Traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention belongs to the technical field of traditional Chinese medicines, and particularly discloses a traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome, which is prepared from the following raw materials in parts by weight: 50-60 parts of purslane, 20-30 parts of rhizoma atractylodis, 50-60 parts of cacumen biotae, 20-30 parts of radix sophorae flavescentis, 20-30 parts of gallnut, 15-20 parts of dandelion, 30-40 parts of folium isatidis, 20-30 parts of garden balsam stem, 10-15 parts of pericarpium zanthoxyli and 10-20 parts of fructus evodiae. The traditional Chinese medicine composition provided by the invention can obviously improve symptoms such as erythema and damage of hand and foot skins, exuded yellow pus, local skin sclerosis, pain and the like of patients with chemotherapy-related hand and foot syndromes.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicines, and specifically discloses a traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome, and a preparation method and application thereof. Background Art

[0002] Malignant tumors are a type of disease that threatens human life and health. Surgical treatment, radiotherapy, chemotherapy, and molecular targeted therapy play a key role in the treatment of cancer patients. With the development and progress of molecular biology technology and modern pharmaceutical technology, it has become possible for most cancer patients to improve their quality of life and prolong their survival. However, the occurrence of adverse reactions related to drug treatment often affects the patient's quality of life and even treatment compliance. Such as hair loss, liver and kidney damage, bone marrow suppression, gastrointestinal reactions, etc. In addition, some patients may experience some skin-related adverse reactions, such as mild rash and severe exfoliative dermatitis, skin capillary reaction syndrome, etc. Among them, hand-foot syndrome (HFS) is the most common.

[0003] The clinical manifestations of HFS vary, mainly manifested as numbness and insensitivity of the hands and feet. Skin pigmentation, itching of the hands and feet, and even skin erythema, swelling, desquamation, cracking, nodular blisters or severe pain are also common. The cause of HFS is mainly due to adverse reactions caused by anti-tumor drugs during clinical application. At present, there are two main types of anti-tumor drugs: 1. Cytotoxic drugs mainly include capecitabine, tegafur, fluorouracil, doxorubicin, oxaliplatin, etc.; the pathogenesis of this type of drug is mainly that the metabolites of the drug metabolism process in the body are easy to accumulate in the body, and they are mostly concentrated in the hands and feet, which leads to the occurrence of HFS; 2. Small molecule targeted drugs such as apatinib, anlotinib, regorafenib, sorafenib, etc.; some scholars believe that small molecule targeted drugs inhibit the release of vascular endothelial growth factor, block the peripheral blood vessels of the limbs, damage the dermal blood vessels, and cause harmful substances to remain in the skin tissue to trigger an inflammatory response, which may also be related to their easy accumulation in places rich in sweat glands.

[0004] Currently, research on HFS is relatively limited. In 2017, the National University of Singapore and the Cancer Research Center found in their research that: there is a correlation between increased serum and red blood cell folate levels, wound healing and cytoskeleton fixation-related gene mutations and increased HFS risk. Serum and red blood cell folate levels are independent predictors of HFS, which also provides a better judgment indicator for the treatment of HFS patients in clinical work. As for the treatment of HFS, the current main model is pre-drug education, early assessment and intervention of related symptoms, and symptomatic supportive treatment. Medication education mainly refers to the relevant education on the adverse reactions that may occur during the medication process in advance. For example, for HFS, guidance on life aspects, such as wearing loose clothing, adjusting diet, and avoiding friction; and early assessment and intervention refers to early intervention after the patient self-evaluates related symptoms, such as local cold compresses; supportive treatment mainly refers to adjusting the drug dosage according to clinical needs, and using oral medications such as celecoxib, methylcobalamin, and vitamin B while taking good protection. 1 At the same time, local medications can be applied on the surface of the hands and feet, especially in the skin creases, such as vitamin E cream, urea cream, vaseline ointment, moist burn ointment, silymarin gel, 2% sildenafil cream, etc.; it can also keep the skin soft, prevent chapped skin, and help alleviate symptoms. Although the above comprehensive treatment system can relieve the symptoms of patients to a certain extent, due to the lack of large-scale clinical efficacy evaluation, the efficacy is inconsistent and there are adverse reactions, so there is an urgent need to explore more effective treatment measures.

