Calcineurin inhibitors presented in modern pharmacies are lactones belonging to the macrolide type. The main features are depressing qualities of the immune system. Among the most famous, the first place rightfully belongs to cyclosporine. It is thanks to the A-type of this substance that organ transplantation became possible. The medication, as shown by tests and confirmed by the experience of use, effectively prevents the rejection of transplanted tissues. True, the dimensions of the molecule turned out to be such that only systemic application was possible. Let's consider what are calcineurin inhibitory substances, what are the nuances of their effectiveness.
General information
Currently, calcineurin inhibitors (topical drugs) are not only cyclosporine A, but also other macrolides, the molecules of which are smaller. Pimecrolimus and tacrolimus are often used as immunomodulators. Studies have shown that these compounds can pass through the skin, therefore, it is possible to manufactureeffective ointments. Tacrolimus is used for the production of medicinal ointments, the concentration of the active substance in which varies between 0.03-0.1%. Pimecrolimus is used to make a 1% medicated cream. There are several promising products that are still in clinical trials. These include sirolimus, also known as Rifampicin.
Topical calcineurin inhibitors (TCIs) affect the patient's body at the cellular level. Complex complexes are formed inside such structures. Cyclosporine also reacts with cyclophilin, the other two substances mentioned above react with the twelfth macrophilin. Due to binding processes, dephophorylation of the nucleus and 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 topically and systemically. For external use, medicines containing pimecrolimus, tacrolimus are most often chosen. These remedies have worked well for atopic eczema. Random studies have been conducted related to the use of these drugs in a variety of inflammatory pathologies. The drugs were used for lichen erythematosus, 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 first days, gradually an undesirable effectpassed. None of the observations showed atrophic processes in 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.
Using nuances
For systemic use, only drugs based on the topical calcineurin inhibitor cyclosporine are currently indicated. It is used for severe psoriasis, with atopic eczema that is not treatable by other methods. Mostly patients with the listed pathologies undergo a phototherapy course, which means that they are at great risk of oncological disease.
Systemically calcineurin inhibitors are prescribed for Behçet's disease and SLE. You can use cyclosporine for pyoderma with signs of gangrene, lichen planus, developing according to a generalized scenario. Consider that systemic treatment is highly likely to cause hypertrichosis and high blood pressure, gingival hyperplasia, kidney failure.
Dangers of treatment
Studies have shown that calcineurin inhibitors increase the risk of squamous cell skin cancer by about a hundredfold after organ transplantation. Increased risk of metastases formation in the shortest possible time. To reduce negative chances, you should carefully protect a person from ultravioletradiation. Continued use of this category of drugs precludes phototherapy in the near future.
Azathioprine
This substance has the enhanced qualities of suppressing the human immune system. This result of the action is explained by the inhibitory effect of iosine monophosphate dehydrogenase. Under the influence of a topical calcineurin inhibitor, the processes occurring in the cell are disrupted, DNA generation is disrupted, and the proliferation of type T and B lymphocytes is inhibited. Mycophenolate mofetil has similar qualities.
These funds are common as elements of a therapeutic course of various 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 funds as part of a complex treatment program for lichen planus. When choosing tablets with azathioprine, the initial dosage is 100-150 mg per kilogram of the patient's 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 for the treatment of a specific disease.
Usage nuances
Belonging to the class of calcineurin inhibitorsdrugs require strict adherence to the rules of use - this is due to the peculiarities of the effectiveness of the formulations. In particular, the mentioned azathioprine shows a pronounced effect only after prolonged use - from a month to one and a half. The initial step is called latent.
The drug may cause side 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 symptoms may occur. Some patients developed profuse hair loss. The use of azathioprine negatively affects liver cells, provoking the death of hepatocytes. Perhaps the development of leukopenia. The initial step of therapy obliges to clearly monitor the work of the liver, blood counts. It is possible to reduce the activity of thiopurine methyltransferase, so these levels must first be determined 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
Calcineurin inhibitor-based drugs based on this substance are the next generation of drugs compared to the previously described azathioprine. MMF is used if the probability of rejection of transplanted tissues is assessed as high enough. The absence of a chemical reaction of interaction with allopurinol is noted. In addition, the nuances of substance processing have no connection with thiopurine methyltransferase. Medicines of this class are less dangerous for the liver. True, they have more pronounced myelotoxic qualities,than drugs with azathioprine.
Imuran
The drug is available in tablet form, one capsule contains 50 mg, one carton - 100 copies and instructions. Azathioprine is the main active ingredient 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 and is classified as an imidazole-type element. Soon after consumption, the drug is transformed into methylnitroimidazole, 6-mercaptopurine. The second compound seeps through cell membranes, where transformation reactions into purine analogs, including nucleotides, begin. The rate of transformation varies significantly from case to case, depending on the nuances of the patient's body.
In the instructions that come with azathioprine tablets, the manufacturer indicates the inability of nucleotides to pass through the cell membrane, which makes it impossible for the compounds to penetrate into organic fluids. 6-mercaptopurine is eliminated in the form of an inactive metabolite - the product of an oxidation reaction that occurs with the participation of the enzyme element xanthine oxidase inhibited by allopurinol. Studies on the activity of methylnitroimidazole have not yet given a clear picture of how the substance works, but it has been established that the effectiveness of azathioprine may depend on it.
When will it help?
Azathioprine, marketed under the trade name Imuran, is reported to give good results as an elementcombination therapy, although it provokes undesirable consequences. Doctors usually prescribe a multi-component course that includes hormonal anti-inflammatory drugs and other substances to suppress 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 in transplantation of the heart, liver, kidneys. A well-designed treatment program helps reduce the need for hormonal drugs.
In foci of inflammation in the intestinal tract (Crohn's disease, colitis), azathioprine, presented under the name "Imuran" in pharmacies, is used if the patient is indicated for a course of corticosteroids, but the patient tolerates it very hard. They resort to Imuran if the standard drug program does not give the desired result.
Reception Features
As the only remedy for the treatment of "Imuran" is chosen if the patient has severe rheumatoid arthritis, as well as pemphigus vulgaris. You can use the remedy for polyarteritis nodosa, hemolytic anemia of the autoimmune type, SLE, dermatomyositis, polymyositis. The drug is prescribed for idiopathic purpura, multiple sclerosis, a tendency to relapse (azathioprine affects memory).
Calcineurin inhibitor should not be taken in case of hypersensitivity to azathioprine, auxiliary compounds included in the medication. Treatment will be limited by 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 within the limits of 1-4 mg/kg. Specific values are selected, evaluating the effectiveness of the previously practiced course, tissue tolerance in a particular case.
Observations and studies prove that an indefinitely long therapeutic course is possible. This helps to prevent tissue rejection in the future, since the risk of such a process remains for a long time after surgery.
If "Imuran" is prescribed against the background of multiple sclerosis, the drug is first used in an amount of 2-3 mg / kg. Daily volumes are divided into 2-3 servings. Sometimes a pronounced effect of treatment is visible by the end of the first year of therapy, in other cases - after two years of continuous use of the drug.
In case of other pathological conditions, at first Imuran is prescribed in the 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 found a therapeutic effect, the volumes of the agent used are gradually reduced until it is possible to identify the lowest possible, still effective in a particular case. If three months after the start of the use of "Imuran" there is still no improvement, the need for this remedy should be reassessed. With a focus of inflammation in the intestinal tract, treatment will last at least a year. With suchdiagnosis take into account that the primary effect of therapy is sometimes observed only by the end of the fourth month of the course.
Old age
There are only limited data on the use of Imuran by elderly patients. The frequency of occurrence of an undesirable response of the body, as can be seen from the statistics, does not differ from that characteristic of younger patients. The manufacturer recommends that you stick 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 stated above, based on calcineurin inhibitor ointments, tablets with a high degree of probability can become a factor initiating cell regeneration. Imuran will not be an exception. Studies have shown that the therapeutic course is accompanied by an increased risk of the formation of non-Hodgkin's lymphoma, melanoma, and sarcoma. The patient may develop myelodysplasia, a malignant tumor of the uterine neck, myeloid leukemia.
The danger of a malignant disease is especially great when taking immunosuppressing drugs 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 remedy for rheumatoid arthritis is associated with significantly higher dangers of non-Hodgkin's lymphoma than the average among the entire human population.
Too much
If you use "Imuran" in excess dosage, hematomas, foci of bleeding, ulcers may appearin the throat area. The patient suffers from unmotivated infection. Symptoms associated with inhibition of bone marrow activity appear one and a half to two weeks after the start of taking excessive amounts. It is known that a single use of 7.5 g of azathioprine caused vomiting, stool disorders, nausea, leukopenia, and liver failure.
The drug has no antidote. If an overdose is detected, it is necessary to wash the stomach, take the patient's condition under control, and regularly check the activity of the hemolytic system. It is not yet known how effective dialysis is, but it has been found that the active component of Imuran can be partially removed 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 disease prone to relapse, associated with the formation of foci of inflammation on the skin. With such a diagnosis, a person is forced to use drugs for stopping inflammation, eliminating symptoms for long courses - atopic dermatitis is one of the incurable pathologies. Hygiene and proper care are important at any stage - the skin requires regular moisturizing, softening through emollients. So far, it has not been possible to identify the features of the effectiveness of such drugs, but it is believed that they cannot stop inflammatory activity.
Undoubtedly, effective in atopic dermatitis arehormonal anti-inflammatory drugs, but those are highly likely to cause side effects. In some cases, performance develops too slowly. Cancellation 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 precisely the approach used today for the topical treatment of atopic dermatitis calcineurin inhibitors.
Subtleties of the issue
Immunosuppressive drugs are prescribed when atopic dermatitis develops in a severe form, proceeds stubbornly. Cyclosporine, methotrexate, azathioprine are used. The classic version is preparations 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 down 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.
Severe atopic dermatitis may be related to substances produced by Staphylococcus aureus. The use of cyclosporine helps to reduce the clinical manifestations of the disease, reduce the concentration of bacteria on the skin. The study involved minor patients. Before starting the use of immunosuppressive drugs, some researchers argue that a course ofantibiotic treatment.
Official and reliable
Almost two decades ago, British scientists drew up an agreement regulating the use of cyclosporine against the background of atopic dermatitis. Particular attention is paid to the status of the reserve. Cyclosporine is used only in severe cases of the disease and ineffectiveness of the standard course. An increased level of toxicity obliges to monitor the patient's condition, check renal function, pressure indicators. It is forbidden to use cyclosporine for the treatment of dermatitis in hepatic, renal disorders, acute infectious pathologies.
They can prescribe not only an ointment, but also an orally used solution. First, the dose is calculated as 5 mg / kg, divided into two doses, then halved. The duration of the therapeutic course varies from one and a half to several months.
The use of cyclosporine is accompanied by a decrease in 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 gives temporary relief from the symptoms of dermatitis, but approximately every second patient complains of increasing manifestations of the disease by the end of the second week after completing the course. On average, only every sixth person 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.
