Sirolimus-associated interstitial pneumonitis in a liver transplant recipient

International Nuclear Information System (INIS)

Claire Berrouet, Marie; Aristizabal, Julian Miguel; Restrepo, Juan Carlos; Correa, Gonzalo

2005-01-01

Sirolimus is an immunosuppressive drug that has been used during the past few years. Sirolimus is indicated in rescue therapies and to reduce the secondary toxic effects of calcineurin inhibitors. This drug has been associated with infrequent but severe pulmonary toxicity. Cases of interstitial pneumonitis, bronchiolitis obliterans with organizing pneumonia, and alveolar proteinosis have been described. We describe a case of pulmonary toxicity associated with the use of sirolimus in a 59-yr-old liver transplant recipient. We also review all reported cases of sirolimus-associated lung toxicity among liver transplantation recipients, with the intention of understanding the risk factors, the clinical picture and the outcomes of this complication. Five cases have been reported since January 2000, including the present case. Clinical presentation is similar, with fever, dyspnoea, fatigue, cough, and hemoptysis. Discontinuation of the drug led to resolution of clinical and radiographic findings. Sirolimus-induced pulmonary toxicity is a serious condition and should be considered in the differential diagnosis of liver recipients presenting with respiratory findings. Discontinuation of the drug is associated with resolution of the pulmonary compromise

Profiling sirolimus-induced inflammatory syndrome: a prospective tricentric observational study.

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Fanny Buron

Full Text Available BACKGROUND: The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive. METHODS: 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch. RESULTS: 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model. CONCLUSIONS: Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Practical recommendations for the early use of m-TOR inhibitors (sirolimus) in renal transplantation.

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Campistol, Josep M; Cockwell, Paul; Diekmann, Fritz; Donati, Donato; Guirado, Luis; Herlenius, Gustaf; Mousa, Dujanah; Pratschke, Johann; San Millán, Juan Carlos Ruiz

2009-07-01

m-TOR inhibitors (e.g. sirolimus) are well-tolerated immunosuppressants used in renal transplantation for prophylaxis of organ rejection, and are associated with long-term graft survival. Early use of sirolimus is often advocated by clinicians, but this may be associated with a number of side-effects including impaired wound-healing, lymphoceles and delayed graft function. As transplant clinicians with experience in the use of sirolimus, we believe such side-effects can be limited by tailored clinical management. We present recommendations based on published literature and our clinical experience. Furthermore, guidance is provided on sirolimus use during surgery, both at transplantation and for subsequent operations.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

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Geissler, Edward K.; Schnitzbauer, Andreas A.; Zülke, Carl; Lamby, Philipp E.; Proneth, Andrea; Duvoux, Christophe; Burra, Patrizia; Jauch, Karl-Walter; Rentsch, Markus; Ganten, Tom M.; Schmidt, Jan; Settmacher, Utz; Heise, Michael; Rossi, Giorgio; Cillo, Umberto; Kneteman, Norman; Adam, René; van Hoek, Bart; Bachellier, Philippe; Wolf, Philippe; Rostaing, Lionel; Bechstein, Wolf O.; Rizell, Magnus; Powell, James; Hidalgo, Ernest; Gugenheim, Jean; Wolters, Heiner; Brockmann, Jens; Roy, André; Mutzbauer, Ingrid; Schlitt, Angela; Beckebaum, Susanne; Graeb, Christian; Nadalin, Silvio; Valente, Umberto; Turrión, Victor Sánchez; Jamieson, Neville; Scholz, Tim; Colledan, Michele; Fändrich, Fred; Becker, Thomas; Söderdahl, Gunnar; Chazouillères, Olivier; Mäkisalo, Heikki; Pageaux, Georges-Philippe; Steininger, Rudolf; Soliman, Thomas; de Jong, Koert P.; Pirenne, Jacques; Margreiter, Raimund; Pratschke, Johann; Pinna, Antonio D.; Hauss, Johann; Schreiber, Stefan; Strasser, Simone; Klempnauer, Jürgen; Troisi, Roberto I.; Bhoori, Sherrie; Lerut, Jan; Bilbao, Itxarone; Klein, Christian G.; Königsrainer, Alfred; Mirza, Darius F.; Otto, Gerd; Mazzaferro, Vincenzo; Neuhaus, Peter; Schlitt, Hans J.

2016-01-01

Background We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). Methods In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor–free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor–free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. Results Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). Conclusions Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC. PMID:26555945

Clinical effects of sirolimus treatment in patients with increased ...

African Journals Online (AJOL)

transplanted kidney function will be lost. However, the development of new immunosuppressors, such as sirolimus (SRL), make it possible to stop CNI treatment [6]. Treating renal transplant patients with immunosuppressive drugs other than CNIs has received more attention in recent years. SRL, a new generation of ...

Interstitial pneumonitis is a frequent complication in liver transplant recipients treated with sirolimus.

LENUS (Irish Health Repository)

Morcos, A

2012-06-01

Sirolimus is a powerful immunosuppressive drug which is being used increasingly after liver transplantation because of its renal sparing and anti-tumour effects. It has been associated with uncommon, but potentially fatal, interstitial pneumonitis.

The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration.

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Albawardi, Alia; Almarzooqi, Saeeda; Saraswathiamma, Dhanya; Abdul-Kader, Hidaya Mohammed; Souid, Abdul-Kader; Alfazari, Ali S

2015-01-01

The purpose of this in vitro study was to develop a useful biomarker (e.g., cellular respiration, or mitochondrial O2 consumption) for measuring activities of mTOR inhibitors. It measured the effects of commonly used immunosuppressants (sirolimus-rapamycin, tacrolimus, and cyclosporine) on cellular respiration in target tissues (kidney, liver, and heart) from C57BL/6 mice. The mammalian target of rapamycin (mTOR), a serine/ threonine kinase that supports nutrient-dependent cell growth and survival, is known to control energy conversion processes within the mitochondria. Consistently, inhibitors of mTOR (e.g., rapamycin, also known as sirolimus or Rapamune®) have been shown to impair mitochondrial function. Inhibitors of the calcium-dependent serine/threonine phosphatase calcineurin (e.g., tacrolimus and cyclosporine), on the other hand, strictly prevent lymphokine production leading to a reduced T-cell function. Sirolimus (10 μM) inhibited renal (22%, P=0.002), hepatic (39%, Prespiration. Tacrolimus and cyclosporine had no or minimum effects on cellular respiration in these tissues. Thus, these results clearly demonstrate that impaired cellular respiration (bioenergetics) is a sensitive biomarker of the immunosuppressants that target mTOR.

Belatacept for Maintenance Immunosuppression in Lung Transplantation

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Christine Hui PharmD

2014-06-01

Full Text Available Belatacept is a novel immunosuppressant that blocks a T-cell costimulation pathway and is approved for use in adult kidney transplant recipients. Its safety and efficacy have not been established after lung transplantation. We present a case of a lung transplant recipient treated with belatacept. A 56-year-old man underwent bilateral lung retransplantation for bronchiolitis obliterans syndrome (BOS. In the third year posttransplant, he developed hemolytic uremic syndrome (HUS attributed to tacrolimus. Tacrolimus was changed to sirolimus. One month later, he presented with worsening renal function and HUS attributed to sirolimus. Plasmapheresis and steroid pulse were initiated with clinical improvement, and sirolimus was switched to belatacept. He experienced no episodes of cellular rejection but developed recurrent BOS. Complications during treatment included anemia and recurrent pneumonias. The safety and efficacy of belatacept in lung transplantation remains unclear; further studies are needed.

Immunosuppressive medication adherence in kidney transplant patients.

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Lalić, Jelena; Veličković-Radovanović, Radmila; Mitić, Branka; Paunović, Goran; Cvetković, Tatjana

2014-01-01

To assess the degree of immunosuppressive medication adherence in kidney transplant patients (KTPs) and to determine if there is a difference in the rate of adherence to tacrolimus (Tac), cyclosporine (CsA) and sirolimus (Sir). From a total of 63 KTPs treated at the Clinic of Nephrology, Clinical Centre Niš, Serbia, 60 participated in the study by responding to questionnaires. They were divided into the adherence group (n = 43) and the nonadherence group (n = 17) according to their degree of adherence which was measured using a validated survey form, the simplified medication adherence questionnaire. The KTP adherence to the different immunosuppressive regimens (Tac, CsA and Sir) was compared. Statistical analysis was performed using the Student t test. Adherence was observed in 43 (71.7%) patients, and only 17 (28.3%) did not follow the prescribed therapy. The estimated glomerular filtration rate was significantly lower in the nonadherence group (38.52 ± 18.22 ml/min) than in the adherence group (52.43 ± 16.91 ml/min, p adherers and the nonadherers (6.30 ± 2.06 vs. 5.0 ± 1.52 ng/ml, p adherence. Nonadherence was associated with worse graft function and a lower Tac level. Knowledge about the degree of adherence could help the early identification of nonadherent patients and the development of strategies to improve this. © 2014 S. Karger AG, Basel

Glycemic Stability Through Islet-After-Kidney Transplantation Using an Alemtuzumab-Based Induction Regimen and Long-Term Triple-Maintenance Immunosuppression.

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Nijhoff, M F; Engelse, M A; Dubbeld, J; Braat, A E; Ringers, J; Roelen, D L; van Erkel, A R; Spijker, H S; Bouwsma, H; van der Boog, P J M; de Fijter, J W; Rabelink, T J; de Koning, E J P

2016-01-01

Pancreatic islet transplantation is performed in a select group of patients with type 1 diabetes mellitus. Immunosuppressive regimens play an important role in long-term islet function. We aimed to investigate the efficacy of islet transplantation in patients with type 1 diabetes and a previous kidney transplantation using an alemtuzumab-based induction regimen and triple maintenance immunosuppression. Patients with type 1 diabetes, who had received a kidney transplant previously, were treated with alemtuzumab as induction therapy for their first islet transplantation and basiliximab induction therapy for subsequent islet transplantations. Maintenance immunosuppression consisted of triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Thirteen patients (age 50.9 ± 9.2 years, duration of diabetes 35 ± 9 years) received a total of 22 islet transplantations. One- and 2-year insulin independence was 62% and 42%, respectively; graft function was 100% and 92%, respectively. HbA1c dropped from 57.2 ± 13.1 (7.4 ± 1.2%) to 44.5 ± 11.8 mmol/molHb (6.2 ± 0.9%) (p = 0.003) after 2 years. Six of 13 patients suffered from severe hypoglycemia before islet transplantation. After transplantation, severe hypoglycemia was restricted to the only patient who lost graft function. Creatinine clearance was unchanged. Islet-after-kidney transplantation in patients with type 1 diabetes using an alemtuzumab-based induction regimen leads to considerable islet allograft function and improvement in glycemic control. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Treatment of Hepatitis C in Patients Undergoing Immunosuppressive Drug Therapy

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Kohtaro Ooka; Joseph K.Lim

2016-01-01

With 185 million people chronically infected globally,hepatitis C is a leading bloodborne infection.All-oral regimens of direct acting agents have superior efficacy compared to the historical interferon-based regimens and are significantly more tolerable.However,trials of both types of regimens have often excluded patients on immunosuppressive medications for reasons other than organ transplantation.Yet,these patients-most often suffering from malignancy or autoimmune diseases-could stand to benefit from these treatments.In this study,we systematically review the literature on the treatment of hepatitis C in these neglected populations.Research on patients with organ transplants is more robust and this literature is reviewed here non-systematically.Our systematic review produced 2273 unique works,of which 56 met our inclusion criteria and were used in our review.The quality of data was low;only 3 of the 56 studies were randomized controlled trials.Sustained virologic response was reported sporadically.Interferon-containing regimens achieved this end-point at rates comparable to that in immunocompetent individuals.Severe adverse effects and death were rare.Data on all-oral regimens were sparse,but in the most robust study,rates of sustained virologic response were again comparable to immunocompetent individuals (40/41).Efficacy and safety of interferoncontaining regimens and all-oral regimens were similar to rates in immunocompetent individuals;however,there were few interventional trials.The large number of case reports and case series makes conclusions vulnerable to publication bias.While firm conclusions are challenging,given the dearth of high-quality studies,our results demonstrate that antiviral therapy can be safe and effective.The advent of all-oral regimens offers patients and clinicians greatly increased chances of cure and fewer side effects.Preliminary data reveal that these regimens may confer such benefits in immunosuppressed individuals as well

Association of time under immunosuppression and different immunosuppressive medication on periodontal parameters and selected bacteria of patients after solid organ transplantation.

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Schmalz, G; Berisha, L; Wendorff, H; Widmer, F; Marcinkowski, A; Teschler, H; Sommerwerck, U; Haak, R; Kollmar, O; Ziebolz, D

2018-05-01

Aim of this study was to investigate the association of the time under immunosuppression and different immunosuppressive medication on periodontal parameters and selected periodontal pathogenic bacteria of immunosuppressed patients after solid organ transplantation (SOT). 169 Patients after SOT (lung, liver or kidney) were included and divided into subgroups according their time under (0-1, 1-3, 3-6, 6-10 and >10 years) and form of immunosuppression (Tacrolimus, Cyclosporine, Mycophenolate, Glucocorticoids, Sirolimus and monotherapy vs. combination). Periodontal probing depth (PPD) and clinical attachment loss (CAL) were assessed. Periodontal disease severity was classified as healthy/mild, moderate or severe periodontitis. Subgingival biofilm samples were investigated for eleven selected potentially periodontal pathogenic bacteria using polymerasechainreaction. The mean PPD and CAL as well as prevalence of Treponema denticola and Capnocytophaga species was shown to be different but heterogeneous depending on time under immunosuppression (pperiodontal condition compared to patients without Cyclosporine (pperiodontal and microbiological parameters of patients after SOT. Patients under Cyclosporine medication should receive increased attention. Differences in subgingival biofilm, but not in clinical parameters were found for Glucocorticoids, Mycophenolate and combination therapy, making the clinical relevance of this finding unclear.

The ORION study: comparison of two sirolimus-based regimens versus tacrolimus and mycophenolate mofetil in renal allograft recipients.

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Flechner, S M; Glyda, M; Cockfield, S; Grinyó, J; Legendre, Ch; Russ, G; Steinberg, S; Wissing, K M; Tai, S S

2011-08-01

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients. ©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

Development and Physicochemical Characterization of Sirolimus Solid Dispersions Prepared by Solvent Evaporation Method

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Shahram Emami

2014-12-01

Full Text Available Purpose: The aim of the present investigation was preparation and characterization of sirolimus solid dispersions by solvent evaporation technique to improve its dissolution properties. Methods: Polyvinylpyrrolidone (PVP, Poloxamer 188 and Cremophore RH40 were used to prepare the solid dispersions of sirolimus. In vitro dissolution study using USP type I apparatus, were performed in distilled water (containing SLS 0.4% for pure sirolimus, physical mixtures, Rapamune and prepared solid dispersions. The characterization of solid dispersions was performed using Fourier Transform Infrared (FTIR Spectroscopy and Differential Scanning Calorimetry (DSC. Results: More than 75% of sirolimus was released within 30 minutes from all prepared solid dispersions. The dissolution rate of all prepared solid dispersion powders were more than physical mixtures. The absence of sirolimus peak in the DSC spectrum of solid dispersions indicated the conversion of crystalline form of sirolimus into amorphous form. The results from FT-IR spectroscopy showed that there was no significant change in the FT-IR spectrum of solid dispersions indicating absence of well-defined interaction between drug and carriers. Conclusion: It was concluded that solid dispersion method, using PVP, Poloxamer 188 and Cremophore RH40 can improve dissolution rate of sirolimus.

