Traditional Chinese medicine compound pill for treating femoral head necrosis and preparation method thereof

Abstract

The invention aims to provide a traditional Chinese medicine compound pill for treating femoral head necrosis and a preparation method thereof, and relates to the technical field of traditional Chinese medicine preparation. The traditional Chinese medicine compound pill for treating femoral head necrosis is prepared on the basis of ground beetles, leeches, pseudo-ginseng, rhizoma drynariae, eucommia ulmoides, herba epimedii, turmeric, red ginseng and exocarpium citri grandis. Long-term clinical practice and examination show that the traditional Chinese medicine compound pill has an obvious curative effect on ischemic necrosis of femoral head, especially has an obvious treatment effect on patients with early-stage femoral head necrosis, and avoids side effects such as jaw necrosis and diabetes induced by western medicines such as anticoagulants, statins and anti-osteoporosis medicines; the medicine is convenient to take, does not need to be decocted for a long time by using a professional vessel, and is not limited by time and space; operation treatment is avoided or delayed to a certain extent, and the advantages and effects of oral administration treatment of traditional Chinese medicine are fully exerted.

Description

Technical Field

[0001] The present invention relates to the technical field related to preparation of traditional Chinese medicines, and in particular to a traditional Chinese medicine compound pill for treating femoral head necrosis and a preparation method thereof. Background Art

[0002] Femoral head necrosis refers to the interruption or damage of blood supply to the femoral head, which causes the death and subsequent repair of bone cells and bone marrow components, followed by changes in the structure and collapse of the femoral head, causing joint pain and joint dysfunction in patients. It is a common and intractable disease in the field of orthopedics.

[0003] Modern medicine often uses Western medicine such as anticoagulants, statins, anti-osteoporosis drugs, physical therapy such as hyperbaric oxygen and extracorporeal shock wave, and surgical treatments such as core decompression and total hip replacement to treat femoral head necrosis.

[0004] Among the current Western medicines, there is a lack of high-quality clinical research evidence for the use of anticoagulants such as low molecular weight heparin in the prevention and treatment of femoral head necrosis, and their efficacy is uncertain; bisphosphonates may cause osteonecrosis of the jaw, causing severe pain and decreased quality of life in patients, and have significant side effects; long-term use of statins is associated with the development of diabetes, increasing the risk of new-onset diabetes by 10% to 12%. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides the following technical solutions:

[0006] A Chinese medicinal compound pill for treating femoral head necrosis, comprising Chinese medicinal ingredients, water and refined honey; the Chinese medicinal ingredients include: Eupolyphaga sinensis, leech, Panax notoginseng, Drynaria fortunei, Eucommia bark, Epimedium, Curcuma longa, Red ginseng and Citrus aurantium, wherein the sum of the weight of Drynaria fortunei, Epimedium and Eucommia bark accounts for more than 45% of the total weight of the Chinese medicinal ingredients.

[0007] Furthermore, the Chinese herbal ingredients account for 60-70%, water accounts for 10-15%, and refined honey accounts for 20-25%.

[0008] Furthermore, the proportions of the various components of the traditional Chinese medicine ingredients are: 10-13% of earthworm, 2-4% of leech, 5-8% of Panax notoginseng, 16-18% of Drynaria, 16-18% of Eucommia, 15-17% of Epimedium, 7-12% of Curcuma, 6-8% of Red Ginseng, and 11-13% of Citrus aurantium.

[0009] A method for preparing a Chinese medicinal compound pill for treating femoral head necrosis comprises the following steps:

[0010] S1, 10 parts of Eupolyphaga sinensis, 3 parts of Hirudo, 5 parts of Panax notoginseng, 15 parts of Drynariae Rhizoma, 15 parts of Eucommia ulmoides, 15 parts of Epimedium, 10 parts of Curcuma longa, 10 parts of Red Ginseng, 10 parts of Citrus aurantium as component A, 31.15 parts of refined honey as component B, drying component A to obtain dry component A, i.e. putting component A into a multifunctional Chinese medicine extract drying and sterilizing cabinet for hot air circulation drying at a temperature of 80°C for 4 hours;

[0011] S2, crushing the dry component A into 100 meshes and then performing dry heat sterilization operation A to obtain a dry sterilized component A, that is, crushing the dry component A into 100 meshes and then performing dry heat sterilization in a multifunctional Chinese medicine extract drying and sterilizing cabinet at a temperature of 105° C. for 3 hours;

[0012] S3, mixing the sterilized and dried component A, component B and 17.8 parts of water uniformly to obtain a sludge;

[0013] S4, repeatedly kneading and beating the mud for 5-10 minutes, putting it into a spherical mold for forming, taking it out, and drying it in the shade for 24 hours to obtain the Chinese medicine compound pills.