[0005] In recent years, traditional Chinese medicine has achieved good results in the treatment of HFS, and RCT clinical studies on HFS have also confirmed the therapeutic effect of traditional Chinese medicine. In addition, local application of traditional Chinese medicine lotions can directly reach the lesion site, effectively relieve local symptoms, and reduce gastrointestinal reactions without being metabolized by the digestive tract, giving full play to the advantages of traditional Chinese medicine of "simple, convenient, effective and cheap".

[0006] There is no relevant record of HFS in ancient Chinese medical books. According to its clinical symptoms, it can be classified as "bi syndrome".

[0007] "Suwen·Changcijielun" says: "If the disease is all over the skin and the pain is muscle paralysis." "Suwen·Five Zang Organs Formation" says:

[0008] "Blood coagulation in the skin is called Bi." The main pathological characteristics of Bi syndrome are deficiency of the root and excess of the symptoms. Most cancer patients suffer from deficiency and stasis, and anti-tumor drugs consume the vital energy. Therefore, the treatment should follow the principle of "treating the symptoms in an emergency and treating the root in a slow manner". External treatment in traditional Chinese medicine can be used to administer drugs through the body surface to penetrate the pathogens nearby, directly reach the diseased area, and quickly resolve the patient's pain.

[0009] It is said in Lihua Pianwen: "The principle of external treatment is the principle of internal treatment, and the medicine for external treatment is the medicine for internal treatment. The only difference is the method." "Yi Zong Jin Jian" records that "malaria grows in the palms and is shaped like cornus officinalis. It grows on two hands facing each other. There are also clusters of them, with yellow and white pustules, itching and pain at all times, breaking the body fluid and yellow juice, sometimes getting better and sometimes getting worse, extremely tired and stubborn, caused by rheumatism invading the skin." "At the beginning of goose palm wind, purple and white spots appear, and white skin is stacked up, hard and thick, dry and cracked, and spreads all over the hands." Traditional Chinese medicine believes that chemotherapy drugs are highly toxic, which not only damage the spleen and stomach, but also consume qi and blood. The defensive qi is not solid, and the exogenous wind, cold, dampness and other evil qi gather in the local area, causing qi and blood stagnation, so numbness of hands and feet, dullness of senses, and those with more severe stasis can see black skin color. Stasis turns into heat and toxicity for a long time, and toxic heat stagnates. If it is not unblocked, it will cause pain, and even accompanied by severe skin toxicity reactions such as pain, swelling, erythema, desquamation, and cracking. Oral administration, external washing and soaking, ointment and other treatments can be used. Hands and feet are distal to the limbs, and external washing and soaking, ointment application and other methods can directly reach the diseased area, achieving a good therapeutic effect. Professor Cui Guijie of Guang'anmen Hospital of China Academy of Chinese Medical Sciences studied the literature and conducted in-depth clinical dialectical classification of HFS, which is divided into qi stagnation and blood stasis syndrome, damp-heat and heat toxic syndrome, blood deficiency and wind dryness syndrome, and stasis and toxicity blockage, and achieved good clinical efficacy by classification and treatment. Professor Lu Wenping summarized and summarized HFS with his profound clinical experience, and simplified it. He divided HFS into dry syndrome and wet syndrome and treated it according to syndrome differentiation, with remarkable curative effect. The adverse reactions of "wet syndrome" hand and foot skin are mainly manifested in the late stage of the disease, with symptoms such as erythema, damage, exudation of yellow pus, local skin hardening, and pain on the hand and foot skin. According to clinical observation, HFS caused by oral anti-tumor angiogenesis drugs often presents symptoms of wet syndrome. Therefore, according to the treatment concept of "different treatments for the same disease, and the same treatment for different diseases" in traditional Chinese medicine, it is particularly important to treat it according to syndrome differentiation, combined with the medication history of HFS patients. Summary of the invention

[0010] In view of the above technical problems, the present invention provides the following technical solutions:

[0011] The invention provides a traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome. The traditional Chinese medicine composition is prepared from the following raw materials by weight: 50-60g of purslane, 20-30g of atractylodes, 50-60g of oriental arborvitae leaves, 20-30g of sophora flavescens, 20-30g of gallnut, 15-20g of dandelion, 30-40g of isatis indigotica, 20-30g of radix scutellariae, 10-15g of Sichuan pepper, and 10-20g of evodia rutaecarpa

[0012] Preferably, it is made of the following raw materials by weight: 50-60g of purslane, 20-30g of atractylodes, 50-60g of oriental arborvitae leaves, 20-30g of sophora flavescens, 20-30g of gallnut, 15-20g of dandelion, 30-40g of isatis indigofera, 20-30g of radix scutellariae, 10-15g of Sichuan pepper, and 10-20g of evodia rutaecarpa.

[0013] The present invention also provides a method for preparing the above-mentioned Chinese medicine composition, comprising the following steps:

[0014] Weigh purslane, atractylodes, arborvitae leaves, sophora flavescens, gallnut, dandelion, isatis indigotica, radix spatholobi, Sichuan pepper, and evodia rutaecarpa according to weight, mix, add water and boil, and filter and concentrate the obtained decoction to obtain the product.

[0015] Preferably, the specific process of decocting with water is to add water equivalent to 8-12 times the total weight of the medicinal materials, and decoct for 2-3 times, each time for 1.0-2.0 hours.

[0016] The present invention also provides the use of the above-mentioned traditional Chinese medicine composition in the preparation of a medicine for treating chemotherapy-related hand-foot syndrome based on the syndrome differentiation of dampness.

[0017] Preferably, the Chinese medicine composition is used to prepare a drug for treating hand-foot syndrome caused by anti-tumor neovascularization drugs.

[0018] Preferably, the anti-tumor angiogenesis drug is apatinib, anlotinib, regorafenib or sorafenib.

[0019] The present invention also provides a traditional Chinese medicine preparation for treating chemotherapy-related hand-foot syndrome, which comprises the above-mentioned traditional Chinese medicine composition, and a pharmaceutically acceptable excipient or carrier.

[0020] The Chinese medicine composition provided by the present invention comprises the following: purslane, which is a main medicine, can clear away heat and dampness, remove toxins and reduce swelling, reduce inflammation, quench thirst and promote diuresis; atractylodes, which is a dry earth medicine, can promote diuresis, eliminate fluid retention and eliminate phlegm, promote blood stasis, relieve depression, eliminate leakage, eliminate tinea and eliminate symptoms; it can regulate acid reflux and remove rot, prevent mountain and river miasma, restore the weakness of tendons and bones, and clear the turbidity of urine; cypress leaf, which can clear blood and cool blood, remove dampness and remove arthralgia; sophora flavescens, which can cool blood and detoxify; gallnut, which can restrain the lung and reduce fire, clear away heat and dry dampness, and reduce local exudation; dandelion, isatis indigo leaf and radix scutellariae, which can clear away heat and detoxify and promote diuresis; Sichuan pepper and evodia rutaecarpa, which can warm and dredge blood vessels, improve circulation, and can assist in treating the cold and cold damage of the above medicines, are the assistants. All the medicines are used together to clear away heat and dampness, promote blood circulation and relieve pain. It can achieve the effects of eliminating local inflammatory reaction, reducing inflammatory exudation, improving blood circulation, and promoting the repair and recovery of skin lesions. The Chinese medicine composition can be used to treat chemotherapy-related hand-foot syndrome, which is dialectically classified as dampness syndrome and has symptoms such as erythema, damage, exudation of yellow pus, local skin hardening, pain and the like on the skin of the hands and feet.

[0021] Compared with the prior art, the beneficial effects of the present invention are:

[0022] The Chinese medicine composition provided by the present invention can significantly improve the symptoms of hand and foot syndrome such as erythema, damage, exudation of yellow pus, local skin hardening, pain, etc. in patients with chemotherapy-related hand and foot syndrome. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the patient's hand skin condition before treatment;

[0024] Figure 2 This is a diagram of the patient's hand skin condition after using the Chinese medicine composition provided by the present invention for one week;

[0025] Figure 3 This is a diagram showing the skin condition of a patient's hand after using the Chinese medicine composition provided by the present invention for one week. DETAILED DESCRIPTION

[0026] In order to enable those skilled in the art to better understand and implement the technical solution of the present invention, the present invention is further described below in conjunction with specific embodiments, but the embodiments are not intended to limit the present invention.