Induction immunosuppressive therapies in renal transplantation.

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Gabardi, Steven; Martin, Spencer T; Roberts, Keri L; Grafals, Monica

2011-02-01

Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed. The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used. No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions.

mTOR Inhibition and Clinical Transplantation: Pancreas and Islet.

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Berney, Thierry; Andres, Axel; Toso, Christian; Majno, Pietro; Squifflet, Jean-Paul

2018-02-01

This brief overview discusses the beneficial and deleterious effects of mammalian target of rapamycin (mTOR) inhibitors on β cells, and how sirolimus- and everolimus-based immunosuppression have impacted on practices and outcomes of pancreas and islet transplantation. Sirolimus was the cornerstone of immunosuppressive regimens in islet transplantation at the turn of the millenium, but utilization of mTOR inhibitors has progressively decreased from greater than 80% to less than 50% of islet transplant recipients in more recent years. For whole pancreas transplantation, mTOR inhibitors were used in approximately 20% of patients in the early 2000s, but this dropped over the years to less than 10% currently. This decrease is arguably due to less well-tolerated side effects without the advantage of better outcomes. Nonetheless, mTOR inhibitors remain extremely valuable as second-line immunosuppressants in pancreas and islet transplantation.

EFFICACY AND SAFETY OF SIROLIMUS IN REDUCING CYST VOLUME IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

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Sreelatha Melemadathil

2016-11-01

Full Text Available BACKGROUND Autosomal-Dominant Polycystic Kidney Disease is by far the most frequent inherited kidney disease. In White populations, its prevalence ranges from one in 400 to one in 1000 (Gabow 1993. Though the corresponding figure in Blacks is not yet available, the incidence of ESRD due to ADPKD is similar in American Blacks and Whites (Yium et al, 1994. Renoprotective interventions in ADPKD are maximal reduction of blood pressure and proteinuria and limit the effects of additional potential promoters of disease progression such as dyslipidaemia, chronic hyperglycaemia or smoking. At present, there is no definitive treatment for reducing cyst volume and hence disease progression. Sirolimus (Rapamycin is an immunosuppressant mostly used for the management of kidney transplant recipients. This drug by specifically and effectively inhibiting mTOR, exerts antiproliferative and growth inhibiting effects and could be important for the inhibition of cyst progression in ADPKD. MATERIALS AND METHODS It is an interventional randomised open label, active control study for six months. ADPKD type 1 patients between the age of 18 to 60 years with a GFR > 40 mL/min/1.73 m2 were included in the study. RESULTS Total number of subjects enrolled – 60. Patients enrolled in sirolimus arm – 40. Patients enrolled in conventional treatment arm - 20. Patients dropped out due to sirolimus side effects - 5. Patients lost to followup - 1. Patients completed treatment in conventional treatment arm - 20. CONCLUSION Treatment with mTOR inhibitor sirolimus for 6 months was effective in reducing total kidney volume, total renal cyst volume and volume of the largest cyst in patients with ADPKD. There was a small, but significant increase in renal parenchymal volume on treatment with sirolimus. Extending the duration of treatment to one year caused further significant reduction in total kidney volume and cyst volume. Major side effect of sirolimus in our patients was

Treatment of geographic atrophy with subconjunctival sirolimus: results of a phase I/II clinical trial.

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Wong, Wai T; Dresner, Samuel; Forooghian, Farzin; Glaser, Tanya; Doss, Lauren; Zhou, Mei; Cunningham, Denise; Shimel, Katherine; Harrington, Molly; Hammel, Keri; Cukras, Catherine A; Ferris, Frederick L; Chew, Emily Y

2013-04-26

To investigate the safety and effects of subconjunctival sirolimus, an mTOR inhibitor and immunosuppressive agent, for the treatment of geographic atrophy (GA). The study was a single-center, open-label phase II trial, enrolling 11 participants with bilateral GA; eight participants completed 24 months of follow-up. Sirolimus (440 μg) was administered every 3 months as a subconjunctival injection in only one randomly assigned eye in each participant for 24 months. Fellow eyes served as untreated controls. The primary efficacy outcome measure was the change in the total GA area at 24 months. Secondary outcomes included changes in visual acuity, macular sensitivity, central retinal thickness, and total drusen area. The study drug was well tolerated with few symptoms and related adverse events. Study treatment in study eyes was not associated with structural or functional benefits relative to the control fellow eyes. At month 24, mean GA area increased by 54.5% and 39.7% in study and fellow eyes, respectively (P = 0.41), whereas mean visual acuity decreased by 21.0 letters and 3.0 letters in study and fellow eyes, respectively (P = 0.03). Substantial differences in mean changes in drusen area, central retinal thickness, and macular sensitivity were not detected for all analysis time points up to 24 months. Repeated subconjunctival sirolimus was well-tolerated in patients with GA, although no positive anatomic or functional effects were identified. Subconjunctival sirolimus may not be beneficial in the prevention of GA progression, and may potentially be associated with effects detrimental to visual acuity. (ClinicalTrials.gov number, NCT00766649.).

Efficacy and safety of sirolimus in lymphangioleiomyomatosis.

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McCormack, Francis X; Inoue, Yoshikazu; Moss, Joel; Singer, Lianne G; Strange, Charlie; Nakata, Koh; Barker, Alan F; Chapman, Jeffrey T; Brantly, Mark L; Stocks, James M; Brown, Kevin K; Lynch, Joseph P; Goldberg, Hilary J; Young, Lisa R; Kinder, Brent W; Downey, Gregory P; Sullivan, Eugene J; Colby, Thomas V; McKay, Roy T; Cohen, Marsha M; Korbee, Leslie; Taveira-DaSilva, Angelo M; Lee, Hye-Seung; Krischer, Jeffrey P; Trapnell, Bruce C

2011-04-28

Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (Plife and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Acute sirolimus overdose: a multicenter case series.

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Alessandro Ceschi

Full Text Available There are few data relating to sirolimus overdose in the medical literature. Our objectives were to describe all cases of overdose with sirolimus reported to Swiss, German and Austrian Poisons Centres between 2002-2013.An observational case-series analysis was performed to determine circumstances, magnitude, management and outcome of sirolimus overdose.Five cases of acute sirolimus overdose were reported--three in young children and two in adults. Four were accidental and one was with suicidal intent. Two patients developed symptoms probably related to sirolimus overdose: mild elevation of alkaline phosphatase, fever and gastroenteritis in a 2.5-year-old male who ingested 3 mg, and mild changes in total cholesterol in an 18-year-old female after ingestion of 103 mg. None of these events were life-threatening. Serial blood concentration measurements were performed starting 24 h after ingestion of 103 mg in a single case, and these followed a similar pharmacokinetic time-course to measurements taken after dosing in the therapeutic range.Acute sirolimus overdose occurred accidentally in the majority of cases. Even large overdoses appeared to be well-tolerated, however children might be at greater risk of developing complications. Further study of sirolimus overdose is needed.

Low Adherence to Immunosuppressants Is Associated With Symptom Experience Among Kidney Transplant Recipients.

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Lee, S Y; Chu, S H; Oh, E G; Huh, K H

2015-11-01

The purpose of this study was to investigate the relationship between immunosuppressant-related symptom experience (SE) and adherence to immunosuppressant regimens among kidney transplant (KT) recipients. A total of 239 KT recipients on an immunosuppressant regimen who were followed up after transplantation participated in this study. Data was collected through a self-reported questionnaire survey (medication adherence, SE, and quality of life) and medical record review. Low adherence in the immunosuppressant group was associated with longer time since KT, less comorbidity (adherence among KT recipients showed significantly greater overall symptom occurrence (P = .001) and symptom distress (P = .002) levels than patients with high or medium adherence after adjusting for a number of covariates. The most common symptom both in terms of occurrence (96.4%) and distress (91.1%) among poorly adherent KT recipients was tiredness. Low adherence to an immunosuppressant regimen was significantly associated with high SE among KT recipients. Strategies to decrease immunosuppressant-related SE are needed to improve adherence to immunosuppressants. Copyright © 2015 Elsevier Inc. All rights reserved.

Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification

OpenAIRE

Seto, Wai-Kay

2015-01-01

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negati...

Sirolimus therapy to halt the progression of ADPKD.

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Perico, Norberto; Antiga, Luca; Caroli, Anna; Ruggenenti, Piero; Fasolini, Giorgio; Cafaro, Mariateresa; Ondei, Patrizia; Rubis, Nadia; Diadei, Olimpia; Gherardi, Giulia; Prandini, Silvia; Panozo, Andrea; Bravo, Rodolfo Flores; Carminati, Sergio; De Leon, Felipe Rodriguez; Gaspari, Flavio; Cortinovis, Monica; Motterlini, Nicola; Ene-Iordache, Bogdan; Remuzzi, Andrea; Remuzzi, Giuseppe

2010-06-01

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Immunosuppressive strategies and management

Institute of Scientific and Technical Information of China (English)

Shi-hui PAN

2008-01-01

Advances in immunosuppressive therapy have significantly improved short-term allograft and patient survival.However,chronic allograft failure,antibody mediated rejection,recurrent diseases and immunosuppressive drug associated adverse effects remain serious barriers to long-term survival and quality of life.New immunosuppressive agents and protocols are being evaluated to combat these problems.Importantly,clinicians must work to manage post-transplant complications and avoid complex medication regimens,which will potentiate drug interactions and non.compliance.Different organs have different immunogenicities and each recipient has a unique clinical and immunologic profile.The clinician must recognize these variations and customize the immunosuppressive regimens and treatment protocols based on the individual condition.The general principles of an individualized immunosuppressive protocol should take the following factors into account:organ type,donor and recipient characteristics,quality of the donor organ,recipienVs medical history,recipient's undedying disease,immunologic risk for acute rejection,potential co-morbidity related to immunosuppression,significant druginteractions,medication costs and patient compliance.In addition,the combination of immunosuppressive drugs must have a pharmacologic rationale to achieve the desired goal of suppressing the individual's immune system to render the patient tolerant to the allograft while minimizing co-morbidities.For the past few years,many clinical strategies have been applied in an attempt to improve graft survival or to reduce immunsuppressants induced side-effects.Specific protocols include steroid or CNI avoidance,minimization or withdraw,desensitization,and treatment for antibody mediated rejection,disease specific,and pediatric specific.The short-term outcomes from these different strategies are promising but the long-term results remain to be determined.Unfortunately,current immunosuppressive agents or strategies

Effects of sirolimus alone or in combination with cyclosporine A on renal ischemia/reperfusion injury

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B.J. Pereira

2010-08-01

Full Text Available Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 ηg/mL; CsA (100 µg/mL; sirolimus (50 and 250 ηg/mL + CsA (100 µg/mL; control; vehicle (20% ethanol. For in vivo studies, 3-week-old Wistar rats (150-250 g were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I in five groups: sham, I, I + SRL (3 mg·kg-1·day-1, po, I + CsA (3 mg·kg-1·day-1, sc, I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 ± 0.1 mL/min but not in rats receiving sirolimus + CsA (0.8 ± 0.1 mL/min despite the reduction in renal blood flow (3.9 ± 0.5 mL/min. Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.

Hidden sources of grapefruit in beverages: potential interactions with immunosuppressant medications.

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Auten, Ashley A; Beauchamp, Lauren N; Joshua Taylor; Hardinger, Karen L

2013-06-01

The interaction between grapefruit-containing beverages and immunosuppressants is not well defined in the literature. This study was conducted to investigate possible sources of grapefruit juice or grapefruit extract in common US-manufactured beverages. The goal was to identify those products that might serve as hidden sources of dietary grapefruit intake, increasing a transplant patient's risk for drug interactions. A careful review of the ingredients of the 3 largest US beverage manufacturer's product lines was conducted through manufacturer correspondence, product labeling examination, and online nutrition database research. Focus was placed on citrus-flavored soft drinks, teas, and juice products and their impact on a patient's immunosuppressant regimens. Twenty-three beverages were identified that contained grapefruit. Five did not contain the word "grapefruit" in the product name. In addition to the confirmed grapefruit-containing products, 17 products were identified as possibly containing grapefruit juice or grapefruit extract. A greater emphasis should be placed upon properly educating patients regarding hidden sources of grapefruit in popular US beverages and the potential for food-drug interactions.

Anemia among HIV-Infected Patients Initiating Antiretroviral Therapy in South Africa: Improvement in Hemoglobin regardless of Degree of Immunosuppression and the Initiating ART Regimen

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Simbarashe Takuva

2013-01-01

Full Text Available Among those with HIV, anemia is a strong risk factor for disease progression and death independent of CD4 count and viral load. Understanding the role of anemia in HIV treatment is critical to developing strategies to reduce morbidity and mortality. We conducted a prospective analysis among 10,259 HIV-infected adults initiating first-line ART between April 2004 and August 2009 in Johannesburg, South Africa. The prevalence of anemia at ART initiation was 25.8%. Mean hemoglobin increased independent of baseline CD4. Females, lower BMI, WHO stage III/IV, lower CD4 count, and zidovudine use were associated with increased risk of developing anemia during follow-up. After initiation of ART, hemoglobin improved, regardless of regimen type and the degree of immunosuppression. Between 0 and 6 months on ART, the magnitude of hemoglobin increase was linearly related to CD4 count. However, between 6 and 24 months on ART, hemoglobin levels showed a sustained overall increase, the magnitude of which was similar regardless of baseline CD4 level. This increase in hemoglobin was seen even among patients on zidovudine containing regimens. Since low hemoglobin is an established adverse prognostic marker, prompt identification of anemia may result in improved morbidity and mortality of patients initiating ART.

Effect of sirolimus on urinary bladder cancer T24 cell line

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Oliveira Paula A

2009-01-01

Full Text Available Abstract Background Sirolimus is recently reported to have antitumour effects on a large variety of cancers. The present study was performed to investigate sirolimus's ability to inhibit growth in T24 bladder cancer cells. Methods T24 bladder cancer cells were treated with various concentrations of sirolimus. MTT assay was used to evaluate the proliferation inhibitory effect on T24 cell line. The viability of T24 cell line was determined by Trypan blue exclusion analysis. Results Sirolimus inhibits the growth of bladder carcinoma cells and decreases their viability. Significant correlations were found between cell proliferation and sirolimus concentration (r = 0.830; p Conclusion Sirolimus has an anti-proliferation effect on the T24 bladder carcinoma cell line. The information from our results is useful for a better understanding sirolimus's anti-proliferative activity in the T24 bladder cancer cell line.