[0014] Compared with the prior art, the technical solution of this application has the following beneficial effects:

[0015] The present invention obtains a Chinese medicinal compound pill for treating femoral head necrosis based on Chinese medicinal materials. The Chinese medicinal compound pill has been tested through long-term clinical practice and has obvious therapeutic effect on treating avascular necrosis of the femoral head, especially on patients with early femoral head necrosis, avoiding the side effects of jaw necrosis, induced diabetes and the like caused by the use of Western medicines such as anticoagulants, statins and anti-osteoporosis drugs. The medicine is easy to take, does not need to be decocted for a long time using professional utensils, does not have time and space restrictions, avoids or delays surgical treatment to a certain extent, and gives full play to the advantages and functions of oral treatment of traditional Chinese medicine. DETAILED DESCRIPTION

[0016] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] Pharmacological analysis of Chinese medicinal materials involved in this application:

[0018] Earthworm: also known as earthworm, ground turtle, The Chinese earthworm is the dried body of the female Chinese earthworm or Chinese earthworm of the family Testudinidae. It belongs to the liver meridian and has the effects of breaking blood, removing blood stasis, and repairing tendons and bones. It is a typical representative of blood-activating and collateral-unblocking insect drugs. Modern pharmacological studies have shown that Chinese earthworms have multiple effects such as anti-coagulation, thrombolysis, bone healing, lipid regulation, anti-tumor, antibacterial, endothelial cell protection, and anti-ischemia and hypoxia. Among them, the Chinese earthworm active peptide component F2 has the strongest fibrinolytic activity. Through the acute blood stasis model rat model, it is proved that F2 may be an important component of Chinese earthworms in promoting blood circulation and removing blood stasis. Studies have shown that feeding rabbits with experimental fractures caused by surgery with feed containing Chinese earthworms can promote the formation of blood vessels in rabbits with fractures, improve local blood circulation, increase the activity and number of osteoblasts, promote the increase in the number of osteoclasts, accelerate calcium salt deposition and callus growth, and thus promote the healing of bone injuries.

[0019] Leech: Also known as leech, horse turtle, horse leech, horse leech, is the dried whole body of leech, leech or willow leaf leech of Hirudinidae family. It tastes salty and bitter, is neutral in nature, slightly toxic, belongs to the liver meridian, has the effects of breaking blood and promoting menstruation, removing blood stasis and eliminating symptoms, and is clinically used for blood stasis, amenorrhea, lumps, hemiplegia caused by stroke, injuries caused by falls, etc. Modern pharmacological studies have shown that the active ingredients in leeches include hirudin, heparin, antithromboxane, histamine, amino acids, pteridines, glycolipids, carboxylates, Steroids and trace elements have pharmacological effects such as anti-apoptosis, anti-cancer metastasis, anti-inflammation, anti-coagulation, anti-thrombosis, and anti-fibrosis. Leeches have the characteristics of multi-component, multi-target, and multi-pathway in preventing and treating ONFH. Its main pathway not only directly participates in the proliferation, apoptosis, and differentiation of bone cells, and regulates the balance of osteoblastic and osteoclast metabolism, but also intervenes and affects the bone microenvironment by regulating immunity, inflammation, and autophagy, so as to achieve the purpose of controlling the occurrence and development of ONFH.

