervous system, the possibility has been raised that a mixture of ginsenoside Rb
1
and ginsenoside Rg
1
(or ginsenoside Rb
1
or ginsenoside Rg
1
at the extracellular concentration from 10
−6
M to 10
−7
M) shows some effect for Alzheimer's disease as a result of activating acetylcholine-containing nerve cells (U.S. Pat. No. 5,137,878: Composition and method for treatment of senile dementia). However, since it can not be said that the main cause of Alzheimer's disease is a functional disturbance of acetylcholine-containing nerve cells, this hypothesis has many problems to be solved.
In addition, the nerve cell-protective or neuroprotective action by a single use of ginsenoside Rb
1
has scarcely been elucidated until the studies on ginsenoside Rb
1
was initiated by us. We have studied until now to show a protective action of ginsenoside Rb
1
for the cells other than acetylcholine-containing nerve cells using the transient forebrain ischemia model of gerbils. It has been proved that in this forebrain ischemia model animal, occlusion of the bilateral common carotid arteries for 3 to 5 minutes while maintaining the brain temperature at 37° C. results in a neuronal loss of the hippocampal CA1 pyramidal cells (containing no acetylcholine) within one week after ischemia depending on the occlusion time (this event is called delayed neuronal death), and that the learning behavioral function of the ischemic animals is deteriorated (Wen T. -C. et al., Acta Neuropathol., 91, 15-22, 1996). These facts mean that the transient forebrain ischemia model of gerbils reflects the human pathologic condition of transient ischemic attack (TIA).
We have proved that administering ginsenoside Rb
1
(10 mg/kg or 20 mg/kg) into the peritoneal cavity of gerbil once a day for one week in advance can significantly prevent delayed neuronal death and learning disability caused by occlusion of the common carotid arteries for 5 minutes (Wen T. -C. et al., Acta Neuropathol., 91, 15-22, 1996). However, intraperitoneal administration of ginsenoside Rb
1
immediately after 3- or 5-minute occlusion of the common carotid arteries showed no effect (Wen T. -C. et al., Acta Neuropathol., 91, 15-22, 1996; Lim J. -H. et al., Neurosci. Res., 28, 191-200, 1997). Consequently, since transition rate and transportation rate to -brain of peripherally (intraperitoneally) administered ginsenoside Rb
1
are thought to be very low, no clinical application of ginsenoside Rb
1
was kept in mind at that stage in view of the protection of hippocampal CA1 pyramidal neurons.
It has been reported that intracerebroventricular infusion of ginsenoside Rb
1
starting immediately after occlusion of the common carotid arteries for 3 or 3.5 minutes in place of the above peripheral (intraperitoneal) administration suppresses the delayed neuronal death and learning disability (Lim J. -H. et al., Neurosci. Res., 28, 191-200, 1997). Further, in spontaneous hypertensive stroke-prone (SH-SP) rats with permanent occlusion of the cortical branch of the left middle cerebral artery (MCA) (cerebral infarction model of rats), intracerebroventricular infusion of ginsenoside Rb
1
starting immediately after permanent occlusion of the MCA caused a significant reduction of the infarcted area in the cerebral cortex and ameliorated the ischemia-induced place navigation disability of the animals (Zhang B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998).
Even though ginsenoside Rb
1
is effective in the direct intracerebroventricular infusion, however, it appears impossible to apply ginsenoside Rb
1
to human transient cerebral ischemic attack (TIA) and cerebral infarction due to the problems in the route of administration, similarly to other peptide growth factors (Sakanaka M. et al., Proc. Natl. Acad. Sci. USA, 95, 4635-4640, 1998; Wen T. -C. et al., J. Exp. Med., 188, 635-649, 1998).
Concerning the mechanism of neuroprotective action by peripheral (intraperitoneal) administration of ginsenoside Rb
1
, we have reported that a culture medium previously admixed with a low concentration (1-100 fg/ml) of ginsenoside Rb
1
reduces neuronal necrosis caused by a hydroxyl radical inducer (ferrous sulfate) (Lim J. -H. et al., Neurosci. Res., 28, 191-200, 1997; Zhang B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998). We have presumed that ginsenoside Rb
1
decreases cell membrane lipid peroxides as a result of scavenging hydroxyl radicals to protect cultured nerve cells, but up to now no one proved this hypothesis.
Several reports concerning the neuroprotective effect of ginsenoside Rb
1
have been made in culture experiments. For example, high concentrations (0.11-11 &mgr;g/ml) of ginsenoside Rb
1
reduce glutamate-mediated neurotoxicity to prevent neuronal cell death (Kim Y. -C., et al., J. Neurosci. Res., 53, 426-432, 1998), and a higher concentration, approximately 500 &mgr;M (550 &mgr;g/ml) of ginsenoside Rb
1
has a possibility to prevent apoptosis-like nerve cell death (Tanaka T. et al., The Ginseng Review, 24, 61-65, 1998). However, according to the results of our culture experiments, high concentrations of ginsenoside Rb
1
has shown an increased neurotoxicity (Lim J. -H. et al., Neurosci. Res., 28, 191-200, 1997; Zhang B. et al., J. Stroke Cerebrovasc. Dis., 7, 1-9, 1998).
Furthermore, such high concentrations of ginsenoside Rb
1
can not be realized in an extracellular fluid in vivo, and we s
Sakanaka Masahiro
Sato Kohji
Tanaka Junya
Alexander John B.
Barts Samuel
Corless Peter F.
Edwards & Angell LLP
Japan Science and Technology Corporation
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