CN114028396A

CN114028396A - Application of tetrandrine in preparation of medicine for treating fibromyalgia

Info

Publication number: CN114028396A
Application number: CN202111510443.1A
Authority: CN
Inventors: 张志玲; 翟所迪; 余斌; 陆纪宏; 蒋红梅
Original assignee: Zhejiang Jinhua Conba Bio Pharm Co ltd; Peking University Third Hospital Peking University Third Clinical Medical College
Current assignee: Zhejiang Jinhua Conba Bio Pharm Co ltd; Peking University Third Hospital Peking University Third Clinical Medical College
Priority date: 2021-12-10
Filing date: 2021-12-10
Publication date: 2022-02-11
Anticipated expiration: 2041-12-10
Also published as: CN114028396B

Abstract

The invention relates to application of tetrandrine in preparing a medicament for treating fibromyalgia. The tetrandrine is used for preparing the medicine for treating the fibromyalgia, and the prepared medicine can effectively relieve the pain feeling and the depressive mood of the fibromyalgia without generating central inhibition.

Description

Application of tetrandrine in preparation of medicine for treating fibromyalgia

Technical Field

The invention relates to fibromyalgia, in particular to a medicament which can effectively relieve pain feeling and depression-like mood of the fibromyalgia without generating central inhibition.

Background

Fibromyalgia (FM) or Fibromyalgia Syndrome (Fibromyalgia Syndrome) is a common chronic generalized pain Syndrome, which is classified as "chronic primary pain" in the new international classification of diseases (ICD-11). Its clinical symptoms include multiple regional pain and fatigue, sleep disturbances, emotional and cognitive dysfunction and psychological problems that severely affect the quality of work and life of the patient. The current diagnostic criteria suggest that diagnosis of fibromyalgia should include cognitive dysfunction, insomnia, anxiety and depression, joint and muscle stiffness, and extensive pain and tenderness. The global prevalence of fibromyalgia is 2-3%. According to the reckoning, about 1400 million fibromyalgia patients exist in China. Research shows that the first diagnosis misdiagnosis rate of fibromyalgia is as high as 87%, and therefore, the number of patients with fibromyalgia is far more than that reported in the prior art.

Although fibromyalgia is very common in the general population, there is no consistent and effective treatment method at present because the pathogenesis of fibromyalgia is very complex, environmental, genetic, psychological and social factors are involved, and the diagnosis and classification criteria, especially the etiology and pathogenesis, of fibromyalgia at home and abroad are not well known so far.

Among the first-line treatments recommended in "China specialist consensus for fibromyalgia clinical practice (2021)," pregabalin, amitriptyline, and 5-hydroxytryptamine and norepinephrine reuptake inhibitors (SNRIs). In 2017, the latest edition of the european antirheumatic alliance (EULAR) fibromyalgia treatment management recommendations, pregabalin and amitriptyline are both weak recommendations. Thus, the current drugs for treating fibromyalgia still have the problems of unsatisfactory curative effect or side effect, and the use of the drugs is still limited. Therefore, there is still a need for new drugs with definite therapeutic effects and low side effects.

In addition, fibromyalgia is significantly different from neuropathic pain. Neuropathic pain is a peripheral or central nervous system injury due to trauma or disease, whereas nervous system injury is not apparent in patients with fibromyalgia. And the perception of pain is different from that of neuralgia, which usually causes the patient to feel numbness, stabbing pain, burning pain or click-like pain at the injured part, and fibromyalgia is mainly seen in extensive pain of deep body tissues. In addition, patients with fibromyalgia develop mood disorders and sleep disorders at a much higher rate than patients with neuropathic pain.

In terms of therapeutic drugs, garbanspouting is a first-line therapeutic drug for treating various types of neuralgia, but currently no high-quality studies have confirmed the effectiveness of garbanspouting in treating fibromyalgia. Clinical studies have found that the 5-hydroxytryptamine-norepinephrine reuptake inhibitor desmethylvenlafaxine has a significant effect on diabetic neuralgia (J Pain Res.2014Jun23; 7:339-51) compared to placebo, but no significant effect on fibromyalgia patients (Clin Pharmacol Drug Dev.2017 May; 6(3): 224-. Although the analgesic effect of pregabalin in the two diseases is clear, clinical studies show that the use and the compliance of patients of pregabalin are greatly limited due to the problem of adverse reaction, so that the treatment effect is not satisfactory.

In summary, there is still a clinical unmet need for a therapeutic drug for fibromyalgia, and there is still a need for a new drug having improved efficacy and little side effects.

Disclosure of Invention

In view of the above analysis, an embodiment of the present invention is directed to the use of tetrandrine in the preparation of a medicament for the treatment of fibromyalgia.