[0020] Panax notoginseng: It is the root of Panax notoginseng, a plant of the genus Panax, in the Araliaceae family. It has the effects of stopping bleeding, dispersing blood stasis and relieving pain. It is often used to treat coughing up blood, vomiting blood, epistaxis, blood in the stool, bleeding due to trauma, and pain caused by bruises. Pharmacological studies have shown that Panax notoginseng can promote the repair of bone injuries and reduce the accumulation of blood stasis in the early stage of skeletal muscle injuries. The active ingredients of Panax notoginseng can promote the formation, differentiation and mineralization of osteoblasts, and at the same time can promote the differentiation of vascular endothelial cells, increase the maturation of blood vessels and the number of capillaries, and improve local osteogenic activity. Specific components in Panax notoginseng can also inhibit the formation of osteoclasts and bone resorption mediated by RANKL. Within a certain concentration range, Panax notoginseng can enhance the proliferation activity of rat osteoblasts by regulating the expression of molecules such as Runx2, OCN, PCNA and Ki-67.

[0021] Drynaria: It is the dried rhizome of the plant Quercus serrata of the Polypodiaceae family. Drynaria is warm in nature, bitter in taste, and belongs to the liver and kidney meridians. According to the results of modern pharmacology and clinical research, Drynaria has a strong anti-osteoporosis and fracture healing effect. Drynaria water extract, alcohol extract, and Drynaria total flavonoids all have certain anti-osteoporosis activity. They can not only promote the osteogenic differentiation of bone marrow mesenchymal stem cells, but also promote the proliferation of osteoblasts, and have a certain inhibitory effect on bone resorption mediated by osteoclasts, which reveals the possible mechanism of Drynaria in osteoporosis. Drynaria can increase the alkaline phosphatase activity in MC3T3-E1 osteoblasts, promote osteocalcin secretion, and accelerate the formation of mineralized nodules, thereby promoting osteoblast differentiation. In the process of fracture healing, Drynaria can promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promote osteoblast proliferation, thereby increasing the thickness of callus and accelerating fracture healing.

[0022] Eucommia ulmoides: a plant belonging to the Eucommia family, its main components include lignans, iridoids, phenylpropanoids and flavonoids, among which lignans and iridoids account for a larger proportion; Chinese medicine believes that Eucommia ulmoides is sweet, slightly spicy and warm in nature, and has the effects of strengthening tendons and bones, nourishing the liver and kidneys, regulating the Chong and Ren meridians, and consolidating menstruation and stabilizing pregnancy; clinical reports show that Eucommia ulmoides is one of the most frequently used single Chinese medicines for the treatment of osteoporotic fractures. Eucommia ulmoides can significantly increase the bone density of osteoporotic fractures and improve the ability to resist fractures. It has significant clinical efficacy and no obvious adverse reactions ; The main effective chemical components of Eucommia ulmoides in treating osteoporotic fractures include cortisol, betulinic acid, beta-sitosterol, kaempferol, OLIVIL, erythrinain, Acanthopanax senticosus extract, etc.; The mechanism of action of Eucommia ulmoides in treating osteoporotic fractures may be that 19 active ingredients in Eucommia ulmoides regulate 59 genes related to osteoporotic fractures, and play a therapeutic role through the combined action of multiple signal pathways such as apoptosis signal pathway, p53 signal pathway, MAPK signal pathway, PI3K-Akt signal pathway, etc.;

[0023] Epimedium: Modern research shows that the flavonoids in epimedium have anti-osteoporosis, cardiovascular system protection, immune system homeostasis maintenance, anti-aging, anti-tumor, anti-inflammatory and antibacterial effects; epimedium contains a large number of flavonoids, which have estrogen-like effects, antioxidant, free radical scavenging effects, and may have pharmacological effects in preventing and treating osteoporosis. At the same time, the compounds in epimedium can interact with multiple target proteins related to sex hormone levels, osteoclast differentiation, bone matrix degradation and reactive oxygen levels in the body for the treatment of osteoporosis, which may be the main mechanism of epimedium in treating osteoporosis;

