CN105288036A

CN105288036A - Pharmaceutical composition for treating myocardial infarction and preparing method thereof

Info

Publication number: CN105288036A
Application number: CN201510698652.1A
Authority: CN
Inventors: 叶宗耀
Original assignee: Individual
Current assignee: Individual
Priority date: 2015-09-30
Filing date: 2015-10-26
Publication date: 2016-02-03

Abstract

The invention belongs to the technical field of traditional Chinese medicine, and relates to a pharmaceutical composition for treating myocardial infarction and a preparing method thereof. The pharmaceutical composition is prepared from, by weight, 8-15 parts of vitex, 8-15 parts of pseudo-ginseng, 6-15 parts of burdock, 3-12 parts of dandelion, 6-15 parts of fennel, 9-12 parts of Chinese yam, 6-12 parts of dogwood, 6-12 parts of cinnamon, 3-12 parts of monkshood, 6-9 parts of red rhodobryum and 1-10 parts of liquorice. The pharmaceutical composition can invigorate blood circulation, remove stasis and tonify spleen and qi and has the advantages of being good in curative effect, mild in side effect, convenient to take, easy to apply and popularize and the like.

Description

A kind of pharmaceutical composition for the treatment of myocardial infarction and preparation method thereof

Technical field

The invention belongs to technical field of Chinese medicines, particularly relate to a kind of pharmaceutical composition for the treatment of myocardial infarction and preparation method thereof.

Background technology

Myocardial infarction is the disease of the part myocardial necrosis caused due to the lasting severe ischemic of cardiac muscle, multiple be born in the middle age after, have the symptom such as the similar anginal front chest pain of violent and lasting character, cardiopalmus, asthma, weak and faint pulse, blood pressure reduction during morbidity.Primary disease incidence rate has and increases trend year by year, and arteriosclerosis accounts for 98% of Pathogenesis of Acute Myocardial Infarction rate, and patient more than 40 years old is in the majority, and many with hypertension, and nearly half is angor medical history intentionally.

In treatment, be broadly divided into two classes: one is take stopgap measures and effect a permanent cure, i.e. " symptomatic treatment in acute condition, radical treatment in chronic case "; Two is routine treatment and contrary treatment, i.e. " treating with drugs opposite to the nature of disease is called routine treatment, contrary treatment means that the remedy coincides with the pseudo-symptom of disease ", and the one that routine treatment is its syndrome character inverse and controls commonly uses therapeutic rules, and contrary treatment is a kind of Therapeutic Method of being obedient to disease illusion and controlling.The present traditional Chinese medical science thinks that the main pathogenesis of coronary heart disease myocardial infarction is deficiency in origin and excess in superficiality, and deficiency in origin is based on the deficiency of vital energy, the deficiency of YIN, and mark is real turbid common with the stagnation of QI, blood stasis, expectorant.The ancient prescription traditional Chinese medical science proposes phlegm and blood stasis theory, thinks body fluid transporting mistake department, stops poly-ly forming expectorant; Escape of blood from meridians, stays in arteries and veins outer or stagnant in arteries and veins, causes blood stasis expectorant to stop or expectorant is poly-hinders blood; Or the expectorant stasis of blood is changed mutually, stagnant in passages through which vital energy circulates to expectorant stasis blocking eventually, phlegm and blood stasis and causing a disease; And myocardial infarction be divided into type of deficiency of both QI and YIN, deficiency of YANG QI weak type, the expectorant stasis of blood to hand over three types such as resistance qi stagnation and blood stasis type, control respectively with supplementing QI and nourishing YIN, QI invigorating warming YANG, dissipating phlegm and removing blood stasis.

China applies for a patent 201410113088.8 and discloses a kind of pharmaceutical composition for the treatment of myocardial infarction, its raw materials comprises: Galla Chinensis, Flos Lonicerae, the Cortex Eucommiae, Radix Cirsii Japonici, Rhizoma Chuanxiong, Radix Rehmanniae, Periostracum Cicadae, Poria, the Radix Paeoniae Alba, Radix Codonopsis and Radix Glycyrrhizae, this pharmaceutical composition has good therapeutic effect in treatment myocardial infarction, there is significant clinical generalization value, but the effect in supplementing QI and nourishing YIN, blood circulation promoting and blood stasis dispelling etc. not very remarkable.