Hepatitis B virus reactivation during immunosuppressive therapy: Appropriate risk stratification.

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Seto, Wai-Kay

2015-04-28

Our understanding of hepatitis B virus (HBV) reactivation during immunosuppresive therapy has increased remarkably during recent years. HBV reactivation in hepatitis B surface antigen (HBsAg)-positive individuals has been well-described in certain immunosuppressive regimens, including therapies containing corticosteroids, anthracyclines, rituximab, antibody to tumor necrosis factor (anti-TNF) and hematopoietic stem cell transplantation (HSCT). HBV reactivation could also occur in HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) positive individuals during therapies containing rituximab, anti-TNF or HSCT.For HBsAg-positive patients, prophylactic antiviral therapy is proven to the effective in preventing HBV reactivation. Recent evidence also demonstrated entecavir to be more effective than lamivudine in this aspect. For HBsAg-negative, anti-HBc positive individuals, the risk of reactivations differs with the type of immunosuppression. For rituximab, a prospective study demonstrated the 2-year cumulative risk of reactivation to be 41.5%, but prospective data is still lacking for other immunosupressive regimes. The optimal management in preventing HBV reactivation would involve appropriate risk stratification for different immunosuppressive regimes in both HBsAg-positive and HBsAg-negative, anti-HBc positive individuals.

Efficacy of risk stratification in tailoring immunosuppression regimens in kidney transplant patients at the national kidney and transplant institute.

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Ledesma-Gumba, M A; Danguilan, R A; Casasola, C C; Ona, E T

2008-09-01

To evaluate the efficacy of tailored immunosuppressive regimens prescribed according to a risk stratification scoring system based on the number of HLA mismatches, donor source, panel-reactive antibodies (PRA), and repeat transplant. Patients in a retrospective cohort of 329 kidney transplantations performed from October 2004 to December 2005 were assigned scores of 0, 2, 4, or 6 with higher scores for > or =1 HLA mismatches, PRA > 10%, repeat transplant, and unrelated or deceased donor. Added scores of or = 6 denoted high risk including a CNI-based regimen with an interleukin-2 receptor antibody. The efficacy analysis compared the incidences of biopsy-proven acute rejection episodes (BPAR) at 1 year. Only 227 (69%) of 329 patients had a complete data set and 84 were excluded because they did not follow the prescribed protocol, yielding 113 low- and 30 high-risk patients in the final population. Low-risk patients had a mean PRA of 5.4%, living related donors in 68%, and primary transplants. High-risk patients had a mean PRA of 18.8% (range = 10%-97%), living nonrelated donors in 84%, four deceased donors, and four repeat transplants. The overall 1-year incidence of BPAR was 5.7%. No significant difference (P = .081) was observed in 1-year BPAR between the low- (4.5%) and high-risk (9.8%) groups. Likewise, no significant difference in the 1-year mean serum creatinine was observed according to the CNI. The mean creatinine was 1.12 for cyclosporine and 1.38 for tacrolimus treatment (P = .06) in the low-risk group and 1.08 for cyclosporine and 1.2 for tacrolimus (P = .61) in the high-risk cohort. There was no significant difference in acute rejection rates between the immunologically low- or high-risk patients using tailored immunosuppression, which was effective to minimize its occurrence with good renal function at 1 year.

Association of Sirolimus Use With Risk for Skin Cancer in a Mixed-Organ Cohort of Solid-Organ Transplant Recipients With a History of Cancer.

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Karia, Pritesh S; Azzi, Jamil R; Heher, Eliot C; Hills, Victoria M; Schmults, Chrysalyne D

2016-05-01

Solid-organ transplant recipients (OTRs) are at an increased risk for skin cancer. Prior studies have demonstrated a reduced incidence of skin cancer in renal OTRs treated with sirolimus. However, little information exists on the use of sirolimus for the prevention of skin cancer in nonrenal OTRs or those already diagnosed as having a posttransplant cancer. To compare subsequent skin cancer formation in a mixed-organ cohort of OTRs who were or were not treated with sirolimus after developing a posttransplant index cancer of any type. A 9-year retrospective cohort study at 2 academic tertiary care centers. Electronic medical records were reviewed for OTRs diagnosed as having a posttransplant cancer of any type to determine the type of organ transplanted, pretransplant and posttransplant cancer, and immunosuppressive medications. Patients underwent transplant from January 1, 2000, to December 31, 2008. Data were collected from July 30, 2011, to December 31, 2012, when follow-up was completed, and analyzed from April 28, 2013, to October 4, 2014. Factors associated with subsequent skin cancer development were evaluated via multivariate Cox regression analysis. Of 329 OTRs with an index posttransplant cancer (100 women and 229 men; mean [SD] age, 56 [19] years), 177 (53.8%) underwent renal transplant; 58 (17.6%), heart transplant; 54 (16.4%), lung transplant; 34 (10.3%), liver transplant; and 6 (1.8%), mixed-organ transplant. Ninety-seven OTRs (29.5%) underwent conversion to sirolimus therapy after diagnosis. One hundred thirty OTRs (39.5%) developed second posttransplant cancers, of which 115 cases (88.5%) were skin cancers. An 11.6% reduction in skin cancer risk was observed in the sirolimus-treated vs non-sirolimus-treated groups overall (26 of 97 [26.8%] vs 89 of 232 [38.4%]; P = .045) and among nonrenal OTRs only (8 of 34 [23.5%] vs 44 of 112 [39.3%], respectively), although the latter difference was not significant (P = .09). Independent predictors of

Genetic factors for individual administration of immunosuppressants in organ transplantation

Institute of Scientific and Technical Information of China (English)

Song-Feng Yu; Li-Hua Wu; Shu-Sen Zheng

2006-01-01

BACKGROUND: The immunosuppressive drugs used worldwide have a narrow therapeutic index, which results in a need to individualize the dose regimen for different recipients. The oxidative enzymes cytochrome P450 (CYP)3A and the drug eflfux pump P-glycoprotein (P-gp) are two potential factors in the processes of metabolism. Pharmacogenetic study of immunosuppressive drugs has focused on these two enzymes. This review was undertaken to assess the role of single nuclear polymorphisms (SNPs) of these two enzymes in the individual administration of immunosuppressive drugs. DATA SOURCES: An English-language literature search was made using MEDLINE for articles on CYP3A and P-gp in organ transplantation. RESULTS: The SNPs of CYP3A and P-gp are closely correlated to the large variations of cyclosporine and tacrolimus dosage between different patients, although conlficting results were obtained by some authors. CONCLUSIONS: More studies should be conducted to elucidate further the pharmacogenetics of immuno-suppressive drugs in organ transplantation, a deep understanding of which would provide an important step toward drug regimen individualization in the posttransplant therapy.

Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

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Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Kaiser, Patricia A; Ayers, Colby R; Mammen, Pradeep P A; Markham, David W; Ring, William Steves; Peltz, Matthias; Drazner, Mark H

2013-01-01

Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution. We retrospectively reviewed records of all adult cardiac transplant recipients living between September 1999 and February 2010 (n = 329) and identified 67 patients (20%) who received sirolimus. The indications for sirolimus were cardiac allograft vasculopathy (67%), renal dysfunction (25%), rejection (4%), and intolerability of tacrolimus (3%). One-third of patients discontinued sirolimus at a median (25th, 75th percentiles) of 0.9 (0.2, 1.6) yr of duration. Over 70% of subjects experienced an adverse event attributed to sirolimus. Adverse events were associated with higher average sirolimus levels (9.1 ng/mL vs. 7.1 ng/mL, p = 0.004). We conclude that sirolimus is frequently used in cardiac transplant recipients (20%) and commonly causes side effects, often necessitating discontinuation. Higher average sirolimus levels were associated with adverse events, suggesting that tolerability may improve if levels are maintained within the lower end of the current therapeutic range; however, the improvement in tolerability would need to be balanced with the potential for decreased efficacy. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Subconjunctival sirolimus in the treatment of diabetic macular edema.

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Krishnadev, Nupura; Forooghian, Farzin; Cukras, Catherine; Wong, Wai; Saligan, Leorey; Chew, Emily Y; Nussenblatt, Robert; Ferris, Frederick; Meyerle, Catherine

2011-11-01

Diabetic macular edema (DME) is a leading cause of blindness in the developed world. Sirolimus has been shown to inhibit the production, signaling, and activity of many growth factors relevant to the development of diabetic retinopathy. This phase I/II study assesses the safety of multiple subconjunctival sirolimus injections for the treatment of DME, with some limited efficacy data. In this phase I/II prospective, open-label pilot study, five adult participants with diabetic macular edema involving the center of the fovea and best-corrected ETDRS visual acuity score of ≤74 letters (20/32 or worse) received 20 μl (440 μg) of subconjunctival sirolimus at baseline, month 2 and every 2 months thereafter, unless there was resolution of either retinal thickening on OCT or leakage on fluorescein angiography. Main outcome measures included best-corrected visual acuity and central retinal thickness on OCT at 6 months and 1 year, as well as safety outcomes. Repeated subconjunctival sirolimus injections were well-tolerated, with no significant drug-related adverse events. There was no consistent treatment effect related to sirolimus; one participant experienced a 2-line improvement in visual acuity and 2 log unit decrease in retinal thickness at 6 months and 1 year, two remained essentially stable, one had stable visual acuity but improvement of central retinal thickness of 1 and 3 log units at 6 months and 1 year respectively, and one had a 2-line worsening of visual acuity and a 1 log unit increase in retinal thickness at 6 months and 1 year. Results in the fellow eyes with diabetic macular edema, not treated with sirolimus, were similar. Subconjunctival sirolimus appears safe to use in patients with DME. Assessment of possible treatment benefit will require a randomized trial.

Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients.

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Fairfield, Cameron; Penninga, Luit; Powell, James; Harrison, Ewen M; Wigmore, Stephen J

2018-04-09

Liver transplantation is an established treatment option for end-stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects. To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017. Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid-containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids. We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed-effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a

Gonadal function and fertility after stem cell transplantation in childhood: comparison of a reduced intensity conditioning regimen containing melphalan with a myeloablative regimen containing busulfan.

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Panasiuk, Anna; Nussey, Stephen; Veys, Paul; Amrolia, Persis; Rao, Kanchan; Krawczuk-Rybak, Maryna; Leiper, Alison

2015-09-01

The occurrence of late sequelae after myeloablative conditioning regimens for stem-cell transplantation (SCT) has prompted the introduction of reduced-intensity chemotherapy (RIC) regimens in an attempt to reduce toxicity and spare fertility. We retrospectively evaluated gonadal function in survivors of SCT in childhood by comparing patients conditioned with a myeloablative regimen containing busulfan and cyclophosphamide (BuCy, N = 51, 28 boys) and a RIC regimen containing fludarabine and melphalan (FluMel, N = 40, 19 boys). Spontaneous puberty occurred in 56% of girls and 89% of boys after BuCy, whereas 90% of females and all males in the FluMel group entered puberty spontaneously (P = 0·012). Significantly more females (61%) conditioned with BuCy required hormone replacement compared with the FluMel group (10·5%, P = 0·012). Females in the FluMel group took significantly longer to develop elevation of serum follicle-stimulating hormone (FSH) concentrations (>10 iu/l) from the onset of puberty than females in the BuCy group (median 5·2 years vs. 2·7 years respectively, P = 0·0135). In males no difference was noted between the two conditioning groups in time to FSH elevation (median 4 years in FluMel versus 6 years in BuCy). Whilst the two regimens have similar effects on the testis, ovarian function seems to be better preserved in females undergoing SCT with RIC. © 2015 John Wiley & Sons Ltd.

Current methods of the analysis of immunosuppressive agents in clinical materials: A review.

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Mika, Adriana; Stepnowski, Piotr

2016-08-05

More than 100000 solid organ transplantations are performed every year worldwide. Calcineurin (cyclosporine A, tacrolimus), serine/threonine kinase (sirolimus, everolimus) and inosine monophosphate dehydrogenase inhibitor (mycophenolate mofetil), are the most common drugs used as immunosuppressive agents after solid organ transplantation. Immunosuppressive therapy, although necessary after transplantation, is associated with many adverse consequences, including the formation of secondary metabolites of drugs and the induction of their side effects. Calcineurin inhibitors are associated with nephrotoxicity, cardiotoxicity and neurotoxicity; moreover, they increase the risk of many diseases after transplantation. The review presents a study of the movement of drugs in the body, including the processes of absorption, distribution, localisation in tissues, biotransformation and excretion, and also their accompanying side effects. Therefore, there is a necessity to monitor immunosuppressants, especially because these drugs are characterised by narrow therapeutic ranges. Their incorrect concentrations in a patient's blood could result in transplant rejection or in the accumulation of toxic effects. Immunosuppressive pharmaceuticals are macrolide lactones, peptides, and high molecular weight molecules that can be metabolised to several metabolites. Therefore the two main analytical methods used for their determination are high performance liquid chromatography with various detection methods and immunoassay methods. Despite the rapid development of new analytical methods of analysing immunosuppressive agents, the application of the latest generation of detectors and increasing sensitivity of such methods, there is still a great demand for the development of highly selective, sensitive, specific, rapid and relatively simple methods of immunosuppressive drugs analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro pharmacokinetics of sirolimus-coated stent for tracheal stenosis

African Journals Online (AJOL)

Further increases in sirolimus: PLGA ratio did not improve stent drug loading. A slow release of ... tracheal stent can damage the airway mucosa, and cause .... Figure 3: Cumulative drug release from sirolimus-coated stents. DISCUSSION.

De novo Renal Transplantation after Kaposi Sarcoma: Favorable Outcome in a Patient Receiving Sirolimus and Mycophenolate-Based Immunosuppression

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F. Friedersdorff

2010-04-01

Full Text Available Immunosuppressive treatment increases the risk of infection and malignancy in organ transplant recipients. We report on a 42-year-old male renal transplant recipient who lost his first graft after reduction of immunosuppressive treatment due to Kaposi sarcoma and who successfully underwent a second renal transplant 10 years later. The patient’s current treatment consists of low-dose prednisone, and the two antiproliferative immunosuppressants mycophenolate mofetil and rapamycin. 4.5 years after his second transplant, the serum creatinine is 1 mg/dl and the patient has no signs of recurrent disease.