[0024] Turmeric: It is the dried rhizome of the plant Curcuma of the ginger family. Its main active ingredients are curcuminoid compounds and volatile oils. Chinese medicine believes that it tastes pungent, bitter, and warm, and it enters the spleen and liver meridians, and has the functions of breaking blood, promoting qi, and relieving pain. It is mainly used to treat chest and flank pain, amenorrhea, masses, rheumatic shoulder and arm pain, and swelling and pain caused by falls. Studies have shown that curcumin can regulate the receptor activator of nuclear factor κB ligand (RANKL) (inducing osteoclast differentiation, activation and function) and reduce inflammatory bone loss. Studies have shown that the number of TRAP(+) cells in preosteoclasts isolated from human peripheral blood treated with 1 and 10 μmol / L curcumin decreased by 56% and 81% respectively compared with the control group, and the bone resorption activity decreased by 56% and 99% respectively, showing a significant dose-related relationship; curcumin (<5 μmol / L) can significantly inhibit homocysteine ​​activity in mouse bone marrow cells, upregulate the expression level and activity of the antioxidant enzyme glutathione peroxidase-1, reduce the level of intracellular ROS generation, and thus inhibit osteoclast differentiation; curcumin can significantly improve various bone tissue morphological indicators impaired by estrogen deficiency, such as bone mass, trabecular thickness and trabecular number; at the same time, curcumin can also significantly increase the number of osteoblasts in OVX rats, inhibit the number of osteoclasts and reduce the area of ​​bone surface erosion;

[0025] Red ginseng: Ginseng is the dried root of the Araliaceae plant Panax ginseng. It has the effects of nourishing yin, benefiting blood, strengthening the stomach, replenishing qi, and strengthening the heart. It is known as the "king of herbs". The chemical components of ginseng include saponins, polysaccharides, polypeptides, enzymes, trace elements, volatile oils, and amino acids. Red ginseng is the dried root and rhizome of ginseng after steaming. After processing, ginseng turns from white to red, producing unique components in red ginseng, which have significant and unique physiological activity. The types of amino acids in the processing of red ginseng remain basically unchanged, but it is easy to cause amino acid loss, with arginine (Arg) losing the most. This is because arginine further undergoes Maillard reaction with maltose or glucose (Maillard reaction) and generate intermediate products arginine monoglucoside and arginine disaccharide; modern research has shown that arginine disaccharide has pharmacological activities such as promoting microcirculation, anti-oxidation, anti-fatigue, and enhancing immune function. Ginsenoside CK in red ginseng can activate the expression of key genes OPN, OCN, OSX and ALP for osteogenic differentiation, and target the Wnt / β-catenin signaling pathway to play an important regulatory role in the differentiation and proliferation of r BMSCs osteoblasts; Ginsenoside CK upregulates the expression of β-catenin and Runx2 in the callus tissue area of ​​the rat femoral fracture model, induces enhanced H-type angiogenesis and coupling with osteogenic differentiation, accelerates calcium salt deposition, vascular reconstruction and bone tissue regeneration, promotes structural repair after femoral fracture, and improves histological manifestations and biomechanical properties;

[0026] Huajuhong: It is the unripe or nearly ripe dried outer peel of Huazhou pomelo, a plant of Rutaceae. Chinese medicine believes that it has a fragrant aroma, bitter and slightly pungent taste, and belongs to the lung and spleen meridians. It has the effects of regulating qi, relieving fullness, drying dampness and resolving phlegm, and is used for cough with phlegm, food accumulation and alcohol damage, nausea and stuffiness; studies have shown that Huajuhong has physiological functions such as anti-inflammatory, antioxidant, anti-thrombotic, alcohol liver detoxification, and hypoglycemic and lipid-lowering. Huajuhong polysaccharides can scavenge superoxide anion free radicals produced by the self-oxidation system of pyrogallol, and have strong antioxidant activity; studies have evaluated the antiplatelet activity of naringin, confirming that naringin can also play a significant antithrombotic role in human blood. Huajuhong naringin plays an antithrombotic role without side effects. The total flavonoid naringin component of Huajuhong has an important anti-inflammatory effect in many diseases, and its mechanism of action is mainly related to inflammatory factors, nuclear factor kappa-B (NF-κB) and NLRP3 inflammasome.

