CN102988401B - Application of adenosine triphosphate or medicinal salt of adenosine triphosphatein in preparation of medicine for treating endometriosis - Google Patents

Abstract

The invention relates to application of ATP (Adenosine Triphosphate) or medicinal salt of adenosine triphosphatein in preparation of a medicine for treating endometriosis. As an animal model shown, the ATP or the medicinal salt can effectively treat endometriosis relative to gestrinone.

Description

The application in the medicine of preparation treatment endometriosis of adenosine triphosphate or its officinal salt

Technical field

The present invention relates to the application in the medicine for the preparation for the treatment of endometriosis of adenosine triphosphate (ATP) or its officinal salt.

Background technology

Endometriosis is the common gynecological benign diseases of period of duration women, and sickness rate can be up to 10%～15%.Its pathological characteristic is that endometrial gland or endometrial stroma appear at uterine cavity coating inner membrance and palace body flesh layer any position in addition.Endometriosis focus is distributed in uterosacral ligament, ovary or rectum gap, uterus more, mainly causes pain, the infertile and large clinical problem of pelvic lump three.Peritoneoscope is the goldstandard of current diagnosis endometriosis and first-selected treatment means.The Therapeutic Principle of endometriosis be according to patient age, symptom, diseased region, coincident with severity degree of condition and scope and patient to fertility require the rounded analysiss such as situation, implement individualized treatment scheme.Can adopt the Therapeutic Method such as medicine, operation or operation combination medicine.

1, operative treatment: object is removal of lesions was and recovers anatomical structure.Comprise laparoscopic surgery and abdominal.But relapse rate is higher, be greater than 20%.This treatment has wound, and cost is higher, has the probability of postoperative complication.

2, Drug therapy: object is first to use Drug therapy before the corrective surgery treatment for clinical definite.Like this, can make endometriosis focus dwindle, soften, be beneficial to operation and carry out smoothly.After operation, drug application treatment can reduce the generation of postoperative recurrence and surgical adhesions.The mechanism of Drug therapy is to reduce estrogen level.Roughly be divided into several classes such as contraceptive, efficient progestogen, androgens derivant, GuRH-A (GnRH-a).Various curative effect of medication are similar, but all have various side effect.In addition,, except contraceptive, other consumption cost is higher.

1) oral contraceptive (OCS): by the growth of blocking-up follicle, reduce estrogenic generation, make atrophy of endometrium, reduce menses and flow backwards, alleviate endometriosis symptom.As the conventional compound recipe desogestrel (Marvelon, Marvelon) of first-line drug or Diane-35.Side effect is that feeling sick appears in some patients were, vomiting, headache, dizzy, body weight increase and anxious state of mind etc.Because female, progestogen in contraceptive can stimulate hysteromyoma to grow up, therefore there is muscular tumor person to be cautious use of.This therapy causes the amenorrhea of similar gestation, claims pseudo pregnancy therapy.Be applicable to slight endometriosis patients.

2) progestogen: can suppress hypothalamic-pituitary-ovarian axis by feedback, reduce body inner estrogen level by ovulation inhibition.In addition, can also directly act on the endometrium of dystopy, make it excessive decidua and become, and then atrophy necrosis.Common drug has norethindrone (norlutin), megestrol (FUNING PIAN) and medroxyprogestetone acetate etc.The similar danazol of norethindrone side reaction, sometimes also have feel sick, the symptom of digestive tract such as vomiting.The androgen untoward reaction of megestrol and medroxyprogestetone acetate is lighter.During medication, should make regular check on liver function.Because progestogen can stimulate hysteromyoma to grow up, there is muscular tumor person to be cautious use of., as the selection medicine of second line treatment endometriosis pain patients, be applicable to light moderate patient.

