CN108030780A - The application of 4-PBA - Google Patents
The application of 4-PBA Download PDFInfo
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- CN108030780A CN108030780A CN201810099464.0A CN201810099464A CN108030780A CN 108030780 A CN108030780 A CN 108030780A CN 201810099464 A CN201810099464 A CN 201810099464A CN 108030780 A CN108030780 A CN 108030780A
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- Prior art keywords
- morphine
- pba
- pain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
Abstract
The present invention relates to pharmaceutical technology field, discloses the application of 4 PBA.The present invention provides 4 PBA in the multiple applications for improving morphine analgesia effect, improving morphine and the quick aspect of caused pain, so as to which for morphine, safe medication is provided and is effectively ensured in Clinical Pain therapeutic process, morphine is issued to preferable analgesic effect in safe dose, avoid heavy dose of morphine and use caused adverse reaction.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to the application of 4-PBA.
Background technology
Morphine is as classical opioid drug, in clinical treatment Acute or chronic pain, neurogenic pain and pain caused by cancer side
Face extensive use.Tolerance is produced after morphine prolonged application and limits application of the medicine in clinic, becomes the problem in pain diagnosis and treatment.
This problem causes scholar's extensive concern, carries out numerous studies from varying level, but the mechanism of current morphine is not yet complete
Illustrate.Morphine is mainly shown as after analgesic activity decrease, decreased duration, drug withdrawal that the pain increased and hyperalgia, faces
Need to give larger dose during bed application and can be only achieved preferable analgesic effect, and heavy dose of morphine can aggravate the bad anti-of medicine
Should.
It is anti-for opiate receptor desensitization, internalization, and the different dimerization with other acceptors, inflammation that morphine is related to main mechanism
Should, glutamate receptor is lowered, other mechanism are still in continuous explore.The research of morphine mechanism was treated for Clinical Pain
Safe medication has great meaning in journey.
The content of the invention
In view of this, the application it is an object of the invention to provide 4-PBA (4-phenylbutyrate) in morphine is improved
And preparing the application in improving morphine medicine；
Another object of the present invention be to provide 4-PBA (4-phenylbutyrate) improve that morphine analgesia is active should
With and prepare improve morphine analgesia drugs with function in application；
Another object of the present invention is to provide 4-PBA (4-phenylbutyrate) in pain caused by alleviating morphine is quick
Using and prepare improve morphine pain sensitizing drug in application；
Another object of the present invention is to provide a kind of analgesic composition so that the composition can improve morphine
Analgesic activity, alleviates morphine and pain caused by it is quick.
4-PBA, Chinese are 4-phenylbutyrate, are a kind of aliphatic acid of small-molecular-weight.At present, it has been a kind of quilt
One kind for the treatment of children's heredity urea metabolism obstacle, sickle-cell anemia and the thalassemia ratifying to use is clinical to be used
Medicine.In a recent study, it can remold type-II diabetes people glucostasis, blocking or the hair for alleviating diabetic nephropathy
It is raw, mitigate diabetic retinopathy progress, reduce hepatocellular apoptosis in hepatic ischemia-reperfusion injury, mitigate brain and ischemia of spinal cord
Property damage etc..But there is no any report still in the relevant application of morphine for it.
The present invention to the 4-PBA and morphine of SD rat intrathecal injection various doses, and to SD rats by carrying out whipping survey
Bitterly, surveyed once every 30 minutes, each whipping maximum duration 10s；The results show that in the range of 0-240min, injection morphine with
And the flick latency of the SD rats of morphine+4-PBA is longer since most, flick latency has all subtracted as time went on
It is few, but the SD rats for injecting morphine substantially reduce as the time elapses flick latency, and the SD for injecting morphine+4-PBA is big
Flick latency reduction is not notable as time went on for mouse, and flick latency is longer than the SD rats of injection morphine and is formed
Significant difference.Similarly, surveyed in continuous 7 days long-time whippings in pain experiment, the SD Rat Tall Flicks of injection morphine+4-PBA are dived
The volt phase also maintains same trend with above-mentioned result of the test, and effect is better than the SD rat treatment groups of individually injection morphine.This shows
Intrathecal injection 4-PBA and morphine can improve the analgesic effect of morphine and alleviate the formation of morphine.
Meanwhile the present invention is surveyed whipping, is reacted by dose of morphine with the injection of morphia SD rats of various dose after half an hour
Curve can be seen that morphine suite line and right side translation occurs, and curve moves to left after giving 4-PBA.On the other hand, intrathecal injection
4-PBA can invert the SD rats for having formed morphine, improve morphine analgesia effect.The result shows that intrathecal injection
4-PBA and morphine can improve morphine.
