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PubMed2006

Untreated rejection in 6-month protocol biopsies is not associated with fibrosis in serial biopsies or with loss of graft function.

Donor age, calcineurin inhibitor nephrotoxicity, and acute rejection are the most significant predictors of chronic allograft nephropathy. Protocol biopsies, both in deceased- and living-donor renal grafts, have shown that cortical tubulointerstitial fibrosis correlates with graft survival and function. The impact of not treating subclinical acute rejection (SAR) is less clear. In this study, 126 de novo renal transplant recipients were randomly assigned to receive area-under-the-curve-controlled exposure of either a cyclosporine or a tacrolimus-based immunosuppressive regimen that included steroids, mycophenolate mofetil, and basiliximab induction. Protocol biopsies were taken before and 6 and 12 mo after transplantation. The prevalence of SAR was determined retrospectively. Fibrosis was evaluated by quantitative digital analysis of Sirius red staining in serial biopsies. Donor age correlated significantly with tubulointerstitial fibrosis in pretransplantation biopsies and inferior graft function at month 6 (rtau = -0.26; P = 0.033). Acute rejection incidence was 11.5%, and no clinical late rejection occurred. The prevalence of SAR at 6 mo was 30.8% but was not associated with differences in serial quantitative Sirius red staining at 6 or 12 mo, proteinuria, or progressive loss of GFR up to 2 yr. No differences were found in donor variables, histocompatibility, rejection history, or exposure of immunosuppressants. Controlled individualized calcineurin inhibitor exposure and subsequent tapering resulted in a low early acute rejection rate and prevented late acute rejection. Because, by design, we did not treat SAR, these results provide evidence that asymptomatic infiltrates in 6-mo surveillance biopsies may not be deleterious in the intermediate term. There is need for reliable biomarkers to prove that not all cell infiltrates are equivalent or that infiltrates may change with time.

Adult↗
PubMed2002

Options for induction immunosuppression in liver transplant recipients.

Immunosuppression administered in the early postoperative period following liver transplantation plays a crucial role in the survival of the graft and the patient. The introduction of cyclosporin was an important landmark in transplantation, and to this day, calcineurin inhibitors form the basis of most induction immunosuppression regimens. New drugs are being developed which are more specifically targeted to prevention of rejection, and multiple drug combinations have been proposed as a means of reducing the adverse effects of individual drugs. Azathioprine and the newer antimetabolite mycophenolate mofetil have been added to calcineurin inhibitor-based regimens with varying amounts of success. Antibody induction has evolved as a potent form of immunosuppression as well as a means of avoiding certain adverse effects, particularly nephrotoxicity. The numerous adverse effects encountered with polyclonal preparations have been reduced with the development of more specific monoclonal antibodies such as muromonab CD3 (OKT3) or interleukin (IL)-2 receptor (IL-2R) antagonists. The anti-IL-2R antibody preparations basiliximab and daclizumab have shown excellent early results due to their potent yet highly targeted immunosuppressive effect and minimal adverse effects. Further study is needed to determine the most appropriate dosage, timing and patient population for these new drugs in the setting of liver transplantation. Although a number of different induction regimens have been described, no single protocol is suitable for all liver transplant recipients. Rather, certain regimens have advantages that could favour their use in a specific subgroup of patients. A number of clinical trials are underway to identify new, more specific drugs and combinations which could be useful in induction immunosuppression.

Animals↗
PubMed2006

Immunotherapy for De Novo renal transplantation: what's in the pipeline?