3) danazol: directly, progesterone receptor female with endometrium is combined, suppresses endo cell hypertrophy, finally causes atrophy of endometrium.Because of its untoward reaction weight, clinical practice reduces gradually.Be applicable to mild endometriosis patient.Major side effects has: play speckle, and hemorrhoid, oily skin, liquid holdup, body weight increases, hirsutism, voice changes, and of short duration liver aminotransferase raises, headache, functional gastrointestinal disorder, hyposexuality, hectic fever, reduction mammaplasty, anxiety, depression, spasmic pain, appetite changes.

4) gestrinone: be synthetic 19-nortestosterone derivant-norgestrienone, domestic person's medicine is called gestrinone.There is estrogen antagonist, gestation and antigonadotrophic effect, can make the atrophy of endometrium of dystopy.Its effect reduces the secretion of the promoting sexual gland hormone of hypencephalon and hypophysis axle, controls the growth of Ectopic Endometrium, directly acts on ectopic focus, and its atrophy is degenerated.Its adverse reaction rate is similar with danazol, and only degree is lighter.

5) gonadotropin releasing hormone analogues (GnRH-a): be that three lines treatments endometriosis pain patients are selected medicines, in being applicable to, severe endometriosis patients.Although GnRH-a can significantly be alleviated endometriosis patients symptom, because its serious low estrogen side reaction limits its long-term treatment continuously.And price is higher.

6) the reverse additive treatment of GnRH-a+: application GnRH-a and another kind or several drugs share, and if steroid hormone, calcitonin, Diphosphonate etc. are to prevent and treat its untoward reaction, are reverse additive treatment.For not tolerant patient, as row hysterectomy not, can place LNG intrauterine device (Man Yuele) and do long-term treatment.

7) mifepristone: be progesterone antagonist, take continuously and can reduce FSH and LH, and then ovulation inhibition, can also occupy endometrium progesterone receptor by competitiveness and produce stronger progestogen antagonism, endometrial gland secretion activity is reduced, and then atrophy.Long-term taking can cause not ovulating, therefore the equal discomfort of adolescence women is selected.Some patients were has slight hectic fever, perspiration, little arthralgia and lower abdominal pain etc.

8) arimedex: endometriosis is estrogen-dependent diseases, aromatase is the crux of estrogen synthesis, therefore the research of aromatase becomes a frontier of endometriosis, arimedex can obtain good curative effect to the endometriosis patients of conventional therapy failure, is promising medicine.Conventional representative medicine has Anastrozole and letrozole at present.But clinical also not generally use.Price is higher.

At present, in uterus the treatment aspect of endometriosis lacks standardized treatment specification, and every kind of method treatment all exists defect to a certain degree.Operative treatment has wound, and relapse rate is higher; Endometriosis patients Drug therapy for middle severe is expensive, and side effect is large, and curative effect is limited.Therefore, be necessary to find treatment endometriosis noinvasive, effective, cheap method and medicine.

Adenosine triphosphate is a kind of energy-rich compound, is made up of 1 molecule adenosine, 1 molecule ribose and 3 molecule phosphoric acid, is called for short ATP.At present conventional adenosine triphosphate disodium salt sheet and injection is mainly used in makeup energy clinically, for progressive myatrophy, and the auxiliary treatment of apoplexy sequela, cardiac insufficiency, myocardosis and hepatitis etc.

Summary of the invention

The present invention relates to the application in the medicine for the preparation for the treatment of endometriosis of adenosine triphosphate (ATP) or its officinal salt.In one embodiment, described officinal salt is sodium salt.In one embodiment, described medicine is oral formulations, ejection preparation or local application preparation.In one embodiment, described medicine is for using with the dosage of 2-7mg/kg.

Brief description of the drawings

Fig. 1 is that the tectology of endometriosis changes.

Detailed description of the invention

Embodiment 1

Set up animal model of endometriosis

In uterus, in the middle of the research of endometriosis, obtaining of the endometriosis tissue of clinical patients is limited, therefore sets up animal model of endometriosis very necessary.

