JP3999487B2 - Stress-induced diarrhea treatment agent and multi-type diarrhea treatment agent - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a therapeutic agent for stress-induced diarrhea (hereinafter also simply referred to as “stress diarrhea”) and a therapeutic agent for multi-type diarrhea, and more specifically, not only diarrhea caused by infection with pathogenic microorganisms, but also other than that Of diarrhea that can alleviate or eliminate the symptoms of stress diarrhea (stress-induced diarrhea), for example, creosote or guaiacol, 4-ethylguaiacol, cresol, orthocresol, paracresol, etc. Cresols, creosote components such as phenol derivatives such as phenol and xylenol, or a mixture containing two or more of these as active ingredients (hereinafter also referred to as “creosote or its component”) Therapeutic agents and multi-type diarrhea treatment On.
[0002]
[Prior art and problems to be solved by the invention]
Traditionally, creosote has been used as an alleviating symptom for so-called “per meal, per water”, a therapeutic agent, ie, an enteric bactericidal agent or an antidiarrheal agent based on intestinal disinfection.
[0003]
That is, creosote is listed as a bactericidal agent in the category of antidiarrheal drugs in column V in the gastrointestinal drug production approval standards of the 240th page of the 1988 edition of the Pharmaceutical Manufacturing Guidelines (edited by the Japan Standards Association). In addition, Hiroshi Ito's “Pharmacology” (Korodo Co., Ltd., published on January 5, 1983, 6th edition), page 416 also states that creosote is used for intestinal preservation. The Japanese Pharmacopoeia also describes that it is used for intestinal abnormal fermentation, food poisoning and the like. In addition, The United States Dispensatory, 27th ed. (1973), page 355, also states that creosote is used as a bactericide.
[0004]
As described above, the present inventor has studied the pharmacological action of cleosote in order to find a new use of intestinal fungicide, antipruritic drug based on intestinal fungicide, or creosote that has been used as a fungicide. The fact that the sort and its constituents have a pharmacological action that is not expected from the conventional knowledge, such as alleviating or eliminating the symptoms of “stress diarrhea” which is a non-pathogenic disease, has been found, and the present invention Was completed based on this finding.
[0005]
Stress diarrhea is not an infectious diarrhea caused by infection with pathogenic microorganisms (for example, bacteria, viruses or molds), but stress given physically or mentally. Is a type of diarrhea caused by a stressor such as noise or cold, trauma, radiation, side effects of drugs, nutritional deficiencies, hypoxia, relationships, anxiety, or tension. The conventional effect of creosote and its constituent components on diarrhea is due to the “effect as a bactericidal agent” as described above. Therefore, it is not necessary to rely on the bactericidal action as in the present invention. With respect to showing a remarkable effect on stress diarrhea, it cannot be explained from the original mechanism of action, and therefore the action and effect of the present invention (the action and effect showing the effectiveness against stress). Must be said to be unpredictable.
[0006]
In addition, diarrhea prevention (a therapeutic agent for diarrhea) that forcibly suppresses intestinal movement, such as loperamide and codeine phosphate, has no effect on the type of stress diarrhea caused by stressors. Furthermore, although antibacterial agents such as fosfomycin have been used for the purpose of alleviating and eliminating the symptoms of infectious diarrhea, they were not effective for stress diarrhea, like loperamide and codeine phosphate.
[0007]
Although diarrhea causes a patient's physical strength to decline quickly, there is not enough time to find out if the symptoms are due to infection with pathogenic microorganisms or non-infection. Anyway, it is necessary to alleviate the symptoms promptly and eliminate any type of diarrhea caused by infection with pathogenic microorganisms and non-infectious types such as stress diarrhea. The appearance of multi-type diarrhea treatment agents that can alleviate or eliminate both diarrhea symptoms has been awaited from the field.
[0008]
In JP-A-8-48635, dead cells of Gram-negative bacteria (such as Salmonella typhi, Salmonella, Shigella and Vibrio cholerae) are used for the prevention or treatment of diarrhea (stress diarrhea) caused by non-infection. It is disclosed that it is effective.
[0009]
However, there is a risk in handling when preparing dead cells by inactivating live cells, and the dead cells of this Gram-negative bacteria are used for the prevention and treatment of diarrhea caused by infection. Multi-type that has no effect and can alleviate and eliminate both diarrhea caused by infection with pathogenic microorganisms and non-infectious diarrhea such as stress diarrhea as described above The emergence of antidiarrheal agents was awaited.
[0010]
Further, in JP-A-6-145152, there is a description that a benzimidazole derivative represented by a specific chemical formula is effective for stress-induced diarrhea and serotonin-induced diarrhea based on 5-HT ₃ receptor antagonism. is there.
[0011]
However, in this respect as well, the benzimidazole derivative is effective against stress diarrhea as described above, but is not effective in preventing or treating diarrhea caused by infectious diseases. I couldn't.
[0012]
[Means for Solving the Problems]
The therapeutic agent for stress-induced diarrhea of the present invention comprises wood creosote .