Enhanced bioavailability of sirolimus via preparation of solid dispersion nanoparticles using a supercritical antisolvent process

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Kim MS

2011-11-01

Full Text Available Min-Soo Kim1, Jeong-Soo Kim1, Hee Jun Park1, Won Kyung Cho1,3, Kwang-Ho Cha1,3, Sung-Joo Hwang2,31College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea, 2College of Pharmacy, 3Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of KoreaBackground: The aim of this study was to improve the physicochemical properties and bioavailability of poorly water-soluble sirolimus via preparation of a solid dispersion of nanoparticles using a supercritical antisolvent (SAS process.Methods: First, excipients for enhancing the stability and solubility of sirolimus were screened. Second, using the SAS process, solid dispersions of sirolimus-polyvinylpyrrolidone (PVP K30 nanoparticles were prepared with or without surfactants such as sodium lauryl sulfate (SLS, tocopheryl propylene glycol succinate, Sucroester 15, Gelucire 50/13, and Myrj 52. A mean particle size of approximately 250 nm was obtained for PVP K30-sirolimus nanoparticles. Solid state characterization, kinetic solubility, powder dissolution, stability, and pharmacokinetics were analyzed in rats.Results: X-ray diffraction, differential scanning calorimetry, and high-pressure liquid chromatography indicated that sirolimus existed in an anhydrous amorphous form within a solid dispersion of nanoparticles and that no degradation occurred after SAS processing. The improved supersaturation and dissolution of sirolimus as a solid dispersion of nanoparticles appeared to be well correlated with enhanced bioavailability of oral sirolimus in rats. With oral administration of a solid dispersion of PVP K30-SLS-sirolimus nanoparticles, the peak concentration and AUC0→12h of sirolimus were increased by approximately 18.3-fold and 15.2-fold, respectively.Conclusion: The results of this study suggest that preparation of PVP K30-sirolimus-surfactant nanoparticles using the SAS process may be a promising approach for improving the bioavailability of sirolimus

Topical sirolimus for the treatment of angiofibromas in tuberous sclerosis

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Salih Levent Cinar

2017-01-01

Full Text Available Background: The skin is one of the most affected organs in tuberous sclerosis complex and angiofibromas are seen in almost 80% of such patients. These benign tumors impose a great psycho-social burden on patients. Objective: The aim of the study was to evaluate the effectiveness and tolerability of topical sirolimus for facial angiofibromas in patients with tuberous sclerosis complex. Methods: This was a prospective, single-blinded, cross-over study which involved twelve patients. We investigated the effect and safety of topical 0.1% sirolimus, which was obtained by crushing sirolimus tablets and mixing it with petrolatum. The patients were asked to apply the cream to one side of their face, and vaseline to the other side. The effect of topical sirolimus was evaluated using the “facial angiofibroma severity index.” Results: There was a significant improvement in the redness and extension of the tumors on the sides to which the active ingredient was applied. Some side effects such as itching and irritation occurred in three patients, which were treated with topical hydrocortisone cream. Conclusion: Topical sirolimus appears to be a promising, fairly well tolerated treatment for facial angiofibromas in patients with tuberous sclerosis complex. Although its efficacy diminishes with time, repetitive usage is effective.

Kinetic study of ultrasonic antisolvent crystallization of sirolimus

Energy Technology Data Exchange (ETDEWEB)

Gandhi, P.J. [Chemical Engineering Department, S. V. National Institute of Technology, Surat 395007, Gujarat (India); Concept Medical Research Pvt. Ltd., Ground Floor, Narayan Darshan, Nr. Rupam Cinema, Salabatpura, Surat 395003, Gujarat (India); Murthy, Z.V.P.

2010-03-15

Sirolimus, generally used in organ transplantation, is derived from bacterium Streptomyces hygroscopicus. Mass transfer controlled ultrasonic antisolvent method was used for determining the precipitation kinetics of sirolimus. The effect of temperature was determined on the particles size, percentage recovery, critical radius of nucleus, mass transfer coefficient, etc. for sirolimus dissolved in methanol and antisolvent water using ultrasonic treatment. The study was done using classical nucleation theory, which can also be applied to precipitation processes. Experiments were carried out at various temperatures; viz: 45, 50, 60 and 70 C and the percentage recoveries of sirolimus were found to be 90.74, 91.5, 92.64 and 93.61%, respectively, for initial amount of 8 mg dissolved in 1 mL of solvent and further introduced into 12 mL of HPLC water. The final average diameters of crystals observed for the temperatures were 1371, 1287, 1063 and 863 nm, respectively. The systems were found to be mass transfer controlling and that the mass diffusivities were found to be about 3.97 x 10{sup -9}, 4.00 x 10{sup -9}, 3.01 x 10{sup -9} and 1.92 x 10{sup -9} m{sup 2}/s, respectively. (copyright 2010 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim) (orig.)

Optimized formulation of solid self-microemulsifying sirolimus delivery systems

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Cho W

2013-04-01

Full Text Available Wonkyung Cho,1,2 Min-Soo Kim,3 Jeong-Soo Kim,2 Junsung Park,1,2 Hee Jun Park,1,2 Kwang-Ho Cha,1,2 Jeong-Sook Park,2 Sung-Joo Hwang1,4 1Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea; 2College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 3Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of Korea; 4College of Pharmacy, Yonsei University, Incheon, Republic of Korea Background: The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results: In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocaprylate (PGMC and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of

Effect of oral sirolimus therapy on inflammatory biomarkers following coronary stenting

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W.C.M. Rosa

2010-08-01

Full Text Available We studied the effect of oral sirolimus, administered to prevent and treat in-stent restenosis (ISR, on the variation of serum levels of inflammatory markers following coronary stenting with bare metal stents. The mean age of the patients was 56 ± 13 years, 65% were males and all had clinically manifested ischemia. Serum levels of high sensitivity C-reactive protein (hs-CRP concentration were determined by chemiluminescence and serum levels of all other biomarkers by ELISA. One group of patients at high risk for ISR received a loading oral dose of 15 mg sirolimus and 5 mg daily thereafter for 28 days after stenting (SIR-G. A control group (CONT-G was submitted to stenting without sirolimus therapy. The increase in hs-CRP concentration was highest at 24 h after stenting in both groups. A significant difference between SIR-G and CONT-G was observed at 4 weeks (-1.50 ± 5.0 vs -0.19 ± 0.4, P = 0.008 and lost significance 1 month after sirolimus discontinuation (-1.73 ± 4.3 vs -0.01 ± 0.7, P = 0.0975. A continuous fall in MMP-9 concentration was observed in SIR-G, with the greatest reduction at 4 weeks (-352.9 ± 455 vs +395.2 ± 377, P = 0.0004, while a positive variation was noted 4 weeks after sirolimus discontinuation (227 ± 708 vs 406.2 ± 472.1, P = 0.0958. SIR-G exhibited a higher increase in P-selectin after sirolimus discontinuation at week 8 (46.1 ± 67.9 vs 5.8 ± 23.7, P = 0.0025. These findings suggest that the anti-restenotic actions of systemic sirolimus include anti-proliferative effects and modulation of the inflammatory response with inhibition of adhesion molecule expression.

[Sirolimus associated pneumonitis in a hematopoietic stem cell transplant patient].

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García, Estefanía; Buenasmañanas, Diana; Martín, Carmen; Rojas, Rafael

2015-07-06

Sirolimus (SR) is a lipophilic macrocytic lactone with immunosuppressive properties (mTOR inhibitor) commonly used in solid organ transplantation and recently introduced in the prophylaxis and treatment of graft-versus-host disease. Its numerous side effects include: hyperlipidemia, arthralgias, noncardiac peripheral edema, thrombotic microangiopathy and interstitial pneumonitis. SR-associated pneumonitis is a rare but potentially serious complication due to its increasing utilization in transplant patients. We report the case of a patient undergoing hematopoietic stem cell transplantation with severe respiratory distress and SR therapy. Microbiological tests were all negative and other complications related to transplantation were discarded. The chest computed tomography of high-resolution showed pneumonitis. The SR therapy was interrupted and treatment was started with steroids with resolution of symptoms. SR associated pneumonitis is a potentially fatal side effect. In patients treated with SR and respiratory failure, we must suspect this complication because early recognition along with drug discontinuation and steroid treatment is essential to reverse this complication. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Enhanced Supersaturation and Oral Absorption of Sirolimus Using an Amorphous Solid Dispersion Based on Eudragit® E

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Youngseok Cho

2015-05-01

Full Text Available The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD on the degradation of sirolimus in simulated gastric fluid (pH 1.2 and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1 solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1 solid dispersion in simulated gastric fluid (pH 1.2, owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1 solid dispersion, the sirolimus/E-SD/TPGS (1/8/1 solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC. Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.

Intravitreal Sirolimus for Noninfectious Uveitis: A Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA).

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Nguyen, Quan Dong; Merrill, Pauline T; Clark, W Lloyd; Banker, Alay S; Fardeau, Christine; Franco, Pablo; LeHoang, Phuc; Ohno, Shigeaki; Rathinam, Sivakumar R; Thurau, Stephan; Abraham, Abu; Wilson, Laura; Yang, Yang; Shams, Naveed

2016-11-01

To evaluate the efficacy and safety of intravitreal sirolimus in the treatment of noninfectious uveitis (NIU) of the posterior segment (i.e., posterior, intermediate, or panuveitis). Phase III, randomized, double-masked, active-controlled, 6-month study with intravitreal sirolimus. Adults with active NIU of the posterior segment (intermediate, posterior, or panuveitis), defined as a vitreous haze (VH) score >1+. Subjects discontinued NIU medications before baseline, except for systemic corticosteroids, which were allowed only for those already receiving them at baseline and were rapidly tapered after baseline per protocol. Intravitreal sirolimus assigned 1:1:1 at doses of 44 (active control), 440, or 880 μg, administered on Days 1, 60, and 120. The primary efficacy outcome was the percentage of subjects with VH 0 response at Month 5 (study eye) without use of rescue therapy. Secondary outcomes at Month 5 were VH 0 or 0.5+ response rate, corticosteroid tapering success rate (i.e., tapering to a prednisone-equivalent dosage of ≤5 mg/day), and changes in best-corrected visual acuity (BCVA). Adverse events during the double-masked treatment period are presented. A total of 347 subjects were randomized. Higher proportions of subjects in the intravitreal sirolimus 440 μg (22.8%; P = 0.025) and 880 μg (16.4%; P = 0.182) groups met the primary end point than in the 44 μg group (10.3%). Likewise, higher proportions of subjects in the 440 μg (52.6%; P = 0.008) and 880 μg (43.1%; P = 0.228) groups achieved a VH score of 0 or 0.5+ than in the 44 μg group (35.0%). Mean BCVA was maintained throughout the study in each dose group, and the majority of subjects receiving corticosteroids at baseline successfully tapered off corticosteroids (44 μg [63.6%], 440 μg [76.9%], and 880 μg [66.7%]). Adverse events in the treatment and active control groups were similar in incidence, and all doses were well tolerated. Intravitreal sirolimus 440 μg demonstrated a significant

Sirolimus-eluting versus bare-metal stent implantation in patients with ostial lesions

DEFF Research Database (Denmark)

Jørgensen, Erik; Kelbæk, Henning; Kløvgaard, Lene

2010-01-01

To investigate the efficacy of implantation of sirolimus-eluting stents (SES) in the ostium of coronary arteries.......To investigate the efficacy of implantation of sirolimus-eluting stents (SES) in the ostium of coronary arteries....

A Novel Quantitative Computed Tomographic Analysis Suggests How Sirolimus Stabilizes Progressive Air Trapping in Lymphangioleiomyomatosis.

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Argula, Rahul G; Kokosi, Maria; Lo, Pechin; Kim, Hyun J; Ravenel, James G; Meyer, Cristopher; Goldin, Jonathan; Lee, Hye-Seung; Strange, Charlie; McCormack, Francis X

2016-03-01

The Multicenter International Lymphangioleiomyomatosis Efficacy and Safety of Sirolimus (MILES) trial demonstrated that sirolimus stabilized lung function and improved measures of functional performance and quality of life in patients with lymphangioleiomyomatosis. The physiologic mechanisms of these beneficial actions of sirolimus are incompletely understood. To prospectively determine the longitudinal computed tomographic lung imaging correlates of lung function change in MILES patients treated with placebo or sirolimus. We determined the baseline to 12-month change in computed tomographic image-derived lung volumes and the volume of the lung occupied by cysts in the 31 MILES participants (17 in sirolimus group, 14 in placebo group) with baseline and 12-month scans. There was a trend toward an increase in median expiratory cyst volume percentage in the placebo group and a reduction in the sirolimus group (+2.68% vs. +0.97%, respectively; P = 0.10). The computed tomographic image-derived residual volume and the ratio of residual volume to total lung capacity increased more in the placebo group than in the sirolimus group (+214.4 ml vs. +2.9 ml [P = 0.054] and +0.05 ml vs. -0.01 ml [P = 0.0498], respectively). A Markov transition chain analysis of respiratory cycle cyst volume changes revealed greater dynamic variation in the sirolimus group than in the placebo group at the 12-month time point. Collectively, these data suggest that sirolimus attenuates progressive gas trapping in lymphangioleiomyomatosis, consistent with a beneficial effect of the drug on airflow obstruction. We speculate that a reduction in lymphangioleiomyomatosis cell burden around small airways and cyst walls alleviates progressive airflow limitation and facilitates cyst emptying.

Renal Transplant Recipients: The Factors Related to Immunosuppressive Medication Adherence Based on the Health Belief Model.