From nineteen twenty-two Jacobson first passage endometrial tissue autotransplantation abdominal cavity, since setting up the model of endometriosis of rabbit, the animal model of endometriosis is day by day ripe.At present, conventional rat, rabbit, macaque, baboon, mice are set up model of endometriosis both at home and abroad.Macaque, baboon be because of expensive, limited its application in endometriosis model in uterus.Muroid is identical with human gene 99%, low price, easily operation with raise, the observation cycle is short, the main selection that therefore becomes people and set up model.In muroid, rat vitality is stronger, and hormonal readiness is higher, and therefore short the and rule of sexual cycle selects rat modeling all comparatively favourable to the observation after the surviving and transplant of graft.

Inventor selects 36 female sexually matured SPF level SD rats, sets up model of endometriosis, has 23 SD rat modeling successes through qualification, and success rate is 64%.Concrete zoopery step is as follows:

(1) obtain not copulation female sd inbred rats of 36 sexually matured SPF level health from The People's Hospital of Peking University's animal center;

(2) 1% pentobarbital sodium (40mg/kg) intraperitoneal injection of anesthesia;

(3) after routine disinfection, get 1cm on rat Ventral Midline, pubic symphysis and do the longitudinal incision of an about 3cm;

(4) find uterus at bladder dorsal part after entering abdominal cavity;

(5) uterus, free right side, near-end is from the about 1cm of cornua uteri place's ligation, and far-end is from the about 1cm of ovary place's ligation;

(6) uterine cancer cell in the middle of excision ligature, is placed in rapidly the culture dish that fills physiological saline solution, three of the endometrial tissues (containing flesh layer) of clip 5mm × 5mm size;

Get one of internal film tissue, be affixed in left ovary fatty tissue around with lining endothelium with the absorbable thread of No. 4-0, and four angle seams are closed;

One of Zai Qu internal film tissue, be affixed on the stomach wall of right side with the absorbable thread of No. 4-0, and four angle seams is closed with lining endothelium;

(7) sew up rectus incision, and splash into a 400000 U/ benzylpenicillin sodium for injection to abdominal cavity;

(8) on incision of abdominal wall right side, between the subcutaneous fascia layer of abdominal muscle, make a call to a tunnel, be advisable just in time can implant another piece endometrial tissue.Get the smooth implantation right side tunnel bottom of last piece endometrial tissue, make lining endothelium be close to abdominal muscle;

(9) residue uterine cancer cell is placed in formalin solution;

(10) the conventional abdomen that closes;

(11) postoperative every rats by intraperitoneal injection 400,000 U benzylpenicillin sodium for injection prevention infection, for three days on end;

(12) postoperative the 5th day starts, every 5 days once (0.1mg/kg) of intramuscular injection estradiol benzoate injection of every SD rat, continuous 3 times;

(13) cleaning ambient is raised, and cuts open the belly to observe and transplant internal film tissue's growing state after 4 weeks.

(14) observe the ectopic endometrium well-grown after transplanting, volume obviously increases, and is the bright little cryptomere of protuberance, and inside is full of hydrops, vascular surface high-visible (Fig. 1).The visible endometrial epithelial cell of morphological examination, body of gland and Interstitial cell growth, and have secretory activity and remote hemorrhage.According to this standard, in 36 rats, there are 23 modeling successes through qualification, being modeled as power is 64%.

Embodiment 2

The therapeutical effect of inspection ATP to endometriosis

The medicine using:

Gestrinone: the gestrinone capsule of being produced by Beijing black bamboo Pharma Inc., use physiological saline solution.ATP: the tribiofosfor injection that Tianjin Pharmaceutical Jiaozuo Co., Ltd. produces, use normal saline dilution.

Experimental procedure:

Successful modeling 23 SD rats are divided into 3 groups at random, be 10 of negative control group (normal saline gavages group), 7 of positive controls (gestrinone gavages group, every day 0.5mg/kg), ATP gavages 6 of groups (tribiofosfor injection gavages group, every day 3.4mg/kg).The injection volume that normal saline consumption and the ATP of matched group gavages group use is identical.Every day was by above-mentioned dosage gavage, continuous 4 weeks.