[0027] Example 1

[0028] A traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome is prepared from the following raw materials: 50g of purslane, 20g of atractylodes, 50g of oriental arborvitae leaves, 20g of sophora flavescens, 20g of gallnut, 15g of dandelion, 30g of isatis indigotica, 20g of radix scutellariae, 10g of Sichuan pepper, and 10g of evodia rutaecarpa.

[0029] Example 2

[0030] A traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome is prepared from the following raw materials: 60g of purslane, 30g of atractylodes, 60g of Platycladus orientalis leaves, 30g of sophora flavescens, 30g of gallnut, 20g of dandelion, 40g of isatis indigotica, 30g of radix scutellariae, 15g of Sichuan pepper, and 20g of evodia rutaecarpa.

[0031] Example 3

[0032] A traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome is prepared from the following raw materials: 60g of purslane, 30g of atractylodes, 60g of Platycladus orientalis leaves, 30g of sophora flavescens, 30g of gallnut, 15g of dandelion, 30g of isatis indigotica, 30g of radix scutellariae, 10g of Sichuan pepper, and 10g of evodia rutaecarpa.

[0033] Example 4

[0034] A traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome is prepared from the following raw materials: 55g of purslane, 25g of atractylodes, 58g of oriental arborvitae leaves, 25g of sophora flavescens, 28g of gallnut, 15g of dandelion, 32g of isatis indigotica, 25g of radix polysaccharidis, 12g of Sichuan pepper, and 18g of evodia rutaecarpa.

[0035] The Chinese medicine compositions provided in the above Examples 1-4 are prepared according to the following preparation method:

[0036] Weigh each raw material, add water 10 times the total weight of the medicinal materials, decoct twice, each time for 2.0 hours, combine the two decoctions, filter, and concentrate to obtain the product.

[0037] Example 5

[0038] A traditional Chinese medicine composition for treating chemotherapy-related hand-foot syndrome, which differs from Example 3 in that the preparation method is different, specifically: weigh each raw material, add water equivalent to 12 times the total weight of the medicinal materials, decoct for 3 times, each time for 1.0 h, combine the three decoctions, filter, and concentrate to obtain.

[0039] Experimental example

[0040] 1. Clinical data

[0041] A total of 20 patients with malignant tumors who were hospitalized in the First Affiliated Hospital of Henan University of Science and Technology from May 2019 to January 2022 were selected. They were diagnosed with HFS after the use of chemotherapy drugs and were clinically diagnosed as wetness, including 12 males and 8 females, 9 patients aged 65 years or older, and 11 patients aged 65 years or younger. The patients were randomly divided into a control group and a treatment group, with 9 cases in the control group and 11 cases in the treatment group. There was no significant difference in the severity and course of the disease between the control group and the treatment group (P>0.05), which was comparable.

[0042] 2. Diagnostic criteria:

[0043] (1) A history of malignant tumor confirmed by pathological diagnosis;

[0044] (2) history of chemotherapy drug use;

[0045] (3) The following symptoms appear: redness and damage to the skin of the hands and feet, exudation of yellow pus, local skin hardening, and pain.

[0046] 3. Methods

[0047] The treatment group used the Chinese medicine composition prepared by Example 3 of the present invention (the effects of the Chinese medicine compositions prepared by Examples 1-5 were basically the same, so only the Chinese medicine composition prepared by Example 3 is used as an example to illustrate the effects). When spraying the medicine, the lesion was first cleaned with warm water, and then the Chinese medicine spray of the present invention was sprayed 5-6 times a day, and the medicine was used continuously, and 5 days was a course of treatment;

[0048] The control group was treated with Western medicine, including urea ointment, which was evenly applied to the wound surface, 3-5 times a day; at the same time, methylcobalamin tablets were taken orally, with a dosage of 1 tablet (0.5 mg) at a time, 3 times a day.