According to an embodiment of the present invention, the tetrandrine is an active ingredient of the drug.

According to an embodiment of the invention, the tetrandrine is the only active component of the drug.

The invention further provides a pharmaceutical composition for treating fibromyalgia, which comprises tetrandrine and a pharmaceutically acceptable carrier.

According to an embodiment of the present invention, the tetrandrine is an active ingredient of the pharmaceutical composition.

According to an embodiment of the present invention, the tetrandrine is the only active ingredient of the pharmaceutical composition.

According to an embodiment of the invention, the pharmaceutical composition is an oral formulation.

According to an embodiment of the present invention, the oral preparation is a tablet, a capsule, a dispersible tablet, a granule, a soft capsule, a chewable tablet, an orally disintegrating tablet, a buccal tablet or a drop pill.

According to one embodiment of the invention, the content of tetrandrine in the oral preparation is 19-21 mg/dose.

According to one embodiment of the present invention, the content of tetrandrine in the oral preparation is 20 mg/dose.

According to the embodiment of the invention, the tetrandrine is used for preparing the medicine for treating fibromyalgia, and the prepared medicine can effectively relieve pain feeling and depression-like mood of the fibromyalgia without generating central inhibition.

In the invention, the technical schemes can be combined with each other to realize more preferable combination schemes. Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention will be realized and attained by the structure particularly pointed out in the written description and drawings.

Drawings

The drawings are only for purposes of illustrating particular embodiments and are not to be construed as limiting the invention.

Wherein:

FIG. 1 is a graph of data from a mechanical hyperalgesia test of an embodiment of the present invention;

FIG. 2 is a graph of data from a thermal hyperalgesia test in accordance with an embodiment of the present invention;

FIG. 3 is a data graph of a forced swim test according to an embodiment of the present invention;

fig. 4 is a data plot of a propofol induced sleep test in accordance with an embodiment of the present invention.

Detailed Description

Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings, which form a part hereof, and which together with the embodiments of the invention serve to explain the principles of the invention and are not intended to limit the scope of the invention.

Tetrandrine (TET), also known as Tetrandrine, is an alkaloid with the strongest biological activity in the traditional Chinese herbal medicine Tetrandrine and belongs to the bisbenzylisoquinoline alkaloid. The previous research finds that the tetrandrine has various pharmacological effects of diminishing inflammation, easing pain, resisting tumors, resisting silicosis and the like. Tetrandrine is clinically applied to treating arthralgia, rheumatalgia and neuralgia, but the application of tetrandrine to fibromyalgia is not reported.

An embodiment of the invention provides an application of tetrandrine in preparing a medicine for treating fibromyalgia. The prepared medicine can effectively relieve the pain feeling of fibromyalgia and depression-like mood disorder, but does not generate central inhibition.

In one embodiment, the pharmaceutical composition is an oral preparation, and the oral preparation can be tablets, capsules, dispersible tablets, granules, soft capsules, chewable tablets, orally disintegrating tablets, buccal tablets, drop pills and the like.

In one embodiment, the oral formulations are tablets, and the content of tetrandrine in each oral formulation is 19-21 mg/dose, for example 20 mg/dose.

In one embodiment, the daily amount of tetrandrine in the oral formulation is 290-310 mg, for example 300 mg.

The subject to which the medicament or pharmaceutical composition of one embodiment of the present invention is administered includes mammals, such as humans.

Hereinafter, the application of tetrandrine in treating fibromyalgia according to an embodiment of the present invention will be further described with reference to the accompanying drawings and specific examples.

Examples

Experiment of tetrandrine for inhibiting mechanical pain sensitivity

Skeletal muscle pain is a major characteristic of fibromyalgia. Nagakura (Pain 146(1-2),26-33) has developed a model associated with human musculoskeletal Pain characterized by mechanical hyperalgesia induced by repeated subcutaneous injections of reserpine.

The experiment is used for evaluating the influence of Tetrandrine (TET) on mechanical abnormal pain, and the mechanical pain sensitivity can well represent muscular pain or tenderness of a patient suffering from fibromyalgia. Repeated subcutaneous injections of reserpine (reserpine) into mice can cause mechanical allodynia in the animals.

Laboratory animal

ICR mice, male, 18-22g, purchased from beijing weitongli laboratory animal science and technology ltd, SPF grade animals, animal certification No.: SCXK (Jing) 2016-.