[0027] Embodiment 1:

[0028] A Chinese medicinal compound pill for treating femoral head necrosis and its preparation method:

[0029] Step 1: Accurately weigh 15g of Drynariae Rhizoma, 15g of Epimedium, 15g of Eucommia, 10g of Eupolyphaga, 10g of Curcuma Longa, 10g of Citrus aurantium, 3g of Leech, 5g of Panax Notoginseng, and 6g of Red Ginseng;

[0030] Step 2: Mix the above medicinal ingredients and dry them for 4 hours, then crush them into 100 mesh and dry-heat sterilize them for 3 hours;

[0031] Step 3: Add 31.15g of refined honey and 17.8g of water to mix into a paste. Beat the paste for 10 minutes and then put it into a spherical mold to dry in the shade for 24 hours to make about 178 pills (the amount of raw medicine is 89g).

[0032] Embodiment 2:

[0033] According to Example 1, this example will use clinical control test data to illustrate the advantages of the Chinese medicine compound pill for treating femoral head necrosis prepared by the present application compared with the prior art;

[0034] The invention discloses a clinical efficacy study of a Chinese medicine compound pill for treating femoral head necrosis in treating patients with kidney deficiency and blood stasis syndrome caused by hormonal femoral head necrosis. A total of 48 patients with kidney deficiency and blood stasis syndrome caused by hormonal femoral head necrosis are included. The diagnostic criteria of kidney deficiency and blood stasis syndrome are as follows: dull pain in both hips, stiff joints, thirst and dry throat, accompanied by irritability and insomnia, flushed face, red tongue, dry or greasy yellow fur, and thready pulse. The patient can be diagnosed if two of the above main symptoms are present, or one of the main symptoms and two of the secondary symptoms are present. The observation indexes for efficacy evaluation include pain, range of motion, joint deformity, function, and imaging changes of X-ray films of both hips in anteroposterior position and frog position. There are 26 patients in the Chinese medicine compound pill group for treating femoral head necrosis and 22 patients in the control group. The course of treatment is 6 months.

[0035] Experimental group: the Chinese medicine compound pills for treating femoral head necrosis prepared in Example 1; the treatment method is oral administration, warm and taken twice a day after meals, about 10g each time, 1 month as a course of treatment, a total of 6 courses of treatment;

[0036] Control group: Oral Henggu bone healing agent (Specification of Sailing Pharmaceutical Technology Group Co., Ltd.: 25mL / bottle, National Medicine Standard No.: Z20025103), main ingredients: dried tangerine peel, safflower, Panax notoginseng, Eucommia bark, ginseng, astragalus, turtle shell, datura flower, and radix scutellariae; efficacy: invigorating blood circulation and replenishing qi, nourishing liver and kidney, strengthening tendons and bones; treatment method: oral administration after meals every other day, 25mL each time, 1 month as 1 course of treatment, a total of 6 courses of treatment;

[0037] Main efficacy indicators: 1. Harris score: Harris hip function scale was used for evaluation, including pain, range of motion, joint deformity, and function, with a full score of 100 points. Scores of 90 to 100 points were excellent, 80 to <90 points were good, 70 to <80 points were fair, and <70 points were poor.

[0038] 2. Visual analogue scale (VAS) was used to assess the intensity of hip pain;

[0039] 3. Clinical and imaging evaluation: Imaging evaluation is mainly based on bilateral hip anteroposterior and frog-shaped X-rays at each follow-up visit, mainly to observe whether the femoral head has collapsed or further collapsed, and whether there is any change in the joint space;

[0040] The results showed: 1. VAS score: There were statistically significant differences between the experimental group and the control group at each follow-up time point before treatment (P<0.05), indicating that the VAS scores of patients in both groups improved over time; there were statistically significant differences in the VAS scores between the two groups at 1, 3, and 6 months after treatment (P<0.05), indicating that both drugs had a positive therapeutic effect on SONFH, and the mean VAS scores of the experimental group at 1 month, 3 months, and 6 months after treatment were significantly lower than those of the control group, indicating that the pain symptoms of the experimental group were significantly improved compared with those of the control group.

[0041] 2. Harris score: There was a statistically significant difference between the experimental group and the control group at each follow-up time at 30 points before treatment (P<0.05), indicating that the Harris scores of the two groups of patients improved over time. During the follow-up period, the Harris scores of both groups improved compared with those before treatment, and the improvement of the experimental group was more significant than that of the control group. The treatment effect was more obvious in the sixth month after treatment than in the third month.

