121 results about "Aspirin" patented technology

The invention relates to a drug delivery system for treating osteoporosis caused by cell aging as well as a preparation method and application of the drug delivery system. The drug delivery system comprises a bone targeting ligand modified drug carrier and an anti-bone cell aging drug entrapped in the drug carrier, the bone targeting ligand is selected from any one of alendronate sodium, bisphosphate and analogues thereof, tetracycline, tartrate-resistant acid phosphatase TRAP binding peptide, pregnancy region protein or e-selectin; the anti-osteocyte senescence medicine comprises any one or a combination of at least two of dasatinib, quercetin, metformin, L-ascorbic acid, aspirin or fisetin. According to the prepared drug delivery system, the bioavailability of the drug can be effectively improved, targeted release of the drug in bone tissue is achieved, senescent cell enrichment is reduced, and the bone microenvironment is improved, so that a new strategy is provided for treating osteoporosis caused by cell senescence.

The invention discloses a glucose responsive composite material as well as a preparation method and application thereof. The composite material sequentially comprises porous metal, a polydopamine layer and a mesoporous silicon dioxide coating from inside to outside, the porous metal is coated with the polydopamine layer, the polydopamine layer is coated with the mesoporous silicon dioxide coating, and preparation raw materials of the mesoporous silicon dioxide coating comprise aminated mesoporous silicon dioxide, aspirin, 4-carboxyphenylboronic acid and sodium alginate. The composite material disclosed by the invention has blood sugar concentration dual-mode response capability, aspirin is suddenly released in a hyperglycemia environment, up-regulation expression of anti-inflammatory factors is remarkably promoted, and an anti-inflammatory effect is dominated; in a normal blood glucose environment, aspirin is slowly released, and the expression of osteogenic factors is remarkably up-regulated, so that osteogenic differentiation is promoted as a leading effect; the dual-mode response realizes accurate regulation and control of ASP dosage, organically combines bone formation promotion and anti-inflammatory functions, and provides a brand new solution for patients with bone defects, especially patients with bone defects caused by diabetes mellitus.

The invention discloses an aspirin enteric-coated micro-tablet capsule and a preparation method thereof. The micro-tablet core auxiliary materials of the enteric-coated micro-tablet capsule comprise an excipient, a disintegrating agent, a stabilizer, a flow aid and a lubricant. Tartaric acid is adopted as a stabilizer of aspirin, gel silicon dioxide is adopted as a flow aid, a moisture absorption agent and a swelling agent, and a direct powder tabletting method is adopted to prepare a micro-tablet core; the invention provides the aspirin enteric-coated micro-tablet capsule which is good in powder flowability, stable and easy to control in process, good in stability, uniform in dissolution and release characteristics, stable in blood concentration and high in bioavailability.

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an aspirin enteric-coated composition and a preparation method thereof.The composition comprises centrifugally granulated particles, an isolating layer and an enteric-coated layer, and the isolating layer and the enteric-coated layer sequentially wrap the centrifugally granulated particles; the centrifugally granulated particles comprise the following components: 19-22% of aspirin, 44-53% of a filler, 3-4% of an adhesive and 0.3-0.5% of a stabilizer, the isolating layer comprises the following components: 3-5% of a film-forming material and 3-5% of an anti-sticking agent, and the enteric-coated layer comprises the following components: 14-19% of an enteric-coated material, 0.4-0.6% of a plasticizer and 2-3% of an anti-sticking agent. According to the invention, aspirin is prepared into enteric-coated particles, and other flavoring auxiliary materials are selectively added, so that the oral preparation for children, which is good in palatability, relatively easy to swallow, easy to divide dosage, more accurate and more convenient, is obtained.

The invention belongs to the technical field of biological medicine, and particularly discloses application of oxidized berberine in preparation of a Hamp inhibitor, and the affinity of the oxidized berberine and FPN protein is obviously higher than that of the existing inhibitor furfurthiamine; the LPS-induced Hamp level rise can be remarkably inhibited, the level of iron output protein FPN can be remarkably up-regulated, and the level of iron storage protein Ferritin in cells is increased; the LPS-induced BV2 cell iron disorder and inflammatory response can be obviously relieved; meanwhile, the activity of inhibiting the interaction of Hamp-FPN and the activity of resisting inflammation are achieved, so that the Hamp level is more effectively inhibited, and FPN expression is up-regulated; the inflammation-like characteristics of BV2 cell rounding, vacuole and the like caused by the LPS effect can be obviously improved; the pharmaceutical composition can effectively inhibit generation and release of LPS-induced inflammatory factors IL6 and IL1beta, and the effect of the pharmaceutical composition is obviously better than that of aspirin.