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Kung, Pen-Chen; Yeh, Mei Chang; Lai, Ming-Kuen; Liu, Hsueh-Erh

2017-10-01

Kidney transplant failures are caused primarily by lack of adherence to immunosuppressive medication regimens by patients after transplantation. A number of studies have indicated that health-related beliefs are an effective predictor of health-related behavior. The aim of this study is to understand the influence of the personal characteristics and health-related beliefs of patients on adherence to treatment with immunosuppressive medication based on the Health Belief Model. This cross-sectional study distributed questionnaires to patients who had been recruited via purposive sampling at one medical center in Taipei. All of the potential participants had undergone kidney transplantation at least 6 months previously. The self-developed questionnaire collected data in three areas: personal characteristics, health-related beliefs regarding transplant rejection, and adherence to the immunosuppressive medication regimen. One hundred twenty-two valid questionnaires were received. The collected data were analyzed using descriptive statistics, independent t test, one-way analysis of variance, Pearson's correlation, and multiple regression. Participants who had received dialysis treatment or had experienced rejection perceived susceptibility to rejection more strongly than those who had not. Participants who had undergone transplantation in Taiwan, had experienced more drug-related symptoms, or had contracted severe to extremely severe infections in the past showed lower rates of adherence to treatment with immunosuppressive medication. Adherence to medication regimens correlated negatively with length of time since transplantation. Length of time since transplantation, drug-related symptoms, perceived susceptibility to rejection, and perceived benefits of treatment were identified as major predictors of adherence to immunosuppressive medication regimens. The results partially conformed to the concepts of the Health Belief Model. Perceived susceptibility to rejection and

The effect of local sustained delivery of sirolimus on the vascular PAI-1 and t-PA expression after angioplasty

International Nuclear Information System (INIS)

E Yajun; He Nengshu; Fan Hailun

2011-01-01

Objective: To investigate the effect of local sustained delivery of sirolimus on the vascular inhibitor of plasminogen activator-1 (PAI-1) and tissue type plasminogen activator (t-PA) expression after angioplasty. Methods: Experimental common carotid artery injury model was established in the rats. A total of 30 male Wistar rats were divided into experimental group (n=20) and control group (n=10). Adventitial administration of drug was applied. Pluronic F-127 gel containing sirolimus was administered to the exposed adventitial surface of injured carotid artery. The experimental group was divided into high concentration (600 μg/100 μl) sub-group and low concentration (300 μg/100μl) sub-group according to the concentration of sirolimus delivered. The effect of local sustained delivery sirolimus on vascular PAI-1 and t-PA expression after percutaneous angioplasty was evaluated by immunohistochemistry. Results: Compared to control group, 15 and 30 days after injury local sustained delivery of sirolimus in both high concentration and low concentration sub-groups the expression of the PAI-1 in neointima was significantly enhanced (P 0.05). At 15 and 30 days after injury, the expression of t-PA in neointima was decreased in both high and low concentration sub-groups (P<0.05), and the expression of t-PA in media was significantly decreased in high concentration sub-group (P<0.05) while on significant difference could be detected in low concentration sub-group. Conclusion: Local sustained delivery of sirolimus can induce the high expression of PAI-1 and low expression of t-PA in neointima although it inhibits the proliferation of neointima in the same time, and the imbalanced expression of t-PA and PAI-1 may probably play an important role in the late formation of thrombosis after the placement of drug-eluting stent. (authors)

Steady-state pharmacokinetics of sirolimus in stable adult Chinese renal transplant patients.

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Wang, Huifen Faye; Qiu, Feng; Wu, Xiongfe; Fang, Juanzhi; Crownover, Penelope; Korth-Bradley, Joan; Schulman, Seth

2014-05-01

This open-label, nonrandomized study was conducted to evaluate the steady-state pharmacokinetics of sirolimus in 24 stable Chinese renal transplant patients receiving daily oral maintenance doses of sirolimus (1-4 mg). Repeated trough and serial whole blood sirolimus concentrations over a 24-hour dosing interval were collected and assayed using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Non-compartmental analysis (NCA) was employed to calculate sirolimus pharmacokinetic parameters. Cytochrome P450 (CYP) 3A5 genotyping was performed. Cyclosporine (CsA) levels were determined for patients who took concomitant CsA. Mean (±SD) sirolimus maximum concentration (Cmax ), area under the concentration-time curve within a dosing interval of τ (AUCτ ), oral clearance (CL/F), and trough concentration (Ctrough ) at steady state were: 14.1 ± 13.4 ng/mL, 199 ± 210 ng · h/mL, 10.1 ± 4.4 L/h, and 5.9 ± 6.3 ng/mL, respectively. Median tmax (range) was 2.49 hours (1-12 hours). A strong correlation was observed between Ctrough and AUCτ . Pharmacokinetics of sirolimus in patients with and without concomitant CsA were comparable. Allele frequency of CYP3A5*3 was 70.9% and a trend of higher oral clearance was observed in CYP3A5 expressers compared with non-expressers although the number of subjects in each genotype was small. © 2014, The American College of Clinical Pharmacology.

A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial

NARCIS (Netherlands)

de Winter, Robbert J.; Katagiri, Yuki; Asano, Taku; Milewski, Krzysztof P.; Lurz, Philipp; Buszman, Pawel; Jessurun, Gillian A. J.; Koch, Karel T.; Troquay, Roland P. T.; Hamer, Bas J. B.; Ophuis, Ton Oude; Wöhrle, Jochen; Wyderka, Rafał; Cayla, Guillaume; Hofma, Sjoerd H.; Levesque, Sébastien; Żurakowski, Aleksander; Fischer, Dieter; Kośmider, Maciej; Goube, Pascal; Arkenbout, E. Karin; Noutsias, Michel; Ferrari, Markus W.; Onuma, Yoshinobu; Wijns, William; Serruys, Patrick W.

2018-01-01

Background MiStent is a drug-eluting stent with a fully absorbable polymer coating containing and embedding a microcrystalline form of sirolimus into the vessel wall. It was developed to overcome the limitation of current durable polymer drug-eluting stents eluting amorphous sirolimus. The clinical

Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration

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Soo-Yon Rhee

2017-04-01

Full Text Available Tenofovir disoproxil fumarate (TDF genotypic resistance defined by K65R/N and/or K70E/Q/G occurs in 20% to 60% of individuals with virological failure (VF on a WHO-recommended TDF-containing first-line regimen. However, the full spectrum of reverse transcriptase (RT mutations selected in individuals with VF on such a regimen is not known. To identify TDF regimen-associated mutations (TRAMs, we compared the proportion of each RT mutation in 2873 individuals with VF on a WHO-recommended first-line TDF-containing regimen to its proportion in a cohort of 50,803 antiretroviral-naïve individuals. To identify TRAMs specifically associated with TDF-selection pressure, we compared the proportion of each TRAM to its proportion in a cohort of 5805 individuals with VF on a first-line thymidine analog-containing regimen. We identified 83 TRAMs including 33 NRTI-associated, 40 NNRTI-associated, and 10 uncommon mutations of uncertain provenance. Of the 33 NRTI-associated TRAMs, 12 – A62V, K65R/N, S68G/N/D, K70E/Q/T, L74I, V75L, and Y115F – were more common among individuals receiving a first-line TDF-containing compared to a first-line thymidine analog-containing regimen. These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen.

Validity and reliability of a novel immunosuppressive adverse effects scoring system in renal transplant recipients.

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Meaney, Calvin J; Arabi, Ziad; Venuto, Rocco C; Consiglio, Joseph D; Wilding, Gregory E; Tornatore, Kathleen M

2014-06-12

After renal transplantation, many patients experience adverse effects from maintenance immunosuppressive drugs. When these adverse effects occur, patient adherence with immunosuppression may be reduced and impact allograft survival. If these adverse effects could be prospectively monitored in an objective manner and possibly prevented, adherence to immunosuppressive regimens could be optimized and allograft survival improved. Prospective, standardized clinical approaches to assess immunosuppressive adverse effects by health care providers are limited. Therefore, we developed and evaluated the application, reliability and validity of a novel adverse effects scoring system in renal transplant recipients receiving calcineurin inhibitor (cyclosporine or tacrolimus) and mycophenolic acid based immunosuppressive therapy. The scoring system included 18 non-renal adverse effects organized into gastrointestinal, central nervous system and aesthetic domains developed by a multidisciplinary physician group. Nephrologists employed this standardized adverse effect evaluation in stable renal transplant patients using physical exam, review of systems, recent laboratory results, and medication adherence assessment during a clinic visit. Stable renal transplant recipients in two clinical studies were evaluated and received immunosuppressive regimens comprised of either cyclosporine or tacrolimus with mycophenolic acid. Face, content, and construct validity were assessed to document these adverse effect evaluations. Inter-rater reliability was determined using the Kappa statistic and intra-class correlation. A total of 58 renal transplant recipients were assessed using the adverse effects scoring system confirming face validity. Nephrologists (subject matter experts) rated the 18 adverse effects as: 3.1 ± 0.75 out of 4 (maximum) regarding clinical importance to verify content validity. The adverse effects scoring system distinguished 1.75-fold increased gastrointestinal adverse

Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

Science.gov (United States)

Solymosi, Tamás; Angi, Réka; Basa-Dénes, Orsolya; Ránky, Soma; Ötvös, Zsolt; Glavinas, Hristos; Filipcsei, Genovéva; Heltovics, Gábor

2015-08-01

The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients.

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Shah, M; Shankar, A; Gee, I; Nash, K; Hoare, M; Gibbs, P; Davies, S; Alexander, G J M

2015-02-01

The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus. To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis. A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%). Patients switched to sirolimus had improved survival (P diabetes (P = 0.03). These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome. © 2014 John Wiley & Sons Ltd.

Simultaneous Determination of Cyclosporine A, Tacrolimus, Sirolimus, and Everolimus in Whole-Blood Samples by LC-MS/MS

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Mustafa Karapirli

2012-01-01

Full Text Available Objectives. Cyclosporine A (CyA, tacrolimus (TRL, sirolimus (SIR, and everolimus (RAD are immunosuppressive drugs frequently used in organ transplantation. Our aim was to confirm a robust sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS method for determination of CyA, TRL, SIR, and RAD in whole-blood samples. Materials and Methods. We used an integrated online solid-phase extraction-LC-MS/MS system and atmospheric pressure ionization tandem mass spectrometry (API-MS/MS in the multiple reaction monitoring (MRM detection mode. CyA, TRL, SIR, and RAD were simultaneously analyzed in whole blood treated with precipitation reagent taken from transplant patients. Results. System performance parameters were suitable for using this method as a high-throughput technique in clinical practice. The high concentration of one analyte in the sample did not affect the concentration of other analytes. Total analytical time was 2.5 min, and retention times of all analytes were shorter than 2 minutes. Conclusion. This LC-MS/MS method can be preferable for therapeutic drug monitoring of these immunosuppressive drugs (CyA, TRL, SRL, and RAD in whole blood. Sample preparation was too short and simple in this method, and it permits robust, rapid, sensitive, selective, and simultaneous determination of these drugs.

Comparable Renal Function at 6 Months with Tacrolimus Combined with Fixed-Dose Sirolimus or MMF: Results of a Randomized Multicenter Trial in Renal Transplantation

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Eveline Van Gurp

2010-01-01

Full Text Available In a multicenter trial, renal transplant recipients were randomized to tacrolimus with fixed-dose sirolimus (Tac/SRL, N = 318 or tacrolimus with MMF (Tac/MMF, N = 316. Targeted tacrolimus trough levels were lower in the Tac/SRL group after day 14. The primary endpoint was renal function at 6 months using creatinine clearance (Cockcroft-Gault and was comparable at 66.4 mL/min (SE 1.4 with Tac/SRL and at 65.2mL/min (SE 1.3 with Tac/MMF (completers. Biopsy-confirmed acute rejection was 15.1% (Tac/SRL and 12.3% (Tac/MMF. In both groups, graft survival was 93% and patient survival was 99.0%. Premature withdrawal due to an adverse event was twice as high in the Tac/SRL group, 15.1% versus 6.3%. Hypercholesterolemia incidence was higher with Tac/SRL (P30 consecutive days in previously nondiabetic patients was 17.8%, Tac/SRL, and 24.8%, Tac/MMF. Evaluation at 6 months showed comparable renal function using tacrolimus/sirolimus and tacrolimus/MMF regimens.

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

Science.gov (United States)

Collins, Peter; Baudo, Francesco; Knoebl, Paul; Lévesque, Hervé; Nemes, László; Pellegrini, Fabio; Marco, Pascual; Tengborn, Lilian; Huth-Kühne, Angela

2012-07-05

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Thymoglobulin induction in liver transplant recipients with a tacrolimus, mycophenolate mofetil, and steroid immunosuppressive regimen: a five-year randomized prospective study.

Science.gov (United States)

Boillot, Olivier; Seket, Belhassen; Dumortier, Jérôme; Pittau, Gabriella; Boucaud, Catherine; Bouffard, Yves; Scoazec, Jean-Yves

2009-11-01

This randomized, comparative study assessed the long-term efficacy and tolerability of thymoglobulin (TMG) induction in 93 liver transplant patients with an initial regimen of tacrolimus (Tac), mycophenolate mofetil (MMF), and steroids. Forty-four patients were randomly allocated to the TMG+ group, and 49 patients were randomly allocated to the TMG- group. In both groups, Tac was given orally at the initial daily dose of 0.075 mg/kg twice daily, and MMF was given at the initial daily dose of 2 g/day. Steroid withdrawal was planned at 3 months after liver transplantation. The results were evaluated with respect to acute rejection incidence, patient and graft survival, graft function, and medical complications until 5 years or death for all patients. No significant differences were found between groups for the incidence of acute rejection at 5 years (11.4% versus 14.3%), 5-year patient survival (77.3% versus 87.8%), graft function, or postoperative renal function. One patient in the TMG- group underwent retransplantation. There was no difference between groups with respect to the incidence of medical complications, excepted for a higher rate of leukopenia in the TMG+ group, during the 5-year follow-up. In conclusion, the results of this prospective randomized study suggest that the addition of TMG to a triple immunosuppressive regimen (Tac, MMF, and steroids) did not modify the incidence of acute rejection episodes or long-term survival and was responsible for increased leukopenia rates.

Randomized controlled study of a novel triple nitazoxanide (NTZ)-containing therapeutic regimen versus the traditional regimen for eradication of Helicobacter pylori infection.

Science.gov (United States)

Shehata, Mona Ah; Talaat, Raghda; Soliman, Samah; Elmesseri, Huda; Soliman, Shaimaa; Abd-Elsalam, Sherief

2017-10-01

Helicobacter pylori infection has become more and more resistant to conventional first-line treatment regimens. So, there is a considerable interest in evaluating new antibiotic combinations and regimens. Nitazoxanide is an anti-infective drug with demonstrated activity against protozoa and anaerobic bacteria including H. pylori. This work is designed to evaluate the efficacy and safety of a unique triple nitazoxanide-containing regimen as a treatment regimen in Egyptian patients with H. pylori infection. Two hundred and 24 patients with upper gastrointestinal tract (GIT) dyspeptic symptoms in whom H. pylori -induced GIT disease was confirmed were included in the study. They have been randomized to receive either nitazoxanide 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40 mg twice daily for 14 days or metronidazole 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40  mg twice daily for 14 days. Laboratory evaluation for H. pylori antigen within the stool was performed 6 weeks after cessation of H. pylori treatment regimens to assess the response. The response to treatment was significantly higher in group 1 of nitazoxanide treatment regimen than group 2 of traditional treatment regimen. One hundred and six cases (94.6%) of 112 patients who completed the study in group 1 showed complete cure, while only 63 cases (60.6%) of 104 patients who completed the study in group 2 showed the same response according to per-protocol (PP) analysis (Ppylori. (ClinicalTrials.gov Identifier: NCT02422706). © 2017 John Wiley & Sons Ltd.

