Calcineurin inhibitors presented in modern pharmacies are lactones belonging to the macrolide type. Main features - depressing immune system quality. Among the most famous, the first place rightfully belongs to cyclosporine. Thanks to the A-type of this substance, organ transplantation became possible. The medication, as tests have shown and confirmed the experience of use, effectively prevents the rejection of transplanted tissues. True, the size of the molecule was such that the use was possible only systemic. Consider what constitute a substance depressing calcineurin, what nuances of effectiveness are inherent in them.
general information
At present, calcineurin inhibitors (topical preparations) are not only cyclosporin A, but also other macrolides, whose molecules are smaller. Pimecrolimus, tacrolimus are often used as immunomodulators. As studies have shown, these compounds can pass through the skin, therefore, it is possible to produce effective ointments. Tacrolimus is used for the production of medicinal ointments, the concentration of the active substance in which varies between 0.03-0.1%. On pimecrolimus make a one percent medicinal cream. There are several promising products that are still undergoing clinical trials. These include sirolimus, also known as Rifampicin.
Topical calcineurin inhibitors (TECs) affect the patient’s body at the cellular level. Complex structures are formed inside such structures. Cyclosporin also reacts with cyclophilin, the other two substances mentioned above react with twelfth macrophilin. Due to the binding processes, the dephosphorylation of the nucleus, lymphocytes is inhibited, the production of IL-2 and other cytokines is prevented. T-lymphocytes are not activated, proliferation slows down, the production of cytokines is blocked.
Features of use
Preparations based on topical calcineurin inhibitors are used locally and systemically. For external use, medications containing pimecrolimus, tacrolimus are most often chosen. These funds have proven themselves in atopic eczema. Random studies related to the use of these medications for a variety of inflammatory pathologies have been carried out. The drugs were used for red lichen, localized on the mucous membranes, pyoderma, accompanied by gangrene, lupus erythematosus. Patients noted a slight burning sensation in the areas of application of medicinal formulations in the early days, gradually an undesirable effect passed. None of the observations showed atrophic processes of the skin.
To ensure maximum safety of use, it is important to avoid ultraviolet radiation during the therapeutic course. Calcineurin inhibitors have been found to increase the risk of skin cancer if a person is exposed to such rays.
The nuances of consumption
For systemic use, only preparations based on the topical calcineurin cyclosporin inhibitor are currently indicated. It is used in severe psoriasis, with atopic eczema that cannot be treated with other methods. Mostly patients with these pathologies undergo a phototherapeutic course, which means that they have a great risk of cancer.
Systemically, calcineurin inhibitors are prescribed for Behcet’s disease and SLE. You can use cyclosporine for pyoderma with signs of gangrene, lichen planus, developing according to a generalized scenario. Take into account that systemic treatment with a high degree of probability can cause hypertrichosis and high blood pressure, gingival hyperplasia, and kidney failure.
The dangers of treatment
Studies have shown that calcineurin inhibitors increase the risk of squamous cell skin cancer by about a hundred times during organ transplantation. The dangers of the formation of metastases in the shortest possible time are increased. To reduce the negative chances, you should carefully protect the person from ultraviolet radiation. Prolonged use of this category of drugs excludes phototherapy in the near future.
Azathioprine
This substance is characterized by increased qualities of suppression of the human immune system. This result of the action is due to the inhibitory effect of iosin monophosphate dehydrogenase. Under the influence of a topical calcineurin inhibitor, the processes occurring in the cell are disrupted, DNA generation is disrupted, the proliferation of T and B lymphocytes is inhibited. Mycophenolate mofetil has similar qualities.
These funds are common as elements of a therapeutic course of a variety of autoimmune pathologies. Topical calcineurin inhibitors can be used for dermatomyositis and bullous rash, areas of suppuration of the skin, accompanied by gangrene. Medicines are used in the fight against lupus erythematosus, severe eczema. You can use the funds as an element of a complex treatment program for lichen planus. When choosing tablets with azathioprine, the initial dosage is 100-150 mg per kilogram of patient weight. For greater effectiveness, the course is supplemented with hormonal anti-inflammatory drugs, the volumes of which are also selected, focusing on the patient's body weight - 0.5-1 mg / kg. Dose reduction is allowed after a significant improvement in the patient's condition. The minimum amount is 50 mg; must be combined with other medicines to treat a specific disease.