Immunosuppressive drugs have been traditionally developed to prevent acute rejection and to improve short-term kidney transplant outcomes. There is still a medical need to improve outcomes among subgroups of patients at higher risk for graft loss and to reduce cardiovascular, infectious and malignancy-associated morbidity and mortality, and improve long-term adherence. Several new immunosuppressive agents and formulations are undergoing clinical investigation and are discussed in this review.A modified release tacrolimus formulation (MR4) for once-daily administration is undergoing phase III trials. It has been developed to be administered de novo or for maintenance using the same therapeutic target tacrolimus trough concentrations as for the original formulation. Belatacept (LEA29Y), a second generation cytotoxic-T-lymphocyte-associated antigen immunoglobulin (CTLA4-Ig), blocks the interaction between CD80/86 and CD28 costimulatory pathways. In phase II trials, belatacept was as effective as ciclosporin (cyclosporine) when administered in combination with basiliximab, mycophenolate mofetil (MMF) and corticosteroids. Currently, belatacept is undergoing phase III trials including one study in recipients of organs from expanded criteria donors. Inhibitors of the Janus protein tyrosine kinase (JAK)-3 show some selectivity for cells of the lymphoid lineage and have been shown to be effective in late preclinical transplant models. The most frequent adverse effects have been related to nonspecific binding to JAK2 kinases. CP-690550, a JAK3 inhibitor is currently in phase II clinical trials.FK778, is a synthetic malononitrilamide that targets the critical enzyme of the de novo pyrimidine synthesis, dihydroorotic acid dehydrogenase, and receptor-associated tyrosine kinases has completed phase II trials. FK778 also shows antiviral activities that have been tested in patients with polyomavirus nephropathy. Fingolimod (FTY720), a synthetic sphingosine phosphate receptor modulator that reduces the recirculation of lymphocytes to blood and peripheral tissues including inflammatory lesions and graft sites is undergoing phase III trials. Although the efficacy of fingolimod is similar to MMF in patients receiving full doses of ciclosporin, safety issues such as a negative chronotropic effect, macular oedema, pulmonary adverse reactions and graft function resulted in premature discontinuation of the development programme for kidney transplantation. Because there was no clear clinical benefit over treatment options, the clinical development programme of FK778 was discontinued.Finally, a new evolving strategy with powerful induction-induced prolonged T-cell depletion followed by low-dose immunosuppressive monotherapy is showing promising results.

Animals↗
PubMed2001

Role of anti-interleukin-2 receptor antibodies in kidney transplantation.

From the early 1960s, the mainstay of immunosuppression for kidney transplantation has been corticosteroids. Since then, many new drugs have been developed to maintain the renal allograft. Current maintenance immunosuppression commonly consists of corticosteroids, antiproliferative agents and calcineurin inhibitors (e.g. cyclosporin). More recently, antihuman antibodies, either monoclonal or polyclonal, have been developed to use for induction at the time of transplantation or to treat rejection. With the advances in molecular technology, a new class of antihuman antibodies [the anti-interleukin-2 receptor (IL-2R) antibodies] has emerged that incorporate a murine antigen-binding site on to a human immunoglobulin backbone. Such methodology creates antihuman antibodies with high affinity for the epitope and with prolonged serum antibody half-lives. Interleukin-2 and its receptor are central to lymphocyte activation and are the main targets of calcineurin inhibitors. In addition, the anti-IL-2R antibodies inhibit a key target in immune activation. Daclizumab and basiliximab have been shown to significantly reduce the incidence of acute rejection in kidney transplantation. Since these anti-IL-2R antibodies are well tolerated and since calcineurin inhibitors are intrinsically nephrotoxic, anti-IL-2R antibodies have been used in an attempt to avoid cyclosporin after transplantation. Data from clinical trials seem to indicate that the addition of an anti-IL-2R antibody is not sufficient to warrant complete withdrawal of calcineurin inhibitors for more than a very short period after transplantation. A more promising role for anti-IL-2R antibodies may be in renal transplant recipients with delayed graft function (DGF). Recent data on the use of either low-dose calcineurin inhibitors or sirolimus (rapamycin) in conjunction with the anti-IL-2R antibodies for patients with DGF showed no increased risk of acute rejection. Long-term graft survival with use of these low-dose calcineurin inhibitor protocols has yet to be established.

Animals↗
PubMed2005

Antibody induction therapy in renal transplant patients receiving calcineurin-inhibitor immunosuppressive regimens: a comparative review.