Immunosuppression for in vivo research: state-of-the-art protocols and experimental approaches

Institute of Scientific and Technical Information of China (English)

Rita Diehl; Fabienne Ferrara; Claudia Müller; Antje Y Dreyer; Damian D McLeod; Stephan Fricke; Johannes Boltze

2017-01-01

Almost every experimental treatment strategy using non-autologous cell,tissue or organ transplantation is tested in small and large animal models before clinical translation.Because these strategies require immunosuppression in most cases,immunosuppressive protocols are a key element in transplantation experiments.However,standard immunosuppressive protocols are often applied without detailed knowledge regarding their efficacy within the particular experimental setting and in the chosen model species.Optimization of such protocols is pertinent to the translation of experimental results to human patients and thus warrants further investigation.This review summarizes current knowledge regarding immunosuppressive drug classes as well as their dosages and application regimens with consideration of species-specific drug metabolization and side effects.It also summarizes contemporary knowledge of novel immunomodulatory strategies,such as the use of mesenchymal stem cells or antibodies.Thus,this review is intended to serve as a state-of-the-art compendium for researchers to refine applied experimental immunosuppression and immunomodulation strategies to enhance the predictive value of preclinical transplantation studies.

Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial.

Science.gov (United States)

Guba, Markus; Pratschke, Johann; Hugo, Christian; Krämer, Bernhard K; Nohr-Westphal, Constanze; Brockmann, Jens; Andrassy, Joachim; Reinke, Petra; Pressmar, Katharina; Hakenberg, Oliver; Fischereder, Michael; Pascher, Andreas; Illner, Wolf-Dieter; Banas, Bernhard; Jauch, Karl-Walter

2010-07-27

De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects. We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids. The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51+/-0.59 vs. 1.87+/-0.98 mg/dL or 64.5+/-25.2 vs. 53.4+/-18.0 mL/min/1.73 m). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%). Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

Science.gov (United States)

Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Long-Term Impact of Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral Nephrectomized Rats: A Comparative Study

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Yehui Chen

2013-01-01

Full Text Available Cyclosporine, tacrolimus, and sirolimus are commonly used in renal transplant recipients to prevent rejection. However, information for comparative effects of these agents on the male productive system is extremely limited and controversial. In a physiologically and clinically relevant rat model of unilateral nephrectomy, we demonstrated that long-term oral administration of both cyclosporine and sirolimus at doses equivalent to the therapeutic levels used for postrenal transplant patients significantly affects testicular development and the hypothalamic-pituitary-gonadal axis accompanied by profound histological changes of testicular structures on both light and electron microscopic examinations. Spermatogenesis was also severely impaired as indicated by low total sperm counts along with reduction of sperm motility and increase in sperm abnormality after treatment with these agents, which may lead to male infertility. On the other hand, treatment with therapeutic dose of tacrolimus only induced mild reduction of sperm count without histological evidence of testicular injury. The current study clearly demonstrates that commonly used immunosuppressants have various impacts on male reproductive system even at therapeutic levels. Our data provide useful information for the assessment of male infertility in renal transplant recipients who wish to father children. Clinical trials to address these issues should be urged.

Zotarolimus-eluting vs. sirolimus-eluting coronary stents in patients with and without acute coronary syndromes

DEFF Research Database (Denmark)

Thim, Troels; Maeng, Michael; Kaltoft, Anne Kjer

2012-01-01

To compare clinical outcomes among patients with acute coronary syndrome treated with zotarolimus-eluting and sirolimus-eluting stents in the SORT OUT III trial.......To compare clinical outcomes among patients with acute coronary syndrome treated with zotarolimus-eluting and sirolimus-eluting stents in the SORT OUT III trial....

What is the impact of immunosuppressive treatment on the post-transplant renal osteopathy?

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Blaslov, Kristina; Katalinic, Lea; Kes, Petar; Spasovski, Goce; Smalcelj, Ruzica; Basic-Jukic, Nikolina

2014-05-01

Although glucocorticoid therapy is considered to be the main pathogenic factor, a consistent body of evidence suggests that other immunosuppressants might also play an important role in the development of the post-transplant renal osteopathy (PRO) through their pleiotropic pharmacological effects. Glucocorticoids seem to induce osteoclasts' activity suppressing the osteoblasts while data regarding other immunosuppressive drugs are still controversial. Mycophenolate mofetil and azathioprine appear to be neutral regarding the bone metabolism. However, the study analyzing any independent effect of antimetabolites on bone turnover has not been conducted yet. Calcineurin inhibitors (CNIs) induce trabecular bone loss in rodent, with contradictory results in renal transplant recipients. Suppression of vitamin D receptor is probably the underlying mechanism of renal calcium wasting in renal transplant recipients receiving CNI. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss. More efforts should be invested to determine the role of CNI in PRO. In particular, data regarding the role of mammalian target of rapamycin inhibitors (mTORi), such as sirolimus and everolimus, in the PRO development are still controversial. Rapamycin markedly decreases bone longitudinal growth as well as callus formation in experimental models, but also lowers the rate of bone resorption markers and glomerular filtration in clinical studies. Everolimus potently inhibits primary mouse and human osteoclast activity as well as the osteoclast differentiation. It also prevents the ovariectomy-induced loss of cancellous bone by 60 %, an effect predominantly associated with a decreased osteoclast-mediated bone resorption, resulting in a partial preservation of the cancellous bone. At present, there is no clinical study analyzing the effect of everolimus on bone turnover in renal

Why do Patients Forget to Take Immunosuppression Medications and Miss Appointments: Can a Mobile Phone App Help?

OpenAIRE

Israni, Ajay; Dean, Carl; Kasel, Brian; Berndt, Lisa; Wildebush, Winston; Wang, C Jason

2016-01-01

Background Kidney transplant recipients must adhere to their immunosuppressive medication regimen. However, non-adherence remains a major problem. Objective The aim of this paper is to determine how kidney transplant recipients remember to take their medications, and assess their perception and beliefs about adherence to immunosuppressive medications and barriers to medication adherence. In addition, we aim to assess perception and beliefs about willingness to use a hypothetical, mobile phone...

Quantitative determination of sirolimus in dog blood using liquid chromatography-tandem mass spectrometry, and its applications to pharmacokinetic studies.

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Lee, Jong-Hwa; Cha, Kwang-Ho; Cho, Wonkyung; Park, Junsung; Park, Hee Jun; Cho, Youngseok; Hwang, Sung-Joo

2010-12-01

A rapid, sensitive method of detecting sirolimus in blood was developed and applied in pharmacokinetic studies employing deionized water for hemolysis and a weakly basic mobile phase to enhance chromatographic peak intensity. Dog blood samples were processed via liquid-liquid extraction and the amounts of sirolimus and tacrolimus, an internal standard, were quantified by LC-MS/MS. Specificity, the lower limit of quantification, linearity, accuracy, precision, dilution, recovery, matrix effects, robustness and stability were within the acceptable range for assay validation. The concentration of sirolimus was quantifiable in blood samples for up to 36 h after the dog had received a 3 mg/kg dose of sirolimus. These observations suggest that sirolimus can be detected at low levels in dog blood using a basic mobile phase and metal-free hemolysis. This method is therefore applicable to pharmacokinetic studies in dogs. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

Directory of Open Access Journals (Sweden)

Catherine Weber

2012-01-01

Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Short and long term in vivo effects of Cyclosporine A and Sirolimus on genes and proteins involved in lipid metabolism in Wistar rats.

Science.gov (United States)

Lopes, Patrícia C; Fuhrmann, Amelia; Sereno, José; Espinoza, Daniel O; Pereira, Maria João; Eriksson, Jan W; Reis, Flávio; Carvalho, Eugenia

2014-05-01

Cyclosporine A (CsA) and sirolimus (SRL) are immunosuppressive agents (IA) associated with new onset diabetes after transplantation and dyslipidemia. We aim to evaluate the molecular effects of CsA (5mg/kg/day) and SRL (1mg/kg/day) treatment for 3 and 9weeks on lipid metabolism, in Wistar rats. Lipolysis was evaluated in isolated adipocytes, while triglycerides (TG) and non-esterified fatty acid (NEFA) were measured in serum. Gene and protein expression involved in lipid metabolism was assessed in adipose tissue and liver. CsA and SRL treatments of rats for 3 and 9weeks increased isoproterenol-stimulated lipolysis by 5-9 fold and 4-6 fold in isolated adipocytes, respectively. While CsA increased adipocyte weight and diameter, as well as NEFA and TG levels in circulation after 9weeks, SRL treatment caused ectopic deposition of TG in the liver after 3weeks. Moreover, ACC1 and FAS protein expression was increased after 3weeks (>100%, p42%, pIAs on expression of lipolytic and lipogenic genes suggest that these agents influence lipid metabolism, thus contributing to the dyslipidemia observed during immunosuppressive therapy. Copyright © 2014 Elsevier Inc. All rights reserved.

Efficiency of sirolimus in prevention of adhesions around vascular

African Journals Online (AJOL)

muhip kanko

Conclusions: Therefore, sirolimus applied around the prosthesis in vascular operations, was determined ... The total score was calculated for each of the test subjects in the statistical assessment. .... occlusion following aortofemoral bypass for.

Sirolimus influence on hepatectomy-induced liver regeneration in rats

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Edimar Leandro Toderke

Full Text Available OBJECTIVE: To evaluate the influence of sirolimus on liver regeneration triggered by resection of 70% of the liver of adult rats. METHODS: we used 40 Wistar rats randomly divided into two groups (study and control, each group was divided into two equal subgroups according to the day of death (24 hours and seven days. Sirolimus was administered at a dose of 1mg/kg in the study group and the control group was given 1 ml of saline. The solutions were administered daily since three days before hepatectomy till the rats death to removal of the regenerated liver, conducted in 24 hours or 7 days after hepatectomy. Liver regeneration was measured by the KWON formula, by thenumber of mitotic figures (hematoxylin-eosin staining and by the immunohistochemical markers PCNA and Ki-67. RESULTS: there was a statistically significant difference between the 24h and the 7d groups. When comparing the study and control groups in the same period, there was a statistically significant variation only for Ki-67, in which there were increased numbers of hepatocytes in cell multiplication in the 7d study group compared with the 7d control group (p = 0.04. CONCLUSION: there was no negative influence of sirolimus in liver regeneration and there was a positive partial effect at immunohistochemistry with Ki-67.

Pulmonary lymphangioleiomyomatosis presenting as spontaneous pneumothorax treated with sirolimus - A case report

Science.gov (United States)

Verma, Ajay Kumar; Joshi, Ambarish; Mishra, Amritesh Ranjan; Kant, Surya; Singh, Arpita

2018-01-01

Spontaneous pneumothorax is a very common medical emergency. Patients are often treated without treating the underlying cause. Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease. Until recently, diagnosis of LAM was a challenge with nearly 100% mortality in 10 years, but better understanding of the disease through research and better radiological techniques and newer drugs such as sirolimus has improved the survival in such patients. We are presenting a rare case of LAM presenting as a secondary spontaneous pneumothorax treated with sirolimus. PMID:29487252

Comparison of the immunosuppressive effect of fractionated total lymphoid irradiation (TLI) vs conventional immunosuppression (CI) in renal cadaveric allotransplantation

International Nuclear Information System (INIS)

Waer, M.; Vanrenterghem, Y.; Ang, K.K.; van der Schueren, E.; Michielsen, P.; Vandeputte, M.

1984-01-01

Beginning in November 1981, eight patients with end stage diabetic nephropathy underwent renal cadaveric transplantation after TLI. Transplantation was done between 2 to 11 days after the end of a fractionated TLI to a total dose of 20 to 30 Gy. During the same observation period, 60 nondiabetic patients with end stage renal disease of different origin also received a cadaveric kidney graft, with a conventional regimen of immunosuppression that consists of anti-lymphocyte-globulin, tapering high doses of prednisone, and azathioprine. Phytohemagglutinin (PHA)-, concanavalin A (con A)-, and pokeweed mitogen (PWM)-induced blastogenesis, as well as the mixed lymphocyte reaction (MLR) and the cell-mediated lympholysis (CML) decreased progressively during the first months after conventional immunosuppression to 50% of the pretransplantation level, and remained there for the first year after transplantation. These tests were much more impaired after TLI and again no recovery occurred during the first year. In the clinic, the more profound immunosuppression in TLI patients was more frequently associated with viral infections (cytomegalovirus and herpes zoster). The incidence of rejections, however, was somewhat less frequent in the TLI-treated group and occurred significantly later. After TLI, the mean cumulative dose of steroids needed for kidney transplantation during the first year after transplantation could be substantially reduced

Everolimus and sirolimus in combination with cyclosporine have different effects on renal metabolism in the rat.

Directory of Open Access Journals (Sweden)

Rahul Bohra

Full Text Available Enhancement of calcineurin inhibitor nephrotoxicity by sirolimus (SRL is limiting the clinical use of this drug combination. We compared the dose-dependent effects of the structurally related everolimus (EVL and sirolimus (SRL alone, and in combination with cyclosporine (CsA, on the rat kidney. Lewis rats were treated by oral gavage for 28 days using a checkerboard dosing format (0, 3.0, 6.0 and 10.0 CsA and 0, 0.5, 1.5 and 3.0 mg/kg/day SRL or EVL, n = 4/dose combination. After 28 days, oxidative stress, energy charge, kidney histologies, glomerular filtration rates, and concentrations of the immunosuppressants were measured along with (1H-magnetic resonance spectroscopy (MRS and gas chromatography- mass spectrometry profiles of cellular metabolites in urine. The combination of CsA with SRL led to higher urinary glucose concentrations and decreased levels of urinary Krebs cycle metabolites when compared to controls, suggesting that CsA+SRL negatively impacted proximal tubule metabolism. Unsupervised principal component analysis of MRS spectra distinguished unique urine metabolite patterns of rats treated with CsA+SRL from those treated with CsA+EVL and the controls. SRL, but not EVL blood concentrations were inversely correlated with urine Krebs cycle metabolite concentrations. Interestingly, the higher the EVL concentration, the closer urine metabolite patterns resembled those of controls, while in contrast, the combination of the highest doses of CsA+SRL showed the most significant differences in metabolite patterns. Surprisingly in this rat model, EVL and SRL in combination with CsA had different effects on kidney biochemistry, suggesting that further exploration of EVL in combination with low dose calcineurin inhibitors may be of potential benefit.

Tuberous Sclerosis Complex in 29 Children: Clinical and Genetic Analysis and Facial Angiofibroma Responses to Topical Sirolimus.

Science.gov (United States)

Wang, Senfen; Liu, Yuanxiang; Wei, Jinghai; Zhang, Jian; Wang, Zhaoyang; Xu, Zigang

2017-09-01

Tuberous sclerosis complex (TSC) is a genetic disorder and facial angiofibromas are disfiguring facial lesions. The aim of this study was to analyze the clinical and genetic features of TSC and to assess the treatment of facial angiofibromas using topical sirolimus in Chinese children. Information was collected on 29 patients with TSC. Genetic analyses were performed in 12 children and their parents. Children were treated with 0.1% sirolimus ointment for 36 weeks. Clinical efficacy and plasma sirolimus concentrations were evaluated at baseline and 12, 24, and 36 weeks. Twenty-seven (93%) of the 29 patients had hypomelanotic macules and 15 (52%) had shagreen patch; 11 of the 12 (92%) who underwent genetic analysis had gene mutations in the TSC1 or TSC2 gene. Twenty-four children completed 36 weeks of treatment with topical sirolimus; facial angiofibromas were clinically undetectable in four (17%). The mean decrease in the Facial Angiofibroma Severity Index (FASI) score at 36 weeks was 47.6 ± 30.4%. There was no significant difference in the FASI score between weeks 24 and 36 (F = 1.00, p = 0.33). There was no detectable systemic absorption of sirolimus. Hypomelanotic macules are often the first sign of TSC. Genetic testing has a high detection rate in patients with a clinical diagnosis of TSC. Topical sirolimus appears to be both effective and well-tolerated as a treatment of facial angiofibromas in children with TSC. The response typically plateaus after 12 to 24 weeks of treatment. © 2017 Wiley Periodicals, Inc.

