CN113181183A - Application of cabergoline in preparing medicine composition for treating anxiety disorder - Google Patents

Abstract

The invention discloses an application of cabergoline in preparing a medicinal composition for treating anxiety disorder, and the experimental result of carrying out tube burying administration on a mouse LS shows that: dopamine receptors in the brain region of LS are involved in regulating anxiety-like behavior in mice. Mice showed a significant reduction in anxiety when injected with the dopamine D2 receptor agonist cabergoline. Therefore, cabergoline is suggested to activate dopamine receptors in the brain region of LS, and can relieve anxiety-like behaviors of mice and generate an anxiolytic effect.

Description

Application of cabergoline in preparing medicine composition for treating anxiety disorder

[ technical field ] A method for producing a semiconductor device

The invention relates to the technical field of anxiolytic drugs, relates to application of cabergoline in preparing a pharmaceutical composition for treating anxiety disorder, and particularly relates to application of cabergoline serving as an agonist of dopamine d2 receptor in preparing a pharmaceutical composition for treating anxiety disorder.

[ background of the invention ]

Anxiety is a common manifestation of psychotic disorders [ PsycholMed, 2005.35(12):1773-83, Int J Methods Psychiator Res, 2012.21(3):169-84 ]. Studies show that, on a global scale, the lifetime prevalence of Anxiety disorders is 5% -25% and the 12-month prevalence is 3.3% -20.4% [ Alonso decompression Anxiety, 2018, 35(3): 195-. Chinese mental health survey published in 2019 shows that Chinese anxiety disorder prevalence is the first of all mental disorders, lifetime prevalence is 7.6, and 12-month prevalence is 5.0%. The core features of anxiety disorders are excessive fear and anxiety and related behavioral disorders, mainly manifested by paroxysmal or persistent stress, fear, avoidance, and accompanying disorder of autonomic nerve function, which causes great pain to patients suffering from anxiety disorders and their families. According to "diagnostic and statistical handbook of mental disorders-fifth edition" (DSM-V), anxiety disorders can be classified as: separation anxiety disorder, selective mutism, Specific Phobia (SP), Social Anxiety Disorder (SAD), panic disorder, agoraphobia, Generalized Anxiety Disorder (GAD), substance/drug induced anxiety disorder, and other drug induced anxiety disorders. Approximately one-fourth of adults suffer from anxiety at some point in their lives. Anxiety patients experience severe physical and emotional discomfort, with higher drug use rates and medical illness. The high prevalence of anxiety disorders and the combination of high functional disability lead to particularly high economic and social costs.

The clinically common treatment modalities for anxiety disorders include psychotherapy and drug therapy. For example chinese patent CN02120351 for the combined treatment of depression and anxiety discloses a method of treating depression or anxiety in a mammal (including a human) by administering to the mammal a monoamine reuptake inhibitor in combination with a dopamine D3 receptor agonist, which comprises: (a) a dopamine D3 receptor agonist, or a pharmaceutically acceptable salt thereof; (b) the compounds of formula I as described and defined, and to pharmaceutical compositions comprising a pharmaceutically acceptable carrier, a monoamine reuptake inhibitor and a dopamine D3 receptor agonist.

At present, drugs for clinically treating anxiety mainly comprise benzodiazepine drugs, spirone drugs, antidepressant drugs and the like. Despite the numerous approaches to treating anxiety, there are still a number of problems with the treatment of anxiety. Anxiolytic drugs that have been approved for clinical use at present do not completely alleviate the symptoms of anxiety, and there are many adverse effects.

Therefore, the comprehensive understanding of the nervous regulation mechanism of anxiety, namely the emotion in the brain, improves the treatment idea of anxiety disorder, and provides more drug choices for anxiety disorder patients.

[ summary of the invention ]

The invention provides application of cabergoline in preparing a pharmaceutical composition for treating anxiety disorder, in particular application of cabergoline serving as an agonist of dopamine d2 receptor in preparing a pharmaceutical composition for treating anxiety disorder, aiming at solving the problems that the anxiolytic medicament which is approved to be clinically used in the prior art cannot completely relieve anxiety symptom and simultaneously has a plurality of adverse reactions.

The use of cabergoline in the manufacture of a pharmaceutical composition for the treatment of anxiety disorders, in particular the use of cabergoline, an agonist of the dopamine d2 receptor, in the manufacture of a pharmaceutical composition for the treatment of anxiety disorders.