Acute rejection during the first year post-transplant is a key predictor of graft survival after renal transplantation. Use of induction therapy with a lymphocyte-depleting agent or an interleukin-2 receptor (IL-2R) antagonist can provide effective protection against rejection in the first critical weeks and months post-transplant. Polyclonal lymphocyte-depleting antibodies are associated with a low incidence of rejection but evidence of their benefit in terms of graft survival is lacking. Thymoglobulin appears to offer superior graft outcomes compared with generic antithymocyte globulin (ATG). The most frequent adverse events are symptoms of cytokine release syndrome, leukopenia, thrombocytopenia, and tachycardia; data on whether polyclonal antibody use increases the risk of lymphoma are conflicting. Muromonab CD3 (OKT3), a monoclonal lymphocyte-depleting antibody, is efficacious but a high incidence of cytokine release syndrome and increased risk of post-transplant lymphoproliferative disease have limited its use. Following their recent introduction, the IL-2R antagonists basiliximab and daclizumab are now used widely, after randomized trials demonstrated that addition to calcineurin inhibitor-based therapy significantly reduced acute rejection by approximately 30-40%. Meta-analyses and registry analysis suggest that addition of an IL-2R antagonist may improve graft survival. The safety profile of IL-2R antagonists is indistinguishable from placebo, with no apparent difference in incidence of infection or post-transplant lymphoproliferative disease. IL-2R antagonists and polyclonal lymphocyte-depleting antibodies (with delayed cyclosporine) offer equivalent efficacy in standard-risk populations; in a trial of high-risk patients, acute rejection rate and graft outcomes were improved with Thymoglobulin. Tolerability is superior with IL-2R antagonists: cytokine release syndrome and hematologic disturbances (notably leukopenia) are significantly more frequent with polyclonal antibodies. Cytomegalovirus infection may also be more common with lymphocyte-depleting antibodies. Thus, in patients at high risk of graft loss, Thymoglobulin may be the preferred choice for induction therapy, while for all other patients, IL-2R antagonists should be considered first-line choice for induction therapy.

Antilymphocyte Serum↗
PubMed1999

Promising new agents in the prevention of transplant rejection.

Promising immunosuppressive drugs designed to prevent rejection have been developed recently. Two monoclonal antibodies directed against the interleukin-2 (IL-2) receptor, daclizumab and basiliximab, have been shown to significantly reduce the incidence of acute rejection without increasing adverse events. Sirolimus (rapamycin), an agent that inhibits T- and B-response at a later stage than cyclosporin, has been shown to be synergistic with cyclosporin in experimental and clinical studies. Ongoing clinical trials have reported that in renal transplantation high doses of sirolimus are as effective as cyclosporin. SDZ-RAD, a derivative of sirolimus, is also under investigation. FTY-720 another promising drug, prolonged the survival of allografts and synergised with cyclosporin and sirolimus in experimental models. Gusperimus (deoxyspergualin), which inhibits IL-1 synthesis, was useful in reversing early and late acute rejection in clinical trials. Antisense oligonucleotides which interfere with intercellular adhesion molecules which are important in rejection, gave encouraging results in primate renal allografts. The availability of these new drugs will be able to further abate the risk of rejection in organ transplantation. However, caution is warranted with their use in order to avoid the risks of over immunosuppression. Today excellent results can be obtained with the available drugs. Newer immunosuppressive schedules should be designed, not only to reduce the risk of rejection, but also to obtain a better therapeutic index that allows a further improvement of the graft survival while minimising the comorbidity and drug-related toxicity.

Animals↗
PubMed2001

Immunosuppressive drugs in paediatric liver transplantation.