After 4 weeks, again cut open the belly, get the endometriotic tissues of corresponding site, be placed in formalin solution, paraffin embedding, HE dyeing after section.Examine under a microscope endometrium form.

Pathological examination interpretation standard

+++ the endometrium growth conditions that represents dystopy growth is good, and interstitial is many, visible multiple bodies of gland;

++ the endometrium growth conditions that represents dystopy growth is not good enough, and interstitial obviously reduces, the lumen of gland of visible 1-2 expansion;

+ representing that the endometrium of dystopy growth is atrophing state, interstitial few (only have ++ 1/2 left and right), only has the lumen of gland of 1 expansion;

-representing to have no obvious internal film tissue, body of gland disappears.

Result

Normal saline group (the 1st group), gestrinone group (the 2nd group) and ATP are gavaged to the effect in group (the 3rd group) +++, ++ ,+,-scoring is 3,2,1,0 respectively.Then record in every group the quantity of every kind of scoring as shown in the table:

Group #	Effect scoring	Quantity
			1	0	0
1	1	5
			1	2	2
1	3	3
			2	0	0
2	1	4
			2	2	3
2	3	0
			3	0	4
3	1	2
			3	2	0
3	3	0

From upper table, the 1st group (normal saline group) scoring is that 0,1,2,3 rat has respectively 0,5,2 and 3, illustrates for ectopic endometrium and does not act on.The 2nd group (gestrinone group) scoring is that 0,1,2,3 rat has respectively 0,4,3,0, the internal film tissue that dystopy the be described not good enough or atrophy of growing, but there is not the situation of disappearance.The 3rd group (ATP gavages group) scoring is 0 have 4, what scoring was 1 has 2, and scoring is not 2 and 3.The equal atrophy of endometrial tissue or the disappearance of dystopy in this group are described.

Inventor also adopts SPSS17.0 software, and above-mentioned these three groups the data of typing, have carried out two independent sample non parametric testss, calculate P value between group, thereby further assess the statistical significance of above-mentioned data.Result is as follows:

1. the variation of negative control group (normal saline gavages group) and positive controls (gestrinone gavages group) ectopic endometrium tectology

Negative control group (normal saline gavages group) and positive controls (gestrinone gavages group) ectopic endometrium tectology change not obvious, and difference does not have statistical significance.

2. negative control group (normal saline gavages group) and ATP gavage the variation of group ectopic endometrium tectology

Negative control group (normal saline gavages group) and ATP gavage group ectopic endometrium tectology to be changed obviously, and difference has significant statistical significance.Body of gland and interstitial that ATP gavages group (3.4 mg/kg) ectopic endometrium obviously reduce compared with negative control group.

From above result, adenosine triphosphate can effectively suppress the growth of Rat Endometriosis body of gland, has pointed out ATP can effectively treat endometriosis.

In addition, above-mentioned experiment shows, in uterus in the treatment of endometriosis, the therapeutic effect of ATP is even better than at present conventional clinically medicine-gestrinone.This is very meaningful and market prospect for the treatment of endometriosis.The medicine that ATP uses as clinical conventional makeup energy, its drug products, dosage form, the mechanism of action and side effect are relatively ripe, and its price is also more cheap.With respect to gestrinone, patient's financial burden is less, and its side effect is also little, suitable to clinical large-scale popularization.

Claims (4)

1. adenosine triphosphate or its officinal salt application in the medicine for the preparation for the treatment of endometriosis.

2. application as claimed in claim 1, wherein said officinal salt is sodium salt.

3. application as claimed in claim 1 or 2, wherein said medicine is oral formulations, ejection preparation or local application preparation.

4. application as claimed in claim 1 or 2, wherein said medicine is for using with the dosage of 2-7mg/kg.