Exploring risk factors of non-adherence to immunosuppressive medication in kidney transplant recipients : improving methodology & reorienting research goals

OpenAIRE

Denhaerynck, Kris

2006-01-01

8.1. Background and aim of the research program Non-adherence to the immunosuppressive therapy is an important issue in kidney transplant patients. About 20% of the kidney transplant patients are non-adherent to the immunosuppressive regimen. Non-adherence contributes to 20% of late acute rejection episodes and 16% of the graft losses, and results in a decreased number of quality adjusted life years. A strategy to increase long-term successful outcome after transplantation i...

Effects of physiotherapy combined with sirolimus in a patient with vascular malformation: A case report.

Science.gov (United States)

Akbayrak, Türkan; Orhan, Ceren; Baran, Emine; Kaya, Serap; Coskun, Gürsoy; Varan, Ali

2016-01-01

The aim of the present case report was to investigate the effects of a physiotherapy program combined with sirolimus in a child patient with upper extremity edema and joint limitation due to low-flow vascular malformation. This case report included an 11-year-old male patient (26 kg, 130 cm) diagnosed with congenital lymphovascular malformation on the left and right chest. The patient, who had edema on the upper left extremity and experienced joint limitations, was administered complete decongestive therapy (CDT) and manual therapy in combination with sirolimus. Physiotherapy included a total of 24 sessions, 3 sessions a week for 8 weeks. Following the physiotherapy, the patient was assigned to a home therapy program, and then the maintenance phase of the CDT was initiated. Evaluations were carried out at baseline, at the end of week 8, and after 12 months. Following the physiotherapy program combined with sirolimus, a decrease in extremity volume, an increase in joint movement range, and an improvement in disease-related complaints were observed. Physiotherapy methods combined with sirolimus may be an effective treatment method in patients with vascular malformations. However, further studies with larger sample size are warranted.

Impact of body weight on virological and immunological responses to efavirenz-containing regimens in HIV-infected, treatment-naive adults

DEFF Research Database (Denmark)

Marzolini, Catia; Sabin, Caroline; Raffi, François

2015-01-01

OBJECTIVE: The prevalence of overweight and obesity is increasing among HIV-infected patients. Whether standard antiretroviral drug dosage is adequate in heavy individuals remains unresolved. We assessed the virological and immunological responses to initial efavirenz (EFV)-containing regimens...... individuals had significantly higher CD4 cell count at baseline, CD4 cell recovery at 6 and 12 months after EFV initiation was comparable to normal-weight individuals. CONCLUSION: Virological and immunological responses to initial EFV-containing regimens were not impaired in heavy individuals, suggesting...

Sirolimus as an alternative to anticalcineurin therapy in heart transplantation: experience of a single center.

Science.gov (United States)

Fernandez-Valls, M; Gonzalez-Vilchez, F; de Prada, J A Vazquez; Ruano, J; Ruisanchez, C; Martin-Duran, R

2005-11-01

We report a series of 26 heart transplant recipients with renal impairment in which sirolimus was used as the basic immunosuppresive drug (without associated calcineurin inhibitors) to avoid further nephrotoxicity. Sirolimus (trough levels 10 to 12 ng/mL, average daily dose 3 mg) was used in two settings: de novo in 7 patients with significant preexistent renal impairment and as a chronic conversion in 19 stable patients with established renal failure (creatinine level >2 mg/dL). In all de novo patients (n = 7), the renal function significantly improved. Creatinine fell from 2.95 +/- 0.9 mg/dL to 1.41 +/- 0.4 mg/dL at follow-up (P = .0017). One patient died suddenly of a massive pulmonary embolism. Only one patient experienced histologic but reversible rejection. In one patient, anemia and diarrhea prompted sirolimus withdrawal. Five patients had infectious episodes: three bacterial pneumonias, one mediastinitis, and two CMV infections. In the chronic conversion group (n = 19), the improvement was mostly limited to patients with moderate renal failure (creatinine < or =2.5 mg/dL) in which creatinine fell from 2.24 +/- 0.2 to 1.9 +/- 0.27 mg/dL, P = .009). When basal creatinine was over 2.5 mg/dL, only one third of the patients improved after conversion. Two patients died: terminal renal failure and cerebrovascular accident. There were no clinical episodes of rejection. Secondary effects prompted the discontinuation of sirolimus in five patients: two definite and one possible interstitial pneumonitis and two cases of anemia). The symptoms resolved after sirolimus withdrawal. Six patients had infection: four pneumonias, one sepsis, and one cutaneous abscess. Sirolimus is an interesting alternative to calcineurin inhibitors in selected patients with renal impairment. It prevents renal failure in de novo recipients at high risk of catastrophic renal damage and ameliorates renal dysfunction in chronic patients with moderate renal dysfunction. Given the high incidence of

Clinical and Cost Comparison Evaluation of Inpatient Versus Outpatient Administration of EPOCH-Containing Regimens in Non-Hodgkin Lymphoma.

Science.gov (United States)

Evans, Sarah S; Gandhi, Arpita S; Clemmons, Amber B; DeRemer, David L

2017-08-01

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin (EPOCH)-containing regimens are frequently utilized in non-Hodgkin's lymphoma, however, the incidence of febrile neutropenia (FN) in patients receiving inpatient versus outpatient EPOCH has not been described. Additionally, no comparisons have been made regarding financial implications of EPOCH administration in either setting. This study's primary objective was to compare hospital admissions for FN in patients receiving inpatient or outpatient EPOCH. A single-center, institutional review board-approved review was conducted for adults receiving EPOCH beginning January 2010. Clinical and financial data were collected through chart review and the institution's financial department. Descriptive statistics were utilized for analysis. A total of 25 patients received 86 cycles of an EPOCH-containing regimen (61 [70.9%] inpatient). Five (8.2%) inpatient cycles resulted in an admission for FN compared to 4 (16%) outpatient cycles. Prophylactic antifungal and antiviral agents were prescribed more often after inpatient cycles (>80%) compared to outpatient cycles (cost savings of approximately US$141 116 for both chemotherapy costs and hospital day avoidance. EPOCH-containing regimens can be safely administered in the outpatient setting, which may result in cost savings for healthcare institutions.

Immunosuppressant therapeutic drug monitoring by LC-MS/MS: workflow optimization through automated processing of whole blood samples.

Science.gov (United States)

Marinova, Mariela; Artusi, Carlo; Brugnolo, Laura; Antonelli, Giorgia; Zaninotto, Martina; Plebani, Mario

2013-11-01

Although, due to its high specificity and sensitivity, LC-MS/MS is an efficient technique for the routine determination of immunosuppressants in whole blood, it involves time-consuming manual sample preparation. The aim of the present study was therefore to develop an automated sample-preparation protocol for the quantification of sirolimus, everolimus and tacrolimus by LC-MS/MS using a liquid handling platform. Six-level commercially available blood calibrators were used for assay development, while four quality control materials and three blood samples from patients under immunosuppressant treatment were employed for the evaluation of imprecision. Barcode reading, sample re-suspension, transfer of whole blood samples into 96-well plates, addition of internal standard solution, mixing, and protein precipitation were performed with a liquid handling platform. After plate filtration, the deproteinised supernatants were submitted for SPE on-line. The only manual steps in the entire process were de-capping of the tubes, and transfer of the well plates to the HPLC autosampler. Calibration curves were linear throughout the selected ranges. The imprecision and accuracy data for all analytes were highly satisfactory. The agreement between the results obtained with manual and those obtained with automated sample preparation was optimal (n=390, r=0.96). In daily routine (100 patient samples) the typical overall total turnaround time was less than 6h. Our findings indicate that the proposed analytical system is suitable for routine analysis, since it is straightforward and precise. Furthermore, it incurs less manual workload and less risk of error in the quantification of whole blood immunosuppressant concentrations than conventional methods. © 2013.

Recommendations of everolimus use in liver transplant.

Science.gov (United States)

Rubín Suárez, Angel; Bilbao Aguirre, Itxarone; Fernández-Castroagudin, Javier; Pons Miñano, José Antonio; Salcedo Plaza, Magdalena; Varo Pérez, Evaristo; Prieto Castillo, Martín

2017-11-01

Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice. Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.

Early Introduction of Everolimus Immunosuppressive Regimen in Liver Transplantation with Extra-Anatomic Aortoiliac-Hepatic Arterial Graft Anastomosis

Directory of Open Access Journals (Sweden)

Emanuele Felli

2014-01-01

Full Text Available Liver transplantation is the treatment of choice for patients with acute and chronic end-stage liver disease, when no other medical treatment is possible. Despite high rates of 1- to 5-year survival, long-term adverse effects of immunosuppressant agents remain of major concern. Current research and clinical efforts are made to develop immunosuppressant agents that minimize adverse effects along with a low rate of graft rejection. Tailoring immunosuppressive therapy to individual patients by the use of proliferation signal inhibitors seems to be the best way to minimize toxicity and increase efficacy. Recently everolimus has been introduced in clinical practice; among its adverse effects an increased incidence of arterial graft thrombosis in renal transplants, vascular anastomosis leakage, impaired wound healing, and thrombotic microangiopathy have been reported. We present the case of a 54-year-old patient submitted to liver transplantation for end-stage liver disease treated by an extra-anatomic aortoiliac-hepatic arterial graft anastomosis and early postoperative introduction of everolimus for acute renal failure. Postoperative period was characterized by two abdominal collections and reactivation of cytomegalovirus infection that were treated by percutaneous drainage and antiviral therapy, respectively; the patient is well after 8-month followup with patency of the arterial conduit and no leakage.

Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

International Nuclear Information System (INIS)

Matsuyama, Takaharu; Kato, Koji

2002-01-01

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 μg/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

Energy Technology Data Exchange (ETDEWEB)

Matsuyama, Takaharu; Kato, Koji [Nagoya First Red Cross Hospital (Japan). Children' s Medical Center; Hanada, Ryoji [Saitama Children' s Medical Center, Iwatsuki (Japan)] [and others

2002-07-01

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 {mu}g/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome

Science.gov (United States)

Teachey, David T.; Greiner, Robert; Seif, Alix; Attiyeh, Edward; Bleesing, Jack; Choi, John; Manno, Catherine; Rappaport, Eric; Schwabe, Dirk; Sheen, Cecilia; Sullivan, Kathleen E.; Zhuang, Hongming; Wechsler, Daniel S.; Grupp, Stephan A.

2010-01-01

Summary We hypothesized that sirolimus, an mTOR inhibitor, may be effective in patients with autoimmune lymphoproliferative syndrome (ALPS) and treated patients who were intolerant to or failed other therapies. Four patients were treated for autoimmune cytopenias; all had a rapid complete or near complete response. Two patients were treated for autoimmune arthritis and colitis, demonstrating marked improvement. Three patients had complete resolution of lymphadenopathy and splenomegaly and all patients had a reduction in double negative T cells, a population hallmark of the disease. Based on these significant responses, we recommend that sirolimus be considered as second-line therapy for patients with steroid-refractory disease. PMID:19208097

No major neurologic complications with sirolimus use in heart transplant recipients

NARCIS (Netherlands)

van de Beek, Diederik; Kremers, Walter K.; Kushwaha, Sudhir S.; McGregor, Christopher G. A.; Wijdicks, Eelco F. M.

2009-01-01

OBJECTIVE: To determine whether sirolimus therapy is associated with neurologic complications, including stroke, among heart transplant recipients. PATIENTS AND METHODS: We retrospectively studied patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988,

Sirolimus alternative to blood transfusion as a life saver in blue rubber bleb nevus syndrome: A case report.

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Wang, Ke-Ling; Ma, Shu-Fang; Pang, Ling-Yu; Zhang, Meng-Na; Hu, Lin-Yan; Liu, Meng-Jia; Zou, Li-Ping

2018-02-01

Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by multiple venous malformations. The gastrointestinal bleeding and secondary iron deficiency anemia are the most common complications. There are currently no effective treatments for BRBNS. Here, we report a case of successful treatment with a small dose of sirolimus of a BRBN patient with a de novo gene mutation. A 12-year-old female was admitted to our hospital with multiple hemangiomas for 12 years. The patient often displayed melena; she recently received transfusion of 2 units of red blood cells once every 2 weeks. Multiple fist-sized hemangiomas were piled up on both sides and back of the neck, and were also noted on the arms, legs, chest, back, and on the tip of the tongue. The laboratory findings demonstrated severe anemia. Blood sample sequencing detected a heterozygous de novo mutation c.2545C > Tin the TEK gene. Based on these findings, final diagnosis of Blue rubber bleb nevus syndrome (BRBNS) was made. After the diagnosis, low-dose sirolimus was orally administered. The patient's hemoglobin was increased after treatment with sirolimus for 1 month. Since the initial treatment with sirolimus, she had not received any blood transfusions. The skin and mucosal hemangioma decreased significantly, and new digestive tract hemorrhage, muscle hematoma, or adverse drug reactions were not observed. we report a case of a mutation in exon 15 of the TEK gene leading to BRBN. It was successfully treated with a small dose of sirolimus as an alternative to blood transfusion in order to save the of BRBN patient's life.

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation.

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Martin, Spencer T; Tichy, Eric M; Gabardi, Steven

2011-04-01

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as

Real-world Direct Health Care Costs for Metastatic Colorectal Cancer Patients Treated With Cetuximab or Bevacizumab-containing Regimens in First-line or First-line Through Second-line Therapy.