Orthotopic liver transplantation is established treatment for children with acute and chronic liver failure. Despite advances in pre- and postoperative management, innovative surgical techniques and new immunosuppressive drugs, acute and chronic rejection remains a problem. In addition, well established adverse effects of commonly used immunosuppressive drugs are no longer accept able. More potent, but less toxic, immunosuppressive agents have been developed and some novel compounds are now entering routine practice. Cyclosporin was the cornerstone of immunosuppressive therapy until the introduction of its novel pharmaceutical form (Neoral) with improved bioavailability, lower inter- and intraindividual pharmacokinetic variability and improved graft survival. Recently, tacrolimus, a macrolide drug with a similar mode of action, but much higher potency, was introduced and, at present, is the only agent which can successfully replace cyclosporin as a first-line immunosuppressive drug. Mycophenolate mofetil has recently been approved for use in adult and paediatric renal transplant recipients. It has a similar mode of action to cyclosporin and tacrolimus, but acts at a later stage of the T cell activation pathway. Administration with standard immunosuppressive drugs reduces the incidence of acute rejection and enables cyclosporin and tacrolimus dose reduction, thus reducing the risk of associated toxic effects. Phase I and II trials with sirolimus (rapamycin), a macrolide antibiotic, have shown comparable immunosuppressive action, when administered in conjunction with standard immunosuppressants. Further clinical trials need to be carried out to establish efficacy, tolerability and pharmacokinetics in paediatric transplant recipients. Monoclonal antibody therapy (daclizumab and basiliximab) is an exciting new development whereby T cell proliferation is inhibited by selective blockade of interleukin (IL)-2 receptors. Preliminary results, when used in combination with a standard immunosuppressive regimen, are good with respect to incidence of acute graft rejection, host immune response and adverse effects. FTY720 is a novel synthetic immunosuppressive compound which induces a reduction in peripheral blood lymphocyte count through apoptotic T cell death or accelerated trafficking of T cells into lymphatic tissues. Experimental animal studies demonstrated synergistic action in combination with low dose cyclosporin or tacrolimus, potentiating their immunosuppressive effects. Further studies are being carried out to determine its potential for application in organ transplantation. Despite this rapid development of novel compounds, it will take many years before they may become part of standard protocols in paediatric transplantation medicine. Further development and research of efficacy and tolerability of existing drugs is, therefore, vital.

Animals↗
PubMed2004

Anti-cytokine therapy for the treatment of graft-versus-host disease.

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases--(I) recipient conditioning, (II) donor T cell activation, and (III) effector cells mediating GVHD. Cytokines have been shown to be extremely important in the initiation and propagation of GVHD. Of note, IL-2 and TNF-alpha lead to cellular activation as well as local tissue damage. There has been a major development in the last few years of monoclonal antibodies that target cytokines. Drugs that target the IL-2 receptor (daclizumab and basiliximab) are now commonly used to prevent renal transplant rejection. Furthermore, drugs that target TNF-alpha (infliximab and etanercept) are used in rheumatoid arthritis and Crohn's disease but are also being tested for a number of other autoimmune diseases. These agents are very selective immunosuppressants that have different mechanisms of action than the calcineurin inhibitors and therefore are potentially promising for treatment or prevention of GVHD. The authors present up-to-date data regarding the use and development of anti-cytokine therapy for GVHD. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.

Animals↗
PubMed2002

New immunosuppressants in clinical trial.

Chemical immunosuppression developed at the beginning of clinical transplantation remains the basis of immunosuppressive protocols used today. Clinical trials of new agents focus on the incremental improvement in one of four areas of immunotherapy: induction, basic maintenance, adjuvant and steroid therapy. Induction immunotherapy developments include the use of humanized antibodies, specific targets (basiliximab, daclizumab) and lymphocyte depletion (anti-thymocyte globulin, campath-1H). Promising results from pilot trials allow for subsequent low dose maintenance monotherapy. New inhibitors of calcineurin isoforms (ISATx247) may disassociate the anti-rejection effect from the toxicity of conventional calcineurin inhibitors. Revived investigation of older anti-proliferative or anti-metabolite drugs (rapamycin, mycophenolic acid, leflunomide) show promise in preventing B-cell responses and reducing chronic rejection but development of derivatives (everolimus, mycophenolate mofetil, ERL 080, MNA 279, MNA 715) may have a stronger commercial than experimental basis. Trials of steroid immunotherapy have focused on steroid elimination but trial of newer locally active steroids may be beneficial.

Animals↗
PubMed2004

Pharmacologic immunosuppression.