The invention belongs to the technical field of pharmaceutical preparations. The invention discloses a nano preparation for inhibiting tumor metastasis, a preparation method and application. The nano preparation for inhibiting tumor metastasis comprises liposome spheres and nano spheres. The liposome sphere provided by the invention comprises an inner-layer core structure and a shell wrapping the outer layer of the inner-layer core structure, wherein the inner-layer core structure comprises lecithin, dioleoyl phosphatidyl ethanolamine, cholesterol succinic acid monoester, cholesterol, imidazolyl-cholesterol and DSPE-PEG2000-CS; the core structure of the inner layer is loaded with aspirin and DNaseI; the housing includes platelets. The nano preparation for inhibiting tumor metastasis can dissolve NET, inhibit the platelet function and disintegrate tumor cell-platelet-NET aggregate, and the nanosphere for inhibiting the far-end metastasis of tumors can deeply permeate into the tumors to play a role in killing the tumors.

The invention relates to a pharmaceutical composition for treating uterine adhesion and application thereof. The kidney reinforcing and miscarriage preventing pills are used for improving endometrial blood perfusion and increasing the endometrial thickness, the kidney reinforcing and miscarriage preventing pills, aspirin and estrogen play a synergistic treatment role, the postoperative re-adhesion rate is remarkably reduced through combined treatment, and the fertility prognosis of a patient is improved; and the molecular mechanism of a TGF-beta1 pathway and EMT is deeply researched, and by inhibiting excessive activation of the TGF-beta1 signaling pathway, reducing endometrial fibrosis, regulating an epithelial-mesenchymal transition (EMT) process and promoting regeneration of endometrial epithelial cells, endometrial repair is further promoted, multi-target treatment is realized, and the treatment effect is remarkable. A brand-new and efficient treatment scheme is provided for treatment of intrauterine adhesion, an individualized treatment scheme can be formulated according to the specific conditions of patients, the treatment accuracy and effectiveness are improved, and important clinical significance and application value are achieved.

The invention discloses application of compound resina draconis in preparation of a medicine for treating acute myocardial infarction. The compound resina draconis has the effects of resisting free radical oxidation and platelet aggregation, expanding coronary artery, inhibiting increase of myocardial enzymology CPK and LDH and reducing myocardial oxygen consumption, so that the myocardial infarction range is reduced, and myocardial ischemic ST segment elevation is improved; the compound is combined with aspirin for treating acute myocardial infarction, and the compound and aspirin have a synergistic effect, play a role in resisting platelet aggregation and inhibit synthesis of thromboxane A2, and show a good ischemic myocardial protection effect. Meanwhile, according to the technical scheme that the compound resina draconis is used independently or combined with aspirin, the application range of the medicine is widened, contribution is made for research and development of the medicine for relieving side effects caused by aspirin treatment, and the application prospect is good.

Provided are compositions and methods for treating multiple sclerosis (MS). One embodiment of the disclosed method entails orally administering to a MS patient a first amount of aspirin and a second amount of fumaric acid or an ester or a salt thereof. In some embodiments, the aspirin is administered at from about 80 mg to about 500 mg per day and the fumaric acid or ester or salt thereof is administered at about 360 mg per day.

The invention discloses a pharmaceutical composition for reversing pancreatic cancer gemcitabine resistance. The pharmaceutical composition is prepared from active ingredients such as a radix sophorae flavescentis extract, a poria cocos extract, emodin, glucosamine, gambogic acid, tranilast and aspirin. The preparation method of the sophora flavescens extract and the poria cocos extract comprises the steps of raw material pretreatment, dynamic ultrasonic-microwave synergistic extraction, membrane separation and nanofiltration, high-efficiency countercurrent chromatography purification, vacuum low-temperature concentration, drying and the like. The pharmaceutical composition can be prepared into a plurality of pharmaceutical preparations such as tablets, capsules, granules, cream, injections and the like. The invention further provides a preparation method of the oral tablet for reversing pancreatic cancer gemcitabine drug resistance, and the pharmaceutical composition has a remarkable treatment effect on a drug resistance mechanism formed by up-regulating expression of SREBP1 by histone lactylation mediated PKM2 through an AKT / mTOR pathway. The pharmaceutical composition provided by the invention provides a new treatment choice for pancreatic cancer patients, and has an important clinical application value.