Determination of mechanical pain threshold

The mice are placed on the wire netting, and are respectively fixed in the frame by a transparent plastic basket with a downward opening, and the size of the frame ensures that the animals have enough activity space. The animals are allowed to acclimate in this environment for 3-4 times, each for 15-20min before testing; the left posterior plantar of the mouse was stimulated with Von-Frey filaments of different thicknesses through the wire mesh in a direction perpendicular to the ball of the foot. The fiber silk is bent to a 90-degree angle and stays for 5s every time, and whether pain reactions such as foot contraction, foot licking, foot lifting and the like can occur in the mouse in the time or not is observed; if the animal has a painful response, replacing the animal with an adjacent lower breaking strength fiber; if the animal has no pain reaction such as foot contraction, the adjacent fiber silk with larger folding strength is used; sequentially and alternately measuring according to the principle, and continuously measuring for 4 times after the first time of the alternate value of the positive and negative (or negative and positive) reaction; and finally, calculating the mechanical pain threshold of the animal by using an up-and-down method.

Induction of mechanical allodynia

Reserpine was injected subcutaneously into mice at a concentration of 1mg/kg (solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline) and a dosing concentration of 10ml/kg 1 time a day for 3 consecutive days, and only the subcutaneous injection solvent was administered to the control group. The mechanical pain threshold of the mice was measured the next day of the last administration of reserpine.

Administration of drugs

A TET solution was prepared using a 0.5% sodium carboxymethylcellulose solution, and a pregabalin (pregabalin) solution was prepared using physiological saline. TET or pregabalin were administered to mice by intragastric administration at a concentration of 45mg/kg, and an administration concentration of 10ml/kg, respectively. TET or pregabalin was administered half an hour before reserpine (1mg/kg, solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline) for 4 days continuously, and the mechanical pain threshold of animals was measured with von frey fiber filaments two hours after the last administration.

Statistics of

GraphPad Prism Version 5(GraphPad Software, Inc., La Jolla, Calif., USA) Software was used for statistical analysis. Data are expressed as mean + -SEM, One-way ANOVA using One-way analysis of variance, with p <0.05 being statistically significant.

Results

The data obtained in the above-mentioned mechanical nociception-inducing test and the mechanical pain threshold measurement test of the administered mice are shown in fig. 1, and compared with the solvent control group (normal group), reserpine significantly reduces the mechanical pain threshold of animals, and TET and pregabalin can significantly inhibit the reduction of the mechanical pain threshold of mice induced by reserpine. And TET has the same inhibiting effect with the positive pregabalin. These results demonstrate that TET is able to inhibit mechanical hyperalgesia in the fibromyalgia model.

Experiment of tetrandrine for inhibiting hot pain sensitivity

The experiment is used for evaluating the influence of tetrandrine on heat stimulation allodynia. Repeated subcutaneous injections of reserpine into mice can cause the animal to produce thermoallodynia.

Laboratory animal

Hot plate experiment

Hot plate experiments were used to determine the central antinociceptive effect of the drug (Le Bars et al, 2001). The hotplate surface was heated to a constant temperature of 50 ℃ and the mice were placed on a hotplate apparatus consisting of a metal plate surrounded by a transparent acrylic cage. Latency of paw lick, paw flick or jump (first arrival) responses was measured. The test was terminated if the animals did not respond within 30 seconds to prevent tissue damage.

Induction of thermal pain threshold allodynia

Measurement of basal pain threshold for rat hot plate experiment: the reserpine was injected into mice at a concentration of 1mg/kg (solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline) and a dosing concentration of 10ml/kg 1 time per day for 3 consecutive days, and the control group was given subcutaneous injection of solvent alone. The incubation time of the mouse hot plate experiment was measured the next day after the last administration of reserpine.

Administration of drugs

A TET solution was prepared using a 0.5% sodium carboxymethylcellulose solution, and a pregabalin solution was prepared using physiological saline. TET or pregabalin were administered to mice by intragastric administration at a concentration of 45mg/kg, and an administration concentration of 10ml/kg, respectively. TET or pregabalin was administered half an hour before reserpine (1mg/kg, solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline), continuously for 4 days, and hot plate experiments were performed two hours after the last administration.

Statistics of

Results

As shown in fig. 2, reserpine significantly reduced the residence time of the animals on the hot plate compared to the solvent control group (normal group), and TET and pregabalin were administered by gavage, which significantly extended the residence time of the mice on the hot plate. These results demonstrate that TET is effective in alleviating thermal hyperalgesia in the fibromyalgia model and acts comparable to the positive drug pregabalin.

Experiment of antidepressant action of tetrandrine

The experiment is used for evaluating the influence of tetrandrine on depression-like mood, and can well represent the symptoms of depression syndrome of patients with fibromyalgia. Repeated subcutaneous injections of reserpine into mice can cause the animals to develop a depressive-like mood.