Clinical organ transplantation only became a viable treatment option after the advent of effective pharmacologic immunosuppression. Azathioprine and steroids were among the first drugs available for pharmacologic immunosuppression allowed for the first long-term successes in kidney and liver transplantation, though survivors experienced significant adverse effects of the immunosuppression. Azathioprine is an antimetabolite which inhibits the de novo and salvage pathways of purine synthesis. This results in lymphocyte suppression but also toxicity to bone marrow, gastrointestinal tract, and liver. Mycophenolate mofetil (MMF), another antimetabolite drug, inhibits only the de novo purine synthesis pathway. Corticosteroids cause immunosuppression mainly by sequestration of CD4+ T-lymphocytes in the reticuloendothelial system and by inhibiting the transcription of cytokines. Corticosteroids have adverse effects on virtually every system in the body, producing many dose-limiting problems such as osteoporosis, obesity and glucose intolerance. The introduction of cyclosporine in 1983 allowed for further improvements in graft survival, and the incidence of acute rejection decreased. Cyclosporine and the more recently-introduced tacrolimus compose the class of immunosuppressive agents called calcineurin inhibitors. By binding calcineurin and preventing its translocation into the nucleus these drugs prevent transcription and subsequent secretion of IL-2. These drugs produce varying degrees of nephrotoxicity, neurotoxicity and glucose intolerance. Rapamycin also inhibits IL-2 expression, though by interaction with the mammalian Target of Rapamycin (mTOR) protein. The use of antibody to produce immunosuppression began with polyclonal sera developed in animals such as horses or goats. The mechanism by which polyclonal sera causes immunosuppression is not well understood, though cell-mediated cytotoxicity of lymphocytes in the circulation may be one major effect. In contrast, the monoclonal antibody OKT3 is specific for the T-cell receptor (TCR)/CD3 complex, thus preventing activation of T-lymphocutes. Most recently, human and chimeric murine monoclonal antibodies daclizumab and basiliximab have provided effective induction therapy with virtually no adverse effects. While the improved efficacy and decreased adverse effects immunosuppressive agents account for much of the progress in the field of transplantation, current immunosuppression medications not perfect. Ideally, medications would inducing graft tolerance while avoiding generalized immunosuppression and non-immunologic adverse effects. Future research will likely focus on molecular- and gene-level mechanisms to achieve this goal.

Adrenal Cortex Hormones↗
PubMedDate not supplied

Clinical pharmacology of immunosuppressive drugs: year 2000--time for alternatives.

Perspectives in immunosuppressive drug therapy have changed rapidly in the past few years with the appearance on the market of several new entities. Used for organ transplantation, bone-marrow transplantation and more recently in some auto-immune diseases, the usual classical scheme consisting of corticoids, azathioprine (1970) and cyclosporin (1980), with or without an induction period with antilymphocyte antibodies, has varied little except for the monoclonal antibody OKT3. The considerable evolution due to the introduction of cyclosporin almost twenty years ago has reached its limits. The new perspectives offer two aspects: (1) on one hand, the specificity of each compound: tacrolimus, Prograf, Fujisawa; mycophenolate mofetyl (MMF), CellCept, Roche; cyclosporin, Neoral, Novartis; basiliximab, Simulect, Novartis; and dacliximab, Zenapax, Roche; monoclonal humanized antibodies, rapamycine or sirolimus, Rapamune, Wyeth; or its derived form RAD Novartis; (2) on the other hand, all these products represent alternatives to the present scheme in a field where coprescription is the rule. These alternatives encounter one main difficulty: the evaluation and the organization of the different possible combinations have to be done within a small series of patients. It is essential to note that the market authorizations have been given on the basis of a precise scheme of dosage regimen from the pivotal studies and that extrapolation from these conditions, in particular choice of the doses, has required thorough reflection. These recent developments need optimization between an improvement of immunosuppression and a higher risk for infection and malignancy.