In addition, the SD rats of different groups intrathecal injection or intraperitoneal injection of drugs twice daily, continuous seven days, are then detected
Mechanical pain and the lower flick latency of Spurs pain, the results showed that intrathecal or intraperitoneal injection 4-PBA and morphine can improve morphine and cause
Pain it is quick.
Based on above-mentioned every experimental result, the present invention proposes multinomial applications of the foregoing 4-PBA during morphine use.
In specific experiment of the invention, intrathecal injection dosage is obtained in 5-50 μ g, intraperitoneal injection dosage under 10-100mg/kg morphines
State result of the test, but according to the trend of result of the test, it can be seen that effect caused by the higher 4-PBA of dosage is more excellent
, therefore in the case where 4-PBA uses dosage safely, can realize every excellent effect proposed by the invention.
Analgesic composition proposed by the invention includes morphine and 4-PBA, both independently exist in the composition, class
Like each component reagent in detection kit, it is recommended to use when intrathecal injection according to morphine：4-PBA=1: 5 mass ratios use,
Intraperitoneal injection is according to morphine：4-PBA=1: 10 ratio uses.
From above technical scheme, the present invention provides 4-PBA improve morphine analgesia effect, improve morphine with
And multiple applications of the caused quick aspect of pain, so that safe medication provides effectively in Clinical Pain therapeutic process for morphine
Ensure, morphine is issued to preferable analgesic effect in safe dose, avoid caused by heavy dose of morphine use not
Good reaction.
Brief description of the drawings
Fig. 1, which show the 4-PBA of intrathecal injection various dose and 10 μ g morphines, influences acute analgesic；Wherein, * is represented
P ＜ 0.05,4-PBA (15 μ g)+Morphine groups significant difference compared with Morphine groups.# represents p ＜ 0.05,4-PBA (50 μ
G)+Morphine groups significant difference compared with Morphine groups.### represents p ＜ 0.001,4-PBA (50 μ g)+Morphine groups
Difference is extremely notable compared with Morphine groups；
Fig. 2 show influences of the 4-PBA to morphine of intrathecal injection various dose；Wherein, ## represents p ＜
0.01, ### represents p ＜ 0.001, and 4-PBA (50 μ g)+Morphine groups difference compared with Morphine groups is extremely notable；* represent
P ＜ 0.05,4-PBA (15 μ g)+Morphine groups significant difference compared with Morphine groups；
Fig. 3 show the amount effect curve figure of morphine；Sham represents physiological saline group, and Morphine represents morphine group,
Morphine+4-PBA represents injection morphine and 4-PBA groups；Curve is followed successively by physiological saline group curve, injection morphine from left to right
With 4-PBA suites line and morphine suite line；
Fig. 4 show the quick influence of machinery pains of the intrathecal injection various dose 4-PBA to morphine induction；Wherein, -1d
(baseline) the mechanical pain on basis before representing morphine model；# represents p ＜ 0.05,4-PBA (15 μ g)+Morphine
Group significant difference compared with Morphine groups, 4-PBA (50 μ g)+Morphine groups significant difference compared with Morphine groups；***
Represent p ＜ 0.001, the difference compared with basic value is extremely notable afterwards for morphine；
Fig. 5 show the quick influence of the Spurs pain pain of the 4-PBA of intrathecal injection various dose to morphine induction；Wherein, -1d
(baseline) Spurs pain basic before making morphine model is represented；## expression p ＜ 0.01,4-PBA (5 μ g)+
Morphine groups difference compared with Morphine groups is extremely notable, and 4-PBA (15 μ g)+Morphine groups are compared with Morphine groups
Difference is extremely notable, and 4-PBA (50 μ g)+Morphine groups difference compared with Morphine groups is extremely notable；* * represent p ＜
0.001, the difference compared with basic value is extremely notable afterwards for morphine；
Fig. 6 show the influence of intraperitoneal injection 4-PBA and morphine to the mechanical pain of morphine induction；* * represent p ＜
0.001；* represents p ＜ 0.01, represents that 4-PBA alleviates the quick effect of pain and its significantly, p=0.051 represents the 4- under the dosage
It is quick effective that PBA alleviates pain；
Fig. 7 show the quick influence of the Spurs pain pain of intraperitoneal injection 4-PBA and morphine to morphine induction；* * represent p ＜
0.001；
Intrathecal injection 4-PBA shown in Fig. 8 inverts the result of morphine；Wherein, * * represent p ＜ 0.05, Morphine+4-
PBA groups are compared with Morphine groups.