Summary of the invention

The technical problem to be solved in the present invention is to provide a kind of pharmaceutical composition for the treatment of myocardial infarction, this pharmaceutical composition has effect of blood circulation promoting and blood stasis dispelling and invigorating the spleen and replenishing QI, also have that preparation technology is simple, good effect, side effect be low, taking convenience and be easy to advantages such as applying, in addition, the present invention also provides corresponding manufacturing process to be made and facilitate easy-to-use preparation under the prerequisite ensureing curative effect by this pharmaceutical composition.

Pharmaceutical composition of the present invention comprises the raw materials of following parts by weight: Herba Viticis Cannabifoliae 8-15 part, Radix Notoginseng 8-15 part, Fructus Arctii 6-15 part, Herba Taraxaci 3-12 part, Fructus Foeniculi 6-15 part, Rhizoma Dioscoreae 9-12 part, Fructus Corni 6-12 part, Cortex Cinnamomi 6-12 part, Radix Aconiti Lateralis Preparata 3-12 part, Rhodobryum roseum Limpr. 6-9 part and Radix Glycyrrhizae 1-10 part.

Preferably, described pharmaceutical composition comprises the raw materials of following parts by weight: Herba Viticis Cannabifoliae 6-10 part, Radix Notoginseng 8-10 part, Fructus Arctii 6-10 part, Herba Taraxaci 6-9 part, Fructus Foeniculi 6-10 part, Rhizoma Dioscoreae 9-12 part, Fructus Corni 6-10 part, Cortex Cinnamomi 6-10 part, Radix Aconiti Lateralis Preparata 5-10 part, Rhodobryum roseum Limpr. 6-9 part and Radix Glycyrrhizae 2-6 part.

Preferably, described pharmaceutical composition comprises the raw materials of following parts by weight: Herba Viticis Cannabifoliae 15 parts, Radix Notoginseng 12 parts, Fructus Arctii 12 parts, Herba Taraxaci 4 parts, 15 parts, Fructus Foeniculi, Rhizoma Dioscoreae 12 parts, Fructus Corni 12 parts, Cortex Cinnamomi 12 parts, Radix Aconiti Lateralis Preparata 10 parts, Rhodobryum roseum Limpr. 9 parts and 10 parts, Radix Glycyrrhizae.

Preferably, described pharmaceutical composition comprises the raw materials of following parts by weight: Herba Viticis Cannabifoliae 10 parts, Radix Notoginseng 6 parts, Fructus Arctii 10 parts, Herba Taraxaci 12 parts, 10 parts, Fructus Foeniculi, Rhizoma Dioscoreae 10 parts, Fructus Corni 9 parts, Cortex Cinnamomi 9 parts, Radix Aconiti Lateralis Preparata 9 parts, Rhodobryum roseum Limpr. 7 parts and 9 parts, Radix Glycyrrhizae.

Preferably, described pharmaceutical composition is made into tablet, capsule, drop pill, granule or powder.

Correspondingly, present invention also offers the preparation method of the pharmaceutical composition of described treatment myocardial infarction, comprise following step:

A) Herba Viticis Cannabifoliae is taken, be ground into coarse powder, be placed in supercritical carbon dioxide extraction apparatus, the volume fraction adding coarse powder weight 30-45% is the ethanol of 60-85%, and regulation and control carbon dioxide flow is 15-20L/h, and extracting pressure is 15-20MPa, extraction temperature is 40-60 DEG C, extraction time is 1.5-2h, and decompression separation obtains Herba Viticis Cannabifoliae extract, retains Herba Viticis Cannabifoliae residue;

B) take Radix Notoginseng, Fructus Arctii, Herba Taraxaci, Fructus Foeniculi, Rhizoma Dioscoreae, Fructus Corni, Cortex Cinnamomi, Radix Aconiti Lateralis Preparata, Rhodobryum roseum Limpr. and Radix Glycyrrhizae, add described Herba Viticis Cannabifoliae residue, pulverize, add 3-6 times amount water soaking after 1-5 hour, boil 30-60 minute, filter, obtain filtrate, 2-5 times of water gaging is added in filtering residue, boil 30-60 minute, then use slow fire boiling 1-2 hour, filter, obtain filtrate, merge twice filtrate;

C) described Herba Viticis Cannabifoliae extract and described twice filtrate are mixed, be concentrated into the thick paste that relative density is 1.20-1.35, vacuum belt type drying is carried out at 50-60 DEG C of temperature, drying pressure is-0.09MPa, charging rate is 15L/h, and material strip transfer rate is 26cm/min, is pulverized by dry extract after drying, cross 100-200 mesh sieve, to obtain final product.