Laboratory animal

Forced swimming experiment

The procedure used was the same as described by Maciel et al (PloS One 8, e 77227). The experiment was carried out using a cylinder (diameter 18.5 cm, height 25 cm) filled with water at a height of 17 cm and maintained at a temperature of 23-25 ℃. Mice were placed in water and the time the mice remained immobile was quantified in seconds over 6 minutes. Where "immobility" is defined as no action other than that required to keep the mouse head above water.

Induction of immobility in forced swimming

Reserpine was injected subcutaneously into mice at a concentration of 1mg/kg (solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline) and a dosing concentration of 10ml/kg 1 time a day for 3 consecutive days, and the control group was given subcutaneous injection of solvent alone. The following day of the last administration of reserpine the mice were tested for forced swim immobility.

Administration of drugs

A TET solution was prepared using a 0.5% sodium carboxymethylcellulose solution, and a pregabalin solution was prepared using physiological saline. TET or pregabalin were administered to mice by intragastric administration at a concentration of 45mg/kg, and an administration concentration of 10ml/kg, respectively. TET or pregabalin was administered half an hour before reserpine (1mg/kg, solvent: 0.1 wt% glacial acetic acid, diluted with physiological saline), continuously for 4 days, and a forced swimming test was performed two hours after the last administration.

Statistics of

Results

As shown in fig. 3, reserpine significantly increased immobility time in forced swimming of mice compared to the vehicle group, TET significantly decreased immobility time in forced swimming due to reserpine after intragastric administration, and pregabalin had no effect on immobility time in forced swimming due to reserpine. These results indicate that TET has the effect of relieving fibromyalgia mood disorders, whereas pregabalin does not relieve the mood disorders associated with fibromyalgia.

Central inhibition experiment of tetrandrine

The experiment is used for evaluating whether tetrandrine has central inhibition effect, and can well compare the safety conditions of pregabalin and TET. Intraperitoneal injection of propofol into mice can cause the animals to sleep.

Laboratory animal

C57 mouse, male, 8 week old, purchased from the experimental animal science and technology ltd, SPF grade animal, beijing vington, SPF grade animal, animal certification No.: SCXK (Jing) 2016-.

Propofol-induced sleep test

The mouse is injected with 75mg/kg of propofol by the intraperitoneal injection to cause the righting reflex to disappear, and the time from the disappearance of the righting reflex to the restoration of the righting reflex of the animal is the sleeping time.

Induction of righting reflex disappearance

75mg/kg propofol was intraperitoneally injected into mice and the time required for the mice to disappear from righting reflex until the righting reflex was restored was recorded.

Administration of drugs

A TET solution was prepared using a 0.5% sodium carboxymethylcellulose solution, and a pregabalin solution was prepared using physiological saline. TET or pregabalin were administered to mice by intragastric administration at a concentration of 45mg/kg and an administration concentration of 10ml/kg, respectively, and 75mg/kg of propofol was intraperitoneally injected 1 hour later. The time from disappearance of righting reflex to restoration of righting reflex in animals following propofol administration was recorded.

Statistics of

Results

The experimental results in fig. 4 show that pregabalin significantly prolongs propofol-induced sleep time compared to the solvent group, whereas TET does not affect propofol-induced sleep time. It is stated that TET may only act on the brain areas involved in controlling pain, whereas pregabalin may act not only on the areas involved in controlling pain, but also on the areas involved in controlling sleep. These results indicate that tetrandrine is much safer than pregabalin in treating fibromyalgia.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.

Claims

1. The application of tetrandrine in preparing medicine for treating fibromyalgia is provided.

2. The use of claim 1, wherein the tetrandrine is the active ingredient of the medicament.

3. The use of claim 1, wherein the tetrandrine is the only active component of the medicament.

4. A pharmaceutical composition for treating fibromyalgia comprises tetrandrine and pharmaceutically acceptable carrier.

5. The pharmaceutical composition of claim 4, wherein the tetrandrine is an active component of the pharmaceutical composition.

6. The pharmaceutical composition of claim 4, wherein the tetrandrine is the only active component of the pharmaceutical composition.

7. The pharmaceutical composition of claim 4, which is an oral formulation.

8. The pharmaceutical composition according to any one of claims 4 to 7, wherein the oral formulation is a tablet, a capsule, a dispersible tablet, a granule, a soft capsule, a chewable tablet, an orally disintegrating tablet, a buccal tablet or a drop pill.

9. The pharmaceutical composition according to any one of claims 4 to 8, wherein the content of tetrandrine in the oral preparation is 19-21 mg/dose.

10. The pharmaceutical composition of claim 9, wherein the tetrandrine is present in the oral formulation in an amount of 20 mg/dose.