The invention provides a pharmaceutical composition. The pharmaceutical composition is prepared from aspirin, atorvastatin, valsartan, hydrochlorothiazide, folic acid substances and pharmaceutically acceptable auxiliary materials. The pharmaceutical composition provided by the invention has the advantages that the pharmaceutical composition provided by the invention has a multi-target synergistic prevention effect on vascular diseases, especially cerebral embolism, that is, the composition not only can reduce blood pressure, blood fat and blood homocysteine level, but also has an effect of preventing thrombosis, and reduces the risk of cerebral apoplexy. In addition, the form of the pharmaceutical composition is beneficial to improving the medication compliance of patients.

According to the aspirin-containing dry suspension and the preparation method thereof, ethyl cellulose and calcium carbonate serve as coating powder and are mixed with ethyl alcohol to prepare a coating solution, aspirin particles are coated, due to the wrapping effect of the ethyl cellulose and the calcium carbonate, aspirin is effectively isolated from dihydroxyaluminum aminoacetate and heavy magnesium carbonate, and the aspirin-containing dry suspension is prepared. Compared with the existing dosage forms in the market, good stability and taste masking effect are accidentally obtained, the preparation method is simple, the operability is high, the content of effective substances in the dry suspension can be increased, and the dry suspension has good dissolution effect, stability, taste masking effect and compliance, is more suitable for the old and children and has great clinical significance compared with the existing dosage forms in the market.

The invention relates to an aspirin modified hydroxy ketone photoinitiator and a preparation method thereof. According to the aspirin modified hydroxy ketone photoinitiator and the preparation method thereof, carboxyl-containing aspirin and a hydroxyl-containing photoinitiator Darocure2959 are used as raw materials, and the aspirin modified hydroxy ketone photoinitiator is prepared through esterification. Aspirin is introduced to Darocure2959 molecules, the molecular weight is high, the light absorption and photo-initiation activity of the Darocure2959 molecules is high, the migration rate and volatility are low, the thermal stability is high, the migration rate of residual photoinitiators is only 10.2% of the migration rate of Darocure2959, the photoinitiators and fragments of the photoinitiators can be effectively fixed in a curing film, and the curing effect is good. Meanwhile, the introduction of the aspirin group endows the initiator with the drug function, and the initiator is suitable for medical light-cured materials such as light-cured teeth, light-cured medical adhesives and light-cured medical instruments. The preparation method has the advantages of easily available raw materials, low cost and simple preparation process.

The invention discloses an idebenone-aspirin splicing compound as well as a preparation method and application of the idebenone-aspirin splicing compound. The idebenone-aspirin splicing compound IDE-4 provided by the invention has good proliferation inhibition activity on rheumatoid arthritis effector cell synovial fibroblasts, and the rheumatoid arthritis effector cell synovial fibroblasts can be used for inhibiting the proliferation of the rheumatoid arthritis effector cell synovial fibroblasts. Pharmacological experiment research shows that the splicing compound IDE-4 can obviously inhibit proliferation of human primary rheumatoid arthritis synovial fibroblasts and human immortalized rheumatoid arthritis synovial fibroblast lines MH7A and migration of human synovial sarcoma cells SW982; the inhibition effect is obviously superior to that of a positive control drug methotrexate and parent nucleus idebenone and aspirin thereof, the good development value is achieved, and a new thought and approach are provided for synthesis of aspirin derivatives and research on rheumatoid arthritis resistance.

The invention belongs to the technical field of biological medicines, and particularly discloses application of aspirin in enhancing the curative effect of tumor infiltrating lymphocyte on treating liver cancer. The invention discloses application of aspirin in preparation of a medicine for enhancing the curative effect of tumor infiltrating lymphocyte on hepatocellular carcinoma. The invention discloses an application of aspirin in enhancing the curative effect of tumor infiltrating lymphocyte on treating liver cancer, the aspirin overcomes the problem of drug resistance of TIL therapy in HCC by adjusting the immune cell function in a tumor microenvironment, and the treatment effect is improved.