Embodiment
The invention discloses the application of 4-PBA, those skilled in the art can use for reference present disclosure, be suitably modified technique ginseng
Number is realized.In particular, all similar substitutions and modifications are apparent to those skilled in the art,
They are considered as being included in the present invention.Application of the present invention is described by preferred embodiment, related personnel
Can substantially present invention be not being departed from, application described herein is being modified in spirit and scope or suitably changes with combining,
To realize and using the technology of the present invention.
In contrast test in a particular embodiment, in addition to the due difference of each group, other experimental conditions ensure one
Cause, it is ensured that the comparability of experimental result.
The application with regard to 4-PBA provided by the present invention is described further below.
Embodiment 1：The influence of 4-PBA On Morphine Analgesias effect
SD rat intrathecal injection 4-PBA and morphine (10ug), survey pain, every 30 points after 30 minutes in 55 degree of water-bath whippings
Clock is surveyed once, each whipping maximum duration 10s, and experiment is respectively divided into five groups：Physiological saline group, morphine group, 4-PBA (5,15,50 μ
G)+morphine group, every group of 7 rats.
The result is shown in Figure 1, by Fig. 1, it is apparent that intrathecal injection 4-PBA is compared with morphine individually injects morphine, SD is big
The flick latency of mouse is longer, and 4-PBA dosage bigger incubation period is longer, and can form significant difference, shows sheath
Interior injection 4-PBA can improve the analgesic effect of morphine.
Embodiment 2：Influences of the 4-PBA to morphine
SD rat intrathecal injection 4-PBA and morphine (10 μ g), pain, each whipping are surveyed after 30 minutes in 55 degree of water-bath whippings
Maximum duration 10s, continuous 7 days.Experiment is respectively divided into five groups：Physiological saline group, morphine group, 4-PBA (5,15,50 μ g)+morphine group,
Every group of 7 rats.
The result is shown in Fig. 2, and by Fig. 2, it is apparent that intrathecal injection 4-PBA is compared with morphine individually injects morphine, SD is big
The flick latency of mouse is longer, and 4-PBA dosage bigger incubation period is longer, and can form significant difference, shows sheath
Interior injection 4-PBA can improve the analgesic effect of morphine.
Embodiment 3：Influences of the 4-PBA to morphine amount effect curve
Set up Sham physiological saline groups, Morphine morphines group and Morphine+4-PBA injection morphines and 4-
PBA groups, morphine group and injection morphine and 4-PBA groups at interval of morphine of half an hour intrathecal injection, dose of morphine from
Low to high (0.5 μ g, 1 μ g, 3 μ g, 6 μ g, 9 μ g, 15 μ g, 48 μ g, 96 μ g) surveys whipping and calculates %MPE, i.e. (experiment value-basis
Value)/(10- basic values) * 100%, stop injecting if the whipping time reaches 10s, experiment is completed in one day.
The result is shown in Fig. 3, there is right side translation in morphine suite line, and analgesic effect reduces after representing morphine, performance
Gradually weaken even disappearance, it is necessary to which equal analgesia could be obtained by increasing the dosage of morphine persistently to give analgesic effect after morphine
Effect, and curve moves to left after giving 4-PBA, illustrates that it is capable of the analgesia time of extended morphine, slows down the formation of tolerance, shows
Intrathecal injection 4-PBA and morphine can improve morphine.
Embodiment 4：Effect quick to pain caused by morphine 4-PBA
1st, intrathecal injection
The SD rats of different groups inject medicine twice daily, continuous seven days, then survey machinery pain, i.e., are placed in rat
In the transparent organic glass case of 22cm × 12cm × 22cm, bottom is metallic sieve, is stimulated using von Frey filaments
Rat right hind leg mid-plantar, it is positive reaction slowly firmly, lift foot occur, hide or lick foot action.Between stimulating at least every time
Every 30s；If paw withdrawal reaction is feminine gender, stimulus intensity is selected to continue to pierce in the incremental adjacent von Frey filaments of logarithm
Swash；If paw withdrawal reaction is the positive, selecting the adjacent stimulus intensity to successively decrease to give stimulates.So repeatedly, with first turning point
Former point be starting point, the results of stimulation of continuous 6 times is final paw withdrawal reaction pattern.It is 5 if being in lasting masculin if paw withdrawal reaction
Secondary stimulation, paw withdrawal reaction are then 4 stimulations in continuing negative, stimulate number to be up to 9 times.Maximum dynamics is 15g, more than this value
Shi Jiwei 26g, minimum dynamics are 0.4g, and less than this value when is denoted as 0.4g.