[0049] 4. Efficacy evaluation indicators

[0050] 4.1 Clinical efficacy

[0051] Cured: HFS completely disappears and the patient can work and live normally;

[0052] Improvement: HFS grade decreases by 1 grade or more;

[0053] Ineffective: HFS has not changed or even worsens, and the HFS grade increases by 1 grade or more.

[0054] Grade 1: Mild skin changes or dermatitis with paresthesias that do not affect daily activities;

[0055] Grade 2: Skin changes remain the same, accompanied by pain, slightly affecting daily activities, and the skin surface is intact;

[0056] Grade 3: Ulcerative dermatitis or skin changes accompanied by severe pain, seriously affecting daily activities, with obvious tissue destruction (such as desquamation, blisters, bleeding, edema).

[0057] 4.2 Pain relief rate

[0058] The numerical rating scale (NRS) was used for evaluation.

[0059] Complete remission (CR): completely pain-free, NRS score is 0;

[0060] Partial relief (PR): pain is significantly relieved compared with before, and the NRS score is reduced by ≥1 / 2;

[0061] Mild relief (MR): Although the pain is less severe than before, there is still significant pain, and the NRS score is reduced by <1 / 2;

[0062] No effect (NR): The pain intensity was not relieved and the NRS score did not decrease.

[0063] 4.3 Quality of life score

[0064] Improvement: Quality of life score increased by ≥10 points;

[0065] Stable: Quality of life score increased by <10 points;

[0066] Decrease: Quality of life score decreases by ≥10 points.

[0067] Quality of life score (QOL) of cancer patients

[0068] (1) Appetite: ① Almost unable to eat; ② Food intake < 1 / 2 of normal; ③ Food intake is 1 / 2 of normal; ④ Food intake is slightly less; ⑤ Food intake is normal.

[0069] (2) Mental state: ① Very poor; ② Poor; ③ Somewhat affected, but sometimes better and sometimes worse; ④ Fairly good; ⑤ Normal, the same as before illness.

[0070] (3) Sleep: ① Difficulty falling asleep; ② Very poor sleep; ③ Poor sleep; ④ Slightly poor sleep; ⑤ Generally normal.

[0071] (4) Fatigue: ① Often tired; ② Feeling weak; ③ Often tired; ④ Sometimes mildly tired; ⑤ No feeling of fatigue.

[0072] (5) Pain: ① severe pain with passive posture or pain duration for more than 6 months; ② severe pain; ③ moderate pain; ④ mild pain; ⑤ no pain.

[0073] (6) Family understanding and cooperation: ① No understanding at all; ② Poor; ③ Average; ④ Family understanding and care are relatively good; ⑤ Good.

[0074] (7) Understanding and cooperation from colleagues (including leaders): ① No understanding at all, no one cares; ② Poor; ③ Average; ④ A few people understand and care about them; ⑤ Most people understand and care about them.

[0075] (8) Self-understanding of cancer: ① Disappointed, completely uncooperative; ② Uneasy, reluctantly cooperative; ③ Uneasy, moderately cooperative; ④ Uneasy, but able to cooperate fairly well; ⑤ Optimistic, confident.

[0076] (9) Attitude towards treatment: ① No hope for treatment; ② Half-believing and half-doubting the treatment; ③ Hoping to see the effect but afraid of side effects; ④ Hoping to see the effect and willing to cooperate; ⑤ Having confidence and actively cooperating.

[0077] (10) Daily life: ① Bedridden; ② Able to move, but need to stay in bed most of the time; ③ Able to move, sometimes bedridden; ④ Live a normal life, unable to work; ⑤ Live and work normally.

[0078] (11) Side effects of treatment: ① Severely affect daily life; ② Affect daily life; ③ No impact on daily life after symptomatic treatment; ④ No impact on daily life without symptomatic treatment; ⑤ No impact on daily life.

[0079] (12) Facial expressions: divided into levels ①-⑤.