The invention belongs to the technical field of biological medicine, and relates to an anticoagulant, in particular to an anticoagulant for a high-precision animal blood cell analyzer and application of the anticoagulant in leukocyte classification. The anticoagulant comprises a buffer and anticoagulation matrix component and an active component, wherein in every 100 mL of the anticoagulant, the buffer and anticoagulation matrix component formula comprises 1.5 to 2 g of citrate, 0.3 to 0.5 g of citric acid and 0.15 to 0.20 g of EDTA-K2 (Ethylene Diamine Tetraacetic Acid), and the active components comprise 0.08 to 0.10 g of low molecular weight enzymolysis carboxymethyl chitosan, 1.0 to 1.2 g of hydroxypropyl-beta-cyclodextrin, 10 to 15 mg of dipyridamole and 8 to 10 mg of aspirin. The anticoagulant effectively inhibits platelet activation, prevents platelet aggregation and leukocyte morphological deformation, realizes accurate identification in leukocyte five-classification, has a classification accuracy rate of 98%, and is suitable for veterinary clinical hematology examination and animal epidemic disease monitoring.

The present invention discloses the application of aspirin combined with abemacili or in combination with other drugs in the treatment of breast cancer, and belongs to the technical field of tumor therapeutic drugs. The present invention firstly finds that, compared with the single application of abemacili, the combined or coordinated use of aspirin and abemacili can significantly inhibit the proliferation of breast cancer MCF7 and MDA-MB-231 cells and promote the apoptosis of breast cancer MCF7 and MDA-MB-231 cells, and the effect of the combined use of aspirin and abemacili is significantly better than the effect of the single application of abemacili or aspirin; compared with the single application of abemacili, the toxicity to normal human breast MCF10A cells is not enhanced, and it is expected to be used for the treatment of breast cancer, and provide a new drug combination for reducing the cost of breast cancer treatment, improving the treatment effect, and alleviating the suffering of patients.

The invention relates to an aspirin sustained-release tablet and a preparation method, belongs to the technical field of medicines, and adopts three dissolution modes for cooperative use to carry out gradient step-by-step controlled release. One group is composed of celery stem dry powder, xanthan gum and ethyl cellulose, and the acetylsalicylic acid with the mass percentage of 40%-50% is subjected to controlled release; the hydroxypropyl methylcellulose, the chitosan and the beta-cyclodextrin form a group and are used for simultaneously carrying out controlled release on 40-50% by mass of acetylsalicylic acid and the rest 50-60% by mass of acetylsalicylic acid; isomaltooligosacharide and resistant dextrin form a group, and the outermost layer of the group is coated with granules, so that the dissolution speed of all acetylsalicylic acid is delayed; in addition, the corn starch is added as a disintegrating component, and the proper addition of the corn starch can prevent the drug from being dissolved out too slowly, so that the drug dissolution amounts in the early and middle stages are ensured; all the components are matched for use, so that the stable controlled release speed of the medicine can be ensured, the problem that the dissolution speed is too high or too low in a certain time period is avoided, and the preparation is safer and more reliable.

The invention relates to an application of a halophenol compound 2, 4 ', 5'-trihydroxy-5, 2 '-dibromo benzophenone in preparation of an analgesic drug. Experiments prove that the compound has a definite analgesic effect, can significantly inhibit mouse writhing reaction induced by acetic acid and II-phase inflammatory pain induced by formalin, and prolongs the thermal stimulation tail retraction incubation period, and the effect is superior to that of aspirin. Furthermore, in a nitroglycerin-induced migraine rat model, the compound can effectively improve behavioral symptoms and brain tissue pathological damage and remarkably regulate key index levels of CGRP, PGE2, ET-1, IL-1beta, IL-6, TNF-alpha, 5-HT and the like in plasma, which shows that the compound can be applied to preparation of analgesic drugs, preparation of drugs for treating migraine, preparation of drugs for treating migraine and the like. The invention particularly has important application value in medicines for preventing and / or treating migraine.