Spurs pain, then holds device heat radiation switch, after infrared source is aligned Rat Right using heat radiation analyzer
Limb mid-plantar, quickly by lower switch, it is 30S to be turned off the switch immediately as the Spurs threshold of pain maximum duration when lift foot occur, hiding,
Using measurement average value three times as final Spurs pain threshold.
The result is shown in Fig. 4 and Fig. 5, show in Fig. 4 continuous seven days and be administered, twice daily, the mechanical pain threshold of detection in the 7th day, as a result
It is quick that display, 15 μ g and 50 μ g 4-PBA can improve mechanical pain.It is administered within continuous seven days in Fig. 5, twice a day, the 7th day Spurs threshold of pain
Value, it is quick that three dosage of 4-PBA can improve Spurs pain pain.Show that intrathecal injection 4-PBA and morphine can improve morphine and draw
The pain risen is quick.
2nd, it is injected intraperitoneally
SD rats by intraperitoneal injection 4-PBA (10 40 100mg/kg) and morphine (10mg/kg), twice daily, continuous seven days,
Machinery pain (Fig. 6) and Spurs pain (Fig. 7) are surveyed according to the method described above within 7th day.
It is quick quick with Spurs pain pain can to improve mechanical pain pain for three dosage of 4-PBA it can be seen from Fig. 6 and Fig. 7.Table
It is quick that bright intraperitoneal injection 4-PBA and morphine can improve pain caused by morphine.
Embodiment 5：4-PBA inverts the phenomenon of morphine
Experiment is divided into two groups, two groups of rats all continuous intrathecal injection morphines (10 μ g), twice daily.From the 7th day to the tenth
My god, one of which gives 4-PBA (50 μ g) and morphine (10 μ g) composition, is named as Morphine+4-PBA groups, another group of sheath
Interior administration morphine (10 μ g), is named as Morphine groups；Whipping is surveyed after daily two groups of administration half an hours, the result is shown in Fig. 8.
Fig. 8 shows that Morphine+4-PBA groups significantly improve the analgesic effect to SD rats, what reversion was formed before
Morphine phenomenon.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (5)
1.4-PBA is preparing the application in improving morphine medicine.
2.4-PBA is preparing the application in improving morphine analgesia drugs with function.
3.4-PBA is preparing the application in improving morphine pain sensitizing drug.
4. apply according to claim 3, it is characterised in that the quick pain is Spurs pain and/or machinery pain.
5. a kind of analgesic composition, it is characterised in that including morphine and 4-PBA.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810099464.0A CN108030780A (en) | 2018-01-31 | 2018-01-31 | The application of 4-PBA |
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| CN201810099464.0A CN108030780A (en) | 2018-01-31 | 2018-01-31 | The application of 4-PBA |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679705A (en) * | 2021-08-31 | 2021-11-23 | 兆科药业（广州）有限公司 | Application of sodium phenylbutyrate and metabolite thereof in preparation of medicine for preventing or treating peripheral nerve pain caused by chemotherapy |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1713911A (en) * | 2002-10-29 | 2005-12-28 | 成均馆大学校 | Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine |
| WO2016133788A1 (en) * | 2015-02-20 | 2016-08-25 | The Regents Of The University Of California | Methods of inhibiting pain |
-
2018
- 2018-01-31 CN CN201810099464.0A patent/CN108030780A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1713911A (en) * | 2002-10-29 | 2005-12-28 | 成均馆大学校 | Medicament component of berberine for the use of prevention and treatment of psycological dependence on and analgesic tolerance to morphine |
| WO2016133788A1 (en) * | 2015-02-20 | 2016-08-25 | The Regents Of The University Of California | Methods of inhibiting pain |
Non-Patent Citations (1)
| Title |
|---|
| TAMAE DOBASHI等: "Bip, an endoplasmic reticulum chaperone, modulates the development of morphin antinociceptive tolerance", 《J. CELL. MOL. MED.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113679705A (en) * | 2021-08-31 | 2021-11-23 | 兆科药业（广州）有限公司 | Application of sodium phenylbutyrate and metabolite thereof in preparation of medicine for preventing or treating peripheral nerve pain caused by chemotherapy |
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Application publication date: 20180515 |
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