Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-04-19
1998-01-27
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31415
Patent
active
057123012
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/F194/00371 filed Aug. 24, 1994.
This invention relates to prevention of neurodegeneration induced by ethanol consumption.
Ethanol exposure causes degeneration of the nervous system. Neurodegeneration occurs during ethanol exposure and continues even long after cessation of ethanol intake (Cadete-Liete et al. Neurosci Lett 86: 45-50, 1988). Neuropathological changes induced by ethanol consumption are associated with the impairment of neuronal functions e.g. cognitive dysfunctions. To our knowledge no succesfull intervention to prevent loss of normal neuronal structure and functional activity due to alcohol exposure has been reported before.
Dexmedetomidine (dextro-4-{1(2,3-dimethylphenyl)ethyl}-1H-imidazole) is a relatively new, selective and potent .alpha.2-adrenoreceptor agonist, which has been disclosed in European patent no. 300652. EP 331374 and EP 424059 disclose dexmedetomidine in perioperative and epidural use, respectively. EP 413487 discloses transdermal delivery of dexmedetomidine and EP 437030 discloses the use of dexmedetomidine in glaucoma.
We have now found that dexmedetomidine is also effective in preventing ethanol-induced neurodegeneration. Thus the present invention provides dexmedetomidine or a pharmaceutically acceptable acid addition salt thereof for use in the prevention of neurodegeneration induced by ethanol consumption, and for use in the manufacture of a pharmaceutical preparation for the prevention of neurodegeneration induced by ethanol consumption.
Dexmedetomidine or a pharmaceutically acceptable acid addition salt thereof is administered before and/or during and/or after the ethanol consumption. One example of the use of the present invention is administration of dexmedetomidine during and after ethanol intoxication. Use of the present invention is not, however, limited to this particular case. The drug is preferably administered perorally, transmucosally, intravenously, intramuscularly or transdermally. The preferable daily dose is 0.1-5.0 .mu.g/kg i.v. or 5-50 .mu.g/kg per os.
EXPERIMENTAL
Rats to which ethanol is given show neuropathological changes in the peripheral symphathetic neurons of the superior cervical ganglion. A loss of neurotransmitter synthetic capacity (reflected by tyrosine hydroxylase immunoreactivity, TH-IR) was observed in several neurons of the ethanol-exposed rats, while another population of neurons showed signs of abnormally high catecholamine turnover. When given perorally during ethanol exposure, dexmedetomidine significantly reduced these changes. The ethanol+dexmedetomide treated ganglia exhibited homogenous TH-IR and catecholamine fluorescence intensities, comparable to those seen in the control ganglia. Dexmedetomidine also inhibited the occurence of vacuolated neurons, which are considered to be an indication of neuronal degeneration. These results indicate that dexmedetomidine has a neuroprotective role in ethanol exposure.
PROCEDURES
Fifteen 4-month old male Wistar rats were used in the study. The rats were housed individually under standard conditions (+21.degree..+-.1.degree. C., lights on between 8 am and 9 pm) and were carefully habituated to handling before the experiment was started.
Dexmedetomidine hydrochloride (Orion Corporation FARMOS, Batch no. ST0531) was dissolved in distilled water, 100 .mu.g/ml, and was given to the treatment group (EtOH+dex) through an intragastric feeding tube with ethanol feed twice a day. Dexmedetomidine volume was 1 ml/kg.
The rats were divided into three groups (five animals in each group): one receiving ethanol (EtOH), one ethanol and dexmedetomidine (EtOH+dex) and one isocaloric sucrose (control). To ensure a high and accurate dosage of ethanol, intragastric intubation of 25% ethanol+5% sucrose was used three times a day (8 am, 2 pm, 8 pm). The daily dose of ethanol was gradually increased to 10 g/kg as absolute alcohol. The duration of the ethanol exposure was 10 days. To avoid deaths during the course of the experiment, severely intoxicated animals were given reduced doses o
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Heinonen Esa Henrik
Hervonen Antti Lauri Juhani
Jaatinen Pia Helena
Nieminen Lauri Sakari
Henley III Raymond
Orion-yhtyma Oy
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