Source, the nature and flavor of the present invention's component used, return through and effect:

Herba Viticis Cannabifoliae: the Herba Viticis Cannabifoliae in the present invention refers to Caulis Viticis Cannabifoliae is the stem of Verbenaceae Herba Viticis Cannabifoliae, and acrid in the mouth, micro-hardship, property are flat; Function cures mainly expelling pathogenic wind from the body surface, reducing swelling and alleviating pain.Flu, sore throat and skin ulcer are swollen etc. and has certain curative effect.

Radix Notoginseng is the dry root welding technology of panax araliaceae plant, has dissipating blood stasis hemostasis, effect of subduing swelling and relieving pain.In addition, also have comprise hemostasis, antithrombotic, promotion hemopoietic, expand blood vessel, blood pressure lowering, resist myocardial ischemia, anti-cerebral ischemia, arrhythmia, atherosclerosis, antiinflammatory, protect the liver, antitumor, the effect such as analgesia, principle active component is PNS, PDS, PTS and Radix Notoginseng propylhomoserin.

Fructus Arctii is Compositae draft taproot class plant, and be a kind of vegetable edible with loose fleshy tap root, petiole and tender leaf also edible, Fructus Arctii and Radix Arctii also can be used as medicine.The fiber of Fructus Arctii can promote intestinal peristalsis, helps defecation, reduces body inner cholesterol, and minimizing toxin, refuse accumulate in vivo, reaches prevention of stroke and the effect of preventing and treating gastric cancer, uterus carcinoma.Doctor trained in Western medicine thinks that it is except having diuresis, removing food stagnancy, eliminating the phlegm except the pharmacological actions such as stopping leak, also for the dietetic therapy of constipation, hypertension, high-cholesterol disease.The traditional Chinese medical science thinks effects such as having wind-dispelling heat-dissipating, lung qi dispersing rash, resolving toxin and disinhibiting the throat.

Dandelion Compositae herbaceos perennial.Head inflorescence, the bobbles that on seed, adularescent pappus is formed, new life is bred in the new place that racks after the flowers are in blossom.Containing multiple health-nutrition compositions such as taraxol, taraxacin, choline, organic acid, inulin in Herba Taraxaci plant, there are the effects such as diuresis, cathartic, jaundice eliminating subcutaneous ulcer, function of gallbladder promoting.Herba Taraxaci containing protein, fat, carbohydrate, trace element and vitamin etc., has abundant nutritive value simultaneously.In addition, also there is heat-clearing and toxic substances removing, effect of dispersing swelling and dissipating binds.

The main component of Fructus Foeniculi is Oleum Anisi Stellati, energy stimulating gastrointestinal neural blood vessel, and facilitating digestion liquid is secreted, and increases gastrointestinal peristalsis, gets rid of the gas accumulated, so there is effect of stomach invigorating, circulation of qi promoting; Sometimes gastrointestinal peristalsis can reduce again after excitement, thus contributes to alleviating spasm, easing the pain.Chinese medicine is used as medicine, and warm in nature, acrid in the mouth, returns liver,kidney,spleen, stomach warp.Function warming the liver kidney, warming the stomach gas, loose plug knot, dispersing cold for relieving pain, regulating qi-flowing for harmonizing stomach.Fructus Foeniculi also has antiulcer, analgesia, gonadotropic Effect etc., and Oleum Anisi Stellati has antibacterial action in various degree.Energy stimulating gastrointestinal neural blood vessel, promotes saliva and gastric secretion, plays appetite stimulator, digestive effect.Be applicable to Deficiency and coldness of spleen and stomach.

Rhizoma Dioscoreae: be the dry rhizome of Dioscoreaceae plant Rhizoma Dioscoreae; Sweet in the mouth, property is put down; Return spleen, lung, kidney channel; Spleen reinforcing nourishing the stomach, promote the production of body fluid lung benefiting, the kidney invigorating arresting seminal emission.