Furthermore, the cabergoline is applied to the preparation of a pharmaceutical composition for treating anxiety disorder, and the pharmaceutical composition is a clinically acceptable pharmaceutical preparation prepared from cabergoline serving as a main component and pharmaceutically acceptable auxiliary materials or auxiliary components.

Furthermore, the cabergoline is applied to the preparation of a pharmaceutical composition for treating anxiety disorder, and the pharmaceutical preparation comprises two dosage forms of oral preparation and injection preparation.

Furthermore, the cabergoline is applied to the preparation of a pharmaceutical composition for treating anxiety disorder, the oral preparation is an oral capsule, and the injection preparation is intravenous injection.

Furthermore, the application of cabergoline in preparing the pharmaceutical composition for treating anxiety disorder is to inject cabergoline into the lateral metakaryotic brain region in a positioning way by means of intracranial administration, so as to generate the effect of antianxiety.

Generally, the drugs are clinically applied after being prepared into preparations. The pharmaceutical composition of the present invention can be prepared according to a method known in the art as a pharmaceutical composition. The pharmaceutical compositions of the present invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the pharmaceutical composition of the present invention in the pharmaceutical composition thereof is usually 0.1-95% (w/w).

The pharmaceutical composition of the invention or the pharmaceutical composition containing the same can be administered in unit dosage form, and the administration route can be intestinal or parenteral, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The pharmaceutical composition can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems. For tableting the pharmaceutical composition of the present invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the adhesive can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

In order to encapsulate the administration unit, the pharmaceutical composition of the present invention as an active ingredient may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the active ingredients of the pharmaceutical composition of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used for preparing the pharmaceutical composition tablets of the invention can also be used for preparing capsules of the pharmaceutical composition of the invention.

In order to prepare the pharmaceutical composition of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

Compared with the prior art, the invention has the following advantages:

1. the application of cabergoline in preparing the pharmaceutical composition for treating anxiety disorder provides a new drug target for treating anxiety disorder.

2. The application of cabergoline in the preparation of the pharmaceutical composition for treating anxiety disorder disclosed by the invention finds that cabergoline is used for treating anxiety disorder, and the application range of cabergoline is expanded.

3. The cabergoline is applied to the preparation of the pharmaceutical composition for treating the anxiety disorder, the administration mode is intracranial fixed-point administration, and compared with other administration modes, the side effect of the medicine is reduced.

[ description of the drawings ]

FIG. 1 is a graph of the effect of administration of LS cabergoline on anxiety-like behavior in mice in open field experiments in an example of the present invention.

FIG. 2 is a graph of the effect of LS dopamine agonist administration on anxiety-like behavior in mice in an elevated plus maze experiment in an example of the invention.

FIG. 3 is a graph of the effect of LS cabergoline administration on anxiety-like behavior in mice in drinking and food intake experiments in an example of the present invention.

FIG. 4 is a graph of the effect of LS cabergoline administration on anxiety-like behavior in mice in a new environmental feeding inhibition experiment in an example of the invention.

FIG. 5 is a graph of the effect of LS cabergoline administration on anxiety-like behavior in sugar water preference experiments in mice in an example of the present invention.

[ detailed description ] embodiments

The following examples are provided to further illustrate the embodiments of the present invention.

Example (b):

1. use of cabergoline for the preparation of a pharmaceutical composition for the treatment of anxiety disorders:

2. experimental methods

2.1 tube-embedding administration:

(1) experimental C57BL/6J mice were weighed, placed in an anesthesia induction box, and anesthetized with isoflurane gas.

(2) After the mice are completely anesthetized, the heads of the mice are fixed on a brain stereotaxic apparatus, so that the heads of the mice are kept horizontal. The scalp is shaved at the top of the head, the fascia of the scalp is incised, and the front fontanel and the back fontanel are clearly exposed by applying a sterile dry cotton ball on the surface of the skull.

(3) The bregma is taken as the origin, the position of the LS brain area is found according to the coordinates of the brain atlas, three points are found on the surface of the skull around the LS brain area for fixing skull nails, and marks are made by a gel pen.

(4) And punching the marked part on the skull by using a dental electric drill, wherein the angle is less than 30 degrees as far as possible, stopping punching until the position of the dura mater, and pricking the dura mater by using the tip of a scalpel to fully expose brain tissues without damaging blood vessels and cortex as far as possible.

(5) The cannula is slowly inserted into the corresponding brain region and cranial nails are embedded in the other three holes.