The nuances of using
Preparations belonging to the class of calcineurin inhibitors require strict observance of the rules of use - this is due to the peculiarities of the effectiveness of the compositions. In particular, the mentioned azathioprine shows a pronounced effect only after prolonged administration - from a month to a half. The initial step is called latent.
The drug can provoke undesirable effects. Studies have shown an increased risk of anemia developing according to the macrocytic scenario, as well as malfunctions of the central nervous system and gastrointestinal tract. Flu-like manifestations may occur. In some patients, profuse hair loss began. The use of azathioprine adversely affects liver cells, causing the death of hepatocytes. Perhaps the development of leukopenia. The initial step of therapy requires a clear control of the liver, blood counts. A decrease in the activity of thiopurine methyltransferase is possible, therefore, it is necessary to first determine these levels, in order to then check the parameters and compare with the initial ones. Do not use allopurinol and the substance in question at the same time.
Mycophenolate Mofetil
Preparations based on this substance belonging to the class of calcineurin inhibitors are next-generation drugs in comparison with the previously described azathioprine. MMF is used if the probability of rejection of transplanted tissues is assessed as quite high. There is a lack of a chemical reaction with allopurinol. In addition, the nuances of processing the substance are not related to thiopurinmethyl transferase. Medicines of this class are less dangerous for the liver. True, they are characterized by more pronounced myelotoxic qualities than drugs with azathioprine.
"Imuran"
The drug is available in tablet form, one capsule contains 50 mg, one cardboard package - 100 copies and instructions. Azathioprine is the main active component of the drug. In addition to it, the manufacturer used additional compounds - starches, acids, lactose. The drug belongs to the transformation products of 6-mercaptopurine, is classified as an element of the imidazole type. Shortly after use, the drug is transformed into methyl nitroimidazole, 6-mercaptopurine. The second compound seeps through cell membranes, where reactions of transformation into purine analogues, including nucleotides, begin. The speed of transformation varies significantly from case to case, depending on the nuances of the patient's body.
In the instructions attached to the tablets on azathioprine, the manufacturer indicates the inability of nucleotides to walk through the cell membrane, due to which it is impossible for the compounds to penetrate into organic liquids. 6-mercaptopurine is eliminated in the form of an inactive metabolite - the product of an oxidation reaction proceeding with the participation of the xanthine oxidase enzyme element suppressed by allopurinol. Studies on methyl nitroimidazole activity have not yet provided a clear picture of how the substance works, but it has been found that the effectiveness of azathioprine may depend on it.
When will it help?
According to reviews, azathioprine, sold under the brand name Imuran, gives good results as an element of combination therapy, although it provokes undesirable consequences. Doctors usually prescribe a multicomponent course, include hormonal anti-inflammatory drugs and other substances to inhibit the activity of the immune system. The main objective of the program is to reduce the risk of rejection of transplanted tissues. The drug is used for transplantation of the heart, liver, kidneys. A well-designed treatment program helps reduce the need for hormonal drugs.
With foci of inflammation in the intestinal tract (Crohn’s disease, colitis), azathioprine is used under the name Imuran in pharmacies if the patient is given a course of corticosteroids, but the patient is very difficult to tolerate. They resort to "Imuran" if the standard drug program does not give the desired result.
Features of the reception
As the only means for treatment, "Imuran" is chosen if the patient has severe rheumatoid arthritis, as well as pemphigus vulgaris . You can use the drug for polyarteritis nodosa, autoimmune type hemolytic anemia, SLE, dermatomyositis, polymyositis. The drug is prescribed for idiopathic purpura, multiple sclerosis, a tendency to relapse (azathioprine affects memory).
Calcineurin inhibitor is forbidden to take with hypersensitivity to azathioprine, auxiliary compounds included in the medication. A limitation for treatment will be a high level of sensitivity to 6-mercaptopurine.
Dosages and Diagnoses
If Imuran is prescribed, if necessary, to prevent rejection of transplanted tissues, in the first days the dose is selected based on weight: up to 5 mg / kg. Daily volumes are divided into 2-3 servings. The maintenance dosage varies between 1-4 mg / kg. Specific values are selected, evaluating the effectiveness of a previously practiced course, tissue tolerance in a particular case.
Observations and studies prove: an indefinitely long therapeutic course is possible. This helps prevent tissue rejection in the future, since the risk of such a process persists for a long time after surgery.
If "Imuran" is prescribed against the background of multiple sclerosis, first use the drug in an amount of 2-3 mg / kg. Daily volumes are divided into 2-3 servings. Sometimes the pronounced effect of treatment is visible at the end of the first year of therapy, in other cases - after two years of constant use of the drug.
