My opinion is that existing immunosuppressive therapy is very applicative and reliable in human medicine, but I think it will take a lot of effort to overcome the HLA barrier between different species, as well as improvement in immunodiagnostics before HLA typing

In the issue that you are completely correct answer, it is clear that you are an accomplished skilled this matter!

Thank you Professor Karamehić

You Welcome!

Does the discovery of new immunosupressants give us better opportunities - better chances for initiation of xenotransplantation in human medicine?

Yes indeed develop novel immunosuppressants increases the possibility - better chances for starting xenotransplantation!

I am interested in this subject a lot since I researched the financial aspects of immunosuppressive therapy. In particular, will the new immunosuppressives be more expensive to existing ones due to R&D. In my opinion, if the problem of xenotransplantation is resolved, then the cost of complications of terminal organ failures (hemodyalisis, diabetes complications, etc.) might be largely mitigated. 

Yes you are absolutely right!

DO you will have to also keep track of the level of concentrations eventual new immunosuppressant as is the case now with (cyclosporine, tacrolimus), which could be use in xenotransplantatation?

Most likely you will have to monitor the level of concentration of this new potential immunosuppressive!

Why?

That his concentration was in Referential therapeutic doses and to avoid possible involuntary its consequences and the organism as a whole but also graft !!

Thanks

You Welcome!

In  your opinion , which kind of immunosupressive th may influence overcoming biological barriers in xenotranspl.?

Well done to all types of immunosuppressive improved but I think that the closest that calcineurin inhibitors something like cyclosporine or tacrolimus, because no specific organic transplants where they gave remarkable results in the inhibition of rejection, acting on the inhibition of T helper cells and other structures (inhibition IL-2), etc.! !

Thank you very much professor, I have no more questions.

You Welcome, again!

That is very interesting question  and for discussion.Xenotransplantation presents  novel medical,legal and ethical issues

I agree you respected professor Resic, these are exactly in that order problems to be solved and much more else!

I think you will agree with me that the work and training of better functioning on the new immunosuppressive agents to improve and reduce immunological barriers that exist between different species-!

What is your opinion, what would be the cost benefit of immunosupresive therapy in xenotransplatntation?

Good question in the field of pharmacoeconomics, which is unusually important, when you introduce something new to be found in everyday life this time in transplant medicine! Of course more it will be able to say, when we know how much costs are investigated new immunosuppressive therapy and determine then only we can cost benefit!

For existing imunospresivnu therapy'm sending you a response his book entitled "The immunosuppressive therapy and its use in organ transplants" issued 2,012 years authors Jasenko Karamehic and Sebija Izetbegovic and especially chapter XII THAT titled "Financial aspects of immunosuppressive therapy" Author Oggi Ridic and associates. the same book is complete with all the chapters in the bibliography in my CV on my Web Page on Research Gate!

I give you an introduction to this chapter which is also my answer to your question, the cost benefit existing immunosuppressive therapy and, in the same way shall be governed by and for potential new anti-rejection drugs !!

Chapter XII FINANCIAL ASPECTS immunosuppressive

                   THERAPY

                 Financial Aspects of immunosuppressive therapy

O. Riđić, F.Gavrankapetanović, Riđić G., T. Jukic, O.Slipičević, J. Karamehic

12.1. Introduction

12.2. immunosuppressive protocols

12.3. Examples of funding immunosuppressive therapy

1. The costs of immunosuppressive drugs

The used second (immunosuppressive) drugs in the period 2006-2008.

        12.3.3. Only the number of patients treated with immunosuppressive lijkekovima and total and

                       average consumption of drugs used (per patient) in FBiH

                       in the period 2006-2008

        12.3.4. Only the number of patients treated with immunosuppressive agents including

                   generic name, number of treated patients, the number of units and the total amount to BAM, in

                       FBiH for the period 2009-2010.

4. Discussion

5. Conclusion

6. References

XII FINANCIAL ASPECTS immunosuppressive therapy

12.1. Introduction

Any time, when we have to transplant an organ or organs from one person to another, the recipient's body tends to reject foreign (implanted) body (eg. Body). In order to prevent the rejection of modern medicine uses potent immunosuppressive agents. Today, immunosuppressive therapy is designed to suppress all immune responses, including those on: bacteria, fungi, viruses, malignant tumors, etc.. The cost of immunosuppressive therapy are an essential part of the cost of whole organ transplantation. In this paper, the authors analyzed the cost of immunosuppressive therapy in the two countries: the United States and entities of the Federation of Bosnia and Herzegovina (ie. The FBiH).

Medical and pharmacological interventions that require changes in the patient's regime, among those patients whose treatment regimes "do not follow the prescribed procedures and rules vary from patient to patient, and from 50 US states. Prominent target companies for patients undergoing organ transplants, slowly but certainly, runs more towards almost complete (ie. universal) approach immunosuppressive drugs, given that this category of costs usually outpace the annual cost of hospital (ie. the hospital) and outpatient eg. ambulatory and home care).

Immunosuppressive regimens are expensive in the socio-economic environment of limited resources and constraints. Recipient body reacts and responds to new transplants trying to discard them. The most common type of rejection is called "acute rejection", which potentially can occur at any time, in inadequate immunosuppressive environment, but usually occurs within a few days after transplantation. In order to diagnose rejection must use expensive procedures (eg. Biopsy, radiological tests, etc.). Cancellation of acute transplant rejection requires more immuno-suppression, increased use of additional therapies, more frequent monitoring, clinical examinations and more intermittent hospitalization, in other words all translate into higher costs of use (1-6). Preliminary research literature shows that the number of patients in FBiH who required immunosuppressive drugs from 2009 to 2010 increased by 35, which is 27.3% more.

In accordance with the rules laid down and issued by the Federal Ministry of Health on treatment with immunosuppressive drugs for all patients who have undergone organ transplants, Commission for immunosuppressive treatment, as part of the Federal Bureau of insurance and reinsurance companies in Bosnia and Herzegovina, giving authorization for the use of immunosuppressive drugs , as a permanent therapy after organ transplantation. In 2009, the immunosuppressant drugs have been used by 128 patients. Immunosuppressive drugs should be used by all patients, during and after organ transplantation.

Treatment options must also be assessed taking into account the socio-economic barriers, which can carry serious consequences of non-acceptance and non-compliance to this treatment to improve life. Examples of these barriers to quality and long-term immunosuppressive treatment, for example: unemployment, chronic low income, insurance status and quality of coverage, insurance (broker or impose terms of the third party), etc. Researchers Himmelstein, Woolhandler and others at Harvard University in Boston, Massachusetts, USA, have found that the majority of all bankruptcies in the United States was a problem caused by medical expenses. In 2009, President Barack Obama is trying to alleviate this problem by signing a law entitled "Protection of the patient and the law on availability." This legislation aims to extend the previously insufficient 36-month period federally sponsored medical care coverage, Medicare. (7-12)

The continuation of my answer to your question:

Assessment of future transplant recipients is another key element in the best socio-economic use of immunosuppressive therapy. When implemented and applied correctly, this assessment can bring long-term benefits of achieving further immunosuppressive therapy. In addition, psychological, cultural and multi-cultural issues need to be evaluated carefully and in a very delicate, balanced and fair way.

In the course of finding the ideal treatment regimen for reducing morbidity and mortality, while maximizing quality of life and optimizing costs a major challenge for the transplant community. Pharmaco-economic analysis can provide useful methods and tools for achieving serious goals. The objectives of this study are to give the readers with a basic understanding of pharmaco-economic principles and review of published pharmaco-economic analysis, relating to immunosuppression as an essential part of organ transplantation. Pharmaco-economic studies are broadly defined as "a description and analysis of the cost of treatment therapies for health systems and society". This is a process in which the costs of certain therapies assessed in relation to outcomes. (13-16)

Regards

The continuation of my answer to your question for dr.Marina:

Dr.Marina  think I'd let this be of interest!

The analyzes in the various countries of the world agree

in that transplantation medicine

provides significant economic savings, but ....

A large number of so far performed transplantations of solid organs (about 1.5 mil.) Has brought significant medical experience, he developed the organization obtaining organ transplants and emerged as a rational and effective way to treat and to preserve the health and lives of a large number of patients. Transplantation medicine is widely accepted, and its results are greatly improved over time. Advances in immunosuppression have brought additional important qualitative developments.

Kidney transplant from a living donor has a longer survival by 20% compared to cadaveric kidney. But transplant from a living donor involves many more, and many unnecessary costs in the selection of donors. Quality of life significantly increases the transplanted people, and cost-effectiveness of transplantation has increased.

The important question is: who is today the rate of knowledge about the viability of transplanting human substance?

Except the area of the kidney, liver and in part, in the literature there are few relevant publications to account cost-effectiveness and cost savings in other solid organ transplantation.

Thank you professor for your precise answer.

You Welcome!

Projections of research/application cost of new immunosuppressives to avoid biological/immunological barriers of different species in xenotransplantation?

The analyzes in the various countries of the world agree

in that transplantation medicine

provides significant economic savings, but ....

A large number of so far performed transplantations of solid organs (about 1.5 mil.) Has brought significant medical experience, he developed the organization obtaining organ transplants and emerged as a rational and effective way to treat and to preserve the health and lives of a large number of patients. Transplantation medicine is widely accepted, and its results are greatly improved over time. Advances in immunosuppression have brought additional important qualitative developments.

Kidney transplant from a living donor has a longer survival by 20% compared to cadaveric kidney. But transplant from a living donor involves many more, and many unnecessary costs in the selection of donors. Quality of life significantly increases the transplanted people, and cost-effectiveness of transplantation has increased.

The important question is: who is today the rate of knowledge about the viability of transplanting human substance?

Except the area of the kidney, liver and in part, in the literature there are few relevant publications to account cost-effectiveness and cost savings in other solid organ transplantation.

Economic cost effectiveness TRANSPLANT TREATMENT

In recent years published a series of studies on the economic assessment of transplant solid organ. The general assessment is that the moss is a sufficiently convincing and thorough work, which would contribute to improving the ways in stable transplant economic evaluation. Profitability of the kidneys and liver tx is namely generally accepted. But this is not a conclusion when it comes to the lungs, heart, small intestine or pancreas, due to many factors such as criteria for screening, long chronological monitoring results or methods of assessing a range of diverse costs and other variables.

Tx failure is due to the inevitable dialysis profitable and brings undeniable savings. Tx liver also brings savings. But when it comes to other organs, it is not possible to categorically define.

Happy Easter to all my friends and all members RG around the world!

I hope and want modern science to find a drug similar to Cyclosporin 1980 Years of the last century, which was very successful in transplanting with other immunosuppressants, because before this discovery, this area seriously stagnated!

I give a basic overview of the previous imo-suppressants, from their book, issued in 2012g. Under the title "Immunosuppressive Therapy and Its Use in Organ Transplantation", their activity and significance, which could further overcome the immunoblotic barrier through xenotransplantation by further training under these same principles. This book is entirely in electronic form on my CV on the web page of RG !

Introduction

Even 40 years ago, the first successful kidney transplant was performed between identical twins. The first attempts were unsuccessful or with a small amount of success because there was no adequate immunosuppressive therapy. The recipient organization sought to reject a foreign body by defensive immune response. Because of this, the experts worked on designing medications to develop effective immunosuppressive therapy. The first results are noticed in the practice of the 60s when the first immunosuppressive agents are being applied. Among the first are azathioprine (Imunran) and steroids. After some time, other medications such as mycophenolate mofetil that are slowly suppressing are occurring. From the age of 80, apart from ciclosporin, monoclonal antibodies block the function of T lymphocytes, resulting in immunosuppression. Monoclonal antibodies, which are routinely used with the CD3 glucoprotein, have a molecular weight of 20 kDa. OKT3 or mouse immunoglobulin, which is commercially used, has the ability to block the function of all T lymphocytes possessing this receptor. In the last 15 years many immunosuppressants have appeared that have a wide clinical application. Dr. Joseph Murray received the Nobel Prize in 1990 for successful work on kidney transplantation. The main strategy of clinical application of immunosuppressive is the reduction of the aloimic response to the transplanted organ. There are 4 major strategies in clinical practice: induction, prophylaxis of acute rejection, maintenance of immunosuppression and acute rejection therapy. Of course, the main goal of transplantation is to achieve absolute tolerance to the transplant, which will take time. For now, preventing transplant rejection is achieved by using powerful immunosuppressive medications at strictly prescribed doses to avoid toxic effects. Acute rejection occurs if no adequate suicide response is achieved. In cases of overactive immunosuppression, complications such as viral infections (Cytomegalo virus) or malignancy such as cancer of the skin, B cell lymphoma, Kaposi's sarcoma etc. may occur. For example, clinicians in the area of transplantation have limited possibilities to achieve effective results.

Anti-suppression drugs (immunosuppressive drugs) have been the success of organ transplantation, which we are witnessing today. Unfortunately, they do not only act to prevent rejection of transplanted organs, but have many unwanted effects on the body. Especially important is reduced resistance to infections caused by immunosuppressive drugs. Treatment protocols are not unique to all transplantation centers. Transplant Centers decide on certain immunosuppression protocols according to the results of published clinical trials and their own experiences.

Immunosuppression, immunoinhibition, immunodeficiency, is the suppression and weakening of the normal immune response of the organism as a consequence of the action of different substances found in the external environment or created in the body. Each transplanted body represents a foreign body that the body is trying to discard. In order to avoid this, it is necessary to take anti-rejection drugs (immunosuppressive medicines). There are numerous medications as well as their combinations, however, all have a common one - they must be taken as long as the function of the transplanted organ takes place. Because immunosuppression of the immune system's function is weakened, there is an increased susceptibility of the organism to infectious diseases and cancer, so not so often immunosuppression can cause undesirable side effects.

Anti-suppression drugs (immunosuppressive drugs) have been the success of organ transplantation, which we are witnessing today. Unfortunately, they do not only act to prevent rejection of transplanted organs, but have many unwanted effects on the body. Especially important is reduced resistance to infections caused by immunosuppressive drugs. Treatment protocols are not unique to all transplantation centers. Transplant Centers decide on certain immunosuppression protocols according to the results of published clinical trials and their own experiences.

Immunosuppression, immunoinhibition, immunodeficiency, is the suppression and weakening of the normal immune response of the organism as a consequence of the action of different substances found in the external environment or created in the body. Each transplanted body represents a foreign body that the body is trying to discard. In order to avoid this, it is necessary to take anti-rejection drugs (immunosuppressive medicines). There are numerous medications as well as their combinations, however, all have a common one - they must be taken as long as the function of the transplanted organ takes place. Because immunosuppression of the immune system's function is weakened, there is an increased susceptibility of the organism to infectious diseases and cancer, so not so often immunosuppression can cause undesirable side effects.

Anti-suppression drugs (immunosuppressive drugs) have been the success of organ transplantation, which we are witnessing today. Unfortunately, they do not only act to prevent rejection of transplanted organs, but have many unwanted effects on the body. Especially important is reduced resistance to infections caused by immunosuppressive drugs. Treatment protocols are not unique to all transplantation centers. Transplant Centers decide on certain immunosuppression protocols according to the results of published clinical trials and their own experiences.

Immunosuppression, immunoinhibition, immunodeficiency, is the suppression and weakening of the normal immune response of the organism as a consequence of the action of different substances found in the external environment or created in the body. Each transplanted organ represents a foreign body that the body is trying to discard. In order to avoid this, it is necessary to take anti-rejection drugs (immunosuppressive medicines). There are numerous medications as well as their combinations, however, all have a common one - they must be taken as long as the function of the transplanted organ takes place. Because immunosuppression of the immune system's function is weakened, there is an increased susceptibility of the organism to infectious diseases and cancer, so not so often immunosuppression can cause undesirable side effect!

Completely agree with you, I have read your answers that transplantation is a cheaper and better solution than classic treatment !

Thanks a lot professor Coric!

What do you think about individual dose of the immunosuppressive drug?

Which immunosupresive drug do you find most important in terapy of organ rejection?

All medications-immunosuppressive agents have less of great value in stopping or rejection think I basic therapy calcineurin inhibitors such as Cyclosporin and Tacrolimus KEY initiation of kalcineuoronski is they inhibit the signal transduction pathway in cells which reduces lymphocyte activation and cytokine production!

New potential immunosuppressants

In addition to agents now commonly found in clinical practice, there are medications that are in some stage of clinical testing, and that because of the good results, could be included in the official list of immunosuppressants used in the phase of post-transplant immunosuppression.

5.1. FTY720

This agent is a synthetic analogue of sphingosine, prepared on myriocina, fungal metabolites extracted from Isaria sinclairii. It is believed that it has the property of removing lymphocytes from peripheral blood, secondary lymphoid compartments enhances, and its specific mechanism of action, will be a new therapeutic agent is an immunosuppressive official. The results of this pilot study showed that the maintenance of immunosuppression using FTY720, everolimus and corticosteroids, in the group of patients at increased risk of DGF is safe, well tolerated.

5.2. FK778

FK778 is malononitrilamide (MNA), a derivative of leflunomide. Is derived from an inhibitor of dihydroorotate dehydrogenase, the key enzyme in the synthesis of pyrimidines. MNA and inhibit T and B cell function by blocking the synthesis of pyrimidines, and inhibits tyrosine kinase. Has shown that the immunosuppressive and anti-proliferative activity. During the second phase of research in kidney transplantation.

T cell activation requires two separate signals, connected to the first presentation of MHC complex, and the second signal is based on receptor / ligand interactions between T cells and antigen-presenting cells. When both signals delivered to T cells secreted IL-2, potent autocrine growth factor that stimulates the T cell proliferation, clonal expansion and the production of cytokines. In the absence of signal 2, T cell becomes non-reactive to the antigen and subsequent exposures not secrete cytokines and undergoes apoptosis. Two major costimulatory signal CD28 / B7 and CD40 / CD154.

Belatacept (CTLA4-IgG)

Abatecepta derived from it differs by the replacement of two specific amino acids. It blocks binding to CD80 co-stimulation and CD86 on antigen presenting cells. This interaction inhibits T cell activation and promotes apoptosis and anergy. It was shown to be useful in the treatment of certain autoimmune diseases, including psoriasis RAi. His research in renal allograft recipients lists the possible benefits when given in combination with other immunosuppressive agents.

Anti-B7 monoclonal antibody

Anti-B7 monoclonal antibody directly block B7 antigen-presenting molecules on cells. Use of an anti-B7 monoclonal antibody together with cyclosporin A in vitro and induces antigen specific tolerance to human cells. cyclosporin A in vitro and induces antigen specific tolerance to human cells. It has been shown that anti-B7-1 and anti-B7-2 and prolong survival of cardiac graft in mouse pancreatic. When these two antibodies used in combination pots synergistic effect.

5.5. Anti-CD154 monoclonal antibody

It blocks the T cell activation signal through the CD154-mediated or indirectly blocks B7-1, B7-2 and intracellular adhesion molecule-1. Has been shown to prolong survival of the graft in the transplantation of pancreas and heart in mouse and recent studies show that the use of human anti-CD154 monoclonal antibodies prevent rejection of renal allografts in Rhesus monkeys.

Monoclonal antibodies which block adhesion molecule

Adhesion molecules are critical in the activation of immune cells and the filling within the allograft. They enhance antigen recognition by increasing the affinity of a T cell receptor and antigen-MHC complex. LFA-1 is a cell superficial protein comprising stimulatory signal for T cell activation. Intercellular adhesion molecules (ICAM-1 and ICAM-2) are specific ligands for LFA-1.

Anti-ICAM-1 monoclonal antibodies, inhibit CD4 + T cell activation in vitro and prolong allograft survival in animal models.

Anti-LFA-1 monoclonal antibody used for the problem of acute rejection with the same efficiency as anti-lymphocyte globulin, and also protects from falling behind in the functioning graft.

5.7. Monoclonal antibodies that block the T cell accessory molecules

Nepolimorfni accessory molecules are membrane proteins that serve as markers superficial cell, which are identical in all T cells. Important in the alloimmune response for stabilizing the interaction of cytotoxic T cells and target cells. They bind their specific ligands on the surface of target cells, two tepružaju signal for T cell activation. CD2 ligand for the LFA-3 molecule expressed antigen-presenting cells and endothelial cells. CD45 is superficial cellular glycoprotein expressed on all leukocytes and is a key regulator of T cell activity.

 LFA3TIP human protein is designed to block CD2-LFA-3 interaction. It has been shown to prolong survival of cardiac allografts in monkeys.

Anti-CD45 monoclonal antibody given during kidney transplantation damages companions leukocyte grafts.

BTI-322 is a rat monoclonal IgG2b antibody directed against CD2.

Clinical application of immunosuppressive

There are four main strategies in clinical practice: induction, prophylaxis of acute rejection, maintenance immunosuppression therapy against acute rejection. The main goal in transplantation is to achieve absolute tolerance for graft. Preventing acute rejecteed is currently achieved by the use of strong immunosuppressive drugs in strictly regulated doses. Today,Many transplant centers are trying to replace the dose of immunosuppressive therapy with other, less toxic drugs, or pull one drug and translate patient for example with double to triple therapy or even find alterative for taking the cheaper drugs. However, any change in the risk for complications such as acute rejection. For patients who regularly performs control, acute rejection is most often detected in time and treatment is usually successful. Hyperacute rejection occurs within 48 hours of transplantation and is caused by pre-existing complement-fixing antibodies to antigens. Hyperacute rejection is characterized by thrombosis of small vessels and myocardial termination. The cases of fungal immunosuppression may occur viral infections, the occurrence of skin cancer and other complications.

Please consider exploring the phyto cannabinoid CBD or Cannabidiol as it has been shown to completely prevent GvHD in stem cell transplant patients. http://www.bbmt.org/article/S1083-8791(15)00375-4/fulltext

This needs to be urgently researched further. Thank you!

Thanks a lot for this information she will  useful for my!

Regards

Jasenko

induction of immunosuppression

Induction of immunosuppression in transplanted kidney is one way to achieve the prevention of kidney transplant rejection in the recipient. The first three months are the most critical period after the transplantation and in this period immunosuppressive therapy must be strong enough to prevent rejection of the kidney. In that purpose, the biological agents such as polyclonal anti-lymphocyte antibodies, and murine monoclonal antibody preparations. Prophylactic immunosuppression antibodies can be prescribed as optional recipients of kidney termination and that for the purpose of reducing the number and level of acute reaction first 3-6 months after transplantation. There are two types of induction which are used to prevent early acute rejection, such as: therapy based on antibodies and aggressive early immunosuppression.

Therapy is based on antibodies is given in the early post-transplant period, and to avoid or reduce the dose of calcineurin inhibitors.

EARLY aggressive immunosuppression is used to maintain the drug at a higher dose to achieve the strongest immunosuppressive effect upon transplantation.

6.2. Prevention of acute rejection and immunosuppression maintenance

After the successful prevention of acute kidney allograft rejection is necessary to maintain the level of immunosuppression at a certain level. In this way reduces the incidence of acute rejection episode during the first six months after the translation. Home immunosuppressive maintenance therapy must be given prior to transplantation or at the time of transplantation. Immunosuppressants must be taken for life. Home immunosuppressive therapy and maintenance therapy, which was previously the most commonly used was a combination of cyclosporine, prednisone and azathioprine. For a long time, clinicians strategy was based on the use of two to three medicament, and thereby had to know which of them is dominant. Over time, regularly went to the reduction of the dose of a dominant immunosuppressive because of avoiding its toxicity. However, most patients showed a tendency toward lower doses of immunosuppressants, and it is considered that this is probably a result of the phenomenon of so-called. Accommodations allograft.

6.3. Therapy of acute rejection

Today there are three strategies against acute rejection. Many critics now use pulse corticosteroids as primary treatment in cases of mild to moderately intense acute rejection. When it comes to more aggressive form of acute rejection, which is typical for patients with arteritis in patients who do not respond to pulse steroids, in patients in whom corticosteroids are contraindicated, etc., Applied much more aggressive strategy of using preparations antimloimfocitnih antibodies. Terapcija of acute rejection can be short-lived success, and is determined by the improvement of the renal function and to an incidence of 90%.

 The strategy in cases of chronic allograft nephropathy

There is a specific approach to act in terms of the reserve. Efforts clinicians are reduced to minimize the influence nefrotosičnih agents such as calcineurin inhibitors, control of hypertension, renal perfusion opzimacija. Unless the cause of rejection is inadequate immune suppression, changes in immunosuppressive therapy are generally not effective in chronic rejection of the reserve. In addition to medications that are already in clinical practice, in the process of clinical evaluation are potential immunosuppressants that could essence involved in post-transplant treatment. Immunosuppressive agents therefore allows the protection of organ transplant rejection and for protection from side effects of recipient. Needle biopsies 11 days after transplant showing inflammatory damage of the small arteries. Sample hepatectomy obtained six weeks after transplantation showed lymphocytic infiltration involving all layers of medium sized arteries. Needle biopsy 4 months after transplantation shows perivenular nerkozu and lymphocyte infiltration.

 Biomarkers excessive immunosuppression

An important goal in transplantation is to adjust immunosuppression the individual needs of patients, avoiding the rejection and excessive immunosuppression. Monotoring immunosuppression is now mainly carried out on the basis of pharmacokinetic properties which do not necessarily foresee clinical outcome in an individual. The definition of a biomarker is actually characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to therapeutic intervention. Biomarkers are used for the prediction and monitoring of clinical response. It's hard to deifnisati adequate immunosuppression because they do not have enough knowledge about successful immunosuppression potrebnj for the prophylaxis or the treatment of rejection in an individual. Although there is no clear and sufficiently accepted definition of us-immunosuppression or excessive immunosuppression, for practical purposes, can be defined in terms of frequency and severity of infections and malignancies in patients during immunosuppressive treatment. Also, over-immunosuppression is shown as a leading cause of death after transplantation in Australia. Over-immunosuppression is a common and important problem after transplantation, and all approved immunosuppressant drugs contain a warning about the increased susceptibility to infection and the potential development of malignancy associated with the use of these drugs.

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 Infections malignancy

Infection and opportunistic infections occur mainly in the first year after transplantation, in response to strong initial immunosuppression. Malignancy occurs mainly after the first sir, an annual rate of 1% per year and it seems that the cumulative immunosuppression is an important factor. Each type of cancer has its own associated risk factors. Some post-transplant malignancies are associated with viruses, providing strong evidence for a close relationship between infection and malignancy.

Strategies for avoiding excessive immunosuppression and the role of biomarkers

The ideal solution to the problem of over-immunosuppression would be the development of protocols tolerance devoid of any immunosuppression, thus completely avoiding excessive immunosuppression. Given that such protocols tolerance currently unknown, closely related approach is the use of biomarkers in identifying tolerant patients. Such patients would no longer require immunosuppression, which would avoid further side effects of immunosuppressants. Sequential monitoring with biomarkers can help in the individualization of immunosuppressive regimens and such monitoring will be a complement to conventional monitoring of medicines. Ideally, these biomarkers to assist in the management of immunosuppressive therapy and would prevent the appearance of excessive immunosuppression without the need for further pharmacokinetic control, because any additional monitoring biomarkers increased burden of treatment. Currently there are a number of biomarkers (Table 1) that are directly (special mark) or indirectly (global markers) related to the pharmacodynamic effects of immunosuppressants.

 The pharmacokinetic biomarkers

Pharmacokinetic markers are routinely used for the conduct of treatment with calcineurin inhibitors, however, their usefulness in monitoring mycophenolate mofetil is debatable. Valid and reliable systems tests are preferable to use pharmacokinetic markers. Numerous studies have attempted to generate a therapeutic window in an attempt to avoid rejection, the toxicity associated with drugs and excessive immunosuppression.

. Pharmacodynamic biomarkers

The pharmacokinetic markers are only surrogates for biological effects, and documented that the same exposure can lead to different results in different individuals. The goal is to directly determine the biological response of the individual immunosuppressants (pharmacodynamics).

 genetic biomarkers

Unlike most of pharmacodynamic biomarkers, genetic and pharmacogenetic markers can be determined by means of clear, certified and reliable system tests.

There are few data on the usefulness of genetic markers for predicting excessive immunosuppression; Studies in larger independent and prospective groups are needed to firmly establish a connection between excessive immunosuppression and genetic markers.

 antiviral biomarkers

Several markers of antiviral immunity were tested in order to improve prediction of viral infection after transplantation. Several markers of antiviral immunity were tested in order to improve prediction of viral infection after transplantation

 The soluble cell markers and markers

Several biomarkers for immune monitoring is investigated in the past. Such an objective biomarker is the measurement of functional and molecular correlations of immune reactivity to provide clinically useful information for decision-making. Generally, these biomarkers can be divided into soluble markers and cellular markers. Cytokines in blood or biological fluids are examples of soluble markers that could help in the detection of rejection.

Beyond the potential utility of cytokines to replace Creaktivni protein as biomarkers for infection / inflammation, there is no data on their ability to predict excessive immunosuppression. Marker T helper type 2 activation, is another potential biomarker that is submitted for assessment pretransplantacijskog immunological risk. One retrospective study published by the weak correlation between PRETRANSPLANTATION soluble CD30 and pneumonia. In short, it needs more data to establish acceptable soluble markers for excessive immunosuppression.

Many cellular immune system markers were studied after transplantation, including lymphocyte proliferation, lymphocyte activation and superficial cell and intracellular markers.

 Essays based multiplexing: ATP test

Standardization of tests and evaluation based on multiplexing are possible, as shown IATP commercial test, which determines the CD4 + cell response measurement IATP synthesis stimulation after night. The test has intra-individual variability of 6-20%. Given the lack of adequate studies in favor of the biomarkers, in detecting infection after transplantation remains open for evaluation.

CONCLUSION

Immunosuppression is a process which suppresses the activity of the immune system and thus ensures the survival of a transplanted organ or tissue. According to the method of formation of immunosuppression may be unintended (undesirable) and intentional (controlled). Immunosuppression may be unintended consequences nastatati as unwanted (secondary) effects of some substances, drugs. Deliberate immunosuppression is administered as a method of prevention of organ transplantation or the treatment of other diseases and specific system. It is worth noting that in suppressing the immune response to a particular antigen suppresses the reaction of the entire immune system.

Immunosuppressive therapy is aimed to protect the patient from transplant rejection, and that without increasing its susceptibility to infection. Although the goal of immunosuppressive therapy reducing unwanted immunoreactivity, very often immunotherapy is accompanied by complications such as infection, tumosti, metabolic disorders, hypertension, etc.

Immunosuppressive drugs act in the induction phase of the immune response, reducing the proliferation of lymphocytes; some also inhibit the effector phase. Drugs used for the purpose of immunosuppression roughly be divided into agents:

• or inhibit the effect of interleukin-2 for example. Cyclosporine, tacrolimus

• inhibit expression of genes for cytokines, eg. corticosteroids

• inhibit the synthesis of purine and pyrimidine, for example. azathioprine, mycophenolate mofetil

• blocking molecule on the surface of T cells involved in the signaling process, for example. monoclonal antibody

Induction of immunosuppression in transplanted kidney is one way to achieve the prevention of kidney transplant rejection in the recipient. There are two types of induction which are used to prevent early acute rejection, such as: therapy based on antibodies and aggressive early immunosuppression. After the successful prevention of acute kidney allograft rejection is necessary to maintain the level of immunosuppression at a certain level. In this way reduces the incidence of acute rejection episode during the first six months after the translation. Home immunosuppressive maintenance therapy must be given prior to transplantation or at the time of transplantation. Immunosuppressants must be taken for life.

REFERENCES

1. Prof. dr. Jasenko Karamehic, Prof. dr. Sebija Izetbegovic and associates. Immunosuppressant therapy and its use in organ transplantation. Sarajevo, 2012.

What kind of immunosuppresive therapy is availible in your country?

All that therapy is required, according to the applicable protocols water after organ transplantation patient!

Fundamentals of immunosuppression

Immunosuppression

Immunosuppression is a common name for the processes and conditions of suppression, suppression of the immune response.

The immune response can be suppressed or weakened in several ways: by giving antigens, administering specific antibodies, biological substances (antisera, hormones), cytokine agonists and antagonists, soluble cytokine receptors, cytostatic agents, immunosuppressive agents, radiation and surgical removal of lymphatic tissues.

The goal of immunosuppressive treatment is to reduce unwanted, immune activity, but the application of immunosuppression is accompanied by complications such as infections, tumors, metabolic disorders, arterial hypertension, and other side effects of treatment.

Immunosuppressive drugs prevent the rejection of the transplanted organ by developing immunotolerance against specific antigens, while preserving the immune function of the organism as a whole

HISTORY OF IMMUNOSUPRESSION

The possibility of prolonging the life of transplanted organs has long been a dream of a doctor. Early efforts on transplantation failed due to shortcomings in surgical technique and lack of basic knowledge about the immune system. Modern medicine has overcome these challenges and prevailed many obstacles to achieving successful organ transplantation (1).

In the XX century we experienced an explosion in the discovery of human organism, pathology and transplantation in a new chapter of research and clinical application in discoveries for the benefit of human existence (2). This is a fascinating story of modern surgery, which has changed and continues to alter the final outcome of numerous states (3).

The idea of transplantation has always been a great interest in medical research, but it is very difficult to determine the date when the idea was born. Many writings from ancient Greece expressed suspicion about the idea that organ transplantation could become a reality (4).

Sushruta (VI century BC) was a famous surgeon of ancient India and author of Sushrut Samhit's book. In this book, he described over 120 surgical instruments, 300 surgical procedures, and classified human surgery into 8 categories (5). This is one of the oldest documents in the Buddhist religion that mentions transplantation. In these documents, for the first time, they mention medical sciences that could be involved in transplantation, such as anatomy, physiology, and pathology. The ancient Greeks translated Samhit Sushrut and his work was analyzed by Hippocrates, who often mentioned him in his works (6.7). Hippocrates himself was heavily involved in ethical and technical transplantation issues. In his writings, he described surgical complications in nose, mouth, etc. operations (8). The Egyptians took over this method and a well-known Alexandrian school was founded. The greatest writers of that era were Hazes and Albucasis of the Cord. These famous Arabic writers have labeled this era of advanced Arabic medicine (9).

DEVELOPMENT OF IMMUNOSUPPRESIVE THERAPIE

The possibility of prolonging the life of transplanted organs has long been a dream of a doctor. Early efforts on transplantation failed due to shortcomings in surgical technique and lack of basic knowledge about the immune system. Modern medicine has overcome these challenges and prevailed many obstacles to achieving successful organ transplantation (1).

In the XX century we experienced an explosion in the discovery of human organism, pathology and transplantation in a new chapter of research and clinical application in discoveries for the benefit of human existence (2). This is a fascinating story of modern surgery, which has changed and continues to alter the final outcome of numerous states (3).

The idea of transplantation has always been a great interest in medical research, but it is very difficult to determine the date when the idea was born. Many writings from ancient Greece expressed suspicion about the idea that organ transplantation could become a reality (4).

Sushruta (VI century BC) was a famous surgeon of ancient India and author of Sushrut Samhit's book. In this book, he described over 120 surgical instruments, 300 surgical procedures, and classified human surgery into 8 categories (5). This is one of the oldest documents in the Buddhist religion that mentions transplantation. In these documents, for the first time, they mention medical sciences that could be involved in transplantation, such as anatomy, physiology, and pathology. The ancient Greeks translated Samhit Sushrut and his work was analyzed by Hippocrates, who often mentioned him in his works (6.7). Hippocrates himself was heavily involved in ethical and technical transplantation issues. In his writings, he described surgical complications in nose, mouth, etc. operations (8). The Egyptians took over this method and a well-known Alexandrian school was founded. The greatest writers of that era were Hazes and Albucasis of the Cord. These famous Arabic writers have labeled this era of advanced Arabic medicine (9).

Development of immunosuppressive drugs

The recipient's organization, therefore, tried to discard a foreign organ or a transplant by defending the response of its immune system. That's why experts have been working intensively on the design of pharmacological drugs in order to develop effective immunosuppressive therapy. The result of these efforts is the fact that the first immunosuppressive agents begin to apply in practice in the early 1960s.

Initial attempts at immunosuppression were radiation of the whole body. Since 1960, 6 mercaptopurin was used, followed by an anti-inflammatory steroid cortisone (40.41). In 1963, Starzl and Marchioro discovered the efficacy of high-dose prednisone in the suppression of acute rejection rejection reactions (42). With the development of 6-mercaptopurine (Purinetol) and then azathioprine (Imuran) in the early 1960s, pharmacological immunosuppression has become the standard of care. After the first series of initial successful transplants performed between 1962 and 1964, in Denver, Colorado, azathioprine, and steroid combination has come into wide use and has become the primary part of an immunosuppressive regimen for the next 20 years. Corticosteroids are used in combination with azathioprine, a chemical derivative of 6-mercaptopurine, and after finding antilimfocitnog globulin (ALG) together made up the standard immunosuppressive protocol (43). As the knowledge of the immune system developed, the therapy focused on the specific side of the immunoregulation became possible. First polyclonal antilymphocyte globulin was used in 1967 and caused the development of other polyclonal and monoclonal antibodies, that its selective mechanism of blocking the function of T-lymphocytes, and the result is immunosuppression. Introduced in 1980, ciclosporin (Sandimmune, later Neoral), calcineurin inhibitor, was used in combination with azathioprine and steroids and was responsible for dramatically improving the survival of the prescription. Antilymphocyte antibody, ALG and later OKT3 or mouse immunoglobulin which is capable of blocking the function of all T cells which have the receptor, were used directly after the transplantation of early immunosuppressive treatment (induction), and for treatment of acute rejection reactions, however, only the introduction of Cyclosporine significantly improved the survival of the prescription and patients (44).

Development of immunosuppressive drugs

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The next progress came in 1994 with the introduction of mycophenolate mofetil (MMF [CellCept]). In the same year, tacrolimus (another calcineurinine inhibitor) became available. Tacrolimus was gradually pushed out ciclosporin in many centers. In contrast, mycophenolate mofetil rapidly replaced azathioprine almost everywhere (45). During the 1990s introduced the newer immunosuppressive drugs, sirolimus (rapamycin), a macrolide antibiotic, and monoclonal antibodies against interleukin-2 receptor (IL-2R, CD25), which led to the further improvement of treatment kidney transplantation.

While short-term results, conditioned by these medicines continues to improve, the consequences of their application have become the subject of intensive control, as well as illnesses because of the toxicity of drugs and side effects that affect patient survival and graft.

LITERATURA:

1. Karamehić J., Mašić I., Škrbo A., Drače Z., Delić-Šarac M., Subašić Đ., Transplantation of Organs: One of the Greatest Achievements in History of Medicine, Medicinski arhiv, 2008; 62(5-6), 307-310

2. Najrian JS Simons LR. Transplantation, Urban and Schwarzenberg, 1972: 3-22.

3. Starzl ET. Experience in Renal Transplantation, Saunders Comp. 1964:363-70.

4. Bošković S. Transplantacija organa i društvo, serija napisa o socio-medicinskim problemima transplantacije u društvu, „Oslobođenje“ 15-30, januar 1981.

5. Bošković S., Transplantacija bubrega, Poglavlje historija transplantacije, 1987: 15-27.

6. Karamehić J. i saradnici, Transplantacija organa, poglavlje istorija transplantacije, 2002: 13-27.

7. Peer, LA. Transplantation of Tissues. Baltimore, Williams and Wilkins Company, 1955: 25-9.

8. Carrel A. Result of the transplantation of blood vessels, organs and limbs. JAMA, 1908, 51: 1662-7.

9. Carrel A. The transplantation of organs, New York Medical Journal, 1914, 25 April:839.

10. Carrel A. La technique operatorie des anstomoses vascularies et la transplantation des visceres. Lyons Med, 1902: 98:589-864.

11. Holman E., Protein sensitization in isoskinggrafting. Is the latter of practical value? Surg. Gynecol. Obstet., 1924; 38:100-6.

12. Hume D., Merrill JP, miller BF: Homologous transplantation of human kidneys. J Clin Invest, 1952; 31:640.

13. Kolff  WJ, Berk HThj. The artificial kidney: a dialyser with great area. Acta med Scan, 19444; 117: 121-34.

14. Merrill JP, Thorn GW, Walter CW et al. The use of artificial kidney. I Techniquel Clin Invest, 1950; 29: 412.

15. Merrill JP, Murray JE, Harrison JH et al.: Successful homo transplantation of the human kidney between identical twins. JAMA 1956; 160:277-82.

16. Medawar PB. A second study of the bahaviour and fate of skin homografts in rabbits, J Anat, 1945; 79: 157-76.

17. Schwartz R, Stack J, Dameshek W. Effect of 6-mercaptopurine on primary and secondary immune responses. J. Clin Invest., 1959; 38:1394-403.

18. Murray JE, Merrill JP, Harrison JH et al. Prolonged survival of human kidney homografts by the immunosuppressive drug therapy, N Engl J Med, 1963; 268: 1315-23.

19. Rapaport FT, Dausset J. Ranks of donor-recipient histocompatibility for human transplantation, Science, 1970; 167: 1260-2.

20. Opelz G Effect of HLA matcing, blood transfuzions and presensitization in cyclosporin-treated kidney transplant recipients: Transplant. Proc., 1985; 17:2179.

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21. Breimer ME, Brynger H, Rydberg L et al. Transplantation of blood group A2 kidneys to O recipients. Biochemical and immunological studies of blood group A antigens in human kidneys. Transplant Proc, 1985; 17: 2640.

22. Welch CS, A note of transplantation of whole liver in dogs. Transpalnation Bull, 1955; 2:54.

23. Moore FD, Smith LL, Buranap TK et al. One stage homotransplantation of the liver following total hepatectomy in dogs. Transplantation Bull, 1959; 6: 103-7.

24. Starzl TE; Marchioro TI, Huntley RT et al. Experimental and clinical homotransplantation of the liver. Ann NY Acad Sci, 1964; 120: 739-65.

25. Borel JF, Feurer C, Magnee C et al. Effect of the new antilymphocytic peotide Cyclosporine A in animals. Immunology, 1977; 32: 1017.

26. Handschumacher RE, Harding MW, Rice J et al. Cyclosporine: a specific cytosolic binding protein for cyclosporine A. Science, 1984; 226: 544.

27. Shaw BW, Gordon RD, Iwatsuki S, Starzl TE, Defining major risk factor in hepatic transplantation. Abstracts. Am Soc of Trans Surg, May 1985: 33.

28. Barnard CN. Human cardiac transplantation: an evaluation of the first two operations performed at the Groote Schuur Hospital, Cape Town. Am J Cardiol, 1982; 22: 584-96.

29. De Veies WC, Anderson JL, The clinical use of total artificial heart. N Engl J Med, 1984; 310: 273-8.

30. Szentpetery S, Morris JS, Hanrahan J et al. Cardiac transplantation in the sixth decade of life. Transplantation Proc Vol XIX, Feb 1987, Proc XI International Congress of the Transplantation Society.

31. Hardy JD, Webb WR, Dalton ML et al. Lung homotranspalntation in man: report of the initial case. JAMA, 1963; 186: 1065-74.

32. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataraman R, Jain A: FK 506 for liver, kidney and pancreas tarnsplantation. Lancet, 1989; 1000-4.

33. Delanay v, Nasir M, Brooklyn NJ. Liver tansplantation. A challenge for nephrologists. Nephron, 1990; 55: 353-60.

34.Storm TB. Therapeutic approach to organ transplantation. Nephrol Dial Transplant, 1996; 11: 1176-81.

35. Cecka JM, Cho YW Terasaki PI, Analysis of the UNOS scientific renal transplant registry at three years early events affecting transplant success. Transplantation, 1992; 53: 59-64.

36. Eleonor LR, Filney NL, Ravenscraft MD, Clinical aspects of renal transplantation in Brenner and Rector WB saunders, 1991; 2361-2407.

37. Karamehic J, Dizdarevic Z et all. Clinical Immunology, Svjetlost, 2007: 613-618.

38. Gibson T, Medawar PB. The fate of skin homografts in man. J Anat 1943; 77: 299.

39. Tilney NL (ed). Petar Medawar and transplantation biology. In: Transplant: from myth to reality. New Haven - London: Yale University Press, 2003; 109-24.

40. Hamburger J, Vaysse S, Crosnier J, Tubiana M, Laianne CM, Antoine B et al.

Transplantation of un rein infrequently induces irradiation. Presse Med 1959; 67: 1771-5.

41. Merill JP, Murray JE, Takats F. Successful transplantation of a kidney from a human cadaver. J Am Med Assoc, 1963; 185: 347-53.

42. Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963; 117: 385-95.

43. Starzl TE. A counterattack on rejection. In: The puzzle people: memoirs of a transplant surgeon. Pittsburgh: University of Pittsburgh Press 2003; 132-44.

44. Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP. Liver transplantation with the use of cyclosporin A and prednisone. N Engl J Med 1981; 305: 266-9.

45. Chan L, Gaston R, Hariharan S. Evolution of immunosuppression and continued importance of acute rejection in renal transplantation. Am J Kidney Dis. Dec 2001; 38 (6 Suppl 6): S2-9.http: //www.medscape.com/medline/abstract/11729001

BASICS OF IMMUNOSUPRES

The ideal immunosuppressive drug should include several characteristics:

(1) Administration in combination with other medicinal products should reduce rejection episodes

(2) Prevention of organ rejection without increased susceptibility to infection or other

adverse effects

(3) Reduction of chronic rejection which is most important in limiting long-term survival of graft

(4) Antiproliferative effects should be higher on lymphocytes than on other cell types, including hematopoietic cells

(5) It should not cause hepatotoxic, nephrotoxic or mutagenic effects.

The ideal immunosuppressive drug should include several characteristics:

MOST IMPORTANT PHARMACOKINETIC PROPERTIES

        BASIC IMMUNOSUPERS

4.1. Cyclosporin

Cyclosporin, a cyclic peptide with 11 amino acid residues, is potent immunosuppressant, but per os taken, with no effect in acute inflammatory reaction (1,2).

Mechanism of action

Cyclosporine exhibits numerous effects on different cell types; In general, the effects relevant to immunosuppression are:

• reduced clonal proliferation of T cells, primarily due to the inhibition of IL-2 release, and also because of possible reduction in IL-2 receptor expression;

• reduced induction and clonal proliferation of cytotoxic T cells from CD8 + precursor T cells;

• reduced effector effect T cells in cell-mediated response (e.g., reduced late hypersensitivity);

• a certain reduction in the response of B cells that is T-cell dependent.

The main effect is the relatively selective inhibition of IL-2 gene transcription, although the effect on transcription of the gene interferon-γ (IFN γ) and IL-3 gene has also been described. Normally, antigen interaction with Th cell receptors increases the intercellular concentration of Ca2 +. Calcium (in complex with calmodulin) stimulates phosphatases, calcineurin; which activates various transcription factors; they then initiate the transcription of the IL-2 gene. Cyclosporin binds to a cystolic protein called cyclophilin (belonging to a group that today has the name immunophilin). Complex drug-immunophilin binds and inhibits calcineurin and in this way affects the activation of Th cells and the formation of IL-2 (3.4.5).

Pharmacokinetic aspects

Ciclosporin can be administered orally or via an intravenous infusion. After oral administration, the maximum plasma concentration is usually achieved after 2-4 h. Metabolism is performed in the liver and most of the metabolites are excreted in the bile. Ciclosporin accumulates in most tissues at a concentration of 3-4 times the plasma concentration. Some medicine is retained in the lymphomas-loose tissues, and later in the fat tissue where there is still some time after cessation of the drug (6).

 Side Effects

The most common and most dangerous side effect of cyclosporin is the nephrotoxicity that is thought to be unrelated to the inhibition of calcineurin. It may be a limiting factor for drug administration in some patients (7). Hepato-toxicity and hypertension can also occur. Less important adverse effects are anorexia, lethargy, chirussitis, tremor, paraesthesia (tingling sensation), gout hypertrophy and gastrointestinal disorders. Ciclosporin has no depressive effect on the bone marrow.

CYCLOSOPORINE (Sandimmun®, Neoral®)

Clinical application

Immunosuppressive - used for the prophylaxis of kidney transplant rejection

Dosage at normal renal function

Oral: 2 - 15 mg / kg / day based on level (see local protocol)

IV: 1/3 to 1/2 oral dose (see local protocol)

Pharmacokinetics

Molecular Weight (Dalton) 1203

% binding to proteins 96 - 99

% excreted unchanged in urine

Side Effects

The most common and most dangerous side effect of cyclosporin is the nephrotoxicity that is thought to be unrelated to the inhibition of calcineurin. It may be a limiting factor for drug administration in some patients (7). Hepato-toxicity and hypertension can also occur. Less important adverse effects are anorexia, lethargy, chirussitis, tremor, paraesthesia (tingling sensation), gout hypertrophy and gastrointestinal disorders. Ciclosporin has no depressive effect on the bone marrow.

Dosage in patients who are on HD

CAPD Not dialysable. Dose as with normal renal function. Adjust according to the level.

HD Not diagnostic. Dose as with normal renal function. Adjust according to the level.

CAV / WHD Not dialysable. Dose as with normal renal function. Adjust according to the level.

Potentially dangerous interactions with other medicines

• Increased risk of hyperkalemia in ACE inhibitors, potassium-saving diuretics.

• Increased risk of nephrotoxicity with non-steroidal inflammatory drugs, aminoglycosides, co-trimoxazole, trimethoprim, 4-quinolones, amphotericin, colchicine, melphalan.

• Increased ciclosporin plasma levels with amiodarone, propafenone, doxycycline, erythromycin, clarithromycin, itraconazole, ketoconazole, myconazole, fluconazole, chloroquine, diltiazem, nicardipine, nifedipine, verapamil, high doses of methylprednisolone, danazol, progestogens and cimetidine.

• Decreased ciclosporin plasma levels with rifampicin, IV trimethoprim, phenobarbital, phenytoin, griseofulvin, octreotide

• Increased risk of nephrotoxicity with doxorubicin

• Increased toxicity with methotrexate

• Increased risk of myopathy with HMG CoA reductase inhibitors

• Increased half-life with tacrolimus.

Preparation

Dilute 1: 20 to 1: 100 with 0.9% sodium chloride or 5% glucose.

Method of application

• Oral, IV peripheral or central

Speed of application

• For 2 hours peripherally or 1 hour centrally

Tacrolimus

Tacrolimus is a macrolide antibiotic with a similar mechanism of action such as cyclosporin, but it is significantly stronger. The main difference with cyclosporin is that the internal receptor for this drug is not cyclophilin, but a protein called FKBP (FK-binding protein, because tacrolimus was originally called FK506). Tacrolimus-FKBP complex inhibits calcineurin and produces effects previously described (8.9).

Pharmacokinetic aspects

Tacrolimus can be administered orally or in the form of intravenous injection. It is metabolised in the liver by 99% and the elimination half-life is about 7 h.

     Side Effects

Undesirable effects of tacrolimus are similar to unwanted effects of cyclosporine, but they are much more serious. The incidence of nephrotoxic and neurotoxic effects is higher, while the incidence of chirzutism is lower. Gastrointestinal and metabolic (hyperglycaemia) disorders may occur. Cases of thrombocytopenia and hyperlipidemia have been reported, but are reversible with dose reduction.

TAKROLIMUS (PROGRAF, FK 506)

Clinical application

An immunosuppressive agent for prophylaxis and treatment of acute rejection in liver and kidney transplantation.

Dosage at normal renal function

Oral: Liver transplantation: 0.1 - 0.2 mg / kg / day in two divided doses. Maximum 0.3 mg / kg / day.

Transplantation of the kidney: 0.15 - 0.3 mg / kg / day in two divided doses

IV: liver transplantation: 0.01 - 0.05 mg / kg as a continuous 24 - hour infusion, start 6 hours after surgery.

Kidney transplantation: 0.05 - 0.1 mg / kg as a continuous 24-hour infusion, begin 24 hours after surgery.

Pharmacokinetics

Molecular mass (Dalton) 822

% binding to proteins> 98

% excreted unchanged in urine

Important drug interactions

CYCLOSPORIN

• Tacrolimus may increase the elimination half-life of cyclosporine and accelerate the toxic effects. They should not be prescribed together. Care should be taken to switch from cyclosporin to tacrolimus.

Potentially dangerous interactions with others

medicines

• The data are limited, but it can be assumed that tacrolimus will show interactions with ciclosporin-related medicinal products.

• Tacrolimus levels increase imidazole, anti-fungicides, macrolides, danazol, omeprazole, broccorin, cortisone, dapson, ethinylestradole, gestodene, lignocaine, nicardipine, nifedipine, quinidine and verapamil.

• Tacrolimus levels lower rifampicin, theophylline, phenobarbitone, carbamazepine and isoniazid.

• Increased nephrotoxicity with amphotericin, ibuprofen, aminoglycosides, vancomycin, cochyrimoxazole, NSAI, ganciclovir and acyclovir.

• Increased risk of hyperkalaemia with potassium-saving diuretics and potentiates the effects of oral anticoagulants and antidiabetic drugs.

Preparation

• Dilute in 5% glucose at a concentration of 4-20 micrograms / mL, i.e. 5 mg in 250-1000 mL

Method of application

• IV

Speed of application

• Continuous infusion for 24 hours

Comment

• Incompatible with PVC. Dissolve in 5% glucose in polyethylene or in a glass container or in 0.9% sodium chloride in a polyethylene resin,

• Contains polyethoxylated castor oil that is associated with anaphylaxis.

Tacrolimus (PROGRAF, FK 506)

Tacrolimus is a fungal metabolite isolated from Streptomyces tsukubaensis in 1984 in Japan. The modes in which tacrolimus inhibits the activation of the immune system in vitro (68) are presented in Table 4. Tacrolimus inhibits early T-cell activation. Although the structure of tacrolimus is very different from cyclosporine, the two drugs similarly begin to bind to intracellular proteins known as immunophilins. In vitro, tacrolimus inhibits T-cell proliferation responsible for mitogenicity and alloantigenosis and inhibits the generation of alloreactive cytotoxic T cells at a concentration of 1 / 50-1 / 200 than that required for cyclosporin.

Although biochemically different from Cyclosporine, it has many identical feautures in term of mechanism  of action and adverse effects. The difference is that is much more potent than ciklosporin  and the therapeutic doses  are much smaller! The mayority of clinical experiences in the use of tacrolimus were obtained on the basis of tests in liver transplantation.

The results show that acute rejection reactions are less common compared to ciklosporin ,and that the need for corticosteroid is less. Side effects are also  similar to ciklosporine, but here thy have  a somewhat more severe clinical form.Tacrolimus  is not yet used in routine kidny transplantation and is more  commonly  used to treat refractory ejection disorders . The results of clinical trials of tacrlimus in  kidney transplant are similar to the re4sults obtained  with the use of this drug in liver transplantation but the use of azathioprine is not required here!

In vitro inhibitory effects of tacrolimus

_____________________________________________________________

Inhibition of T-cell receptor activity of cytokine

The production of interleukin 2, 3 and 4, interferon-γ, factor necrosis tumor,

and granulocyte macrophage stimulating factor

Expression of interleukin-2 receptors

Activation of interleukin-7 receptors

Inhibition of T-cell activity

Proliferative response to aloanthigen

Long-term interleukin-2 stimulated survival

Primary and secondary generation of cytotoxic T cells

Inhibition of B-cell activity

Proliferative response to interleukin-4 and anti-IgM

Pharmococinetics:

It is cbound to plasma proteins and distributed to all tissues ( does not pass the hematoencephephalic barrier).It is metabolized primarily in the liver  by the cytochrome P450 IIIA, and elimineated by the bile .The half life  of tacrolimus is 8-9 hours.Intereactions  with other drugs are similiar to those of ciclosporine.Tacrolimus has good and constant reabsorption from the gastrointestinal tract so it shoud not be given in i.v. form.Unlike ciclosporin , its absorption from the gastrintestinal tract does not depend on bile.

Method of application:

TACROLIMUS AND CYCLOSPORIN SHOULD NOT BI GIVEN  CONCURRETLY DUE TO POSSIBLE  SYNERGISTIC  NEPHROTOXIC EFFECTS.TACROLIMUS IS AVAILABLE IN AMPOULE FOR I.V.USE AND IN THE FORM OF CAPSULES FOR ORAL USE.

THE RECOMENDED DOSE AT THE START OF THE THERAPY IS 0,15-03 MG/KG TT DIVIDED INTO TWO DAILY DOSES, ORALLY! FOR I.V. ADMINISTRATION OF THE DOSE IS 0,05-0,1MGKG/ DAY AS AS CONTINUOUS INFUSION.

Monitoring drug concentration is blood is performed by elisa technique and the level et level the beginninig at treatment shoulde be maintained between 10/20 ng/ml.Effective drug serum concentration thought to be between  0,5-3 ng/ml.

Clinical trials

Transplantation of liver

Three randomized trials compared  tacrolimus with cyclosporin.All trials of grafts  and patients surviving for 6 months or 1 year after transplantation were good with tacrolimus and cyclosporine.  However  use reduce of  tacrolimus the incidence of rejection by  11-43%.

Transplantation of kydneys:

The most interesting results on the role tacrolimus in kidneys transplantation were presented by a multicenter randomized comparative study conducted in USA.The study was conducted  in 19 centers of a total 412 patients, 205 were on tacrolimus and 207 cyclosporin! There were not demographic or HLA  DIFFERENCES  in treated groups among patients and donors. The results showed significantly reduce incidence of rejection in the group receieving tacrolimus, similar to the results obtained liver transplantation.

Pancreatic transplantation:

The efficacy and safety of treatment with tacrolimus (conversion of cyclosporin to tacrolimus) following pancreatic transplantation was studied in a multicentre study in the United States (71). 250 patients underwent pancreatic transplantation in the introductory group and 96 patients in the rescue group. The encouraging results of tacrolimus administration in this study are shown in Table 5.

Table 5. Results of multicentric testing on the efficacy and safety of tacrolimus for introduction and safety (conversion of cyclosporin to tacrolimus) after pancreatic transplantation (SPK: concomitant pancreas and renal transplantation; PAK: pancreas after renal transplant; PTA: pancreatic transplant alone).

___________________________________________________

Introductory group

Transplants, N = 250 One-Year Incidence

                                              survival of graft rejection

SPK (80%) 84% 49%

PAK (20%) 84% 36%

PTA (8%) 63% 75%

Global One-Year Survival of Patients: 93%.

A rescue groupe, Transplants a 250, one year incidence survival rejection rate

                                          graft after conversion 90% SURVIVAL 

SPK (80)%         INCIDENCA REJECTION AFTER  CONVERSION 47% 

PAK (7%)  AFTER ONE YEAR 71% AFTER CONVESION 33%

PTA (13 %        AFTER ONE YEAR 58% AFTER CONVERSION  35%

GLOBAL ONE YEAR SURVIVAL OF PATIENTS 96%

Toxicity:

The results initial clinical trials showed that in 42 of patients treated with tacrolimus i.v. and 87 percent  of patients oral  tacrolimus not adwerse effect  were found!

Headeache, nauzea,vomiting ,hyperesthesia were promlems after intravenous administration and insomonia, tremor and headaches most common in patients after oral administration of tacrolimus! The most common consequence of tacrolimus use nephrotocity and neurotoxcity.

Toxicity:

A large clinical experience has shown that tacrolimus is very tolerated as well as cyclosporin but does cause hirsutizm, gingival hyperplasia, cyclosporin induced fascal  dysmorphism.In two or three clinical  randomised trials comparing tacrolimus with cyclosporin in the prevention   of liver rejection allograft the incidence of infection was significantly lower in the tacrolimus treated group!

The main adverse effect of tacrolimus are nephrotocity, neurotoxkcity,( insomnia, tremor, headache) , gastrointestinal disorder (diarrhea, vomiting, hyperkaelemia,hyperglycemia on the set diabetes mellitus. Tacrolimus has less pronounced vasoconstrictor effect of hypertension is less commonly seen! Cosmetic compilation  hirsutism and gingival hyperplasia.are extremly rare and the loss of hair is more common.Anaphylactic reactions more common after intravenous administration!

Pregnancy and breast feeding :

Tacrolimus passes placental barrier, but limited available does not scow an increased risk of adverse effects on the course and outcome of pregnancy compared wit other immunological agents.

Taccrolimus can be considered in pregnant women when there  is not safer alternative and wehen the treatment benefits overcome the risk for the fetus!

Pregnancy and breastfeeding

There the a risk premature the birth and newborn is at risk transient hyperkalemia!

Neonates should  also be monitored for potential complications, including liver function.

Tacrolimus is esxreted breast milk  and mothers should not breast -feeding because the harmful effects can not be exluded!

NUCLEOTIDE BIOSYNTHESIS BLOCATOR

AZATHIOPRINE:

Azathoiprine is one first immunnossupresants that was still in 1962 applied in human kidney transplantation It is pharmacologically classified into a substance that inhibits tomor growth i.e antimetabolite.

Today more than 10 % patients with organ transplant are treated  less frequently given non selective effect on lymphocites

Mechanism of action

It functions  sa an antimetabolite for reducing for synthesis of DNA  and RNA. In other words after absorbtion in the  body AZA rapidly metabolized into the 6 mercaptopurine and than to acidic acid that is an active metabolite in the inhibition  of DNA chain synthesis. This inhibition results in the suppression of proliferation of B and T   lymphocytes, which suppression of the immune response!

AZA  has broadly suppressive effect on myelocyte lozenge by inhibiting proliferation of the promyelocyte in the bone marrow there bay reducing the number of cyrculating monocytes capable of ripening in macrophages!

AZA  strongly inhibits the primary immune response  but not effective in the treating rejection crisis! It exibiths its activity trough several mehanisms inhibition of DNA synthesis, inhibition of purine meatabolisms, inhibition of nucleotide,synthesis and blocking synthesis CD28 of the costymulatory pathway!

A very important enzyme for the synthesis of purine hypoxantine-guanine-phosphoribosyl transferaze and it also participates in the tansformation of 6 mercaptopurine into tioinosine mercaptopurine which inhibits enzyme involved in the synthesis adenosine monophosphate (AMP)  and guanosine monophosphate (GMP) resulting in the inhibition of purine synthesis.In this way , the mechanisms of action of AZA results in inhibition-suppression of all lines hemathopoietic cells!

Pharmacokinetics

The pharmacokinetic properties of AZA compared to mercaptopurine are better, have less nausea, better tolerability, and a better therapeutic index. Cytostatic is also immunosuppressant, a similar activity as mercaptopurine in which it passes into the body. AZA is well absorbed from the gastrointestinal tract. It is biotransformed first to mercaptopurine, which is then further transformed. Both AZA and mercaptopurine bind to plasma proteins in an amount of about 30%. Applied orally or intravenously, AZA is rapidly eliminated from the circulation, in the form of a metabolite whose mutual relationship varies from patient to patient. Only a small part is eliminated by urine in unchanged form.

After intravenous injection, half-life is 6-28 minutes. The half-life of 6-mercaptopurine is also short and amounts to 38-114 minutes. It is eliminated as 6-thouric acid via the kidneys.

Dosage in kidney transplantation

Prophylactic administration is 3-10 mg / kg / day, 1-2 days before kidney transplantation or on day of surgery, and maintenance dose is 1-4 mg / kg / day.

Side effects and interactions with other medicines

Undesirable side effects of AZA are leukopenia, thrombocytopenia, anemia, bone marrow depression, hepatitis, cholestasis, alopecia, rarely pancreatitis. Interestingly, AZA showed good results in gout therapy and in combination with allopurinol and xanthine oxidase inhibitor. When allopurinol is prescribed for patients already receiving AZA, its metabolism is reduced which can lead to the accumulation of intact AZA and its metabolites, which ultimately can lead to neutropenia and sepsis. Myelosuppression may be improved by discontinuing the drug. With ACE inhibitors it can lead to anemia. AZA is compatible with cyclosporin and tacrolimus.

Pregnancy and breast-feeding

Data on teratogenicity in humans are ambiguous. Preterm labor and low birth weight during treatment with AZA have been reported, especially when given in combination with glucocorticoids. There are very rare reports of physical abnormalities during treatment with AZA.

6-mercaptopurine was found in breast milk, and mothers should be advised not to breast-feed!

Mycophenolate mofetil

 Mycophenolate Mycophenolate (MMF) is an MFP. It is obtained semisynthetic, esterification of mycophenolic acid which is isolated from mold Penicillium stoloniferum. It is metabolized into the active metabolite of mycophenolic acid that inhibits the proliferation of lymphocytes by reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), a key enzyme in de novo synthesis of purines, which are constituents of nucleic acids, causing depleciation of immunocompetent cells. Unlike azathioprine, MMF selectively affects lymphocytes.

Mechanism of action

MFA in activated lymphocytes inhibits purine synthesis and the formation of guanosine nucleotides from inosins, thereby blocking the G1 phase of the cell cycle (proliferation of T lymphocytes in the IL-2 dependent pathway). MFA suppresses the formation of antibodies by inhibiting the formation of cytolytic T cells and reduces the adhesion of molecules to lymphocytes.

The effect of MFA on the reduction of guanosine nucleotide production has an effect on the selective antiproliferative effect on T and B lymphocytes, as they mainly use this pathway to create their purine bases. In this way, MMF is a selective metabolite. The mechanism of action differs from cyclosporin, tacrolimus and sirolimus in that it does not affect the production of cytokines or processes that occur during antigenic recognition.

Pharmacokinetics

The MMF is rapidly and completely absorbed from the gastrointestinal tract. Before entering the systemic circulation, the IMF is subject to metabolism to MFA.

MFA is subject to enterohepatic recirculation and a secondary increase in plasma concentration of mycophenolic acid is observed between 6 and 12 hours after administration of mycophenolate mofetil sodium. 97% of MFA is related to plasma albumin.

After oral administration, the drug's bioavailability is 90% and the elimination half-life is 12 hours.

MFA is metabolized by glucuronidation to inactivated mycophenolate, which is excreted in the urine as glucuronide with a small amount of mycophenolic acid.

Method of application

MMF is used in the form of capsules, and MFK is in the form of acid-resistant tablets. The drug is very rarely administered intravenously. The daily dose of 2 g of mycophenolate mofetil corresponds to 720 mg of mycophenolic acid.

Side effects

Side effects are mainly related to the digestive system (nausea, vomiting, diarrhea, gastritis, ulcer, etc.) or for suppression of bone marrow (anemia, leukopenia, thrombocytopenia).

The unique possibility of the IMF is the lack of cardiovascular risk and chronic nephrotoxic side effects. During the liver or kidney insufficiency there is no accumulation of the drug, and the MMF and MPA are not dialysable.

The safety of this drug is relatively good. Clinical trials have shown that diarrhea, leukopenia, frequent tissue infections with cytomegalovirus (esophagitis, gastritis) in the 10% of patients are more common in comparison with AZA in the MMF.

To continue side effect:

This rate of CMV infection may be associated with frequent gastroscopy of these patients due to subjective complaints from the gastrointestinal tract.

In one-third of patients, diarrhea, esophagitis and gastritis occur in 5% of patients, while bleeding occurs in about 4% of patients. These undesirable effects usually respond positively to reduced doses of the drug. Due to leukopenia and anemia, it should not be given at the same time as AZA. The incidence of lymphoproliferative diseases in clinical trials was around 1%, which fits the incidence of this disease in immunosuppressive patients. Nephrotoxicity, neurotoxicity and hepatotoxicity are not described, nor is pregnancy safe.

Clinical application

A significant reduction in the incidence of renal allograft rejection can be achieved by the use of MMF in combination with cyclosporin and corticosteroids. In combination with cyclosporin and prednisone, the MMF proved to be more effective than azathioprine in preventing acute renal failure in cadaveric transplantation. It is not used with azathioprine due to hematologic toxicity. The MMF is used to maintain immunosuppression and in chronic rejection. The currently published results indicate a lower incidence of acute rejection reactions (50% to 31%) and less frequent use of high doses of corticosteroids and OKT3 in the treatment of acute rejection reactions in the MMF group of subjects.