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Incarvillea Sinensis

(a new way to the role of non-morphine-free into a hidden analgesics)

 An agent comprising or other monoterpene alkaloid extracted from Incarvillea  Lam. as an effective component shows an and anti-inflammatory action (first phase) similar to those give by the conventional narcotic such as morphine, etc. and consequently also shows an analgetic and anti-inflammatory action (second phase) as given by the ordinary analgetics such as aspirin, etc. and also shows a distinguished analgetic and anti-inflammatory action not only on headache, stomachache, neuralgia, etc., but also on cancer pain.


The highly substituted 1,3-dicarboxy-cyclobutane Incarvillateine occurs in the plant Incarvillea .
 The name of the genus, Incarvillea, came from the botanist Petrus d'Incarville who lived in Peking from 1740 to 1757. The plant is distributed from Yunnan in the south to Siberia in the north and Tibet in the West.
Incarvillea also contains the macrocyclic spermine alkaloids C and Verballocine, the monoterpene alkaloids Incarvilline, and Methoxycarvillateine and the flavonoid Isoliquiritin. It is one of the traditional herbal medicines in China, and Mongolia and is mainly used to treat rheumatism and relieve pain. Besides it is for detoxification, against , as , , cramps, eczemas, inflammations in the mouth, carbuncle, skin ailments, spongy gums, ulcers and wounds in medicine.
And against chronic bronchitis, dry cough, lung abscess, otitis media, disease, flatulence and dry in medicine.
The analgesic index (ED50) of Incarvillateine is better than Morphine (1,06-1,33 times) and appears to have a lower ceiling effect than Morphine!
Responsible for the analgesic properties is an agonistic action on mu-and kappa-opioid- receptors and an antagonistic on adenosine-receptors:

Incarvillea acts on the same receptors as many of the best-known pain medications

Since 1990, a new class of monoterpene alkaloids  have been isolated and identified by Chi and co-workers from the plant Incarvilla sinensis, which has been used in treating rheumatism and relieving pain in Traditional Chinese Medicine (TCM) (Figure 1).1 Incarvillateine 1, one of the novel monoterpene alkaloids, has been found to exhibit more potent antinociceptive activity comparable to that of morphine in a formalin-induced pain model in mice. The mechanism of action was also regarded to be different from that of morphine.2 So, incarvillateine has potential to become an important lead compound for developing new nonopioid analgesic drugs. The structural characteristics of 1 include a unique dimeric structure, and five contiguous stereocenters on the bicyclic piperidine moiety. The unique structural features and interesting biological profile of 1 make it an attractive target for total synthesis.3 Kibayashi’s and Ellman’s groups have achieved its total synthesis.

DESCRIPTION
The present invention relates to an analgetic agent and more particularly an analgetic agent comprising a plant extract as an effective component.

2. DESCRIPTION OF RELATED ART
It is an important nursing task to cure various diseases accompanying intolerable pains, particularly cancer pain accompanied by cancer. Causes the cancer pain include tumor proper, side effects of cancer-curing agents, psychologic pain, etc., to which a Brompton cocktail and WHO prescription are applied.
According to these prescriptions, administration starts from a small dose, which is gradually increased until pain can be substantially completely released, where morphine is used as a basic drug. Continuous administration of such a drug leads to formation of a drug resistance, resulting in formation of considerable mental and physical dependency thereon. Once such a chronic intoxication is formed, abrupt abstinence symptoms appear upon interruption of the administration, resulting in recurrence of pain and deterioration of mental and physical functions such as anxiety, phobias, insomnia, etc. Even if the drug is administered again in the same dose as the last one, no satisfactory effect can be obtained.
Many compounds showing an analgetic and anti-inflammatory action on cancer pain have been so for reported. Particularly popular crude drug showing an analgetic and anti-inflammatory action is opium poppy (
Papaver ). Though the opium poppy has good analgetic, antispastic, antitussive and constipating actions, it is designated as narcotic due to its strong dependency. Main components of opium extracted from the opium poppy are morphine-based opium alkaloids and morphine derivatives, and various side effects inevitably appear due to their nature in of continuous administration thereof, as mentioned above.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an analgetic agent without any substantial side effects, which comprises a plant extract as an effective component.
Incarvillea
. is a plant of trumpet creeper family (Bignoniaceae), which is considered to have a cold or rheumatism-curing action and also have an antidotal action, and is used as a folk medicine in China. In the present invention, extraction is made of its whole plant, but it has not been so far known at all that its extract has an analgetic and anti-inflammary action.
Extraction of the whole plant of Incarvillea sinensis
. can be made from crude plants or dried and pulverized plants, using an organic solvent or water including hot water. A combination of an organic solvent and water may be used, when required. Organic solvents for extraction includes, for example, methanol, ethanol, n-butanol, ethyl acetate, chloroform, etc., among which methanol and ethanol are preferable. Extraction with these extracting solvents can be carried out at a temperature ranging from room temperature to reflux temperature.
Among these extracts, a component having a particularly remarkable analgetic and anti-infammatory action is a 60% methanol eluate fraction (Sample 6 as will be described later) of methanol extracts by polystyrene-based column chromatography, and incarvillateine is isolated from the eluate fraction as a compound having a good analgtetic and anti-inflammatory action. It is well known that incarvillateine itself is a compound isolated from 95% ethanol extract of Incarvillea sinensis
., but it is the present inventors that have found for the first time that the compound has a distinguished analgetic and anti-inflammatory action.
The analgetic and anti-inflammatory action can be observed among other monoterpene alkaloids extracted from Incarvillea sinensis
., together with . Such monoterpene alkaloids include the following compounds:

  • Incarvilline
  • Oxyincarvilline
  • Incarvine A or its N-oxide
  • Incarvine B
  • Incarvine C
  • Incarvine D
  • Incarvillateine N-oxide
  • 3''-methoxyincarvillateine

Incarvillateine and its derivatives are represented by the following chemical formula:

where R=H provides and R=OMe provides 3''-.
Organic solvent extracts or water extracts of Incarvillea Lam
., particularly organic solvent extracts of Incarvillea Lam
. containing , other monoterpene alkaloids or these compounds together can be formulated in the form of powder, granules, tablets, sugar-coated tablets, capsules, liquid preparation, etc. and can be administered orally, parenterally, by inhalation, transrectally, locally, etc. Parenteral administration includes, for example, subcutaneous injection, intravenous injection, intramuscular administration, nasal administration or infusion, etc. Dose is usually in a range of about 0.1 to about 200 mg/kg of body weight per administration. Exact dose is selected from the above-mentioned range usually in view of age, body weight, of patients, administration route, etc., and administration is carried out 1 to 5 times in a day. Their toxicity is low, and investigation on wistar male rats for acute toxicity by oral admininistration showed no case of death even at a dose of 3,000 mg/kg(p.o.).
The present invention provides an analgetic agent comprising or other monoterpene alkaloids extracted from Incarvillea

. as an effective component. The above-mentioned plants are used originally as a folk medicine and thus has no fear of chronic intoxication. Furthermore, the analgetic and anti-inflammatory action given by the present analgetic agent is a similar action (first phase) to the analgetic and anti-inflammatory action given by the conventional narcotic analgetic such as morphine, etc. and consequently is also an analgetic and anti-inflammatory action (second phase) given by the ordinary analgetic such as aspirin, etc. Thus, the present analgetic agent has a distinguished analgetic and anti-inflammatory action not only on headache, stomachache, neuralgia, etc. but also on cancer pain.



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