(6) The sleeve, the skull and the skull nail are tightly adhered by adopting denture cement, the setting time is 5-10min after the powder and the solvent are mixed according to the proportion, and the surface of an adhered object is prevented from having water, otherwise, the adhesion is not firm.

(7) After the denture powder self-solidifying plastic is completely solidified, the device for fixing the sleeve is loosened, and lincomycin lidocaine gel is smeared after the operation to prevent infection.

(8) The mice are returned to the cages, and rest for 5-7 days, and then subsequent experiments are carried out after recovery.

(9) When in administration, the inner core is taken out, and the administration needle enters the administration from the sleeve. The inner core is inserted after the administration is finished.

2.2 drug concentration:

2.2.1 injection of the agonist Cabergoline of dopamine D2 receptor into the brain region of LS (Cabergoline, selelck) in a volume of 0.5. mu.l, at an injection concentration of 2. mu.g/. mu.l, at an injection rate of 0.05. mu.l/min, at an injection time of 10min, with 5min needle retention.

2.2.2 injection of the agonist Cabergoline of the poly D2 dopamine receptor into the brain region of LS (Cabergoline, selelck) in a volume of 0.5. mu.l, injection concentration of 4. mu.g/. mu.l, injection rate of 0.05. mu.l/min, injection time of 10min, needle retention of 5 min.

2.3 behavioural experiments

2.3.1 open field experiment: the experiment was performed by the Anymaze software, in which the bottom of the open field was evenly divided into 25 cells, nine cells in the middle were set as the central area, and 16 cells in the periphery were set as the peripheral area. The mouse is placed in the central area of the bottom of the box body by pulling the tail of the mouse by hands, and simultaneously, a software start button is clicked to start recording and analyzing, the observation time is 5min, and the period is required to be kept quiet. After the arrival time, the animals were retrieved, the animal excreta on the inner wall of the open field was washed with alcohol, and the above operation was repeated after the animals were replaced.

2.3.2 elevated plus maze experiment: this experiment is most often used to assess anxiety in mice that normally stay in the closed arm due to high natural fear, but occasionally go to open arm for exploration due to curiosity. The mouse was gently placed in the center of the elevated plus maze facing the open arm side. And recording for 5min, and counting the time and times for the mice to open and close arms, and the behavioral parameters such as immobility, stagnation and the like related to anxiety. After the time is reached, the animal is retrieved, the open and closed arms and animal waste are rinsed with alcohol, and the procedure is repeated after the animal is replaced.

2.3.3 Drinking and eating experiments: animals were not restricted to food and water before the start of the experiment and were housed individually in a single cage per mouse. After the experiment is started, the mice are placed in experimental cages, 20g of food and 200g of water are weighed in each cage, and the residual food and water amount at the 30 th, 60 th and 90 th min are recorded respectively.

2.3.4 New environmental feeding inhibition experiments: the sugar water preference experiment is divided into an adaptive training part and a testing part.

In the adaptation training part, two bottles of 1% (w/v) sucrose solution are placed in each cage of the mice in the first 24 hours, one of the bottles of sucrose solution is changed into purified water in the second 24 hours, and after the adaptation period is finished, the food and water of the mice are removed and the mice are fasted for 24 hours.

In the test period, 200g of 1% sugar water and 200g of purified water were weighed in advance, and the mouse was allowed to move freely between two water bottles containing equal volumes, and the sugar water consumption and the purified water consumption were measured at 30min, 60min, and 90min, respectively. Two bottles were taken and weighed and the total liquid consumption, sugar water consumption and pure water consumption of the mice were recorded.

2.3.5 sugar water preference experiments: animals were fasted for 24h before the start of the experiment and food-fixed white filter paper was fixed in the bottom central region before the experiment. During the experiment, a mouse is placed into the box from any corner of the box, the camera above the box records the 5min movement of the mouse in the box, and meanwhile, the time (feeding latency) from the time when the mouse is placed to the time when the forelimb of the mouse holds the food to eat is calculated, the times of entering the area where the food is located are calculated, and the time of waiting in the area where the food is located is calculated.

3. Results of the experiment

3.1 Effect of administration of lateral synucleinergrine on anxiety-like behavior in open field experiments in mice

A cannula was embedded in the LS brain region of a wild type mouse, and after one week of sterilization and repair, Cabergoline (Cabergoline, select Co., injection volume 0.5. mu.l, injection concentration 2. mu.g/. mu.l, injection concentration 4. mu.g/. mu.l, injection rate 0.05. mu.l/min, injection time 10min, needle retention 5 min) which is an agonist of dopamine receptors was injected into the LS brain region by a micro-injection pump.