Fructus Corni officinalis contains abundant nutrient substance and functional component, and the experience of the Compendium of Material Medica collection ancient Chinese medicine doctor application Fructus Corni of Ming Dynasty's Li Shizhen (1518-1593 A.D.), the medicine that Fructus Corni is classified as controlling nocturnal emission with astringent drugs of enriching blood, liver and kidney tonifying, regulating QI, tonify deficiency, improving eyesight and keeps fit.

Cortex Cinnamomi is the dry bark of canella Cortex Cinnamomi; Acrid in the mouth, sweet, extremely hot in nature; Return kidney, spleen, the heart, Liver Channel; Mend fire supporing yang, let the fire back to its origin, dispersing cold for relieving pain, promoting blood circulation to restore menstrual flow.

Radix Aconiti Lateralis Preparata, has another name called Aconitum carmichjaelii Debx. or Radix Aconiti Lateralis Preparata, the processed goods of the daughter root of Ranunculaceae, aconitum plant.Function cures mainly: recuperating depleted YANG and rescuing the patient from collapse, mend fire supporing yang, dispersing cold for relieving pain.

Rhodobryum roseum Limpr. is a kind of Chinese herbal medicine, and plant body is little, the micro-hardship of taste, can as the treatment of heart disease or other mental disorder.Specially control that heart disease is nervous, cardiopalmus, the symptoms such as neurasthenia.

Radix Glycyrrhizae is the dry root of glycyrrhizic legume, Glycyrrhiza inflata Bat. or Glycyrrhiza glabra L., and Radix Glycyrrhizae contains glycyrrhizic acid, liquiritin isoreactivity composition, has the effects such as heat-clearing and toxic substances removing, invigorating the spleen and replenishing QI, expelling phlegm for arresting cough.

Compared with prior art, the present invention has following beneficial effect:

1, compared with the Chinese medicine of other treatment myocardial infarction, pharmaceutical composition of the present invention has more remarkable efficacy in blood circulation promoting and blood stasis dispelling and invigorating the spleen and replenishing QI etc.

2, compared with chemotherapeutic agent, pharmaceutical composition of the present invention is natural pure Chinese medicinal preparation, and untoward reaction significantly reduces, and pharmaceutical composition effect of the present invention is comprehensive, medication effect is better, is used for the treatment of myocardial infarction disease, has good effect, taking convenience and is easy to advantages such as applying.

Detailed description of the invention

It will be understood by those skilled in the art that technology disclosed in following examples represents the technology playing good action in the practice of the invention of the present inventor's discovery.But, many changes can be made in disclosed specific embodiments, and still obtain same or analogous result, and not depart from the spirit and scope of the present invention.

embodiment 1

Pharmaceutical composition of the present invention is prepared from by the raw material of following parts by weight: Herba Viticis Cannabifoliae 6 parts, Radix Notoginseng 10 parts, Fructus Arctii 6 parts, Herba Taraxaci 9 parts, 6 parts, Fructus Foeniculi, Rhizoma Dioscoreae 9 parts, Fructus Corni 6 parts, Cortex Cinnamomi 6 parts, Radix Aconiti Lateralis Preparata 5 parts, Rhodobryum roseum Limpr. 6 parts and 2 parts, Radix Glycyrrhizae.

Preparation method is as follows: take Herba Viticis Cannabifoliae, be ground into coarse powder, be placed in supercritical carbon dioxide extraction apparatus, the volume fraction adding coarse powder weight 30% is the ethanol of 75%, and regulation and control carbon dioxide flow is 20L/h, and extracting pressure is 15MPa, extraction temperature is 50 DEG C, extraction time is 2h, and decompression separation obtains Herba Viticis Cannabifoliae extract, retains Herba Viticis Cannabifoliae residue; Take Radix Notoginseng, Fructus Arctii, Herba Taraxaci, Fructus Foeniculi, Rhizoma Dioscoreae, Fructus Corni, Cortex Cinnamomi, Radix Aconiti Lateralis Preparata, Rhodobryum roseum Limpr. and Radix Glycyrrhizae, add described Herba Viticis Cannabifoliae residue, pulverize, add 4 times amount water soakings after 3 hours, boil 60 minutes, filter, obtain filtrate, 2 times of water gagings are added in filtering residue, boil 60 minutes, then use slow fire boiling 1 hour, filter, obtain filtrate, merge twice filtrate; Described Herba Viticis Cannabifoliae extract and described twice filtrate are mixed, be concentrated into the thick paste that relative density is 1.25, vacuum belt type drying is carried out at 60 DEG C of temperature, drying pressure is-0.09MPa, charging rate is 15L/h, and material strip transfer rate is 26cm/min, is pulverized by dry extract after drying, cross 100 mesh sieves, obtain pharmaceutical composition.