The application relates to the technical field of aspirin pharmaceutical chemistry, in particular to an aspirin-sulfonamide hybrid, a preparation method and application thereof. The preparation method can synthesize a plurality of novel aspirin-sulfonamide hybrids by taking piperazine as a bridge, and by a three-step continuous method of "acyl chlorination, sulfonamidation and N-acylation" according to a "molecular hybridization principle". In the process, only one separation and purification is performed, and the preparation steps are simple. The aspirin-sulfonamide hybrid prepared by the method is most effective on human non-small cell lung cancer cells A549, and the activity is more than 33 times higher than that of a parent aspirin, and is similar to the activity of an anticancer drug irinotecan. The aspirin-sulfonamide hybrid 3k prepared by the method has a certain inhibitory effect on various cancer cells. The hybrid can induce human non-small cell lung cancer A549 cell apoptosis in a concentration-dependent manner, and can induce human non-small cell lung cancer A549 cell cycle arrest in the G0 / G1 phase, and inhibit cell growth.

The present disclosure provides compositions and methods for inducing protein-protein heterodimerization in the presence of salicylic acid or a synthetic derivative thereof, useful for modulating signal transduction, protein activation, and gene expression in response to chemical stimuli.

The invention relates to an anti-inflammatory plasma matrix as well as a preparation method and application thereof. The anti-inflammatory plasma matrix comprises a plasma matrix and aspirin chitosan nanoparticles, the preparation method of the anti-inflammatory plasma matrix comprises the step of pressing a mixture of the plasma matrix and the aspirin chitosan nanoparticles to obtain the anti-inflammatory plasma matrix. Leukocyte contained in the plasma matrix in the anti-inflammatory plasma matrix can play an antibacterial role, aspirin can be slowly released by the aspirin chitosan nano-particles, the function of regulating and controlling bone regenerative cycle in an inflammatory state is achieved, and a chitosan shell also has certain antibacterial and anti-inflammatory effects. The prepared anti-inflammatory plasma matrix can be applied to preparation of drugs for treating periodontitis and peri-implantitis.

The application belongs to the technical field of biological medicine, and relates to an anticoagulant and application thereof in white blood cell classification for high-precision animal blood cell analyzers. The anticoagulant comprises two parts of buffer and anticoagulant matrix components and active components. In the anticoagulant, the buffer and anticoagulant matrix component formula comprises 1.5-2 g of citrate, 0.3-0.5 g of citric acid and 0.15-0.20 g of EDTA-K2 per 100 mL of the anticoagulant, and the active component comprises 0.08-0.10 g of low-molecular enzymatic hydrolysis carboxymethyl chitosan, 1.0-1.2 g of hydroxypropyl-beta-cyclodextrin, 10-15 mg of dipyridamole and 8-10 mg of aspirin. The anticoagulant effectively inhibits platelet activation, prevents platelet aggregation and white blood cell morphological deformation, accurately identifies in white blood cell five classification, and has a classification accuracy as high as 98%, and is suitable for veterinary clinical hematology examination and animal disease monitoring.

The invention provides a method for detecting nine antipyretic and analgesic drugs in feed, and belongs to the field of food safety detection. The method comprises the following steps: pretreating a feed sample to obtain a sample to be detected; detecting the nine antipyretic and analgesic drugs in the to-be-detected sample by adopting a liquid chromatography-mass spectrometry method; the nine kinds of antipyretic and analgesic medicines are antipyrine, phenylbutazone, acetaminophen, analgin, naproxen, diclofenac, indometacin, aspirin and ibuprofen. According to the pretreatment method provided by the invention, the problems of tedious steps, long consumed time and low accuracy of a detection result can be improved. By adopting liquid chromatography-mass spectrometry, simultaneous determination of multiple types of drugs can be realized, qualitative and quantitative analysis of multiple drugs can be rapidly and accurately completed in a short time, the timeliness requirement of actual detection is met, and the method can be used for feed quality safety monitoring.

The application belongs to the technical field of regenerative medicine, and particularly relates to an ASP / BFP-1 sustained-release nanofiber membrane and a preparation method and application thereof. In the initial stage of bone repair, matrix metalloproteinase-2 (MMP-2) secreted by a large number of stem cells can effectively degrade gelatin and polylysine in the nanofiber membrane coating, so as to sequentially release aspirin and bone formation peptide-1 in the drug-loaded coating. The released aspirin can control inflammation, and the bone formation peptide-1 can enhance the osteogenic potential of stem cells and guide bone tissue regeneration.