[0080] Quality of life grading: The full score for quality of life is 60 points, good is 51-60 points, better is 41-50 points, average is 31-40 points, poor is 21-30 points, and extremely poor quality of life is <20 points.

[0081] 5. Results

[0082] 5.1 Clinical efficacy

[0083] The results are shown in Table 1.

[0084] Table 1 Clinical efficacy results of each group

[0085] Grouping Total number of cases (n) get well Improvement invalid Total effective rate (%) Control group 9 2(22.22) 2(22.22) 5(55.56) 44.44 Treatment Group 11 3(27.27) 6(54.55) 2(18.18) 81.82

[0086] Note: Total effective rate = (cured + improved) / total number of cases*100%.

[0087] 5.2 Pain relief rate

[0088] The results are shown in Table 2.

[0089] Table 2 Pain relief rate in each group

[0090]

[0091] Note: Total effective rate = (CR + PR + MR) / total number of cases * 100%.

[0092] 5.3 Quality of life score

[0093] The results are shown in Table 3.

[0094] Table 3 Quality of life scores of each group

[0095] Grouping Number of cases (n) improve Stablize reduce Total effective rate (%) Control group 9 2(22.22) 6(66.67) 1(11.11) 88.89 Treatment Group 11 5(45.45) 5(45.45) 1(9.09) 90.91

[0096] Note: Total effective rate = (improvement + stability) / total number of cases * 100%.

[0097] Figure 1-3 The figures show the skin conditions of the patients' hands before treatment, after using the Chinese medicine composition provided by the present invention for 1 week and 2 weeks respectively. By comparison, it can be seen that the symptoms of erythema, damage, exudation of yellow pus and local skin hardening on the patients' hands are significantly improved by using the Chinese medicine composition provided by the present invention.

[0098] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A Chinese medicine composition for treating chemotherapy-related hand-foot syndrome, characterized in that: The invention is prepared from the following raw materials by weight: 50-60 parts of purslane, 20-30 parts of atractylodes, 50-60 parts of oriental arborvitae leaves, 20-30 parts of sophora flavescens, 20-30 parts of gallnut, 15-20 parts of dandelion, 30-40 parts of isatis indigotica, 20-30 parts of radix scutellariae, 10-15 parts of Sichuan pepper and 10-20 parts of evodia rutaecarpa.

2. The Chinese medicine composition for treating chemotherapy-related hand-foot syndrome according to claim 1, characterized in that: The invention is prepared from the following raw materials by weight: 60 parts of purslane, 30 parts of atractylodes, 60 parts of oriental arborvitae leaves, 30 parts of sophora flavescens, 30 parts of gallnut, 15 parts of dandelion, 30 parts of isatis indigotica, 30 parts of radix spatholobi, 10 parts of Sichuan pepper and 10 parts of evodia rutaecarpa.

3. A method for preparing a Chinese medicine composition for treating chemotherapy-related hand-foot syndrome according to claim 1 or 2, characterized in that: The following steps are involved: Weigh purslane, atractylodes, arborvitae leaves, sophora flavescens, gallnut, dandelion, isatis indigotica, radix spatholobi, Sichuan pepper, and evodia rutaecarpa according to weight, mix, add water and boil, and filter and concentrate the obtained decoction to obtain the product.

4. The preparation method according to claim 3, characterized in that: The specific process of decocting with water is as follows: adding water in an amount equivalent to 8-12 times the total weight of the medicinal materials, decocting 2-3 times, each time for 1.0-2.0 hours.

5. Use of the Chinese medicine composition according to claim 1 or 2 in the preparation of a medicament for treating chemotherapy-related hand-foot syndrome based on the syndrome differentiation of dampness.

6. The use according to claim 5, characterized in that: The traditional Chinese medicine composition is used for preparing medicine for treating hand-foot syndrome caused by anti-tumor neovascularization drugs.

7. The use according to claim 6, characterized in that: The anti-tumor angiogenesis drug is apatinib, anlotinib, regorafenib or sorafenib.

8. A Chinese medicine preparation for treating chemotherapy-related hand-foot syndrome, characterized in that: It comprises the Chinese medicine composition according to claim 1 or 2, and a pharmaceutically acceptable auxiliary material or carrier.

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