Animals↗
PubMedDate not supplied

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Aciclovir, alemtuzumab, alendronic acid sodium salt, alicaforsen sodium, alteplase, amifostine hydrate, antithymocyte globulin (equine), aspirin, atorvastatin calcium, azathioprine; Bacillus Calmette-Guérin, basiliximab, bicalutamide, bimatoprost, BMS-214662, brimonidine tartrate, buprenorphine hydrochloride; Cabergoline, carbamazepine, carboplatin, ciclosporine, cisplatin, cyclophosphamide; Daclizumab, desmopressin acetate, dihydroergotamine mesylate, dorzolamide hydrochloride, doxorubicin, dutasteride; Everolimus; Fluocinolone acetonide, frovatriptan, FTY-720, fulvestrant; Gabapentin, galantamine hydrobromide, ganciclovir, gemcitabine, glatiramer acetate; Hydrocodone bitartrate; Interferon beta, interferon beta-1a, interferon beta-1b, ipratropium bromide; Ketotifen; Lamivudine, latanoprost, levodopa, lidocaine hydrochloride, lonafarnib; Metformin hydrochloride, methylprednisolone, metoclopramide hydrochloride, mirtazapine, mitoxantrone hydrochloride, modafinil, muromonab-CD3, mycophenolate mofetil; NS-2330; Olopatadine hydrochloride, omalizumab, oxcarbazepine, oxycodone hydrochloride; Paclitaxel, paracetamol, piribedil, pramipexole hydrochloride, pravastatin sodium, prednisone; Quetiapine fumarate; Raloxifene hydrochloride, rituximab, rizatriptan sulfate, Ro-63-8695, ropinirole hydrochloride, rosiglitazone maleate; Simvastatin, siplizumab, sirolimus; Tacrolimus, tegaserod maleate, timolol maleate, tiotropium bromide, tipifarnib, tizanidine hydrochloride, tolterodine tartrate, topiramate, travoprost; Unoprostone isopropyl ester; Valganciclovir hydrochloride, visilizumab; Zidovudine.

Drug Therapy↗
PubMed2002

First kidney transplantation from a non-heart-beating donor in the Czech Republic.

The long-lasting decline in the number of kidney donors with brain death in recent years is the reason for a quest for new sources of kidney donors in the Czech Republic. One possible source to increase the number of donor kidneys is the program of obtaining kidneys from non-heart-beating donors (NHBDs). Based on previous experience abroad, optimum hospital conditions, and, first of all, three years of experimental work, it was possible to realise an NHBD program for the first time in the Czech Republic, in the Transplant Centre of the Plzen Hospital in early 2002. The first two kidneys were obtained from a donor with a devastating gunshot brain injury (Maastricht criteria, Class III). After machine perfusion (RM3 renal perfusion system, Waters Medical) both kidneys were transplanted into two recipients with chronic renal insufficiency (chronic glomerulonephritis, nephrosclerosis). Both kidneys resumed their function immediately. For immunosuppression, basiliximab (Simulect, Novartis), rapamycin (Rapamune, Wyeth), and methylprednisolone (Urbason solubile forte, Hoechst) were used. To improve renal function, cyclosporine A (Sandimmune Neoral, Novartis) was started later in the course, simultaneously reducing the dose of rapamycin. The postoperative course was uneventful and both patients could be discharged on the twenty-first day of hospitalisation for further care at home.

Creatinine↗
PubMed2002

Gateways to Clinical Trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Adalimumab, aeroDose insulin inhaler, agomelatine, alendronic acid sodium salt, aliskiren fumarate, alteplase, amlodipine, aspirin, atazanavir; Bacillus Calmette-Guérin, basiliximab, BQ-788, bupropion hydrochloride; Cabergoline, caffeine citrate, carbamazepine, carvedilol, celecoxib, cyclosporine, clopidogrel hydrogensulfate, colestyramine; Dexamethasone, diclofenac sodium, digoxin, dipyridamole, docetaxel, dutasteride; Eletriptan, enfuvirtidie, eplerenone, ergotamine tartrate, esomeprazole magnesium, estramustine phosphate sodium; Finasteride, fluticasone propionate, fosinopril sodium; Ganciclovir, GBE-761-ONC, glatiramer acetate, gliclazide, granulocyte-CSF; Heparin sodium, human isophane insulin (pyr), Hydrochlorothiazide; Ibuprofen, inhaled insulin, interferon alfa, interferon beta-1a; Laminvudine, lansoprazole, lisinopril, lonafarnib, losartan potassium, lumiracoxib; MAb G250, meloxicam methotrexate, methylprednisolone aceponate, mitomycin, mycophenolate mofetil; Naproxen sodium, natalizumab, nelfinavir mesilate, nemifitide ditriflutate, nimesulide; Omalizumab, omapatrilat, omeprazole, oxybutynin chloride; Pantoprazole sodium, paracetamol, paroxetine, pentoxifylline, pergolide mesylate, permixon, phVEGF-A165, pramipexole hydrochloride, prasterone, prednisone, probucol, propiverine hydrochloride; Rabeprazole sodium, resiniferatoxin, risedronate sodium, risperidone, rofecoxib rosiglitazone maleate, ruboxistaurin mesilate hydrate; Selegiline transdermal system, sertraline, sildenafil citrate, streptokinase; Tadalafil, tamsulosin hydrochloride, technosphere/Insulin, tegaserod maleate, tenofovir disoproxil fumarate, testosterone heptanoate, testosterone undecanoate, tipifarnib, tolterodine tartrate, topiramate, troglitazone; Ursodeoxycholic acid; Valdecoxib, valsartan, vardenafil, venlafaxine hydrochloride, VX-745.