embodiment 2:

Pharmaceutical composition of the present invention is prepared from by the raw material of following parts by weight: Herba Viticis Cannabifoliae 15 parts, Radix Notoginseng 12 parts, Fructus Arctii 12 parts, Herba Taraxaci 4 parts, 15 parts, Fructus Foeniculi, Rhizoma Dioscoreae 12 parts, Fructus Corni 12 parts, Cortex Cinnamomi 12 parts, Radix Aconiti Lateralis Preparata 10 parts, Rhodobryum roseum Limpr. 9 parts and 10 parts, Radix Glycyrrhizae.

Preparation method is as follows: take Herba Viticis Cannabifoliae, be ground into coarse powder, be placed in supercritical carbon dioxide extraction apparatus, the volume fraction adding coarse powder weight 45% is the ethanol of 70%, and regulation and control carbon dioxide flow is 15L/h, and extracting pressure is 18MPa, extraction temperature is 45 DEG C, extraction time is 2h, and decompression separation obtains Herba Viticis Cannabifoliae extract, retains Herba Viticis Cannabifoliae residue; Take Radix Notoginseng, Fructus Arctii, Herba Taraxaci, Fructus Foeniculi, Rhizoma Dioscoreae, Fructus Corni, Cortex Cinnamomi, Radix Aconiti Lateralis Preparata, Rhodobryum roseum Limpr. and Radix Glycyrrhizae, add described Herba Viticis Cannabifoliae residue, pulverize, add 5 times amount water soakings after 2 hours, boil 45 minutes, filter, obtain filtrate, 4 times of water gagings are added in filtering residue, boil 30 minutes, then use slow fire boiling 2 hours, filter, obtain filtrate, merge twice filtrate; Described Herba Viticis Cannabifoliae extract and described twice filtrate are mixed, be concentrated into the thick paste that relative density is 1.35, vacuum belt type drying is carried out at 60 DEG C of temperature, drying pressure is-0.09MPa, charging rate is 15L/h, and material strip transfer rate is 26cm/min, is pulverized by dry extract after drying, cross 100 mesh sieves, obtain pharmaceutical composition.

embodiment 3:

Pharmaceutical composition of the present invention is prepared from by the raw material of following parts by weight: Herba Viticis Cannabifoliae 15 parts, Fructus Arctii 15 parts, Radix Notoginseng 9 parts, Herba Taraxaci 12 parts, 15 parts, Fructus Foeniculi, 9 parts, Flos Carthami, Fructus Crataegi 12 parts, Fructus Corni 12 parts, Cortex Cinnamomi 12 parts, Radix Aconiti Lateralis Preparata 10 parts, Rhodobryum roseum Limpr. 9 parts and 10 parts, Radix Glycyrrhizae.

Preparation method is similar to Example 1.

clinical observation on the therapeutic effect

1, case selection: in 300 routine myocardial infarction clinical patients volunteers, male 150 example, female patient 150 example, age bracket be 40-60 year, all patients all has typical myocardial infarction clinical symptoms, and in sex, age, the course of disease no difference of science of statistics.

2, diagnostic criteria:

(1) typical myocardial ischemia symptom (chest pain or discomfort uncomfortable in chest);

(2) typical cardiac electrical figure change;

(3) Serum fibrosis markers raises.

3, efficacy assessment standard:

Cure: after drug administration, malaise symptoms disappears completely;

Effective: after drug administration, malaise symptoms alleviates or partial disappearance;

Invalid: after drug administration, malaise symptoms is unchanged;

Total effective rate=(cure+effectively)/total number of cases × 100%.