[0042] 3. Radiological evaluation: There was a significant difference in the effective rate between the two groups of patients at 1 month and 3 months after treatment (P < 0.05), but there was no significant difference in the effective rate at 6 months after treatment (P > 0.05). After 1 month of follow-up, 28 cases (71.29%) in the experimental group and 15 cases (44.12%) in the control group showed significant improvement; after 3 months of follow-up, there was 1 case of hip deterioration in the experimental group (2.59%) and 4 cases (11.76%) in the control group; after 6 months of treatment, there was little difference in the effective rate between the two groups, and there was no statistical difference (P > 0.05), and the therapeutic effect was relatively stable.

[0043] It can be seen that the methods of the Chinese herbal compound pills for treating femoral head necrosis and the Henggu bone healing agent for treating hormonal femoral head necrosis in this study are both safe and effective, but statistical analysis shows that the former is more effective than the latter in treating early and middle-stage hormonal femoral head necrosis, which is mainly reflected in relieving hip pain, improving hip joint mobility and delaying the progression of femoral head collapse; in summary, the present invention provides an effective treatment plan for hormonal femoral head necrosis of kidney deficiency and blood stasis type.

[0044] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A Chinese medicinal compound pill for treating femoral head necrosis, characterized in that: It includes Chinese medicinal ingredients, water, and refined honey; the Chinese medicinal ingredients include earthworm, leech, Panax notoginseng, Drynaria fortunei, Eucommia bark, Epimedium, Curcuma longa, red ginseng, and Citrus aurantium; the sum of the weight of Drynaria fortunei, Epimedium, and Eucommia bark accounts for more than 45% of the total weight of the Chinese medicinal ingredients.

2. A Chinese medicinal compound pill for treating femoral head necrosis according to claim 1, characterized in that: The Chinese medicinal ingredients account for 60-70%, water accounts for 10-15%, and refined honey accounts for 20-25%.

3. A Chinese medicinal compound pill for treating femoral head necrosis according to claim 1, characterized in that: The components of the traditional Chinese medicine ingredients account for: 10-13% of earthworm, 2-4% of leech, 5-8% of Panax notoginseng, 16-18% of Drynaria, 16-18% of Eucommia, 15-17% of Epimedium, 7-12% of Curcuma, 6-8% of Red Ginseng, and 11-13% of Citrus aurantium.

4. The method for preparing the Chinese medicinal compound pill for treating femoral head necrosis as claimed in any one of claims 1 to 3, characterized in that: The following steps are involved: S1, taking 10 parts of Eupolyphaga sinensis, 3 parts of Leech, 5 parts of Panax notoginseng, 15 parts of Drynariae Rhizoma, 15 parts of Eucommia ulmoides, 15 parts of Epimedium, 10 parts of Curcuma longa, 10 parts of Red Ginseng, and 10 parts of Citrus aurantium as component A, and taking 31.15 parts of refined honey as component B, drying component A to obtain dry component A; S2, crushing the dry component A into 100 meshes and then performing dry heat sterilization operation A to obtain a dry sterilized component A; S3, mixing the sterilized and dried component A, component B and 17.8 parts of water uniformly to obtain a sludge; S4, repeatedly kneading and beating the mud for 5-10 minutes, putting it into a spherical mold for forming, taking it out, and drying it in the shade for 24 hours to obtain the Chinese medicine compound pills.

5. A method for preparing a Chinese medicinal compound pill for treating femoral head necrosis according to claim 4, characterized in that: In S1, the drying operation is: putting component A into a multifunctional Chinese medicine extract drying and sterilizing cabinet for hot air circulation drying at a temperature of 80° C. for 4 hours.

6. A method for preparing a Chinese medicinal compound pill for treating femoral head necrosis according to claim 4, characterized in that: In S2, the dry heat sterilization operation is: the dry component A is crushed into 100 meshes and then dry-sterilized in a multifunctional Chinese medicine extract drying and sterilizing cabinet at a temperature of 105° C. for 3 hours.