Clinical Trials as Topic↗
PubMed2002

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Abacavir sulfate, abciximab, acetylcysteine, adefovir dipivoxil, alfuzosin hydrochloride, aliskiren fumarate, alosetron hydrochloride, amlodipine besilate, apomorphine hydrochloride, atazanavir, atorvastatin, atorvastatin calcium, atrasentan; Basiliximab, beraprost sodium, bevacizumab, bivalirudin, botulinum toxin type A, botulinum toxin type B; Celecoxib, cetuximab, cilansetron, cilomilast; Daclizumab, darbepoetin alfa, docetaxel, duloxetine hydrochloride; Efalizumab, efavirenz, eletriptan,, entecavir, eplerenone, epoetin alfa, eptifibatide, esomeprazole magnesium. ezetimibe; Filgrastim, finasteride, fluvastatin sodium, follitropin alfa; Gemcitabine, gemeprost, ghrelin (human); HE-2000; Infliximab, 111In-Pentetreotide, interferon alfa-2 alpha, interferon alfa-2 beta, interferon beta-1 alpha, irbesartan, irinotecan hydrochloride; Ketamine hydrochloride; L-778123, lafutidine, lamivudine, lamivudine/zidovudine, latanoprost, letrozole, licofelone, lopinavir, losartan potassium, loxiglumide, lubeluzole; Magnesium sulfate, MeGLA, meloxicam, mycophenolate mofetil; NBI-6024, nelfinavir mesilate, nesiritide, nevirapine, niacin, NN-2211; Octreotide, orlistat; PC-515, peginterferon alfa-2 alpha, peginterferon alfa-2b, pemetrexed disodium, pibrozelesin hydrochloride, pimagedine, pirfenidone, pitavastatin calcium, premarin/trimegestone, prucalopride; Rabeprazole sodium; reboxetine, risedronate sodium, ritonavir, rituximab, rofecoxib, roflumilast, rosuvastatin calcium; Sertraline, sibutramine hydrochloride monohydrate, sildenafil citrate, spironolactone, stavudine; Tacrolimus, tadalafil, tamsulosin hydrochloride, tenecteplase, thalidomide, travoprost; Valsartan; Zoledronic acid monohydrate.

Clinical Trials as Topic↗
PubMed2002

[A clinical study of haploidentical and G-CSF primed bone marrow transplantation by using CD25 for aGVHD prophylaxis].