In open field experiments, mice injected with dopamine agonist showed a decrease in anxiety state compared to the saline group. The effect of the medicine is optimal after two hours of administration in three times of half an hour, 2 hours and 24 hours. The time for the mice administered to seek the central region increased (fig. 1A, two-way anova, F-6.419, p-0.014, F-6.716, p-0.019, F-5.126, p-0.020). The mice were administered with increased locomotor speed in the open field compared to the control group and were statistically significant (fig. 1B, two-factor analysis of variance, F-5.266, p-0.002, F-17.3006, p-0.000, F-16.86, p-0.001). There was no significant difference between the time-administered group and the control group, which were immobilized in the open field (fig. 1C).

FIG. 1 Effect of administration of LS cabergoline on anxiety-like behavior in mice in open field experiments

A：SD：control＝15.22％±14.03％，2hDA(+)2ug-ul＝33.47％±6.72％，2hDA(+)4ug-ul＝31.62％±6.77％，24hDA(+)4ug-ul＝31.40％±8.68％；

B：SD：control＝0.85±0.34，30minDA(+)2ug-ul＝1.44±0.26，2hDA(+)2ug-ul＝1.54±0.81，24hDA(+)2ug-ul＝1.50±0.29

3.2 Effect of administration of lateral Compartment cabergoline on anxiety-like behavior in the elevated plus maze test in mice

In the elevated plus maze experiment, the dopamine agonist injection group showed a decrease in anxiety level at both concentrations of 2. mu.g/. mu.l and 4. mu.g/. mu.l as compared with the saline administration group. The time for searching the arm-removed area of the mice administered with the drug was significantly increased compared to the control mice (fig. 2B, two-factor analysis of variance, F-5.118, p-0.006, F-3.76, p-0.026, F-10.47, p-0.007, F-8.760, p-0.000, F-3.24, p-0.016). Both immobility time and clotting time were reduced in the mice dosed compared to the control group (FIGS. 2C-D). The mice given the drug had no significant difference in locomotor speed in the open field compared to the control group (fig. 2E).

FIG. 1 Effect of LS dopamine agonist administration on anxiety-like behavior in mice in an elevated plus maze experiment

B：SD：control＝2.21％±2.86％，2hDA(+)2ug-ul＝18.34％±17.20％，24hDA(+)2ug-ul＝15.13％±8.77％，30minDA(+)4ug-ul＝17.34％±11.25％，2hDA(+)4ug-ul＝25.16％±13.51％，24hDA(+)4ug-ul＝16.32％±11.19％

C：SD：control＝66.84％±13.31％，2hDA(+)2ug-ul＝40.26％±31.66％，30minDA(+)4ug-ul＝40.58％±11.39％，2hDA(+)4ug-ul＝40.76％±9.17％，24hDA(+)4ug-ul＝49.21％±14.17％

D：SD：control＝66.88％±12.05％，2hDA(+)2ug-ul＝47.96％±26.29％，30minDA(+)4ug-ul＝42.18％±6.55％，2hDA(+)4ug-ul＝49.38％±15.00％，24hDA(+)4ug-ul＝47.36％±20.60％

3.3 Effect of administration of lateral septate Carbergoline on anxiety-like behavior in mice in Water intake and Drinking experiments

In the experiment of eating and drinking water, the mice in the group injected with dopamine agonist had no change in food intake compared with the group given physiological saline (fig. 3A-C). The water intake of the mice administered was significantly reduced (fig. 3D-F, single factor analysis of variance, water intake in 30min p 0.036, p 0.006, 60min p 0.005, p 0.034, 90min p 0.002).