[0013]
The multi-type diarrhea treatment agent of the present invention is a multi-type agent that can alleviate or eliminate both diarrhea caused by infection with pathogenic microorganisms and non-infectious diarrhea such as stress diarrhea. This type of diarrhea treatment agent consists of wood creosote .
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Creosote (wood creosote, wood creosote)
Creosote itself is conventionally known and contains cresols such as guaiacol, 4-ethylguaiacol, cresol, ortho-cresol, para-cresol, and phenol derivatives such as phenol and xylenol. Creosote is listed in the Japanese Pharmacopoeia (13th revision), the US National Formulary XII, and the like. The creosote is a so-called wood creosote obtained by distilling wood tar obtained from trees such as beech, oak, maple, pine, etc., especially hardwood, and collecting fractions of about 200-230 ° C. (760 mmHg) by fractional distillation. (Wood creosote), which is clearly distinguished from creosote obtained from coal tar (Norio Ogata, Tatsuya Baba, Research Communications in Chemical Pathology and Pharmacology, 66, pp. 411-423) 1989 (N. Ogata and T. Baba, Res. Commun. Chem. Pathol. Pharmacol. 66, 411423, 1989)). As described in the above documents and the like, creosote, which is an active ingredient of the drug of the present invention, includes guaiacol (about 20 to 35%) and cresol (about 15 to 25%) as well as phenol as described above. It is a mixture containing various phenol derivatives such as cresols and xylenols, and is a colorless to pale yellow liquid having a characteristic smoke odor and taste that burns the tongue, and has a specific gravity of 1.064 or more.
[0015]
Form and other (additives, etc.)
In the present invention, the creosote or a component thereof is used in the form of a general pharmaceutical preparation. That is, it is prepared according to a conventional method using excipients or diluents that are pharmaceutically acceptable and usually used, and can be in various forms depending on the therapeutic purpose. As typical examples, dosage forms suitable for oral administration such as tablets, pills, powders, capsules, granules, liquids for internal use, intravascular administration such as injections, intramuscular administration, subcutaneous or intradermal administration And a dosage form suitable for rectal administration such as a suppository.
[0016]
In preparing tablets, granules, powders, conventionally known carriers can be widely used. For example, excipients such as lactose, sucrose, glucose, starch, crystalline cellulose, such as hydroxypropylcellulose, methylcellulose, Binders such as gelatin, tragacanth, gum arabic, and sodium alginate, for example, disintegrating agents such as starch, carboxymethylcellulose, and calcium carbonate, and lubricants such as magnesium stearate, talc, and stearic acid can be used. If necessary, the tablet can be given a normal coating, for example, a sugar-coated tablet, a film-coated tablet, or the like, and may be a bilayer tablet or a multilayer tablet. Granules and powders can also be given a normal coating.
[0017]
To prepare in the form of pills, various carriers conventionally known in this field can also be used, for example, excipients such as licorice powder, glucose, flour, such as glycerin, water syrup, gum arabic, Binders such as tragacanth and gelatin, disintegrants such as medicinal yeast, arrow root and laminaria powder are used.
[0018]
For preparation in the form of capsules, various carriers conventionally known in this field, for example, excipients such as lactose, olive oil and soybean oil are used.
[0019]
The internal solution may be in the form of an aqueous or oily suspension, solution, syrup, or other form. For such liquid preparations, commonly used additives such as suspending agents such as sorbit syrup, methylcellulose, gelatin, carboxymethylcellulose, emulsifiers such as lecithin, sorbitan monoolefinate, gum arabic and the like are used. it can.
[0020]
For preparation in an injectable form, the composition may be in the form of a suspension, solution, emulsion in an oily or aqueous vehicle, such as a suspending, stabilizing and dispersing agent. Various prescription agents.
[0021]
Conventionally known carriers can be widely used for preparing suppositories. For example, bases such as cacao butter, glycero gelatin, and macrogol can be used. For suppositories, emulsifiers and suspending agents can be used as necessary. Furthermore, a coloring agent, a flavoring agent, etc. can also be added to the chemical | medical agent of this invention as needed.
[0022]
The amount of creosote or its constituents contained as an active ingredient in the drug of the present invention is not particularly limited, and may be appropriately selected according to the form of the preparation, etc., but generally 0.2% of the total weight of the preparation. About 60% is preferable.
[0023]
The dosage of the therapeutic agent for stress diarrhea (creosote or a component thereof) of the present invention is appropriately selected depending on the sex, age, weight, degree of symptoms, etc. of the patient. For adults, the active ingredient creosote or its constituents may be about 1 to 500 mg, preferably about 2 to 100 mg, more preferably about 2 to 25 mg per kg of body weight per day. When administered parenterally as an injection, it is also about 0.2 to 300 mg, preferably about 0.2 to 50 mg of creosote or its component as an active ingredient for 1 kg of body weight per day for adults. More preferably, it may be about 0.5 to 5 mg. These may be divided into 2 to 4 times a day.
[0024]
【Example】
One embodiment of the present invention will be described below.
[0025]
1. Rat acclimatization Two male Wistar-Kyoto (270-330 g) rats were placed in a case and raised at 21 ° C. with a 12 hour light / dark cycle and fed with standard food and water. To avoid unnecessary stress, the same experimenter handled and acclimated the rat for 10 minutes daily. All rats used in the experiment were transferred to a fasting cage and fasted for 15 hours before the start of the experiment.