To explore the feasibility of using CD25 monoclonal antibody (Basiliximab) in T-cell undepleted allo-BMT with graft from haplotype-matched related donor for acute GVHD prophylaxis. Twenty-eight patients with leukemia received allo-BMT from HLA two or three loci mismatched related donors. The donors were given G-CSF (Lenograstim) 250 micro g/d for 7 doses prior to marrow harvest. CSA, MTX, ATG and mycophenolate mofetil (MMF) were combined for GVHD prophylaxis. ATG 5 mg/(kg.d) was infused from day 4 to day 1 before transplantation and MMF was administered from day 7. In the study group, the patients received additional CD25 monoclonal antibody for aGVHD prophylaxis. CD25 20 mg each by 30 min intravenous infusion on 2 hours before transplantation and day 4 after transplantation was administered while no application of CD25 in the controls. The outcomes of transplantation were compared between the stud y and control groups. The results showed that the median number of CD34(+) cell in graft was 5.9 x 10(6)/kg in the control group and 7.9 x 10(6)/kg in the study group. The median number of CD3(+) cell was 48 x 10(6)/kg and 52 x 10(6)/kg respectively (P > 0.05). All patients showed 100% donor-typed hematopoietic cells after transplantation by cytogenetic evidence. Five out of fifteen patients in the control group experienced II - IV acute GVHD. While none of thirteen in the study group developed the II - IV acute GVHD. However, none in both groups developed extensive cGVHD. The median follow-up duration was 8 (3-15) months in the study group and 26 (15-36) months in control. In the study group, one patient died from transplant related mortality (CMV infection); no one relapsed; and 12/13 patients survived in disease-free situation within the period of follow-up. In the control group, six patients died from transplant related mortality (3 GVHD, 2 infection and 1 relapsed) and 9/15 patients survived in disease-free situation. The one-year probabilities of disease-free survival (DFS) in two groups were significantly different (P < 0.05). It is concluded that the transplant from haploidentical donors used CD25 antibody is effective and feasible in preventing acute severe GVHD and improving DFS. The major histocompatibility barrier in the haploidentical related allo-BMT could be crossed by donors primed with G-CSF and GVHD prophylaxis with CD25 antibody in the hosts.

Adolescent↗
PubMed2002

[Initial experience with transplantation of a kidney from a non-beating heart donor (NHBD)].

The authors present their initial experience with transplantations of the kidneys from a donor with a non-beating heart (NHBD). This programme was developed because of the permanently declining number of cadaverous kidney donors with a beating heart. Since January 2002 the authors collected a total of three kidneys from NHBD 3 kidneys of which were used for transplantation. The first two started to function immediately, the third one restored its function three weeks after transplantation. The viability and suitability of use of kidneys from NHBD is evaluated with regard to vascular resistance and flow of the perfusion fluid through the kidneys when using a perfusion pump and by means of totalglutathione-S-transferase (tGST) assessed at intervals in the perfusion fluid. The values of the above parameters are limiting between the 6th and 8th hour after the onset of instrumental perfusion of the collected kidneys when the perfusion values should be within the range of 30-50 ml/min/100 g and the vascular resistance should be < 0.7 mmHg and tGST < 100 U/l. For immunosuppression the authors use during the fist days after transplantation basiliximab, rapamycin and corticoids, later in case of satisfactory function of the graft they add cyclosporin A. The initial results of renal transplantation from NHBD are promising and the programme will be developed further.

Cadaver↗
PubMed2003

[New immunological weapons for medicine in the 21st Century: biological therapy based on the use of the latest generation monoclonal antibodies].

The fusion of a murine B cell and a myeloma cell generates a hybridoma that produces monoclonal antibody (mAb). These murine mAb induce the HAMA (human anti-mouse antibodies) response. Murine mAb have been modified by genetic engineering, producing molecules with a higher proportion of human protein. At present, chimeric, humanized and fully human mAb are available. mAb block interactions between target molecules and their ligands or trigger the lyses of mAb-coated tumor cells. Numerous mAb have been developed using the recombinant DNA technology and several are available in the market. Trastuzumab, against HER2/neu, is useful in breast cancer; rituximab, against CD20 in B lymphocytes is useful in lymphoma; alemtuzumah, against CD52 is used in lymphoma and leukemia; daclizumab and basiliximab block the IL-2 receptor interaction and reduce acute rejection in kidney transplantation; abciximab, an antagonist of GPIIb/IIIa platelet receptor, is used in patients undergoing acute coronary syndromes. In autoimmunity diseases, blocking tumor necrosis factor by infliximab and adalimumab has demonstrated excellent results. Thus, infliximab is useful in the treatment of rheumatoid arthritis (RA), Crohn's disease and ulcerative colitis while adalimumab is the first fully human mAb available for RA. Infliximab and adalimumab reduce signs and symptoms in RA and they also interfere with progression of joint damage. Finally, the direct benefits of antagonist treatment can occur at the expense of a major adverse effect in some other biological function.

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