FIG. 2 Effect of LS cabergoline administration on anxiety-like behavior in mice in Water and food intake experiments

D：SD：saline＝0.467±0.144，DA(+)2ug-ul＝0.267±0.172，DA(+)4ug-ul＝0.192±0.132

E：SD：saline＝1.050±0.126，DA(+)2ug-ul＝0.850±0.230，DA(+)4ug-ul＝0.542±0.180

F：SD：saline＝1.517±0.178，DA(+)2ug-ul＝1.358±0.412，DA(+)4ug-ul＝1.108±0.220

3.4 Effect of administration of lateral septate Carbergoline on anxiety-like behavior in New environmental feeding inhibition experiments in mice

In the new environment feeding inhibition experiment, the time for searching the food-free area of the dopamine agonist-injected mice was increased compared to the saline-injected mice (fig. 4A, two-factor analysis of variance, F-5.560, p-0.002, F-9.887, p-0.005, F-14.887, p-0.000), the feeding latency was decreased (fig. 4B, two-factor analysis of variance, F-6.893, p-0.000, F-4.792, p-0.002, F-7.42, p-0.004, F-9.748, p-0.001), and the number of food-free areas was significantly increased (fig. 4C, two-factor analysis, F-3.211, p-0.010).

FIG. 3 Effect of LS cabergoline administration on anxiety-like behavior in mice in New Environment feeding inhibition experiments

A：SD：saline＝21.16％±12.80％，2hDA(+)2ug-ul＝56.88％±17.90％，30minDA(+)4ug-ul＝53.36％±29.01％，2hDA(+)4ug-ul＝69.72％±14.89％

B：SD：saline＝123.33±87.42，30minDA(+)2ug-ul＝21.33±11.27，2hDA(+)2ug-ul＝15.83±4.79，30minDA(+)4ug-ul＝40.50±16.97，2hDA(+)4ug-ul＝30.00±19.75

C：SD：saline＝26.83±7.41，2hDA(+)2ug-ul＝58.67±18.21

3.5 Effect of administration of lateral septate Carbergoline on anxiety-like behavior in sugar Water preference experiments in mice

In the sugar preference experiment, the sugar preference of the dopamine agonist-injected mice was increased and statistically significant compared to the saline-injected mice (fig. 5A-C, one-way anova, sugar prediction in 30min p 0.000, sugar prediction in 60min p 0.000, sugar prediction in 90min p 0.000, p 0.000).

FIG. 4 Effect of LS cabergoline on anxiety-like behavior in mice in sugar Water preference experiments

A：SD：saline＝49.56％±8.53％，DA(+)2ug-ul＝95.22％±4.74％，DA(+)4ug-ul＝96.81％±3.91％

B：SD：saline＝44.36％±6.11％，DA(+)2ug-ul＝91.81％±6.58％，DA(+)4ug-ul＝93.65％±2.56％

C：SD：saline＝46.49％±3.54％，DA(+)2ug-ul＝88.77％±4.59％，DA(+)4ug-ul＝90.55％±2.85％

And (4) conclusion:

the results of the experiments with the drug administration in mouse LS for the tube-embedding showed: dopamine receptors in the brain region of LS are involved in regulating anxiety-like behavior in mice. Mice showed a significant reduction in anxiety when injected with the dopamine D2 receptor agonist cabergoline.

Therefore, cabergoline is suggested to activate dopamine receptors in the brain region of LS, and can relieve anxiety-like behaviors of mice and generate an anxiolytic effect.

The above description is intended to describe in detail the preferred embodiments of the present invention, but the embodiments are not intended to limit the scope of the claims of the present invention, and all equivalent changes and modifications made within the technical spirit of the present invention should fall within the scope of the claims of the present invention.

Claims (5)

1. Use of cabergoline for the preparation of a pharmaceutical composition for the treatment of anxiety disorders, characterized in that: in particular to the application of cabergoline which is an agonist of dopamine d2 receptor in preparing a medicinal composition for treating anxiety disorder.

2. Use of cabergoline according to claim 1 for the preparation of a pharmaceutical composition for the treatment of anxiety disorders, characterized in that: the pharmaceutical composition is a clinically acceptable pharmaceutical preparation prepared by taking cabergoline as a main component and adding pharmaceutically acceptable auxiliary materials or auxiliary components.

3. Use of cabergoline according to claim 2 for the preparation of a pharmaceutical composition for the treatment of anxiety disorders, characterized in that: the pharmaceutical preparation comprises two dosage forms of an oral preparation and an injection preparation.

4. Use of cabergoline according to claim 3 for the preparation of a pharmaceutical composition for the treatment of anxiety disorders, characterized in that: the oral preparation is an oral capsule, and the injection preparation is intravenous injection.

5. Use of cabergoline according to claim 1 for the preparation of a pharmaceutical composition for the treatment of anxiety disorders, characterized in that: cabergoline is injected into the lateral metakaryotic brain region by intracranial administration, and has anxiolytic effect.

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