[0026]
2. Cold restraint stress ( CRS )
The rat was fixed with a restraint device and placed in a 2-7 ° C. refrigerated room for 2 hours, after which the restraint device was removed and returned to a fasting cage and left at 22 ° C. for 2 hours (CRS rat). In order to minimize the influence of circadian rhythm, the experiment was started between 8 and 10 o'clock. Non-CRS control rats were left in a fasting cage for 4 hours at 22 ° C. (see FIG. 1).
[0027]
3. Ushing chamber experiment CRS rats or non-CSR control rats were anesthetized with isoflurane, then decapitated and euthanized. The jejunum or colon was excised and immersed in Krepes buffer chilled in ice, at which time it was bubbled with 5% CO ₂ / O ₂ . After digesting the digestive tract to an appropriate size, the muscle layer is peeled off, attached to a Wushing chamber (World Precision Instruments), Krebs buffer solution is placed in the chamber, heated to 37 ° C., and 5% CO ₂ / O. ₂ was bubbled. A short-circuit current (Isc) was measured as an index of ion secretion from the serosal side of the gastrointestinal epithelial cells to the mucosal side (see FIG. 1).
[0028]
(result)
CRS increased rat jejunum and colonic lsc compared to non-CRS control rats. This indicates that CRS enhances ion secretion in the jejunum and colon (see FIGS. 2 and 3).
[0029]
4). Creosote cumulative addition Creosote was cumulatively added to a Wushing chamber equipped with a digestive tract extracted from a CRS-treated rat (see FIG. 4).
[0030]
(result)
Creosote added cumulatively directly to the mucosal or serosal side of the jejunum or colon removed from CRS-treated rats was reduced to a level almost as high as lsc of non-CRS control rats. This has shown that creosote suppresses the ion secretion enhancement by CRS (refer FIGS. 5-10).
[0031]
5. Creosote was orally administered at a dose of 15 mg / kg 30 minutes before and immediately after CRS. As a control, physiological saline was orally administered (see FIG. 11).
[0032]
(result)
The jejunum or colon lsc removed from rats treated orally with creosote and treated with CRS was lower than that of the jejunum or colon in rats orally administered with saline. This indicates that creosote administered orally suppresses enhanced ion secretion by CRS (see FIG. 12).
[0033]
Components of creosote As described above, creosote also suppressed the symptoms of stress diarrhea, but this action is due to 4-ethyl guaiacol, orthocresol, and the components of creosote, It has also been confirmed with phenol.
[0034]
【The invention's effect】
INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a multi-type diarrhea therapeutic agent that can alleviate or eliminate both diarrhea caused by pathogenic microorganism infection and non-infectious diarrhea such as stress diarrhea.
[Brief description of the drawings]
FIG. 1 is an explanatory diagram of an experimental design of a Ushing chamber experiment.
FIG. 2 is a graph showing the results of the experiment shown in the explanatory diagram of FIG. 1, showing the change over time in the short-circuit current in the jejunum of control and stress rats.
FIG. 3 is a graph showing the results of the experiment shown in the explanatory diagram of FIG. 1 and showing the change in short-circuit current with time in the colons of control and stress rats.
FIG. 4 is an explanatory diagram of an experimental design of a creosote cumulative addition experiment.
FIG. 5 is a graph showing the effect (jejunum) of the creosote added to the mucosa side on the stress-induced short-circuit current as a result of the experiment shown in the explanatory diagram of FIG. 4;
6 is a graph showing the effect (colon) on the stress-induced short-circuit current of creosote added to the mucosal side, as a result of the experiment shown in the explanatory diagram of FIG. 4. FIG.
7 is a graph showing the results (jejunum) of the results of the experiment shown in the explanatory diagram of FIG. 4 and the effect of creosote added to the serosa side on the stress-induced short-circuit current. FIG.
8 is a graph showing the results of the experiment shown in the explanatory diagram of FIG. 4 and the effect of the creosote added to the serosa side on the stress-induced short-circuit current (colon). FIG.
FIG. 9 is a table showing the results of the experiment shown in the explanatory diagram of FIG. 4 and the short-circuit currents of the jejunum and colon subjected to creosote treatment.
FIG. 10 is a table showing the 50% inhibitory concentration of creosote in vitro as a result of the experiment shown in the explanatory diagram of FIG.
FIG. 11 is an explanatory diagram of an experimental design of a creosote oral administration experiment.
FIG. 12 is a graph showing the effect of oral creosote on stress-induced short-circuit current (jejunum, colon) as a result of the experiment shown in the explanatory diagram of FIG. 11;

Claims (2)

A therapeutic agent for stress-induced diarrhea, characterized by comprising wood creosote . And symptoms of diarrhea infection of pathogenic microorganisms is caused due to a multi-type diarrhea therapeutic agents capable of both the relaxation or elimination of the symptoms of diarrhea uninfected type as stress diarrhea, wood Cleo Multi-type diarrhea treatment agent characterized by comprising sort .

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