For other pathological conditions, initially, "Imuran" is prescribed in an amount of 1-3 mg / kg. Dosage adjustment is carried out by monitoring the body's response to the selected course of treatment. Sometimes this can be seen only months after the start of the program. Having discovered a therapeutic effect, the volume of the used agent is gradually reduced, until it is possible to identify the lowest, still effective in a particular case. If three months after the start of the use of Imuran, there are still no improvements, the need for this remedy should be evaluated again. With a focus of inflammation in the intestinal tract, the treatment will last at least a year. With this diagnosis, it is taken into account that the primary effect of therapy is sometimes observed only at the end of the fourth month of the course.
Old age
There is only limited data on the use of Imuran by elderly patients. The frequency of the unwanted response of the body, as can be seen from the statistics, does not differ from that characteristic of younger patients. The manufacturer recommends adhering to the lowest possible dosage. It is important to regularly check the blood picture and reduce the volume of the composition used, if possible.
Dangers: neoplasms
As indicated above, based on calcineurin ointment inhibitors, tablets are highly likely to become a factor initiating cell degeneration. Imuran is no exception. Studies have shown that the therapeutic course is accompanied by an increased risk of the formation of non-Hodgkin lymphoma, melanoma, sarcoma. The patient may develop myelodysplasia, a malignant tumor of the uterine neck, myelogenous leukemia.
The danger of a malignant disease is especially great when taking drugs that suppress immunity against the background of transplantation of organic tissues. To reduce the risks, you need to use "Imuran" in the lowest possible dose. From medical statistics it is known that the use of the described drug for rheumatoid arthritis is associated with significantly higher dangers of non-Hodgkin lymphoma than the average among the entire population of people.
Too much!
If you use "Imuran" in excess dosage, the appearance of hematomas, foci of blood discharge, ulcers in the throat. The patient suffers from unmotivated infection. Symptoms are associated with inhibition of bone marrow activity, appears one and a half to two weeks after the start of taking excess volumes. It is known that a single use of 7.5 g of azathioprine caused vomiting, impaired stool, nausea, leukopenia, and liver function failure.
The drug has no antidote. If an overdose is discovered, it is necessary to rinse the stomach, take the patient’s condition for control, regularly check the activity of the hemolytic system. It is not yet known how effective dialysis is, but it has been revealed that the active component of Imuran can be partially withdrawn in this way.
Atopic dermatitis and its treatment
For external therapy, calcineurin inhibitors are used, as a rule, if the patient has atopic dermatitis.
The term refers to a relapse-prone disease associated with the formation of foci of inflammation on the skin. With this diagnosis, a person is forced to use means for stopping inflammation and eliminating symptoms for long courses - atopic dermatitis is one of incurable pathologies. At any stage, hygiene and proper care are important - the skin requires regular hydration, softening through emollients. So far, it has not been possible to identify features of the effectiveness of such drugs, but it is believed that they cannot stop inflammatory activity.
Undoubtedly, hormonal anti-inflammatory drugs are considered effective in atopic dermatitis, but those with a high degree of probability cause side effects. In some cases, performance develops too slowly. Withdrawal of glucocorticosteroids is often accompanied by a sharp deterioration in the condition of patients. These problems are forcing scientists to look for new ways to fight the disease, and this is the approach used today by calcineurin inhibitors for external treatment of atopic dermatitis.
Subtleties of the question
Immunosuppressive drugs are prescribed when atopic dermatitis develops in a severe form and proceeds stubbornly. Use cyclosporine, methotrexate, azathioprine. The classic option is drugs with cyclosporine of a polypeptide nature. The active substance was first obtained from specific fungi. Observations have shown that the use of cyclosporine helps to slow the degranulation of cellular mast skin structures, the generation of leukotrienes. The substance inhibits the production of cytokines, the activity of T-lymphocytes, without affecting the allergic response of the body. However, the use of ointments effectively relieves itching.
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The use of cyclosporine is accompanied by weakening of itching and the elimination of hyperemia of the skin. Such effects can be seen already in the first few days of the drug program. A reduced dosage of drugs that suppress the immune system provides temporary relief of the symptoms of dermatitis, but approximately every second patient by the end of the second week after completing the course again complains of the increasing manifestations of the disease. On average, only one in six is in good condition for up to a year. A specialized study of randomly selected patients, organized in the recent past, showed that the use of cyclosporine does not affect the quality of life of people with atopic dermatitis.