The application discloses a magnesium complex taking aspirin or an oxygen-deficiency promoting derivative thereof as a ligand, a preparation method and application thereof in preparation of a medicine for treating coronary heart disease. The structural formula of the magnesium complex is shown in the following formula I-IV: the magnesium carbonate is reacted with nitric acid to obtain magnesium nitrate; the aspirin is reacted with sodium bicarbonate to obtain a neutral sodium salt of aspirin; the neutral sodium salt of aspirin is reacted with the magnesium nitrate according to a molar ratio of 1:1 or 2:1 to obtain the magnesium complex shown in the formula I or II. The aspirin is reacted with p-nitrobenzyl alcohol to obtain an oxygen-deficiency promoting derivative of aspirin; the oxygen-deficiency promoting derivative of aspirin is reacted with the magnesium nitrate according to a molar ratio of 1:1 or 2:1 to prepare the magnesium complex shown in the formula III or IV. The application has a remarkable repairing effect on heart damage caused by myocardial ischemia and the like.

The invention relates to a vase solution for preserving cut lily flowers of an OT hybrid line and application of the vase solution. The vase solution takes water as a solvent and comprises salicylic acid, citric acid, calcium chloride, 6-benayl aminopurine, aspirin, ascorbic acid, silver thiosulfate and cane sugar. The vase solution can improve the ornamental quality of cut flowers, remarkably prolong the service life of flowering branches and delay turbidity of the vase solution; in addition, the soluble sugar content and peroxidase content of the petals can be increased, and the malondialdehyde content of the petals can be reduced. The vase solution provided by the invention has the advantages of low cost, and simple and easy preparation and use.

The invention provides an isoquinoline derivative with a novel structure, a pharmaceutically acceptable salt thereof, a preparation method of the isoquinoline derivative, a pharmaceutical composition containing the isoquinoline derivative and pharmaceutical application of the isoquinoline derivative, and belongs to the technical field of medicines. In-vitro experiments show that the isoquinoline derivative has significant inhibitory activity on arachidonic acid-induced platelet aggregation, and the antiplatelet activity of part of compounds is superior to that of aspirin. In a rat carotid artery thrombosis model induced by FeCl3, the isoquinoline derivative remarkably prolongs thrombosis time and reduces thrombus weight, and the in-vivo antithrombotic curative effect of the isoquinoline derivative is equivalent to that of aspirin and ticagrelor. A mouse tail bleeding model shows that the side effects of bleeding amount and bleeding time of the isoquinoline derivative are obviously lower than those of aspirin and ticagrelor. Therefore, the series of isoquinoline derivatives have the advantages of efficient antithrombotic effect and low bleeding risk, and have good application prospects in preparation of drugs for preventing and treating thrombotic diseases. In addition, the preparation method provided by the invention has the advantages of easily available raw materials, simple steps and strong operability, and the obtained target product has high quality and good efficiency.

The invention belongs to the field of medical technology, and specifically relates to an aluminum-magnesium aspirin pharmaceutical composition and a preparation method thereof; specifically relates to a composition of aluminum-magnesium aspirin tablets, the tablet composition comprising: aspirin, aluminum glyoxylate, heavy magnesium carbonate, weakly alkaline or neutral gastric-soluble polymer, plasticizer, microcrystalline cellulose, neutral fast-dissolving material, filler, and adhesive; the product of the invention is a single-layer tablet, which reduces the complexity of process and equipment and reduces costs compared with double-layer tablets; improves tablet hardness, is more wear-resistant and stronger, and avoids defects such as separation of two layers of double-layer tablets and easy discoloration near the contact surface; the product of the invention is simple and easy to produce and operate, and is suitable for industrial production.

Provided are 2-(diethylamino)ethyl acetoxybenzoate hydrochloride, other highly permeable prodrugs of aspirin and other NSAIDs, and pharma- ceutically acceptable salts thereof, for use in and methods of preventing or treating cardiovascular diseases and conditions. Disclosed are pharmaceutical compositions, treatment kits, and devices comprising 2-(diethylamino)ethyl acetoxybenzoate hydrochloride, other highly permeable prodrugs of aspirin and other NSAIDs, and pharma- ceutically acceptable salts thereof, as well as dosage forms, dosage amounts, and methods of their use by topical administration.