4, instructions of taking: 300 patient volunteers are divided into 3 groups at random, often organize 100 people, is respectively treatment A group, treatment B group and positive controls, treatment A group and treatment B component do not take the pharmaceutical composition that the embodiment of the present invention 1,2 prepares, every day 3 times, each 10-20g, serve on 1 month.Positive controls takes FUFANG DANSHEN DIWAN (Tianjin Tasly Pharmaceutical Co., Ltd, the accurate word Z10950111 of traditional Chinese medicines), and oral or sublingual administration, 10 balls, 3 times on the one, serve on 1 month.

5, therapeutic outcome: as shown in table 1.

table 1 therapeutic outcome

Group	Number	Cure	Effectively	Invalid	Total effective rate
						Treatment A group	100	84	10	6	94％
Treatment B group	100	83	8	9	91％
						Positive controls	100	69	10	21	79％

Compared by the therapeutic effect of pharmaceutical composition of the present invention and FUFANG DANSHEN DIWAN, the curative effect of medicine composite for curing myocardial infarction aspect of the present invention can be found out.Make inventor surprisingly, the cure rate of pharmaceutical composition of the present invention reaches more than 80%, total effective rate reaches more than 90%, far above cure rate and the total effective rate of positive controls, wherein best with the therapeutic effect for the treatment of A group, visible, the good effect of pharmaceutical composition of the present invention, cure rate is high, can be used as the drug use for the treatment of myocardial infarction.

Owing to describing the present invention by above preferred embodiment, in spirit of the present invention and/or scope, any for replacement/of the present invention or combination implement the present invention, be all apparent for a person skilled in the art, and be included among the present invention.

Claims

1. treat the pharmaceutical composition of myocardial infarction for one kind, it is characterized in that, comprise the raw materials of following parts by weight: Herba Viticis Cannabifoliae 8-15 part, Radix Notoginseng 8-15 part, Fructus Arctii 6-15 part, Herba Taraxaci 3-12 part, Fructus Foeniculi 6-15 part, Rhizoma Dioscoreae 9-12 part, Fructus Corni 6-12 part, Cortex Cinnamomi 6-12 part, Radix Aconiti Lateralis Preparata 3-12 part, Rhodobryum roseum Limpr. 6-9 part and Radix Glycyrrhizae 1-10 part.

2. the pharmaceutical composition for the treatment of myocardial infarction as claimed in claim 1, it is characterized in that, comprise the raw materials of following parts by weight: Herba Viticis Cannabifoliae 6-10 part, Radix Notoginseng 8-10 part, Fructus Arctii 6-10 part, Herba Taraxaci 6-9 part, Fructus Foeniculi 6-10 part, Rhizoma Dioscoreae 9-12 part, Fructus Corni 6-10 part, Cortex Cinnamomi 6-10 part, Radix Aconiti Lateralis Preparata 5-10 part, Rhodobryum roseum Limpr. 6-9 part and Radix Glycyrrhizae 2-6 part.

3. the pharmaceutical composition for the treatment of myocardial infarction as claimed in claim 1, it is characterized in that, comprise the raw materials of following parts by weight: Herba Viticis Cannabifoliae 15 parts, Radix Notoginseng 12 parts, Fructus Arctii 12 parts, Herba Taraxaci 4 parts, 15 parts, Fructus Foeniculi, Rhizoma Dioscoreae 12 parts, Fructus Corni 12 parts, Cortex Cinnamomi 12 parts, Radix Aconiti Lateralis Preparata 10 parts, Rhodobryum roseum Limpr. 9 parts and 10 parts, Radix Glycyrrhizae.

4. the pharmaceutical composition for the treatment of myocardial infarction as claimed in claim 1, it is characterized in that, comprise the raw materials of following parts by weight: Herba Viticis Cannabifoliae 10 parts, Radix Notoginseng 6 parts, Fructus Arctii 10 parts, Herba Taraxaci 12 parts, 10 parts, Fructus Foeniculi, Rhizoma Dioscoreae 10 parts, Fructus Corni 9 parts, Cortex Cinnamomi 9 parts, Radix Aconiti Lateralis Preparata 9 parts, Rhodobryum roseum Limpr. 7 parts and 9 parts, Radix Glycyrrhizae.

5. the pharmaceutical composition of the treatment myocardial infarction according to any one of Claims 1-4, is characterized in that, described pharmaceutical composition is made into tablet, capsule, drop pill, granule or powder.

6. the preparation method of the pharmaceutical composition of the treatment myocardial infarction as described in any one of claim 1-5, is characterized in that, comprises following step: