Introduction
Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. It belongs to the early endothelial damage syndromes together with veno-occlusive disease or sinusoidal obstruction syndrome of the liver, diffuse alveolar hemorrhage, engraftment syndrome and capillary leak syndrome. TA-TMA manifests itself as generalized microangiopathy causing organ injury particularly in the kidneys but also in other organs [1].
The reported incidences of TA-TMA have varied greatly, in allogeneic transplantation between 0 and 76 per cent [2, 3]. At the present time, the incidences of clinically significant TA-TMA may commonly be 5-10%, depending on several factors including patient material, transplantation methods and the diagnostic criteria used. In autologous transplantation the incidence is generally lower; incidence figures between 0 and 27% have been reported [2].
The pathophysiology of TA-TMA is complex [3]. The central feature is endothelial injury. Important etiological factors include pretransplant conditioning, calcineurin inhibitors, infections and graft-versus-host disease. The role of complement activation in the pathophysiology has been increasingly recognized.
TA-TMA differs from idiopathic acquired TTP in several respects. There is an absence of severe ADAMTS 13 deficiency, the spectrum of clinical symptoms is different, and, in contrast to idiopathic TTP, the response to plasmapheresis is usually poor.
Significant developments have taken place in recent years, both in the diagnosis, understanding of the pathophysiology, and the treatment of TA-TMA.
Diagnosis of TA-TMA
A large variety of diagnostic criteria have been used over the years [4]. Recently, three sets of criteria have been mainly used, those produced by the International Working Group [5], the American Bone Marrow Transplant Clinical Trials Network criteria [6], and the “overall TA-TMA” criteria by Cho et al [7]. The most important components of these definitions have been the presence of schistocytes, thrombocytopenia, anemia or increased need for red cell transfusions, increased lactate dehydrogenase (LDH) concentration, decreased haptoglobin level, and negative Coombs test, in various combinations.
Recently, Jodele and coworkers [1] have presented new criteria for TA-TMA. In addition to the central elements of the previous definitions, schistocytes, LDH, thrombocytopenia and anemia/red cell transfusion need, two new criteria have been added: proteinuria/hypertension and the soluble complement factor C5b-9. Table 1 shows the diagnostic criteria by Jodele et al. Five or more of the listed TA-TMA-associated markers indicate a severe disease [8]. An important finding was that some of these signs, proteinuria, hypertension and LDH increase, manifest early and can be used to predict the development of advanced TA-TMA. If proteinuria and an increased level of sC5b-9 concentration are observed, there is a great risk of poor outcome, indicating the need for aggressive treatment.
Table 1. Diagnostic criteria for TA-TMA by Jodele et al [8]
Some clinical and morphological practices in the diagnosis of transplant-associated microangiopathy should be standardized, particularly schistocyte counts. A study was recently performed on behalf of the Transplant Complications Working Party of the EBMT on this issue [9]. A questionnaire of the diagnostic methods of TA-TMA was sent to clinicians and morphologists. Also, sets of blood slides from 10 patients with TA-TMA and from 10 controls were distributed among the transplant centers, and the morphologists were asked to assess the slides as to the presence and proportion of schistocytes.
The survey showed that the International Working Group criteria and the “Overall TA-TMA” criteria were used by 41% of the centers each, in 18% of the centers the diagnosis was made individually by the physician. Interestingly, the interpretation of the percentage of schistocytes varied greatly. This was mainly based on differences in institutional practices, caused by different morphological criteria for schistocytes at different laboratories leading to substantial differences in the interpretation of the presence and degree of schistocytosis (Fig. 1). There is a number of different morphological forms of schistocytes, and the centers differ in which types of abnormal erythrocytes are counted as schistocytes.
Figure 1. Variability of the schistocyte counts in blood smears
of 10 patients with TA-TMA (blue circles) and 10 control patients (red circles)
reported by different transplant centers [9]
Role of Complement in TA-TMA
In a proportion of TA-TMA patients the complement cascade has been shown to become activated resulting in the formation of the membrane attack complex and endothelial injury [10]. This is probably caused by inherited or acquired defects in the complement regulatory system, becoming apparent in HSCT-induced stress conditions [10]. Associations between TA-TMA and certain complement-related gene variants have been demonstrated. Complement regulators, gene variants of which have been suggested to be implicated in the pathophysiology of TA-TMA include complement factor H (CFH), complement factor I (CFI), thrombomodulin (THBD), CD46 or membrane cofactor protein (MCP), and CD55. Similarly, complement activators, with gene variants implicated, include complement factor B (CFB), C3, and C5 [2].
The role of complement-activating mechanisms in TA-TMA suggests wider application of complement-inhibiting treatments, especially anti-complement antibodies in the management of this complication.
Treatment of TA-TMA
The treatment of TA-TMA has been difficult and the outcome of severe cases poor. The discontinuation or dose reduction of possibly causative agents, such as cyclosporine, tacrolimus or sirolimus is a general policy, although the documentation of the efficacy of this approach is not completely solid [8]. Therapeutic plasma exchange is usually not effective in TA-TMA and its use has been discouraged in many reports, but this treatment may be indicated in some cases to remove mutated complement, antibodies against complement, or other triggering factors for endothelial dysfunction [11].
Defibrotide has been occasionally used for the treatment of TA-TMA since many years. More recent studies have reported encouraging results, approximately half or more of the patients with a severe TA-TMA responding without any major adverse effects documented [12, 13, 14]. Other agents including rituximab, daclizumab, etanercept, infliximab, and bosentan have been used without major success [3]. With the increasing understanding of the role of complement in the pathophysiology of TA-TMA, the possible use of complement-inhibiting treatments, especially anti-complement antibodies has recently been a topic of great interest. Most of the clinical experience is with equlizumab.
Equlizumab is a humanized monoclonal antibody. It is a C5 inhibitor and prevents the formation of the membrane attack complex (C5b-9) [15, 16]. The dosing schedule is not well established. Marked individual variation has been documented in the pharmacokinetics, and monitoring the concentrations to confirm adequate dosing may be indicated [8]. Equlizumab treatment can be discontinued after the resolution of TA-TMA, usually without relapse of this complication [3]. The treatment causes increased susceptibility to infections caused by encapsulated bacteria, but this problem may be ameliorated by adequate antibiotic prophylaxis [17]. The cost of this treatment is substantial, and its availability is limited in many countries. Most of the experience of equlizumab treatment is from pediatric studies. Jodele [10] treated 50 pediatric patients with TA-TMA and multiorgan dysfunction. Seventy-two per cent of the patients survived, compared to less than 10% among historical controls. Bohl et al [13] treated 15 adult patients. The response rate was 93%, but only 33% finally survived. Vasu et al. [18] treated 5 adult patients. Three of them recovered while two died of sepsis.
Several other complement inhibitors, targeting components of the classical, lectin or alternate pathway, are under development and are likely to affect the treatment scene in the next few years [3].
Conclusion
TA-TMA remains a challenging complication of HSCT, leading to increased morbidity and mortality. The understanding of the pathophysiology is increasing and may lead to improvements in the diagnostics. Aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.
Conflict of interest
No conflicts of interest are reported.
References
- Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124(4): 645-653.
- Gavriilaki E, Sakellari I, Anagnostopoulos A, Brodsky RA. Transplant-associated thrombotic microangiopathy: opening Pandora's box. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Bone Marrow Transplant. 2017; 52(10): 1355-1360.
- Khosla J, Yeh AC, Spitzer TR, Dey BR. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies. Bone Marrow Transplant. 2018; 53(2): 129-137.
- George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 2004; 44: 294-304.
- Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lämmle B, Moake JL, Richardson P, Socié G, Zeigler Z, Niederwieser D, Barbui T. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007; 92: 95-100.
- Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11: 571-575.
- Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW. Validation of recently proposed consensus criteria for thrombotic micoangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation 2010; 90: 918-926.
- Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, Goebel J, Dixon BP. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 2015; 29(3): 191-204.
- Moiseev IS, Tsvetkova T, Aljurf M, Alnounou RM, Bogardt J, Chalandon Y, Drokov MYu, Dvirnyk V, Faraci M, Smidstrup Friis L, Giglio F, Greinix HT, Kornblit BT, Koelper C, Koenecke C, Lewandowski K, Niederwieser D, Passweg JR, Peczynski C, Penack O, Peric Z, Piekarska A, Ronchi PE, Rovo A, Rzepecki P, Scuderi F, Sigrist D, Siitonen SM, Stoelzel F, Sulek K, Tsakiris DA, Wilkowojska U, Duarte RF, Ruutu T, Basak GW. Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT. Bone Marrow Trasplant 2018, Oct 25. doi: 10.1038/s41409-018-0374-3.
- Jodele S: Complement in pathophysiology and treatment of transplant-associated thrombotic microangiopathies. Semin Hematol 2018; 55: 159-166.
- Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic miroangiopathy. Bone Marrow Transplant 2016; 51: 891-897.
- Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, Morreale G, Lanino E, Annaloro C, Volpe AD, Alessandrino P, Longoni D, Locatelli F, Sangalli H, Rovelli A. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation 2006; 82: 638-644.
- Bohl SR, Kuchenbauer F, von Harsdorf S, Kloevekorn N, Schönsteiner SS, Rouhi A, Schwarzwälder P, Döhner H, Bunjes D, Bommer M. Thrombotic microangiopathy after allogeneic stem cell transplantation: A comparison of eculizumab therapy and conventional therapy. Biol Blood Marrow Transplant. 2017; 23(12): 2172-2177.
- Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, Willekens A, Hwang WHY, Uderzo C, Bader P, Gennery AR. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant 2017; 52: 762-764.
- Kim S, Patel M, Yum K, Keyzner A. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion. 2015; 55: 452-458.
- Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, Lazear D, Lane A, Myers KC, Dandoy CE, Davies SM. Variable eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016; 22: 307-315.
- Jodele S, Dandoy CE, Danziger-Isakov L, Myers KC, El-Bietar J, Nelson A, Wallace G, Teusink-Cross A, Davies SM. Terminal complement blockade after hematopoietic stem cell transplantation is safe without meningococcal vaccination. Biol Blood Marrow Transplant. 2016a; 22: 1337-1340.
- Vasu S, Wu H, Satoskar A, Puto M, Roddy J, Blum W, Klisovic R, Andritsos L, Hofmeister C, Benson DM, Efebera Y, Jaglowski S, Penza S, Cohen D, Devine S, Cataland S. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2016; 51(9): 1241-1244.
Introduction
Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. It belongs to the early endothelial damage syndromes together with veno-occlusive disease or sinusoidal obstruction syndrome of the liver, diffuse alveolar hemorrhage, engraftment syndrome and capillary leak syndrome. TA-TMA manifests itself as generalized microangiopathy causing organ injury particularly in the kidneys but also in other organs [1].
The reported incidences of TA-TMA have varied greatly, in allogeneic transplantation between 0 and 76 per cent [2, 3]. At the present time, the incidences of clinically significant TA-TMA may commonly be 5-10%, depending on several factors including patient material, transplantation methods and the diagnostic criteria used. In autologous transplantation the incidence is generally lower; incidence figures between 0 and 27% have been reported [2].
The pathophysiology of TA-TMA is complex [3]. The central feature is endothelial injury. Important etiological factors include pretransplant conditioning, calcineurin inhibitors, infections and graft-versus-host disease. The role of complement activation in the pathophysiology has been increasingly recognized.
TA-TMA differs from idiopathic acquired TTP in several respects. There is an absence of severe ADAMTS 13 deficiency, the spectrum of clinical symptoms is different, and, in contrast to idiopathic TTP, the response to plasmapheresis is usually poor.
Significant developments have taken place in recent years, both in the diagnosis, understanding of the pathophysiology, and the treatment of TA-TMA.
Diagnosis of TA-TMA
A large variety of diagnostic criteria have been used over the years [4]. Recently, three sets of criteria have been mainly used, those produced by the International Working Group [5], the American Bone Marrow Transplant Clinical Trials Network criteria [6], and the “overall TA-TMA” criteria by Cho et al [7]. The most important components of these definitions have been the presence of schistocytes, thrombocytopenia, anemia or increased need for red cell transfusions, increased lactate dehydrogenase (LDH) concentration, decreased haptoglobin level, and negative Coombs test, in various combinations.
Recently, Jodele and coworkers [1] have presented new criteria for TA-TMA. In addition to the central elements of the previous definitions, schistocytes, LDH, thrombocytopenia and anemia/red cell transfusion need, two new criteria have been added: proteinuria/hypertension and the soluble complement factor C5b-9. Table 1 shows the diagnostic criteria by Jodele et al. Five or more of the listed TA-TMA-associated markers indicate a severe disease [8]. An important finding was that some of these signs, proteinuria, hypertension and LDH increase, manifest early and can be used to predict the development of advanced TA-TMA. If proteinuria and an increased level of sC5b-9 concentration are observed, there is a great risk of poor outcome, indicating the need for aggressive treatment.
Table 1. Diagnostic criteria for TA-TMA by Jodele et al [8]
Some clinical and morphological practices in the diagnosis of transplant-associated microangiopathy should be standardized, particularly schistocyte counts. A study was recently performed on behalf of the Transplant Complications Working Party of the EBMT on this issue [9]. A questionnaire of the diagnostic methods of TA-TMA was sent to clinicians and morphologists. Also, sets of blood slides from 10 patients with TA-TMA and from 10 controls were distributed among the transplant centers, and the morphologists were asked to assess the slides as to the presence and proportion of schistocytes.
The survey showed that the International Working Group criteria and the “Overall TA-TMA” criteria were used by 41% of the centers each, in 18% of the centers the diagnosis was made individually by the physician. Interestingly, the interpretation of the percentage of schistocytes varied greatly. This was mainly based on differences in institutional practices, caused by different morphological criteria for schistocytes at different laboratories leading to substantial differences in the interpretation of the presence and degree of schistocytosis (Fig. 1). There is a number of different morphological forms of schistocytes, and the centers differ in which types of abnormal erythrocytes are counted as schistocytes.
Figure 1. Variability of the schistocyte counts in blood smears
of 10 patients with TA-TMA (blue circles) and 10 control patients (red circles)
reported by different transplant centers [9]
Role of Complement in TA-TMA
In a proportion of TA-TMA patients the complement cascade has been shown to become activated resulting in the formation of the membrane attack complex and endothelial injury [10]. This is probably caused by inherited or acquired defects in the complement regulatory system, becoming apparent in HSCT-induced stress conditions [10]. Associations between TA-TMA and certain complement-related gene variants have been demonstrated. Complement regulators, gene variants of which have been suggested to be implicated in the pathophysiology of TA-TMA include complement factor H (CFH), complement factor I (CFI), thrombomodulin (THBD), CD46 or membrane cofactor protein (MCP), and CD55. Similarly, complement activators, with gene variants implicated, include complement factor B (CFB), C3, and C5 [2].
The role of complement-activating mechanisms in TA-TMA suggests wider application of complement-inhibiting treatments, especially anti-complement antibodies in the management of this complication.
Treatment of TA-TMA
The treatment of TA-TMA has been difficult and the outcome of severe cases poor. The discontinuation or dose reduction of possibly causative agents, such as cyclosporine, tacrolimus or sirolimus is a general policy, although the documentation of the efficacy of this approach is not completely solid [8]. Therapeutic plasma exchange is usually not effective in TA-TMA and its use has been discouraged in many reports, but this treatment may be indicated in some cases to remove mutated complement, antibodies against complement, or other triggering factors for endothelial dysfunction [11].
Defibrotide has been occasionally used for the treatment of TA-TMA since many years. More recent studies have reported encouraging results, approximately half or more of the patients with a severe TA-TMA responding without any major adverse effects documented [12, 13, 14]. Other agents including rituximab, daclizumab, etanercept, infliximab, and bosentan have been used without major success [3]. With the increasing understanding of the role of complement in the pathophysiology of TA-TMA, the possible use of complement-inhibiting treatments, especially anti-complement antibodies has recently been a topic of great interest. Most of the clinical experience is with equlizumab.
Equlizumab is a humanized monoclonal antibody. It is a C5 inhibitor and prevents the formation of the membrane attack complex (C5b-9) [15, 16]. The dosing schedule is not well established. Marked individual variation has been documented in the pharmacokinetics, and monitoring the concentrations to confirm adequate dosing may be indicated [8]. Equlizumab treatment can be discontinued after the resolution of TA-TMA, usually without relapse of this complication [3]. The treatment causes increased susceptibility to infections caused by encapsulated bacteria, but this problem may be ameliorated by adequate antibiotic prophylaxis [17]. The cost of this treatment is substantial, and its availability is limited in many countries. Most of the experience of equlizumab treatment is from pediatric studies. Jodele [10] treated 50 pediatric patients with TA-TMA and multiorgan dysfunction. Seventy-two per cent of the patients survived, compared to less than 10% among historical controls. Bohl et al [13] treated 15 adult patients. The response rate was 93%, but only 33% finally survived. Vasu et al. [18] treated 5 adult patients. Three of them recovered while two died of sepsis.
Several other complement inhibitors, targeting components of the classical, lectin or alternate pathway, are under development and are likely to affect the treatment scene in the next few years [3].
Conclusion
TA-TMA remains a challenging complication of HSCT, leading to increased morbidity and mortality. The understanding of the pathophysiology is increasing and may lead to improvements in the diagnostics. Aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.
Conflict of interest
No conflicts of interest are reported.
References
- Jodele S, Davies SM, Lane A, Khoury J, Dandoy C, Goebel J, Myers K, Grimley M, Bleesing J, El-Bietar J, Wallace G, Chima RS, Paff Z, Laskin BL. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Blood. 2014; 124(4): 645-653.
- Gavriilaki E, Sakellari I, Anagnostopoulos A, Brodsky RA. Transplant-associated thrombotic microangiopathy: opening Pandora's box. Diagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults. Bone Marrow Transplant. 2017; 52(10): 1355-1360.
- Khosla J, Yeh AC, Spitzer TR, Dey BR. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: current paradigm and novel therapies. Bone Marrow Transplant. 2018; 53(2): 129-137.
- George JN, Li X, McMinn JR, Terrell DR, Vesely SK, Selby GB. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: a diagnostic dilemma. Transfusion 2004; 44: 294-304.
- Ruutu T, Barosi G, Benjamin RJ, Clark RE, George JN, Gratwohl A, Holler E, Iacobelli M, Kentouche K, Lämmle B, Moake JL, Richardson P, Socié G, Zeigler Z, Niederwieser D, Barbui T. Diagnostic criteria for hematopoietic stem cell transplant-associated microangiopathy: results of a consensus process by an International Working Group. Haematologica. 2007; 92: 95-100.
- Ho VT, Cutler C, Carter S, Martin P, Adams R, Horowitz M, Ferrara J, Soiffer R, Giralt S. Blood and Marrow Transplant Clinical Trials Network Toxicity Committee consensus summary: thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2005; 11: 571-575.
- Cho BS, Yahng SA, Lee SE, Eom KS, Kim YJ, Kim HJ, Lee S, Min CK, Cho SG, Kim DW, Lee JW, Min WS, Park CW. Validation of recently proposed consensus criteria for thrombotic micoangiopathy after allogeneic hematopoietic stem-cell transplantation. Transplantation 2010; 90: 918-926.
- Jodele S, Laskin BL, Dandoy CE, Myers KC, El-Bietar J, Davies SM, Goebel J, Dixon BP. A new paradigm: Diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev 2015; 29(3): 191-204.
- Moiseev IS, Tsvetkova T, Aljurf M, Alnounou RM, Bogardt J, Chalandon Y, Drokov MYu, Dvirnyk V, Faraci M, Smidstrup Friis L, Giglio F, Greinix HT, Kornblit BT, Koelper C, Koenecke C, Lewandowski K, Niederwieser D, Passweg JR, Peczynski C, Penack O, Peric Z, Piekarska A, Ronchi PE, Rovo A, Rzepecki P, Scuderi F, Sigrist D, Siitonen SM, Stoelzel F, Sulek K, Tsakiris DA, Wilkowojska U, Duarte RF, Ruutu T, Basak GW. Clinical and morphological practices in the diagnosis of transplant-associated microangiopathy: a study on behalf of Transplant Complications Working Party of the EBMT. Bone Marrow Trasplant 2018, Oct 25. doi: 10.1038/s41409-018-0374-3.
- Jodele S: Complement in pathophysiology and treatment of transplant-associated thrombotic microangiopathies. Semin Hematol 2018; 55: 159-166.
- Obut F, Kasinath V, Abdi R. Post-bone marrow transplant thrombotic miroangiopathy. Bone Marrow Transplant 2016; 51: 891-897.
- Uderzo C, Bonanomi S, Busca A, Renoldi M, Ferrari P, Iacobelli M, Morreale G, Lanino E, Annaloro C, Volpe AD, Alessandrino P, Longoni D, Locatelli F, Sangalli H, Rovelli A. Risk factors and severe outcome in thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Transplantation 2006; 82: 638-644.
- Bohl SR, Kuchenbauer F, von Harsdorf S, Kloevekorn N, Schönsteiner SS, Rouhi A, Schwarzwälder P, Döhner H, Bunjes D, Bommer M. Thrombotic microangiopathy after allogeneic stem cell transplantation: A comparison of eculizumab therapy and conventional therapy. Biol Blood Marrow Transplant. 2017; 23(12): 2172-2177.
- Yeates L, Slatter MA, Bonanomi S, Lim FLWI, Ong SY, Dalissier A, Barberi W, Shulz A, Duval M, Heilmann C, Willekens A, Hwang WHY, Uderzo C, Bader P, Gennery AR. Use of defibrotide to treat transplant-associated thrombotic microangiopathy: a retrospective study of the Paediatric Diseases and Inborn Errors Working Parties of the European Society of Blood and Marrow Transplantation. Bone Marrow Transplant 2017; 52: 762-764.
- Kim S, Patel M, Yum K, Keyzner A. Hematopoietic stem cell transplant-associated thrombotic microangiopathy: review of pharmacologic treatment options. Transfusion. 2015; 55: 452-458.
- Jodele S, Fukuda T, Mizuno K, Vinks AA, Laskin BL, Goebel J, Dixon BP, Chima RS, Hirsch R, Teusink A, Lazear D, Lane A, Myers KC, Dandoy CE, Davies SM. Variable eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016; 22: 307-315.
- Jodele S, Dandoy CE, Danziger-Isakov L, Myers KC, El-Bietar J, Nelson A, Wallace G, Teusink-Cross A, Davies SM. Terminal complement blockade after hematopoietic stem cell transplantation is safe without meningococcal vaccination. Biol Blood Marrow Transplant. 2016a; 22: 1337-1340.
- Vasu S, Wu H, Satoskar A, Puto M, Roddy J, Blum W, Klisovic R, Andritsos L, Hofmeister C, Benson DM, Efebera Y, Jaglowski S, Penza S, Cohen D, Devine S, Cataland S. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant. 2016; 51(9): 1241-1244.
Тапани Рууту
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Клинический исследовательский институт, Университетский госпиталь Хельсинки,
Финляндия
Трансплант-ассоциированная тромботическая микроангиопатия (ТА-ТМА) является сравнительно частым осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.
Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения.
Ключевые слова
Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.
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Keywords
Hemopoietic stem cell transplantation, thrombotic microangiopathy, diagnostic techniques, standardization, therapy, complement inhibitors.
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Keywords
Hemopoietic stem cell transplantation, thrombotic microangiopathy, diagnostic techniques, standardization, therapy, complement inhibitors.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(21) "Description / Summary" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(958) "Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. The pathophysiology is complex, the central feature is endothelial injury. The role of complement activation in the pathophysiology has been increasingly recognized. The diagnostic procedures and interpretations vary considerably between centers, and aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.
Keywords
Hemopoietic stem cell transplantation, thrombotic microangiopathy, diagnostic techniques, standardization, therapy, complement inhibitors.
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осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.<br> Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения. </p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(1807) "Трансплант-ассоциированная тромботическая микроангиопатия (ТА-ТМА) является сравнительно частым осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.
Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения.
Ключевые слова
Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(1807) "Трансплант-ассоциированная тромботическая микроангиопатия (ТА-ТМА) является сравнительно частым осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.
Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения.
Ключевые слова
Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.
" } ["ORGANIZATION_RU"]=> array(37) { ["ID"]=> string(2) "26" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(22) "Организации" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(15) "ORGANIZATION_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "26" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20968" ["VALUE"]=> array(2) { ["TEXT"]=> string(202) "<p> Клинический исследовательский институт, Университетский госпиталь Хельсинки,<br> Финляндия </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(184) "
Клинический исследовательский институт, Университетский госпиталь Хельсинки,
Финляндия
Клинический исследовательский институт, Университетский госпиталь Хельсинки,
Финляндия
Introduction
Additional therapeutic effects of “old”, drugs for novel clini-cal indications have been studied over last decades. Novel suggestions for repurposing of different medical drugs for cancer treatment have been made over recent years [1, 2].
There are three main reasons for these proposals: (1) limited efficiency of novel inhibitors or specific monoclonal antibodies targeted for oncogene-specific molecules; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) eventual decline of development costs for the new therapies performed by the “old” drugs.
A variety of drugs used in different somatic disorders is now considered as complementary tool for treatment of malignancies. These candidate compounds are listed in several indexes available online, e.g., the Drug Repurposing Portal supported by Excelra [3]. In addition, a number of recent review articles concern different aspects of old drug applications in cancer therapy [1, 4, 5].
It should be noted, however, that most cytostatic and anticancer effects of the repurposed drugs are shown in the in vitro models, or in experimental animals, thus suggesting a long way until their clinical implication. The big data collected from drug screening in different models are analyzed by different bioinformatic approaches, e.g. [6], thus accelerating the drug selection process to some degree.
The specific aim of our study was to discuss probable anticancer effects of some anti-infectious drugs which are now widely used in hematopoietic stem cell transplantation protocols.
Some candidate drugs intended for repurposing in cancer treatment are listed in Table 1.
Table 1. Summary of drugs used for treatment of common disorders, their primary indication, non-cancer and cancer targets
Drug repositioning for leukemia treatment
Metformin
This well-known anti-diabetic drug activates the AMF-regulated protein kinase pathway dependent on the tumor suppressor LKB1. The LKB1/AMPK signaling may be suppressed by ERK which is activated in a half of acute myeloid leukemia (AML) cases with appropriate mutations, e.g., FLT3-ITD mutation. These cases may be susceptible for metformin and the treatment efficiency may be increased in combination with sorafenib or other novel drugs [25, 26].
Chloroquines
Pre-clinical studies of the last decade have repeatedly confirmed distinct anticancer effects of well-known antimalarial drug chloroquine and its derivatives. In particular, chloroquine and hydroxychloroquine have relatively well-characterized toxicity profiles. Previously published review articles provide an excellent overview on diversity of chloroquine effects on cancer cells, both in the cell culture as well as on human tumors grafted into mice; and suggest incorporation of hydroxychloroquine in prospective combination schemes for clinical studies [9]. The authors discuss some common features in cancer cells that could be targeted by quinacrine and its derivatives, aiming for potential pharmaceutical intervention in oncology.
A recent work by Eriksson et al. [11] dealt with more specific quinacrine effects upon malignant blood cells. The authors have earlier selected quinacrine as the most plausible compound for its antileukemic effects, and tested this drug in vitro in combination with some common cytostatic agents (daunorubicin, cytarabine, azacitidine, etc.). Acute myeloid leukemia (AML) cell lines were cultured as a target population, then tested for cytotoxicity by fluorometric microculture. In most in vitro systems, the workers have shown distinct synergism between quinacrine and cytarabine, or azacitidine added to these cell cultures. Moreover, the in vivo usage of quinacrine (100 mg/kg, six injections for two weeks) in SCID mice bearing human AML cells caused a significant decrease in circulating blast cells and increased the median survival time of the animals. Hence, further studies may offer an “old-new”, less toxic drug for combined treatment of leukemia.
Fluoroquinolones
Quinolone-based antibiotics, especially, fluoroquinolones are used over decades to manage different bacterial and protozoal infections. Their microbicidal action is caused by inhibition of the ligase domain of the type II DNA topoisomerase, thus releasing endonuclease activities and irreversible DNA decay in the target cells, as reviewed by Idowu and Schweizer [12]. Such a universal cytotoxic effect presumes possible applications of fluoroquinolones for cancer treatment. These studies, however, are still in progress and should be substantiated in pre-clinical trials.
Tetracycline, and its derivatives
This class of antibacterials is known since 1948. Tetracyclines are widely used in medicine and agriculture to combat broad spectrum of bacteria [14]. Despite high proportion of tetracyclin-resistant microorganisms (due to powerful drug efflux), a new generation of these drugs was developed later on (e.g., Doxycycline, Tigecycline) which are now administered for empiric treatment, e.g., in immunocompromised patients following severe cytostatic treatment and bone marrow transplantation. Interestingly, doxorubicin, a popular anticancer antibiotic belongs to the same family of bioactive compounds.
All the tetracyclines inhibit protein assembly in Gram(+) and Gram(-) microbes by preventing the aminoacyl-tRNA binding to the acceptor sites at the ribosomes. Meanwhile, tetracyclines were also tested for treatment of a number of inflammatory diseases, due to their inhibition of matrix metalloproteinases, antiapoptotic, antioxidative, and antiinflammatory effects in humans [14].
Hence, the major antimicrobial effect of tetracyclines is due to their protein-inhibiting actions in bacteria. Moreover, they possess antiproliferative and pro-apoptotic effects in mammalian cancer cells, by suppressing mitochondrial ribosomes and energy metabolism [16]. More recently, they are also considered potential anticancer drugs. E.g., Tigecycline a structural homologue of tetracycline, being a potent glycylcycline antibiotic, is mostly used as a broad-spectrum drug against gram-positive and gram-negative pathogens. It reversibly binds the 30S subunit of the bacterial ribosomes, being also an inhibitor of mitochondrial biogenesis [27].
Ten malignant tumor cell lines of different origin were tested in vitro with tigecycline and doxycycline (another tetracycline derivative), showing. Tigecycline has shown its ability to inhibit the MCF7 and T47D spheroid cell growth, at the concentrations from 10 µM to 50 µM [16]. Moreover, tigecycline was previously shown to kill human AML differentiated blasts as well as leukemic stem cells in vitro and in vivo by blocking mitochondrial protein synthesis [28].
Another work concerned in vitro cytostatic effects of tigecycline on the acute lymphoblastic leukemia (ALL) showing decreased survival and suppression of clonogenic growth in malignant cell cultures [29]. Toxic effects upon normal hematopoietic cells were less pronounced. Pharmacokinetics and potential antitumor effects make this drug a promising option when sensitizing ALL cells for chemotherapy [30].
In particular, tigecycline was studied in the Phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled [27]. The authors have shown relative safety and assessed maximal tolerable doses for the drug infused into the patients with relapsed/refractory AML, however, with no evident anticancer effects revealed.
Moreover, some small clinical trials with doxycycline were performed over last years in cancer clinics (primarily aiming for infection therapy, but not cancer treatment) showing some antitumor effects in cancer patients as reviewed by Lamb et al. [16]. Initial positive results of doxycycline trials obtained in advanced or treatment-resistant cases of B-cell lymphoma [30]. This clinical effect was not, however, confirmed in more extensive studies.
Erythromycin and other macrolides
These antibacterials may also inhibit various microflora by suppressing ribosome functions. Similarly, they can inhibit mitochondrial ribosomes in eukaryotic cells, as shown in several cancer cell lines [16]. Azithromycin is an improved erythromycin derivative which is widely used in post-transplant patients, being more slowly eliminated than erythromycin. Its anti-infectious effect is exploited for prevention of bacterial complications in chronic infectious conditions, e.g., at later terms post-HSCT.
Surprisingly, a probable antitumor effect of azithromycin was revealed in a study by Shamoun et al. [17] published as a short abstract, where a long-term drug administration (14 days) aimed to ameliorate chronic graft-versus-graft disease (GvHD) was accompanied by decreased rates of relapse and improved survivals in a combined group of with acute leukemia, MDS, malignant lymphomas, and chronic leukemia patients.
Clarithromycin (6-O-methyl erythromycin) is also a widely used semi-synthetic macrolide drug which also has previously shown a sufficient anticancer activity against some experimental tumors [31] when used after a course of cancer chemotherapy in mice.
A recent review by van Nuffel et al. [18] has summarized numerous data obtained in human studies showing complementary effects of clarithromycin as an antibacterial drug in combined treatment of multiple myeloma, CML and other blood malignancies, especially MALT lymphomas and Hodgkin’s disease studied over last 2 decades. Their general impression is that the effects of Clarithromycin may be also due to antibacterial action of the drug, thus requiring a search for tumor-targeted effects in these conditions. Clarithromycin significantly enhanced effect of cytostatic treatment by increasing natural killer cell activity and CD8+ T cell cytotoxicity, thus causing recovery from immunosuppression caused by the chemotherapy.
Studies on GvHD prevention
Distinct positive effects of azithromycin were shown in murine model of experimental GVHD were reported by a Japanese group [32]. Azithromycin was administered per os to recipient BALB/c mice during H-2 incompatible BMT. The treatment was performed from day -2 to day +2. As a result, the drug-treated animals exhibited significant suppression of lethal GVHD without sufficient inhibition of donor cell engraftment. Azithromycin administration was associated with mice 70% survival of transplanted animals versus death of all mice in control group. Accordingly, the typical GvHD lesions of intestinal and liver epithelium were only minimally expressed in AZM-treated animals. The authors suggest inhibition of recipient DCs as a possible cause of GVHD suppression.
Similar results were obtained by Radhakrishnan et al. [33] in lethally irradiated B6D2F1 mice in whom acute GVHD and noninfectious lung injury were induced by injection of bone marrow and spleen cells from allogeneic C57BL/6 mice. In experimental animals, azithromycin was given for a long time orally from day +14 until 6 or 14 weeks after transplantation. Generally, Azithromycin treatment resulted in improved survival and decreased lung injury, as shown by respiratory tests, and improved GvHD-associated injury of intestines and liver, depending, however, on the schedule of drug gavage.
A small clinical study with azithromycin for GVHD prophylaxis has yielded disappointing results in a randomized, placebo-controlled trial performed by Iranian group [34]. 96 patients with acute leukemia were subjected to HSCT from full-matched donors. All the patients received high-dose chemotherapy, standard immunosuppressive regimens. Azithromycin was administered 500 mg daily in 48 cases from day -6 to +12 posttransplant, and placebo was given in other 48 cases. As a result, incidence of acute GvHD grade III-IV and chronic graft-versus-host disease did not significantly differ between the two groups. Meanwhile, oral mucositis occurred in significantly lower number of patients treated with azithromycin.
Niclosamide
Niclosamide as an approved anthelmintic agent potential anticancer agent by various high-throughput screening campaigns [24]. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells. Therefore, some in vitro screening studies have shown its anticancer activity. In the study by Hamdoun et al. [23], niclosamide showed distinct suppressive effects upon cancer cell lines. Worth of note, it revealed higher activity against leukemia cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines. Cytocidal action of niclosamide may be associated with increase in reactive oxygen species and glutathione (GSH) in malignant cells, thus suggesting GSH synthetase (GS) as a target for niclosamide.
Salinomycin
Salinomycin is an ionophore successfully used in the patients with coccidiosis seems also to express anti-leukemic effects [22]. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Interestingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, thus promising safer usage of this drug in further clinical trials.
Antifungal drugs
Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including P-glycoprotein-mediated resistance by modulating the Hedgehog signaling pathways which are a target of rapamycin and Wnt/β-catenin in cancer cells. Angiogiogenesis suppression is another known effect of itroconazole in the cancer microenvironment [35]. Small clinical trials suggested the clinical benefits of itraconazole monotherapy in different solid tumors [21].
Possible clinical effects of antibacterials due to posttransplant changes of gut microbiota
Firstly, antibacterial antibiotics, especially, for oral use, are prone for suppression of gut microbiota. E.g., Shono et al [36] have shown that some widely used antibacterials, e.g., piperacillin/tazobactam or imipenem/cilastatin are followed by higher GVHD-related death at 5 years, due to gut microflora imbalance. Therefore, an extending viewpoint suggests damaging effects of antibacterials upon normal microbiota, thus being potentially harmful to immune reconstitution after HSCT and affect clinical outcomes in the patients [37].
Conclusion
At the present time, there is a wide list of repurposed drugs potentially applicable in cancer therapy. Of course, most of these “old” drugs are tested in vitro or in pre-clinical animal models. Hundreds of the candidate compounds are subjected to screening in susceptible malignant cell lines, then treated by means of bioinformatics techniques. Only some drugs are proposed for further pre-clinical and clinical studies, thus presentibg some hopes for successful introduction of these medications within combined schedules of cancer chemotherapy.
Introduction of the “old-new” anticancer drugs should inevitably pass the step of cell culture testing, animal experiments and clinical trials, in order to confirm antitumor activities for different malignancies. Their testing for the therapy of oncohematological disorders has made a sufficient progress over last years, first of all, by in vitro screening studies of leukemic cell lines performed worldwide. The searched additional effects upon biological pathways in malignant cells may be discerned by means of functional genomics and “big data” mining technologies, thus providing comprehensive information concerning the drug targets [6]. The authors propose a novel functional concept of pharmacology implying artificial intelligence techniques for mining and knowledge discovery in “big data” providing comprehensive information about the drugs associated with activation or suppression of appropriate biological pathways. By this approach, the workers have designed indexes of optimal drugs for treatment of hypertension, analgesia, and candidate drugs for treatment of chronic lymphocytic leukemia. Likewise, the strategy provides successful selection of candidate drugs for repurposing tasks.
Conflict of interest
No conflicts of interest are reported.
References
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Introduction
Additional therapeutic effects of “old”, drugs for novel clini-cal indications have been studied over last decades. Novel suggestions for repurposing of different medical drugs for cancer treatment have been made over recent years [1, 2].
There are three main reasons for these proposals: (1) limited efficiency of novel inhibitors or specific monoclonal antibodies targeted for oncogene-specific molecules; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) eventual decline of development costs for the new therapies performed by the “old” drugs.
A variety of drugs used in different somatic disorders is now considered as complementary tool for treatment of malignancies. These candidate compounds are listed in several indexes available online, e.g., the Drug Repurposing Portal supported by Excelra [3]. In addition, a number of recent review articles concern different aspects of old drug applications in cancer therapy [1, 4, 5].
It should be noted, however, that most cytostatic and anticancer effects of the repurposed drugs are shown in the in vitro models, or in experimental animals, thus suggesting a long way until their clinical implication. The big data collected from drug screening in different models are analyzed by different bioinformatic approaches, e.g. [6], thus accelerating the drug selection process to some degree.
The specific aim of our study was to discuss probable anticancer effects of some anti-infectious drugs which are now widely used in hematopoietic stem cell transplantation protocols.
Some candidate drugs intended for repurposing in cancer treatment are listed in Table 1.
Table 1. Summary of drugs used for treatment of common disorders, their primary indication, non-cancer and cancer targets
Drug repositioning for leukemia treatment
Metformin
This well-known anti-diabetic drug activates the AMF-regulated protein kinase pathway dependent on the tumor suppressor LKB1. The LKB1/AMPK signaling may be suppressed by ERK which is activated in a half of acute myeloid leukemia (AML) cases with appropriate mutations, e.g., FLT3-ITD mutation. These cases may be susceptible for metformin and the treatment efficiency may be increased in combination with sorafenib or other novel drugs [25, 26].
Chloroquines
Pre-clinical studies of the last decade have repeatedly confirmed distinct anticancer effects of well-known antimalarial drug chloroquine and its derivatives. In particular, chloroquine and hydroxychloroquine have relatively well-characterized toxicity profiles. Previously published review articles provide an excellent overview on diversity of chloroquine effects on cancer cells, both in the cell culture as well as on human tumors grafted into mice; and suggest incorporation of hydroxychloroquine in prospective combination schemes for clinical studies [9]. The authors discuss some common features in cancer cells that could be targeted by quinacrine and its derivatives, aiming for potential pharmaceutical intervention in oncology.
A recent work by Eriksson et al. [11] dealt with more specific quinacrine effects upon malignant blood cells. The authors have earlier selected quinacrine as the most plausible compound for its antileukemic effects, and tested this drug in vitro in combination with some common cytostatic agents (daunorubicin, cytarabine, azacitidine, etc.). Acute myeloid leukemia (AML) cell lines were cultured as a target population, then tested for cytotoxicity by fluorometric microculture. In most in vitro systems, the workers have shown distinct synergism between quinacrine and cytarabine, or azacitidine added to these cell cultures. Moreover, the in vivo usage of quinacrine (100 mg/kg, six injections for two weeks) in SCID mice bearing human AML cells caused a significant decrease in circulating blast cells and increased the median survival time of the animals. Hence, further studies may offer an “old-new”, less toxic drug for combined treatment of leukemia.
Fluoroquinolones
Quinolone-based antibiotics, especially, fluoroquinolones are used over decades to manage different bacterial and protozoal infections. Their microbicidal action is caused by inhibition of the ligase domain of the type II DNA topoisomerase, thus releasing endonuclease activities and irreversible DNA decay in the target cells, as reviewed by Idowu and Schweizer [12]. Such a universal cytotoxic effect presumes possible applications of fluoroquinolones for cancer treatment. These studies, however, are still in progress and should be substantiated in pre-clinical trials.
Tetracycline, and its derivatives
This class of antibacterials is known since 1948. Tetracyclines are widely used in medicine and agriculture to combat broad spectrum of bacteria [14]. Despite high proportion of tetracyclin-resistant microorganisms (due to powerful drug efflux), a new generation of these drugs was developed later on (e.g., Doxycycline, Tigecycline) which are now administered for empiric treatment, e.g., in immunocompromised patients following severe cytostatic treatment and bone marrow transplantation. Interestingly, doxorubicin, a popular anticancer antibiotic belongs to the same family of bioactive compounds.
All the tetracyclines inhibit protein assembly in Gram(+) and Gram(-) microbes by preventing the aminoacyl-tRNA binding to the acceptor sites at the ribosomes. Meanwhile, tetracyclines were also tested for treatment of a number of inflammatory diseases, due to their inhibition of matrix metalloproteinases, antiapoptotic, antioxidative, and antiinflammatory effects in humans [14].
Hence, the major antimicrobial effect of tetracyclines is due to their protein-inhibiting actions in bacteria. Moreover, they possess antiproliferative and pro-apoptotic effects in mammalian cancer cells, by suppressing mitochondrial ribosomes and energy metabolism [16]. More recently, they are also considered potential anticancer drugs. E.g., Tigecycline a structural homologue of tetracycline, being a potent glycylcycline antibiotic, is mostly used as a broad-spectrum drug against gram-positive and gram-negative pathogens. It reversibly binds the 30S subunit of the bacterial ribosomes, being also an inhibitor of mitochondrial biogenesis [27].
Ten malignant tumor cell lines of different origin were tested in vitro with tigecycline and doxycycline (another tetracycline derivative), showing. Tigecycline has shown its ability to inhibit the MCF7 and T47D spheroid cell growth, at the concentrations from 10 µM to 50 µM [16]. Moreover, tigecycline was previously shown to kill human AML differentiated blasts as well as leukemic stem cells in vitro and in vivo by blocking mitochondrial protein synthesis [28].
Another work concerned in vitro cytostatic effects of tigecycline on the acute lymphoblastic leukemia (ALL) showing decreased survival and suppression of clonogenic growth in malignant cell cultures [29]. Toxic effects upon normal hematopoietic cells were less pronounced. Pharmacokinetics and potential antitumor effects make this drug a promising option when sensitizing ALL cells for chemotherapy [30].
In particular, tigecycline was studied in the Phase 1 dose-escalation study of tigecycline administered intravenously daily 5 of 7 days for 2 weeks to patients with AML. A total of 27 adult patients with relapsed and refractory AML were enrolled [27]. The authors have shown relative safety and assessed maximal tolerable doses for the drug infused into the patients with relapsed/refractory AML, however, with no evident anticancer effects revealed.
Moreover, some small clinical trials with doxycycline were performed over last years in cancer clinics (primarily aiming for infection therapy, but not cancer treatment) showing some antitumor effects in cancer patients as reviewed by Lamb et al. [16]. Initial positive results of doxycycline trials obtained in advanced or treatment-resistant cases of B-cell lymphoma [30]. This clinical effect was not, however, confirmed in more extensive studies.
Erythromycin and other macrolides
These antibacterials may also inhibit various microflora by suppressing ribosome functions. Similarly, they can inhibit mitochondrial ribosomes in eukaryotic cells, as shown in several cancer cell lines [16]. Azithromycin is an improved erythromycin derivative which is widely used in post-transplant patients, being more slowly eliminated than erythromycin. Its anti-infectious effect is exploited for prevention of bacterial complications in chronic infectious conditions, e.g., at later terms post-HSCT.
Surprisingly, a probable antitumor effect of azithromycin was revealed in a study by Shamoun et al. [17] published as a short abstract, where a long-term drug administration (14 days) aimed to ameliorate chronic graft-versus-graft disease (GvHD) was accompanied by decreased rates of relapse and improved survivals in a combined group of with acute leukemia, MDS, malignant lymphomas, and chronic leukemia patients.
Clarithromycin (6-O-methyl erythromycin) is also a widely used semi-synthetic macrolide drug which also has previously shown a sufficient anticancer activity against some experimental tumors [31] when used after a course of cancer chemotherapy in mice.
A recent review by van Nuffel et al. [18] has summarized numerous data obtained in human studies showing complementary effects of clarithromycin as an antibacterial drug in combined treatment of multiple myeloma, CML and other blood malignancies, especially MALT lymphomas and Hodgkin’s disease studied over last 2 decades. Their general impression is that the effects of Clarithromycin may be also due to antibacterial action of the drug, thus requiring a search for tumor-targeted effects in these conditions. Clarithromycin significantly enhanced effect of cytostatic treatment by increasing natural killer cell activity and CD8+ T cell cytotoxicity, thus causing recovery from immunosuppression caused by the chemotherapy.
Studies on GvHD prevention
Distinct positive effects of azithromycin were shown in murine model of experimental GVHD were reported by a Japanese group [32]. Azithromycin was administered per os to recipient BALB/c mice during H-2 incompatible BMT. The treatment was performed from day -2 to day +2. As a result, the drug-treated animals exhibited significant suppression of lethal GVHD without sufficient inhibition of donor cell engraftment. Azithromycin administration was associated with mice 70% survival of transplanted animals versus death of all mice in control group. Accordingly, the typical GvHD lesions of intestinal and liver epithelium were only minimally expressed in AZM-treated animals. The authors suggest inhibition of recipient DCs as a possible cause of GVHD suppression.
Similar results were obtained by Radhakrishnan et al. [33] in lethally irradiated B6D2F1 mice in whom acute GVHD and noninfectious lung injury were induced by injection of bone marrow and spleen cells from allogeneic C57BL/6 mice. In experimental animals, azithromycin was given for a long time orally from day +14 until 6 or 14 weeks after transplantation. Generally, Azithromycin treatment resulted in improved survival and decreased lung injury, as shown by respiratory tests, and improved GvHD-associated injury of intestines and liver, depending, however, on the schedule of drug gavage.
A small clinical study with azithromycin for GVHD prophylaxis has yielded disappointing results in a randomized, placebo-controlled trial performed by Iranian group [34]. 96 patients with acute leukemia were subjected to HSCT from full-matched donors. All the patients received high-dose chemotherapy, standard immunosuppressive regimens. Azithromycin was administered 500 mg daily in 48 cases from day -6 to +12 posttransplant, and placebo was given in other 48 cases. As a result, incidence of acute GvHD grade III-IV and chronic graft-versus-host disease did not significantly differ between the two groups. Meanwhile, oral mucositis occurred in significantly lower number of patients treated with azithromycin.
Niclosamide
Niclosamide as an approved anthelmintic agent potential anticancer agent by various high-throughput screening campaigns [24]. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells. Therefore, some in vitro screening studies have shown its anticancer activity. In the study by Hamdoun et al. [23], niclosamide showed distinct suppressive effects upon cancer cell lines. Worth of note, it revealed higher activity against leukemia cell lines CCRF-CEM, CEM/ADR5000, and RPMI-8226 compared to the solid tumor cell lines. Cytocidal action of niclosamide may be associated with increase in reactive oxygen species and glutathione (GSH) in malignant cells, thus suggesting GSH synthetase (GS) as a target for niclosamide.
Salinomycin
Salinomycin is an ionophore successfully used in the patients with coccidiosis seems also to express anti-leukemic effects [22]. AML and MLLr cell lines, primary cells and patient samples were sensitive to submicromolar salinomycin. Interestingly, colony formation of normal hematopoietic cells was unaffected by salinomycin, thus promising safer usage of this drug in further clinical trials.
Antifungal drugs
Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including P-glycoprotein-mediated resistance by modulating the Hedgehog signaling pathways which are a target of rapamycin and Wnt/β-catenin in cancer cells. Angiogiogenesis suppression is another known effect of itroconazole in the cancer microenvironment [35]. Small clinical trials suggested the clinical benefits of itraconazole monotherapy in different solid tumors [21].
Possible clinical effects of antibacterials due to posttransplant changes of gut microbiota
Firstly, antibacterial antibiotics, especially, for oral use, are prone for suppression of gut microbiota. E.g., Shono et al [36] have shown that some widely used antibacterials, e.g., piperacillin/tazobactam or imipenem/cilastatin are followed by higher GVHD-related death at 5 years, due to gut microflora imbalance. Therefore, an extending viewpoint suggests damaging effects of antibacterials upon normal microbiota, thus being potentially harmful to immune reconstitution after HSCT and affect clinical outcomes in the patients [37].
Conclusion
At the present time, there is a wide list of repurposed drugs potentially applicable in cancer therapy. Of course, most of these “old” drugs are tested in vitro or in pre-clinical animal models. Hundreds of the candidate compounds are subjected to screening in susceptible malignant cell lines, then treated by means of bioinformatics techniques. Only some drugs are proposed for further pre-clinical and clinical studies, thus presentibg some hopes for successful introduction of these medications within combined schedules of cancer chemotherapy.
Introduction of the “old-new” anticancer drugs should inevitably pass the step of cell culture testing, animal experiments and clinical trials, in order to confirm antitumor activities for different malignancies. Their testing for the therapy of oncohematological disorders has made a sufficient progress over last years, first of all, by in vitro screening studies of leukemic cell lines performed worldwide. The searched additional effects upon biological pathways in malignant cells may be discerned by means of functional genomics and “big data” mining technologies, thus providing comprehensive information concerning the drug targets [6]. The authors propose a novel functional concept of pharmacology implying artificial intelligence techniques for mining and knowledge discovery in “big data” providing comprehensive information about the drugs associated with activation or suppression of appropriate biological pathways. By this approach, the workers have designed indexes of optimal drugs for treatment of hypertension, analgesia, and candidate drugs for treatment of chronic lymphocytic leukemia. Likewise, the strategy provides successful selection of candidate drugs for repurposing tasks.
Conflict of interest
No conflicts of interest are reported.
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Алексей Б. Чухловин
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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(22) "Организации" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } } ["SUMMARY_RU"]=> array(36) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20995" ["VALUE"]=> array(2) { ["TEXT"]=> string(4025) "<p style="text-align: justify;">В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов. <p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3969) "
В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов.
Ключевые слова
Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.
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R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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Keywords
Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation.
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Alexey B. Chukhlovin
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Over last decade, a number of studies has concerned possible implications of “old” medical drugs, as additional tools for cancer treatment. The main reasons for extension of drug indications are as follows: (1) limited efficiency or high costs of targeted oncogene protein inhibitors or specific monoclonal antibodies for therapy; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) sufficient decline of development costs for the new therapies performed by the “old” drugs. The list of such repurposed drugs now includes dozens of medications commonly used for treatment of cardiovascular diseases, diabetes mellitus, epilepsia, different inflammatory disorders. The present review deals, mainly, repurposing of anti-infectious drugs, including those used in prevention and management of infectious complications occurring in cytostatic therapy of leukemia and lymphomas, e.g., tetracyclines, erythromycin derivatives, as well as fluoroquinolones, antiviral compounds etc.
The antitumor effects were of these candidates for repurposing were demonstrated upon screening of their cytostatic effects in leukemic and other cancer cell lines. Some studies were performed in experimental tumor-bearing animals. Only few clinical trials were carried out in patients with leukemias and lymphomas following hematopoietic stem cell transplantation (HSCT), which showed some positive effects of antibacterial drugs in terms of graft-versus-host disease (GvHD) prevention, or prolonged survival of the patients. Controlled clinical trials of common anti-infectious drugs are required for this repurposing.
Keywords
Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation.
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Keywords
Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation.
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Chukhlovin" ["LINK_ELEMENT_VALUE"]=> bool(false) } ["SUMMARY_RU"]=> array(37) { ["ID"]=> string(2) "27" ["TIMESTAMP_X"]=> string(19) "2015-09-02 18:01:20" ["IBLOCK_ID"]=> string(1) "2" ["NAME"]=> string(29) "Описание/Резюме" ["ACTIVE"]=> string(1) "Y" ["SORT"]=> string(3) "500" ["CODE"]=> string(10) "SUMMARY_RU" ["DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["PROPERTY_TYPE"]=> string(1) "S" ["ROW_COUNT"]=> string(1) "1" ["COL_COUNT"]=> string(2) "30" ["LIST_TYPE"]=> string(1) "L" ["MULTIPLE"]=> string(1) "N" ["XML_ID"]=> string(2) "27" ["FILE_TYPE"]=> string(0) "" ["MULTIPLE_CNT"]=> string(1) "5" ["TMP_ID"]=> NULL ["LINK_IBLOCK_ID"]=> string(1) "0" ["WITH_DESCRIPTION"]=> string(1) "N" ["SEARCHABLE"]=> string(1) "N" ["FILTRABLE"]=> string(1) "N" ["IS_REQUIRED"]=> string(1) "N" ["VERSION"]=> string(1) "1" ["USER_TYPE"]=> string(4) "HTML" ["USER_TYPE_SETTINGS"]=> array(1) { ["height"]=> int(200) } ["HINT"]=> string(0) "" ["PROPERTY_VALUE_ID"]=> string(5) "20995" ["VALUE"]=> array(2) { ["TEXT"]=> string(4025) "<p style="text-align: justify;">В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов. <p> <h2>Ключевые слова</h2> <p style="text-align: justify;">Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.</p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(3969) "
В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов.
Ключевые слова
Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.
" ["TYPE"]=> string(4) "HTML" } ["~DESCRIPTION"]=> string(0) "" ["~NAME"]=> string(29) "Описание/Резюме" ["~DEFAULT_VALUE"]=> array(2) { ["TEXT"]=> string(0) "" ["TYPE"]=> string(4) "HTML" } ["DISPLAY_VALUE"]=> string(3969) "В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов.
Ключевые слова
Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.
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НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
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Introduction
Autologous nerve transplantation still remains a golden standard for reconstruction of peripheral nerves. Autologous sural nerve is mostly often harvested and transplanted into the gap dividing two ends of the damaged nerve. The main problem of this approach occurs due to the area of the nerve harvesting which may be associated with its functional loss and risk of painful neurinoma. Moreover, the material for grafting is available only in limited amounts. Hence, full reconstruction seems to be impossible, especially in extensive nerve lesions (i.e., of brachial plexus) [1].
This problem may be resolved by means of an implant (conduit) allowing to join the ends of damaged nerve, thus promoting invasion of nervous fibers from its central segment to peripheral part. Different materials were proposed for implantation that may be classified into distinct groups, i.e., biological implants (veins, skeletal muscles) [2, 3], or synthetic materials. Moreover, the synthetic conduits may be resorbable, such as chitosan conduit, polylactide tubule, conduits of biodegradable polyurethane, neurotube of polyglycolic acid), and non-resorbable implants, e.g., silicon tubes [1]. Therefore, we present a review of literature on the surgery of peripheral nerves ruptures with diastasis. We have collected the data of efficiency of different methods used for overcoming diastasis of the injured peripheral nerves.
Biological implant materials
Usage of venous grafts in order to overlap a gap between the ends of damaged nerve shows some benefits including simple access, minor associated injury during the vein harvest, wide choice of veins with different-diameters. Moreover, the venous wall is permeable for the nutrients; basal lamina of veins is enriched with laminin, thus improving nerve regeneration, whereas the venous matter is a non-immunogenic substance [2, 3].
Meanwhile, Guerra et al. [2] have shown that the empty venous graft tends for collapse. Therefore, it is reasonable to fill the conduit with different substances in order to provide its structural properties and improve the nerve regeneration processes [2].
Synthetic materials
An ideal material for a synthetic conduit should meet the following requirements: biocompatibility, structural and mechanical properties corresponding to natural nervous tissue, appropriate biodegradation rates that should provide structural support during the entire regeneration period, however, without a risk of nerve compression. The biodegradation products should be non-toxic and optimal porosity of this material should be of 70-98%; It should be hard and flexible [4, 5].
Over last years, a number of workers have proposed different synthetic biodegradable materials meeting these criteria, i.e., chitosan, polylactide, their derivates, as well as electroconductive polymers.
Figure 1. Chitosan structure [4]
Chitosan is a derivative obtained by alkaline deacelylation of the chitin polymer (Fig. 1). I.e., the deacetylation degree in chitosan is a key characteristic which determines its physical, chemical and biological features. This parameter sufficiently determines the rates of the polymer degradation, due to controlled deacetylation processes during chitosan preparation (the chitosan degradation rate is reversely proportional to the polymer crystallinity and, therefore, to its decatylation degree). Moreover, the regulated porosity of the chitosan scaffolds (80 to 90%, with the pore size of 50 to 250 mcm) is faforable to angiogenesis which plays a fundamental role in survival and functioning of regenerated nerve fibres. Chitosan is depolymerized in the tissues by means of enzymatic hydrolysis mediated by different hydrolases including lysozyme, pectinases, cellulases, hemicellulases, lipases and amylases. The chitin degradation results into oligosaccharides and monosaccharides, netural metabolites of glucosaminoglycanes, or glucoaminoproteins [4].
Due to all these characteristics, chitosan is considered plausible material for usage in the nerve tubulization. When performing comparative evaluation of axon repair after the defect reconstruction by hollow chitosan conduits of different acetylation degrees, donor nerve autograft, and silicon tube, the best results were obtained in the “golden standard” group. The least efficiency was documented with the silicon conduits. Moreover, they have revealed better regeneration with chitosan acetylated for 5%, than with 2% acetyl groups [7].
The results comparable with autoneural inserts could be achieved by endoneurium modeling due to supplement of a hollow chitosan conduit by the biologically active filler medium consisting of stabilized collagen and enriched by fibronectin [8].
Addition of pro-regenerative cells (Schwann, mesenchimal cells) to the mentioned enriched scaffold restores a natural nerve environment which could be provided by autotransplant. Some workers (Gonzalez-Perez et al.) report on 100% success in nerve regeneration when using the given method with Schwann cell supplementation. E.g., usage of the scaffolds the scaffolds enriched by mesenchymal cells and extracellular matrix substances is associated with 90% success in nerve repair, whereas hollow chitosan tubes bring about 75% success rates [9].
Hence, a combination of chitosan conduits with enriched extracellular matrix and pro-regeneration cells represents a good alternative to the usage of autotransplants in order to restore longitudinal gaps after the nerve injury [8, 9].
A number of other works described chitosan applications combined with other substances, both as conduit, or filling medium (Table 1) [11]. The authors report on good results of nerve regeneration when using tubulization with composite polymeric grafts based on chitosan with polyglycols [10]. Wang et al. [10] did not reveal any statistically significant differences in nerve recovery when testing the mentioned polymeric tubes and “gloden standard”.
Table 1. Results of chitosan application combined with other substances and polymers [11]
Otherwise, the chitosan conduits have shown good results when applying them for restoration of the human nerve integrity (Fan et al.) [12].
Polylactide
Polylactide is a biodegradable thermoplastic polyesther. Polylactide was used as a hollow tibe as a conduit for the nerve reconstruction, as well as a component of composite polymers combined with polycaprolactone or polyglycolide. Polylactide tube was superior to polycaprolactone scaffold, having been compatible with autoneural transplant by its efficiency [13].
Copolyesther-based conduits comprising combinations of polylactide and polycaprolactone, (Neurolac1), and those based on a combination of polylactide and polyglycolide (PLGA) did not show statistically significant differences against the model with autologous donor nerve. However, the polyesther-based scaffolds exhibited a longer biodegradation period as compared with PLGA scaffolds (16-20 and 12 weeks, respectively). Moreover, the biodegradation rate for PLGA conduites correlates with its monomeric composition (i.e., the glycolic-to-lactic acid ratio). The authors also note that degradation products of this polymer show acid reaction, thus leading to decreased tissue pH and development of immune response. Co-polyester provides lesser amounts of acid products upon its biodegradation. PLGA, however, has a benefit due to its microporosity [14].
Some authors reported on better recovery nerve functions when using the co-polyesther when compared to the approved “golden standard” [15, 16]. Moreover, some studies dealt with abovementioned hollow polymeric tubes combined with different filling media (Table 2, 3) [11].
Table 2. Studies with PLGA-based conduites with different filling substances [11]
Table 3. Conduites based on caprolactone with different fillers [11]
Electroconductive polymers
Due to limited nerve regeneration capacity, their reconstitution often requires different biological factors which may control cellular metabolic activity including cell adhesion, differentiation and cytokine secretion. Electric signals are among such factors [17]. Therefore, development of a biodegradable scaffold able to conduct electricity was an important challenge to the workers.
A need for electroconductive polymers was initiated by a study which led to a 10-million-fold increase of polyacetylene conductivity by means of oxydation in iodine vapor. (Normally, polyacethylene is a semi-conductor). This modification, called doping, is the major condition for acquiring the polymer conductivity. The doping process proceeds during the polymer synthesis, or it may be performed by chemical, electrochemical methods, or by means of photo-doping. Moreover, this process may proceed in two ways: p-doping with polymer oxidation and getting the positive charge; and n-doping with polymer reduction and its negative charging. In brief, the polymer (semi-conductor, insulator) is supplied with small amounts of an additive agent which removes or adds an electron to the polymeric chain which eliminates or adds an electron to the polymer chain, this resulting into a delocalized electric charge (Fig. 2, А) [18]. Thereafter, a localization of the charge by a point distorsion of a crystal grid, i.e., the polaron formation (Fig. 2, В, С) [18]. Polaron is able to migrate along the polymer chain, thus allowing it to conduct electricity (Fig. 2, D) [18].
Figure 2. Simplified description of electroconductivity for conducting polymers: (А) removal or addition of an electron to the polymer chain using a doping additive, thus leading to formation of a delocalized charge; (B, C), the charge localization and its surrounding by a local distortion of crystal grid (polaron formation); (D), polaron migration along the polymer chain, thus providing electric conductivity [18]
Polypyrrole is the most studied electroconductive polymer. Chen et al. [19] have used a polypyrrole tube for reconstitution of injured N.ischiadicus in rats. As a result, the authors have revealed that the given polymer is biocompatible and suitable for the nerve electrostimulation procedures [19].
A derivative of polytiophen (PEDOT) is also a promising electroconductive polymer for applications in the nerve regeneration, due to its biocompatibility, electroconductivity and higher electric stability than in polypyrrols. Moreover, carboxymethylchitosan (CMCS), a composite electroconductive polymer was also developed and used. CMSC served as the main macromolecular network able for biodegradation, whereas poly-3,4-ethylenedioxythophen (PEDOT) was applied as a conductive polymeric layer. Herewith, the samples of such polymer show maximal electric conductivity at the polyethylenedioxythophen concentration of 0.2 M. Worth of note, this composite scaffold dose not exert any toxic effect upon the cells, and, alternatively, supports their adhesion survival and proliferation [20]. These characteristics make it an appropriate material for designing a scaffold for the nerve regeneration.
Therefore, usage of the nerve tubulization techniques with biodegradable polymeric conduits is mostly showing a statistically and clinically significant regeneration efficiency which is comparable with autoneural insertion. Upon the conduit functionalization by a biologically active medium and pro-regeneratory cells, one may achieve even better results than with autologous transplants [2, 8, 9, 10, 12, 13, 14]. Additionally, this approach may avoid some problems with harvesting of donors’ nerve which occur in autotransplantation method, the approved “golden standard” [1, 5, 7, 11]. Moreover, when developing electroconductive polymeric scaffolds, one may combine the benefits of biodegradable polymers with electroconductivity, as a factor enabling nerve cell differentiation, enhance neurite growth and peripheral nerve regeneration. Therefore, this mode of bioengineering is quite promising for usage in the surgery of peripheral nerves, thus requiring further studies in the field [17-20].
Conclusion
Injury of peripheral nerves is often accomplished by a sufficient diastasis (gap) between the ends of damaged nerve, thus making it difficult to perform a standard manual suture using surgical threads. As based on analysis of published data, some effective methods are proposed for surgical treatment of peripheral nerve injuries with diastasis. Moreover, some problems of autoneural plastics are revealed. Thus, the aspects of overcoming such diastasis remain to be timely, especially in cases of longitudinal and multiple nerve defects. An alternative option in resolving such problems is offered, i.e., usage of implants allowing to connect the ends of a damaged nerve and promoting invasion of neural fibres from the central to peripheral processus of the damaged nerve. Usage of biocompatible and biodegradable polymers as a neural prosthesis promotes a more safe regeneration, and does not require switching off the donor nerve and its function. Moreover, some new options allow to influence regeneration rates and quality of the damaged peripheral nerves. As shown by the mentioned data, one may state that application of the proposed methods in many observations brings about statistically and clinically significant results that may objectively compete with results of autoneural grafting. Hence, further studies of the tubulization method open a prospective in surgical treatment of damaged peripheral nerves with diastasis. Therefore, further studies in tubulization method is a promising direction in this field, providing a serious potential for successful reconstructive surgical interventions.
Conflict of interests
None of the authors report any conflicts of interest.
References
- Comparative neuro tissue engineering using different nerve guide implants / N. Sinis, H.-E. Schaller, C. Schulte-Eversum, T. Lanaras, B. Schlosshauer, M. Doser, K. Dietz, H. Rоsner, H.-W. Muller, M. Haerle. Acta Neurochir (Suppl). 2007 100: 61-64.
- Sabongi RG, Fernandes M, Dos Santos JB. Peripheral nerve regeneration with conduits: use of vein tubes. Neur Regener Res. 2015;10(4):529-533.
- Bueno CRS, Pereira M, Aparecido I Favaretto-Júnior, Buchaim RL, Andreo JC, Rodrigues AC, Marco G Rosa-Júnior. Comparative study between standard and inside-out vein graft techniques on sciatic nerve repair of rats. Muscular and functional analysis. Acta Cir Bras. 2017;32(3):287-296.
- Yao K, Li J, Yao F, Yin Y. Chitosan-based hydrogels: functions and applications. 2012 by Taylor & Francis Group, LLC: 408-409.
- Bauback S, Buncke G. Autograft substitutes conduits and processed nerve allografts. Hand Clin. 2016; 32: 127-140.
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- Gonzalez-Perez F, Cobianchi S, Heimann C, Phillips JB, Udina E, Navarro X. Stabilization, rolling, and addition of other extracellular matrix proteins to collagen hydrogels improve regeneration in chitosan guides for long peripheral nerve gaps in rats. Neurosurgery. 2017; 80(3):465-474.
- Gonzalez-Perez F, Hernández J, Heimann C, Phillips JB, Udina E, Navarro X. Schwann cells and mesenchymal stem cells in laminin- or fibronectin-aligned matrices and regeneration across a critical size defect of 15 mm in the rat sciatic nerve. J Neurosurg Spine 2017; 28(1): 109-118.
- Wang X, Hu W, Cao Y, Yao J, Wu J, Gu X. Dog sciatic nerve regeneration across a 30-mm defect bridged by a chitosan/PGA artificial nerve graft Brain. 2005; 128(8): 1897-1910.
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- Fan W, Gu J, Hu W, Deng A, Ma Y, Liu J, Ding F, Gu X. Repairing a 35-mm-long median nerve defect with a chitosan/PGA artificial nerve graft in the human: a case study. Microsurgery. 2008; 28(4):238-242.
- Goulart CO, Lopes FR, Monte ZO, Dantas SV Jr, Souto A, Oliveira JT, Almeida FM, Tonda-Turo C, Pereira CC, Borges CP, Martinez AM. Evaluation of biodegradable polymer conduits – poly (L-lactic acid) – for guiding sciatic nerve regeneration in mice. Methods. 2015; 99:28-36.
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- Den Dunnen WFA, Van der Lei B, Schakenraad JM, Stokroos I, Blaauw E, Bartels H, Pennings AJ, Robinson PH. Poly(DL-lactide-e-caprolactone) nerve guides perform better than autologous nerve grafts. Microsurgery 1996; 17: 348-357.
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Introduction
Autologous nerve transplantation still remains a golden standard for reconstruction of peripheral nerves. Autologous sural nerve is mostly often harvested and transplanted into the gap dividing two ends of the damaged nerve. The main problem of this approach occurs due to the area of the nerve harvesting which may be associated with its functional loss and risk of painful neurinoma. Moreover, the material for grafting is available only in limited amounts. Hence, full reconstruction seems to be impossible, especially in extensive nerve lesions (i.e., of brachial plexus) [1].
This problem may be resolved by means of an implant (conduit) allowing to join the ends of damaged nerve, thus promoting invasion of nervous fibers from its central segment to peripheral part. Different materials were proposed for implantation that may be classified into distinct groups, i.e., biological implants (veins, skeletal muscles) [2, 3], or synthetic materials. Moreover, the synthetic conduits may be resorbable, such as chitosan conduit, polylactide tubule, conduits of biodegradable polyurethane, neurotube of polyglycolic acid), and non-resorbable implants, e.g., silicon tubes [1]. Therefore, we present a review of literature on the surgery of peripheral nerves ruptures with diastasis. We have collected the data of efficiency of different methods used for overcoming diastasis of the injured peripheral nerves.
Biological implant materials
Usage of venous grafts in order to overlap a gap between the ends of damaged nerve shows some benefits including simple access, minor associated injury during the vein harvest, wide choice of veins with different-diameters. Moreover, the venous wall is permeable for the nutrients; basal lamina of veins is enriched with laminin, thus improving nerve regeneration, whereas the venous matter is a non-immunogenic substance [2, 3].
Meanwhile, Guerra et al. [2] have shown that the empty venous graft tends for collapse. Therefore, it is reasonable to fill the conduit with different substances in order to provide its structural properties and improve the nerve regeneration processes [2].
Synthetic materials
An ideal material for a synthetic conduit should meet the following requirements: biocompatibility, structural and mechanical properties corresponding to natural nervous tissue, appropriate biodegradation rates that should provide structural support during the entire regeneration period, however, without a risk of nerve compression. The biodegradation products should be non-toxic and optimal porosity of this material should be of 70-98%; It should be hard and flexible [4, 5].
Over last years, a number of workers have proposed different synthetic biodegradable materials meeting these criteria, i.e., chitosan, polylactide, their derivates, as well as electroconductive polymers.
Figure 1. Chitosan structure [4]
Chitosan is a derivative obtained by alkaline deacelylation of the chitin polymer (Fig. 1). I.e., the deacetylation degree in chitosan is a key characteristic which determines its physical, chemical and biological features. This parameter sufficiently determines the rates of the polymer degradation, due to controlled deacetylation processes during chitosan preparation (the chitosan degradation rate is reversely proportional to the polymer crystallinity and, therefore, to its decatylation degree). Moreover, the regulated porosity of the chitosan scaffolds (80 to 90%, with the pore size of 50 to 250 mcm) is faforable to angiogenesis which plays a fundamental role in survival and functioning of regenerated nerve fibres. Chitosan is depolymerized in the tissues by means of enzymatic hydrolysis mediated by different hydrolases including lysozyme, pectinases, cellulases, hemicellulases, lipases and amylases. The chitin degradation results into oligosaccharides and monosaccharides, netural metabolites of glucosaminoglycanes, or glucoaminoproteins [4].
Due to all these characteristics, chitosan is considered plausible material for usage in the nerve tubulization. When performing comparative evaluation of axon repair after the defect reconstruction by hollow chitosan conduits of different acetylation degrees, donor nerve autograft, and silicon tube, the best results were obtained in the “golden standard” group. The least efficiency was documented with the silicon conduits. Moreover, they have revealed better regeneration with chitosan acetylated for 5%, than with 2% acetyl groups [7].
The results comparable with autoneural inserts could be achieved by endoneurium modeling due to supplement of a hollow chitosan conduit by the biologically active filler medium consisting of stabilized collagen and enriched by fibronectin [8].
Addition of pro-regenerative cells (Schwann, mesenchimal cells) to the mentioned enriched scaffold restores a natural nerve environment which could be provided by autotransplant. Some workers (Gonzalez-Perez et al.) report on 100% success in nerve regeneration when using the given method with Schwann cell supplementation. E.g., usage of the scaffolds the scaffolds enriched by mesenchymal cells and extracellular matrix substances is associated with 90% success in nerve repair, whereas hollow chitosan tubes bring about 75% success rates [9].
Hence, a combination of chitosan conduits with enriched extracellular matrix and pro-regeneration cells represents a good alternative to the usage of autotransplants in order to restore longitudinal gaps after the nerve injury [8, 9].
A number of other works described chitosan applications combined with other substances, both as conduit, or filling medium (Table 1) [11]. The authors report on good results of nerve regeneration when using tubulization with composite polymeric grafts based on chitosan with polyglycols [10]. Wang et al. [10] did not reveal any statistically significant differences in nerve recovery when testing the mentioned polymeric tubes and “gloden standard”.
Table 1. Results of chitosan application combined with other substances and polymers [11]
Otherwise, the chitosan conduits have shown good results when applying them for restoration of the human nerve integrity (Fan et al.) [12].
Polylactide
Polylactide is a biodegradable thermoplastic polyesther. Polylactide was used as a hollow tibe as a conduit for the nerve reconstruction, as well as a component of composite polymers combined with polycaprolactone or polyglycolide. Polylactide tube was superior to polycaprolactone scaffold, having been compatible with autoneural transplant by its efficiency [13].
Copolyesther-based conduits comprising combinations of polylactide and polycaprolactone, (Neurolac1), and those based on a combination of polylactide and polyglycolide (PLGA) did not show statistically significant differences against the model with autologous donor nerve. However, the polyesther-based scaffolds exhibited a longer biodegradation period as compared with PLGA scaffolds (16-20 and 12 weeks, respectively). Moreover, the biodegradation rate for PLGA conduites correlates with its monomeric composition (i.e., the glycolic-to-lactic acid ratio). The authors also note that degradation products of this polymer show acid reaction, thus leading to decreased tissue pH and development of immune response. Co-polyester provides lesser amounts of acid products upon its biodegradation. PLGA, however, has a benefit due to its microporosity [14].
Some authors reported on better recovery nerve functions when using the co-polyesther when compared to the approved “golden standard” [15, 16]. Moreover, some studies dealt with abovementioned hollow polymeric tubes combined with different filling media (Table 2, 3) [11].
Table 2. Studies with PLGA-based conduites with different filling substances [11]
Table 3. Conduites based on caprolactone with different fillers [11]
Electroconductive polymers
Due to limited nerve regeneration capacity, their reconstitution often requires different biological factors which may control cellular metabolic activity including cell adhesion, differentiation and cytokine secretion. Electric signals are among such factors [17]. Therefore, development of a biodegradable scaffold able to conduct electricity was an important challenge to the workers.
A need for electroconductive polymers was initiated by a study which led to a 10-million-fold increase of polyacetylene conductivity by means of oxydation in iodine vapor. (Normally, polyacethylene is a semi-conductor). This modification, called doping, is the major condition for acquiring the polymer conductivity. The doping process proceeds during the polymer synthesis, or it may be performed by chemical, electrochemical methods, or by means of photo-doping. Moreover, this process may proceed in two ways: p-doping with polymer oxidation and getting the positive charge; and n-doping with polymer reduction and its negative charging. In brief, the polymer (semi-conductor, insulator) is supplied with small amounts of an additive agent which removes or adds an electron to the polymeric chain which eliminates or adds an electron to the polymer chain, this resulting into a delocalized electric charge (Fig. 2, А) [18]. Thereafter, a localization of the charge by a point distorsion of a crystal grid, i.e., the polaron formation (Fig. 2, В, С) [18]. Polaron is able to migrate along the polymer chain, thus allowing it to conduct electricity (Fig. 2, D) [18].
Figure 2. Simplified description of electroconductivity for conducting polymers: (А) removal or addition of an electron to the polymer chain using a doping additive, thus leading to formation of a delocalized charge; (B, C), the charge localization and its surrounding by a local distortion of crystal grid (polaron formation); (D), polaron migration along the polymer chain, thus providing electric conductivity [18]
Polypyrrole is the most studied electroconductive polymer. Chen et al. [19] have used a polypyrrole tube for reconstitution of injured N.ischiadicus in rats. As a result, the authors have revealed that the given polymer is biocompatible and suitable for the nerve electrostimulation procedures [19].
A derivative of polytiophen (PEDOT) is also a promising electroconductive polymer for applications in the nerve regeneration, due to its biocompatibility, electroconductivity and higher electric stability than in polypyrrols. Moreover, carboxymethylchitosan (CMCS), a composite electroconductive polymer was also developed and used. CMSC served as the main macromolecular network able for biodegradation, whereas poly-3,4-ethylenedioxythophen (PEDOT) was applied as a conductive polymeric layer. Herewith, the samples of such polymer show maximal electric conductivity at the polyethylenedioxythophen concentration of 0.2 M. Worth of note, this composite scaffold dose not exert any toxic effect upon the cells, and, alternatively, supports their adhesion survival and proliferation [20]. These characteristics make it an appropriate material for designing a scaffold for the nerve regeneration.
Therefore, usage of the nerve tubulization techniques with biodegradable polymeric conduits is mostly showing a statistically and clinically significant regeneration efficiency which is comparable with autoneural insertion. Upon the conduit functionalization by a biologically active medium and pro-regeneratory cells, one may achieve even better results than with autologous transplants [2, 8, 9, 10, 12, 13, 14]. Additionally, this approach may avoid some problems with harvesting of donors’ nerve which occur in autotransplantation method, the approved “golden standard” [1, 5, 7, 11]. Moreover, when developing electroconductive polymeric scaffolds, one may combine the benefits of biodegradable polymers with electroconductivity, as a factor enabling nerve cell differentiation, enhance neurite growth and peripheral nerve regeneration. Therefore, this mode of bioengineering is quite promising for usage in the surgery of peripheral nerves, thus requiring further studies in the field [17-20].
Conclusion
Injury of peripheral nerves is often accomplished by a sufficient diastasis (gap) between the ends of damaged nerve, thus making it difficult to perform a standard manual suture using surgical threads. As based on analysis of published data, some effective methods are proposed for surgical treatment of peripheral nerve injuries with diastasis. Moreover, some problems of autoneural plastics are revealed. Thus, the aspects of overcoming such diastasis remain to be timely, especially in cases of longitudinal and multiple nerve defects. An alternative option in resolving such problems is offered, i.e., usage of implants allowing to connect the ends of a damaged nerve and promoting invasion of neural fibres from the central to peripheral processus of the damaged nerve. Usage of biocompatible and biodegradable polymers as a neural prosthesis promotes a more safe regeneration, and does not require switching off the donor nerve and its function. Moreover, some new options allow to influence regeneration rates and quality of the damaged peripheral nerves. As shown by the mentioned data, one may state that application of the proposed methods in many observations brings about statistically and clinically significant results that may objectively compete with results of autoneural grafting. Hence, further studies of the tubulization method open a prospective in surgical treatment of damaged peripheral nerves with diastasis. Therefore, further studies in tubulization method is a promising direction in this field, providing a serious potential for successful reconstructive surgical interventions.
Conflict of interests
None of the authors report any conflicts of interest.
References
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Олег В. Галибин1, Герман В. Медведев2, Павел В. Попрядухин3, Павел А. Кулагин1, Александр А. Гусев1, Галина П. Косякова1, Наталья В. Михайлова1, Вероника Д. Новак1, Денис Н. Соломицкий1, Игорь О. Шемякин1, Вадим С. Гаджиагаев1, Максат Х. Гурбанназаров1
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2 Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия
3 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
Повреждение периферических нервов нередко сопровождается значительным диастазом (первичным или вторичным) между концами поврежденного нерва, что затрудняет выполнение стандартного ручного шва нерва с помощью хирургических нитей. На основании анализа данных опубликованных исследований выявлены эффективные способы хирургического лечения повреждений периферических нервов с диастазом. Кроме того, достоверно выявлены недостатки метода аутоневральной пластики, в связи с чем проблема преодоления диастаза поврежденного периферического нерва остается актуальной и в настоящее время, особенно при протяженных и множественных дефектах нервных стволов. Альтернативным вариантом в решении данной проблемы может служит использование имплантов, позволяющих соединить концы поврежденного нерва и способствующих прорастанию нервных волокон из центрального в периферический отросток поврежденного нерва. Использование биосовместимых и биодеградируемых полимеров в качестве неврального протеза способствует более безопасной регенерации и не требует выключения донорского нерва и связанной с ним функции, кроме того, разработаны и продолжают совершенствоваться опции, позволяющие влиять на скорость и качество регенерации поврежденного периферического нерва.
Ключевые слова
Нерв, травма, диастаз, имплант, полимерная основа, хитозан.
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2 Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia
3 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia
Damage of peripheral nerves is often accompanied by a primary or secondary diastasis (gap, spread) between the neural ends, thus complicating a standard manual nerve stitching by means of surgical threads. As based on analysis of published data, the effective techniques were proposed for surgical treatment of peripheral nerve damage accompanied by diastasis. Moreover, some limitations of autoneural plastics are clearly revealed. Therefore, overcoming of nerve diastasis following damage remains to be a strong need, especially when treating prolonged and multiple defects of nerve trunks. Usage of implants providing repair and junction of the damaged nerve seems to be an alternative option allowing end-to-end connection of the damaged nerve from its central to distal segment. Application of biocompatible and bio-degradable polymers as a neural prosthesis promotes more safe regeneration and does not require switching-off a donor nerve and its functions. Moreover, the options are improved which allow to influence rates and quality of the nerve damage repair.
Keywords
Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan.
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Galibin<sup>1</sup>, German V. Medvedev<sup>2</sup>, Pavel V. Popryadukhin<sup>3</sup>, Pavel A. Kulagin<sup>1</sup>, Alexandr A. Gusev<sup>1</sup>, Galina P. Kossyakova<sup>1</sup>, Natalia V. Mikhailova<sup>1</sup>, Veronika D. Novak<sup>1</sup>, Denis N. Solomitskiy<sup>1</sup>, Igor O. Shemiakin<sup>1</sup>, Vadim S. Gadzhiagaev<sup>1</sup>, Maksat Kh. Gurbannazarov<sup>1</sup> </p>" ["TYPE"]=> string(4) "HTML" } ["DESCRIPTION"]=> string(0) "" ["VALUE_ENUM"]=> NULL ["VALUE_XML_ID"]=> NULL ["VALUE_SORT"]=> NULL ["~VALUE"]=> array(2) { ["TEXT"]=> string(401) "Oleg V. Galibin1, German V. Medvedev2, Pavel V. Popryadukhin3, Pavel A. Kulagin1, Alexandr A. Gusev1, Galina P. Kossyakova1, Natalia V. Mikhailova1, Veronika D. Novak1, Denis N. Solomitskiy1, Igor O. Shemiakin1, Vadim S. Gadzhiagaev1, Maksat Kh. Gurbannazarov1
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Keywords
Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan.
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Keywords
Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan.
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2 Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia
3 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia
1 First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2 Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia
3 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia
Олег В. Галибин1, Герман В. Медведев2, Павел В. Попрядухин3, Павел А. Кулагин1, Александр А. Гусев1, Галина П. Косякова1, Наталья В. Михайлова1, Вероника Д. Новак1, Денис Н. Соломицкий1, Игорь О. Шемякин1, Вадим С. Гаджиагаев1, Максат Х. Гурбанназаров1
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На основании анализа данных опубликованных исследований выявлены эффективные способы хирургического лечения повреждений периферических нервов с диастазом. Кроме того, достоверно выявлены недостатки метода аутоневральной пластики, в связи с чем проблема преодоления диастаза поврежденного периферического нерва остается актуальной и в настоящее время, особенно при протяженных и множественных дефектах нервных стволов. Альтернативным вариантом в решении данной проблемы может служит использование имплантов, позволяющих соединить концы поврежденного нерва и способствующих прорастанию нервных волокон из центрального в периферический отросток поврежденного нерва. Использование биосовместимых и биодеградируемых полимеров в качестве неврального протеза способствует более безопасной регенерации и не требует выключения донорского нерва и связанной с ним функции, кроме того, разработаны и продолжают совершенствоваться опции, позволяющие влиять на скорость и качество регенерации поврежденного периферического нерва.
Ключевые слова
Нерв, травма, диастаз, имплант, полимерная основа, хитозан.
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Ключевые слова
Нерв, травма, диастаз, имплант, полимерная основа, хитозан.
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2 Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия
3 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова
2 Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия
3 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
Обзорные статьи
Тапани Рууту
Алексей Б. Чухловин
Олег В. Галибин1, Герман В. Медведев2, Павел В. Попрядухин3, Павел А. Кулагин1, Александр А. Гусев1, Галина П. Косякова1, Наталья В. Михайлова1, Вероника Д. Новак1, Денис Н. Соломицкий1, Игорь О. Шемякин1, Вадим С. Гаджиагаев1, Максат Х. Гурбанназаров1
Обзорные статьи
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Клинический исследовательский институт, Университетский госпиталь Хельсинки,<br>
Финляндия
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[TEXT] => <p style="text-align: justify;">Трансплант-ассоциированная тромботическая микроангиопатия (ТА-ТМА) является сравнительно частым осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.<br>
Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения. </p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.</p>
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Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения.
Ключевые слова
Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.
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Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. The pathophysiology is complex, the central feature is endothelial injury. The role of complement activation in the pathophysiology has been increasingly recognized. The diagnostic procedures and interpretations vary considerably between centers, and aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.</p>
<h2 style="text-align: justify;">Keywords</h2>
<p style="text-align: justify;">Hemopoietic stem cell transplantation, thrombotic microangiopathy, diagnostic techniques, standardization, therapy, complement inhibitors.</p>
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Transplant-associated thrombotic microangiopathy (TA-TMA) is a relatively common complication of hematopoietic stem cell transplantation. The pathophysiology is complex, the central feature is endothelial injury. The role of complement activation in the pathophysiology has been increasingly recognized. The diagnostic procedures and interpretations vary considerably between centers, and aims at standardizing the criteria of this complication are important especially for study purposes. The therapy is improving, particularly due to the introduction of complement inhibitors. However, the indications and policy of administration of these drugs are not well established and need further study.
Keywords
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Тапани Рууту
Клинический исследовательский институт, Университетский госпиталь Хельсинки,
Финляндия
Трансплант-ассоциированная тромботическая микроангиопатия (ТА-ТМА) является сравнительно частым осложнением трансплантации гемопоэтических стволовых клеток (ТГСК). Ее патогенез весьма сложен, а центральным звеном является повреждение эндотелия. Все больше выясняется роль активации комплемента в патофизиологии процесса. Диагностические процедуры и интерпретация результатов существенно различаются между клиническими центрами, и здесь важны задачи стандартизации критериев диагностики этого осложнения особенно в исследовательских целях. Происходит совершенствование терапии, главным образом, благодаря применению ингибиторов комплемента.
Однако показания и тактика назначения этих препаратов еще недостаточно установилась и требует дальнейшего изучения.
Ключевые слова
Трансплантация гемопоэтических клеток, тромботическая микроангиопатия, диагностические методы, стандартизация, терапия, ингибиторы комплемента.
Обзорные статьи
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[TEXT] => <p style="text-align: justify;">В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов. <p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.</p>
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Ключевые слова
Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.
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R.Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, The First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
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[TEXT] => <p style="text-align: justify;">Over last decade, a number of studies has concerned possible implications of “old” medical drugs, as additional tools for cancer treatment. The main reasons for extension of drug indications are as follows: (1) limited efficiency or high costs of targeted oncogene protein inhibitors or specific monoclonal antibodies for therapy; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) sufficient decline of development costs for the new therapies performed by the “old” drugs. The list of such repurposed drugs now includes dozens of medications commonly used for treatment of cardiovascular diseases, diabetes mellitus, epilepsia, different inflammatory disorders. The present review deals, mainly, repurposing of anti-infectious drugs, including those used in prevention and management of infectious complications occurring in cytostatic therapy of leukemia and lymphomas, e.g., tetracyclines, erythromycin derivatives, as well as fluoroquinolones, antiviral compounds etc. <br>
The antitumor effects were of these candidates for repurposing were demonstrated upon screening of their cytostatic effects in leukemic and other cancer cell lines. Some studies were performed in experimental tumor-bearing animals. Only few clinical trials were carried out in patients with leukemias and lymphomas following hematopoietic stem cell transplantation (HSCT), which showed some positive effects of antibacterial drugs in terms of graft-versus-host disease (GvHD) prevention, or prolonged survival of the patients. Controlled clinical trials of common anti-infectious drugs are required for this repurposing.</p>
<h2>Keywords</h2>
<p style="text-align: justify;">Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation. </p>
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[TEXT] => Over last decade, a number of studies has concerned possible implications of “old” medical drugs, as additional tools for cancer treatment. The main reasons for extension of drug indications are as follows: (1) limited efficiency or high costs of targeted oncogene protein inhibitors or specific monoclonal antibodies for therapy; (2) new molecular targets were revealed for some drugs traditionally used to other therapeutic purposes; and (3) sufficient decline of development costs for the new therapies performed by the “old” drugs. The list of such repurposed drugs now includes dozens of medications commonly used for treatment of cardiovascular diseases, diabetes mellitus, epilepsia, different inflammatory disorders. The present review deals, mainly, repurposing of anti-infectious drugs, including those used in prevention and management of infectious complications occurring in cytostatic therapy of leukemia and lymphomas, e.g., tetracyclines, erythromycin derivatives, as well as fluoroquinolones, antiviral compounds etc.
The antitumor effects were of these candidates for repurposing were demonstrated upon screening of their cytostatic effects in leukemic and other cancer cell lines. Some studies were performed in experimental tumor-bearing animals. Only few clinical trials were carried out in patients with leukemias and lymphomas following hematopoietic stem cell transplantation (HSCT), which showed some positive effects of antibacterial drugs in terms of graft-versus-host disease (GvHD) prevention, or prolonged survival of the patients. Controlled clinical trials of common anti-infectious drugs are required for this repurposing.
Keywords
Antibacterial drugs, repurposing, anticancer effects, leukemia treatment, hematopoietic stem cell transplantation.
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Алексей Б. Чухловин
НИИ детской онкологии, гематологии и трансплантологии им. Р. М. Горбачевой, Первый Санкт-Петербургский государственный медицинский университет им. И. П. Павлова, Санкт-Петербург, Россия
В течение последнего десятилетия появился целый ряд исследований, касающихся возможного применения «старых» медицинских препаратов в качестве дополнительных средств для лечения злокачественных новообразований. Есть следующие главные причины подобного расширения показаний для этих препаратов: (1) ограниченная эффективность и высокая стоимость новых таргетных ингибиторов онкогенных белков, или моноклональных антител для терапии; (2) выявление новых молекулярных мишеней для ряда препаратов, ранее внедренных по другим показаниям; (3) существенное снижение затрат на разработку новых средств терапии, осуществляемой «старыми» препаратами. Перечень таких «перенацеленных» препаратов сейчас включает десятки лекарств, которые часто используются, в частности, для лечения сердечно-сосудистых заболеваний, сахарного диабета, эпилепсии, различных воспалительных заболеваний. Данный обзор касается, главным образом, «переназначения» антиинфекционных препаратов, в т.ч. тех, которые используются для профилактики и лечения инфекционных осложнений, возникающих при цитостатической терапии лейкозов и лимфом, в частности – тетрациклинов, производных эритромицина, а также фторхинолонов, антивирусных препаратов и др. Противоопухолевые эффекты этих препаратов-кандидатов для «переназначение» были показаны при скрининге их цитостатических эффектов на линиях лейкозных и других злокачественных клеток. Некоторые исследования проведены на экспериментальных животных-опухоленосителях. Немногие клинические испытания были проведеныe в группах пациентов с лейкозами и лимфомами после трансплантации гемопоэтических стволовых клеток (ТГСК), которые показали некоторые позитивные эффекты антибактериальных препаратов в плане профилактики реакции «трансплантат против хозяина» (РТПХ) или увеличения продолжительности жизни пациентов. В этих целях необходимы контролируемые клинические исследования часто применяемых антиинфекционных препаратов.
Ключевые слова
Антибактериальные препараты, переназначение, противоопухолевые эффекты, терапия лейкозов, трансплантация гемопоэтических стволовых клеток.
Обзорные статьи
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[TEXT] => <p>Олег В. Галибин<sup>1</sup>, Герман В. Медведев<sup>2</sup>, Павел В. Попрядухин<sup>3</sup>, Павел А. Кулагин<sup>1</sup>, Александр А. Гусев<sup>1</sup>, Галина П. Косякова<sup>1</sup>, Наталья В. Михайлова<sup>1</sup>, Вероника Д. Новак<sup>1</sup>, Денис Н. Соломицкий<sup>1</sup>, Игорь О. Шемякин<sup>1</sup>, Вадим С. Гаджиагаев<sup>1</sup>, Максат Х. Гурбанназаров<sup>1</sup></p>
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[TEXT] => <p><sup>1</sup> Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова <br>
<sup>2</sup> Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия<br>
<sup>3</sup> Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия </p>
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2 Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия
3 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
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[TEXT] => <p style="text-align: justify;">Повреждение периферических нервов нередко сопровождается значительным диастазом (первичным или вторичным) между концами поврежденного нерва, что затрудняет выполнение стандартного ручного шва нерва с помощью хирургических нитей. На основании анализа данных опубликованных исследований выявлены эффективные способы хирургического лечения повреждений периферических нервов с диастазом. Кроме того, достоверно выявлены недостатки метода аутоневральной пластики, в связи с чем проблема преодоления диастаза поврежденного периферического нерва остается актуальной и в настоящее время, особенно при протяженных и множественных дефектах нервных стволов. Альтернативным вариантом в решении данной проблемы может служит использование имплантов, позволяющих соединить концы поврежденного нерва и способствующих прорастанию нервных волокон из центрального в периферический отросток поврежденного нерва. Использование биосовместимых и биодеградируемых полимеров в качестве неврального протеза способствует более безопасной регенерации и не требует выключения донорского нерва и связанной с ним функции, кроме того, разработаны и продолжают совершенствоваться опции, позволяющие влиять на скорость и качество регенерации поврежденного периферического нерва. </p>
<h2>Ключевые слова</h2>
<p style="text-align: justify;">Нерв, травма, диастаз, имплант, полимерная основа, хитозан. </p>
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[TEXT] => Повреждение периферических нервов нередко сопровождается значительным диастазом (первичным или вторичным) между концами поврежденного нерва, что затрудняет выполнение стандартного ручного шва нерва с помощью хирургических нитей. На основании анализа данных опубликованных исследований выявлены эффективные способы хирургического лечения повреждений периферических нервов с диастазом. Кроме того, достоверно выявлены недостатки метода аутоневральной пластики, в связи с чем проблема преодоления диастаза поврежденного периферического нерва остается актуальной и в настоящее время, особенно при протяженных и множественных дефектах нервных стволов. Альтернативным вариантом в решении данной проблемы может служит использование имплантов, позволяющих соединить концы поврежденного нерва и способствующих прорастанию нервных волокон из центрального в периферический отросток поврежденного нерва. Использование биосовместимых и биодеградируемых полимеров в качестве неврального протеза способствует более безопасной регенерации и не требует выключения донорского нерва и связанной с ним функции, кроме того, разработаны и продолжают совершенствоваться опции, позволяющие влиять на скорость и качество регенерации поврежденного периферического нерва.
Ключевые слова
Нерв, травма, диастаз, имплант, полимерная основа, хитозан.
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[TEXT] => <p>Oleg V. Galibin<sup>1</sup>, German V. Medvedev<sup>2</sup>, Pavel V. Popryadukhin<sup>3</sup>, Pavel A. Kulagin<sup>1</sup>, Alexandr A. Gusev<sup>1</sup>, Galina P. Kossyakova<sup>1</sup>, Natalia V. Mikhailova<sup>1</sup>, Veronika D. Novak<sup>1</sup>, Denis N. Solomitskiy<sup>1</sup>, Igor O. Shemiakin<sup>1</sup>, Vadim S. Gadzhiagaev<sup>1</sup>, Maksat Kh. Gurbannazarov<sup>1</sup>
</p>
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[TEXT] => <p><sup>1</sup> First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia<br>
<sup>2</sup> Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia<br>
<sup>3</sup> Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia</p>
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[TEXT] => 1 First St. Petersburg State I. Pavlov Medical University, St. Petersburg, Russia
2 Russian R. R.Wreden Research Institute of Traumatology and Orthopedy, St. Petersburg, Russia
3 Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg, Russia
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[TEXT] => <p style="text-align: justify;">Damage of peripheral nerves is often accompanied by a primary or secondary diastasis (gap, spread) between the neural ends, thus complicating a standard manual nerve stitching by means of surgical threads. As based on analysis of published data, the effective techniques were proposed for surgical treatment of peripheral nerve damage accompanied by diastasis. Moreover, some limitations of autoneural plastics are clearly revealed. Therefore, overcoming of nerve diastasis following damage remains to be a strong need, especially when treating prolonged and multiple defects of nerve trunks. Usage of implants providing repair and junction of the damaged nerve seems to be an alternative option allowing end-to-end connection of the damaged nerve from its central to distal segment. Application of biocompatible and bio-degradable polymers as a neural prosthesis promotes more safe regeneration and does not require switching-off a donor nerve and its functions. Moreover, the options are improved which allow to influence rates and quality of the nerve damage repair. <p>
<h2>Keywords</h2>
<p style="text-align: justify;">Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan. </p>
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[TEXT] => Damage of peripheral nerves is often accompanied by a primary or secondary diastasis (gap, spread) between the neural ends, thus complicating a standard manual nerve stitching by means of surgical threads. As based on analysis of published data, the effective techniques were proposed for surgical treatment of peripheral nerve damage accompanied by diastasis. Moreover, some limitations of autoneural plastics are clearly revealed. Therefore, overcoming of nerve diastasis following damage remains to be a strong need, especially when treating prolonged and multiple defects of nerve trunks. Usage of implants providing repair and junction of the damaged nerve seems to be an alternative option allowing end-to-end connection of the damaged nerve from its central to distal segment. Application of biocompatible and bio-degradable polymers as a neural prosthesis promotes more safe regeneration and does not require switching-off a donor nerve and its functions. Moreover, the options are improved which allow to influence rates and quality of the nerve damage repair.
Keywords
Nerve, damage, diastasis, implant, polymeric scaffolds, chitosan.
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Олег В. Галибин1, Герман В. Медведев2, Павел В. Попрядухин3, Павел А. Кулагин1, Александр А. Гусев1, Галина П. Косякова1, Наталья В. Михайлова1, Вероника Д. Новак1, Денис Н. Соломицкий1, Игорь О. Шемякин1, Вадим С. Гаджиагаев1, Максат Х. Гурбанназаров1
1 Первый Санкт-Петербургский государственный медицинский университет им. акад. И. П. Павлова
2 Российский НИИ травматологии и ортопедии им. Р. Р. Вредена, Санкт-Петербург, Россия
3 Институт высокомолекулярных соединений РАН, Санкт-Петербург, Россия
Повреждение периферических нервов нередко сопровождается значительным диастазом (первичным или вторичным) между концами поврежденного нерва, что затрудняет выполнение стандартного ручного шва нерва с помощью хирургических нитей. На основании анализа данных опубликованных исследований выявлены эффективные способы хирургического лечения повреждений периферических нервов с диастазом. Кроме того, достоверно выявлены недостатки метода аутоневральной пластики, в связи с чем проблема преодоления диастаза поврежденного периферического нерва остается актуальной и в настоящее время, особенно при протяженных и множественных дефектах нервных стволов. Альтернативным вариантом в решении данной проблемы может служит использование имплантов, позволяющих соединить концы поврежденного нерва и способствующих прорастанию нервных волокон из центрального в периферический отросток поврежденного нерва. Использование биосовместимых и биодеградируемых полимеров в качестве неврального протеза способствует более безопасной регенерации и не требует выключения донорского нерва и связанной с ним функции, кроме того, разработаны и продолжают совершенствоваться опции, позволяющие влиять на скорость и качество регенерации поврежденного периферического нерва.
Ключевые слова
Нерв, травма, диастаз, имплант, полимерная основа, хитозан.