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Johnston, Stephen; Wilson, Kathleen; Varker, Helen; Malangone-Monaco, Elisabetta; Juneau, Paul; Riehle, Ellen; Satram-Hoang, Sacha; Sommer, Nicolas; Ogale, Sarika

2017-12-01

The present study examined real-world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first-line (1L) bevacizumab (BEV)- or cetuximab (CET)-containing regimen in 1L or 1L-through-second-line (1L-2L) therapy. Using a large US insurance claims database, patients with mCRC initiating 1L BEV- or 1L CET-containing regimen from January 1, 2008 to September 30, 2014 were identified. The per-patient per-month (PPPM) all-cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic-containing regimen, 1L-2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV- versus 1L CET-containing regimen. A total of 6095 patients initiating a 1L BEV- and 453 initiating a 1L CET-containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV- and 134 initiating a 1L CET-containing regimen were evaluated for 1L-2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were $3135 (95% confidence interval [CI], $1174-$5040; P < .001) greater on average than 1L BEV. In 1L-2L therapy, 1L BEV-2L CET had adjusted PPPM costs that were $1402 (95% CI, $1365-$1442; P = .010) greater than those for 1L BEV-2L BEV, and 1L CET-2L BEV had adjusted PPPM costs that were $4279 (95% CI, $4167-$4400; P = .001) greater on average than those for 1L BEV-2L BEV. The adjusted PPPM cost differences for 1L BEV-2L other biologic or 1L CET-2L other biologic agent were numerically greater but statistically insignificant. PPPM total health care costs for 1L and 2L therapy tended to be greater for patients treated with 1L CET-containing regimens than for 1L BEV-containing regimens. Also, continuing treatment with BEV-containing regimens 1L-2L was less costly than switching between BEV and CET. The cost differences between BEV and CET hold important implications for treatment decisions of mCRC patients in real-world clinical

肾移植术后并发恶性肿瘤患者免疫抑制剂方案的选择%The choice of the immunosuppressant for the patients of the malignant tumors after kidney transplantation

Institute of Scientific and Technical Information of China (English)

Haihao Wang; Weijie Zhang; Zhishui Chen; Qi Mei; Ke Ma

2008-01-01

Objective:To evaluate the efficacy and safety of the immunosuppressant treatment among 10 post-renal transplantation recipients with malignant tumors.Methods:Conversion to sirolimus (SRL) treatment was performed for 10 cases which had found malignant tumors after kidney transplantation.During the follow-up period,the recurrence and diffusion of the tumor,the renal function and rejection were monitored.Results:All these cases despite the death had been followed up for at least 1 year.9 cases had no recurrence and diffusion.1 case died due to the tumor diffusion 7 months after the drug conversion.1 case suffered once acute rejection 2 months after the drug conversion.This acute rejection had been inhibited by flushing dose MP.Conclusion:As a new immunosuppressant,SRL not only can prevent the generation of AR,but inhibit proliferation and development of malignant tumors in kidney transplantation recipients as well.

Distinct deleterious effects of cyclosporine and tacrolimus and combined tacrolimus-sirolimus on endothelial cells: protective effect of defibrotide.

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Carmona, Alba; Díaz-Ricart, Maribel; Palomo, Marta; Molina, Patricia; Pino, Marc; Rovira, Montserrat; Escolar, Ginés; Carreras, Enric

2013-10-01

Endothelial dysfunction seems to be a key factor in the development of several complications observed early after hematopoietic stem cell transplantation (HSCT). The conditioning regimen and many other factors associated with the procedure are responsible for this endothelial damage. The effects of immunosuppressive agents on endothelial function have not been explored in detail. We evaluated the effects of 3 drugs commonly used in HSCT: 2 calcineurin inhibitors, cyclosporine A (CSA) and tacrolimus (TAC), and an inhibitor of mTOR, sirolimus (SIR). We also evaluated the effect of the combination of TAC and SIR (TAC+SIR), which is used increasingly in clinical practice. Microvascular endothelial cells (HMEC-1) were exposed to these drugs to evaluate changes in (1) intercellular adhesion molecule (ICAM)-1 expression on the cell surface, assessed by immunofluorescence labeling and expressed as the mean gray value (MGV); (2) reactivity of the extracellular matrix (ECM) toward platelets, upon exposure of the ECM to circulating blood; and (3) whole-blood clot formation, assessed by thromboelastometry. Studies were conducted in the absence and presence of defibrotide (DF) to assess its possible protective effect. The exposure of HMEC-1 to CSA and TAC+SIR significantly increased the expression of ICAM-1 (157.5 ± 11.6 and 153.4 ± 9.5 MGV, respectively, versus 105.7 ± 6.5 MGV in controls [both P < .05]). TAC applied alone increased ICAM-1 slightly (120.3 ± 8.2 MGV), and SIR had no effect (108.9 ± 7.4 MGV). ECM reactivity increased significantly only in response to CSA (surface covered by platelets of 41.2% ± 5.4% versus 30.1% ± 2.0%, P < .05). DF attenuated all these changes. No significant changes in the viscoelastic properties of clot formation were observed in any condition with blood samples incubated in vitro. In conclusion, CSA and TAC+SIR had a proinflammatory effect, but only CSA exhibited an additional prothrombotic effect. Interestingly, DF exerted clear

The performance of five different dried blood spot cards for the analysis of six immunosuppressants.

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Koster, Remco A; Botma, Rixt; Greijdanus, Ben; Uges, Donald R A; Kosterink, Jos G W; Touw, Daan J; Alffenaar, Jan-Willem C

2015-01-01

The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut DMS DBS cards. We found that all DBS cards showed the same hematocrit and concentration-dependent recovery patterns for sirolimus, everolimus and temsirolimus. At high concentrations, the total hematocrit effects were much more pronounced than at low concentrations for tacrolimus, sirolimus, everolimus, ascomycin and temsirolimus. The tested card types showed differences in performance, especially at extreme concentrations and hematocrit values. It may be useful to investigate the performance of different types of DBS cards prior to analytical method validation.

The Immunosuppressive drug – Rapamycin – Electroanalytical Sensing Using Boron- Doped Diamond electrode

International Nuclear Information System (INIS)

Stanković, Dalibor M.; Kalcher, Kurt

2015-01-01

Graphical abstract: Display Omitted -- Abstract: This paper presents for the first time the study of electrochemical behavior of well known immunosuppressant drug – rapamycin (sirolimus) using boron-doped diamond electrode. Rapamycin provided single and oval-shaped oxidation peak at +1.1 V vs. Ag/AgCl electrode in Britton–Robinson buffer solution at pH 3 confirming highly irreversible behavior of analyte at boron-doped diamond electrode. A differential pulse voltammetry was used for quantification of tested drug under the optimum experimental conditions. The calibration curve was linear over the range from 0.5 to 19.5 μM (R 2 = 0.9976) with detection limit of 0.22 μM. Repeatability of ten successfully measurements of three different concentrations (5, 10 and 15 μM) was 2.5, 1.9 and 1,7 %, respectively. Influence of most common biomolecules presented in urine samples was evaluated. The suggested analytical methodology was successfully applied for determination of rapamycin in four urine samples with excellent recoveries. The developed approach could be beneficial in analysis of rapamycin in biological samples using boron-doped diamond electrode as up-to-date electrochemical sensor and could represent inexpensive analytical alternative to separation methods

The influence of the dried blood spot drying time on the recoveries of six immunosuppressants

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Remco A. Koster

2015-10-01

Full Text Available Investigation of the drying time of dried blood spots (DBS is currently not included in DBS validations. The influence of the DBS drying time on the recovery of tacrolimus, ascomycin, sirolimus, everolimus, cyclosporin A and temsirolimus was evaluated by measuring DBS with a fixed blood volume at a hematocrit range between 0.1 and 0.6 L/L at 3, 24 and 48 hours of drying time. Results showed that the recovery of sirolimus, everolimus, temsirolimus and cyclosporin A was influenced by the DBS drying time, while the recovery of tacrolimus and ascomycin was not. A drying time of at least 24 hours is advised in order to stabilize hematocrit and concentration related recovery effects of sirolimus, everolimus, temsirolimus and cyclosporin A.

Cancer-Associated Fibroblasts from lung tumors maintain their immuno-suppressive abilities after high-dose irradiation

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Laia eGorchs

2015-05-01

Full Text Available Accumulating evidence supports the notion that high-dose (>5 Gy radiotherapy (RT regimens are triggering stronger pro-immunogenic effects than standard low-dose (2 Gy regimens. However, the effects of RT on certain immunoregulatory elements in tumors remain unexplored. In this study we have investigated the effects of high-dose irradiation (HD-RT on the immunomodulating functions of cancer-associated fibroblasts (CAFs. Primary CAF cultures were established from lung cancer specimens derived from patients diagnosed for non-small cell lung cancer. Irradiated and non-irradiated CAFs were examined for immunomodulation in experiments with peripheral blood mononuclear cells from random, healthy donors. Regulation of lymphocytes behavior was checked by lymphocyte proliferation assays, lymphocyte migration assays and T-cell cytokine production. Additionally, CAF-secreted immuno-regulatory factors were studied by multiplex protein arrays, ELISAs and by LC-MS/MS proteomics. In all functional assays we observed a powerful immuno-suppressive effect exerted by CAF-conditioned medium on activated T-cells (p>0,001, and this effect was sustained after a single radiation dose of 18 Gy. Relevant immuno-suppressive molecules such as prostaglandin E2, interleukin-6 and -10, or transforming growth factor-β were found in CAF conditioned medium, but their secretion was unchanged after irradiation. Finally, immunogenic cell death responses in CAFs were studied by exploring the release of high motility group box-1 and ATP. Both alarmins remained undetectable before and after irradiation. In conclusion, CAFs play a powerful immuno-suppressive effect over activated T-cells, and this effect remains unchanged after HD-RT. Importantly, CAFs do not switch on immunogenic cell death responses after exposure to HD-RT.

The influence of intrauterine exposure to immunosuppressive treatment on changes in the immune system in juvenile Wistar rats.

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Kabat-Koperska, Joanna; Kolasa-Wołosiuk, Agnieszka; Wojciuk, Bartosz; Wojciechowska-Koszko, Iwona; Roszkowska, Paulina; Krasnodębska-Szponder, Barbara; Paczkowska, Edyta; Safranow, Krzysztof; Gołembiewska, Edyta; Machaliński, Bogusław; Ciechanowski, Kazimierz

2016-01-01

In our study, we assessed the impact of immunosuppressive drug combinations on changes in the immune system of juvenile Wistar rats exposed to these drugs during pregnancy. We primarily concentrated on changes in two organs of the immune system - the thymus and the spleen. The study was conducted on 40 (32+8) female Wistar rats administered full and half dose of drugs, respectively, subjected to regimens commonly used in therapy of human kidney transplant recipients ([1] cyclosporine A, mycophenolate mofetil, and prednisone; [2] tacrolimus, mycophenolate mofetil, and prednisone; [3] cyclosporine A, everolimus, and prednisone). The animals received drugs by oral gavage 2 weeks before pregnancy and during 3 weeks of pregnancy. There were no statistically significant differences in the weight of the thymus and spleen, but changes were found in the results of blood hematology, cytometry from the spleen, and a histologic examination of the examined immune organs of juvenile Wistar rats. In the cytokine assay, changes in the level of interleukine 17 (IL-17) after increasing amounts of concanavaline A were dose-dependent; the increase of IL-17 was blocked after administration of higher doses of immunosuppressive drugs. However, after a reduction of doses, its increase resumed. Qualitative, quantitative, and morphological changes in the immune system of infant rats born to pharmacologically immunosuppressed females were observed. Thymus structure, spleen composition, and splenocyte IL-17 production were mostly affected in a drug regimen-dependent manner.

Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study

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Wüthrich Rudolf P

2007-09-01

Full Text Available Abstract Background Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD. Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD. Method/design This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune® in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus. Discussion The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD. Trial registration NCT00346918

The Effects of Lyophilization on the Physico-Chemical Stability of Sirolimus Liposomes

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Parvin Zakeri-Milani

2013-02-01

Full Text Available Purpose: The major limitation in the widespread use of liposome drug delivery system is its instability. Lyophilization is a promising approach to ensure the long-term stability of liposomes. The aim of this study was to prepare sirolimus-loaded liposomes, study their stability and investigate the effect of lyophilization either in the presence or in the absence of lyoprotectant on liposome properties. Methods: Two types of multi-lamellar liposomes, conventional and fusogenic, containing sirolimus were prepared by modified thin film hydration method with different ratio of dipalmitoylphosphatidylcholine (DPPC, cholesterol and dioleoylphosphoethanolamine (DOPE, and were lyophilized with or without dextrose as lyoprotectant. Chemical stability investigation was performed at 4°C and 25°C until 6 months using a validated HPLC method. Physical stability was studied with determination of particle size (PS and encapsulation efficiency (EE % of formulations through 6 months. Results: Chemical stability test at 4°C and 25°C until 6 months showed that drug content of liposomes decreased 8.4% and 20.2% respectively. Initial mean EE % and PS were 72.8 % and 582 nm respectively. After 6 months mean EE % for suspended form, lyophilized without lyoprotectant and lyophilized with lyoprotectant were 54.8 %, 62.3% and 67.1 % at 4°C and 48.2%, 60.4 % and 66.8 % at 25°C respectively. Corresponding data for mean PS were 8229 nm, 2397 nm and 688nm at 4°C and 9362 nm, 1944 nm and 737 nm at 25°C respectively. Conclusion: It is concluded that lyophilization with and without dextrose could increase shelf life of liposome and dextrose has lyoprotectant effect that stabilized liposomes in the lyophilization process.

Local delivery of sirolimus nanoparticles for the treatment of in-stent restenosis.

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Zago, Alexandre C; Raudales, José C; Attizzani, Guilherme; Matte, Bruno S; Yamamoto, German I; Balvedi, Julise A; Nascimento, Ludmila; Kosachenco, Beatriz G; Centeno, Paulo R; Zago, Alcides J

2013-02-01

To test the local delivery of sirolimus nanoparticles following percutaneous transluminal coronary angioplasty (PTCA) to treat in-stent restenosis (ISR) in a swine model. Coronary bare-metal stent (BMS) implantation reduces major adverse cardiac events when compared with PTCA; however, ISR rates remain high. Eighteen swine underwent BMS deployment guided by intravascular ultrasound (IVUS). Of these, 16 developed ISR (1 stent/swine) and underwent angioplasty with a noncompliant balloon (PTCA-NC). The animals were then randomized into four groups for local infusion of sirolimus nanoparticles through a porous balloon catheter, as follows: (1) PTCA-NC alone (control); (2) PTCA-NC + (polylactic acid)-based nanoparticle formulation (anionic 1); (3) PTCA-NC + (polylactic-co-glycolic acid)-based nanoparticle formulation (anionic 2); and (4) PTCA-NC + Eudragit RS nanoparticle formulation (cationic). Coronary angiography and IVUS follow-up were performed 28 days after ISR treatment. There was one episode of acute coronary occlusion with the cationic formulation. Late area loss was similar in all groups at 28 days according to IVUS. However, luminal volume loss (control = 20.7%, anionic 1 = 4.0%, anionic 2 = 6.7%, cationic = 9.6%; P = 0.01) and neointimal volume gain (control = 68.7%, anionic 1 = 17.4%, anionic 2 = 29.5%, cationic = 31.2%; P = 0.019) were significantly reduced in all treatment groups, especially in anionic 1. PTCA-NC followed by local infusion of sirolimus nanoparticles was safe and efficacious to reduce neointima in this model, and this strategy may be a promising treatment for BMS ISR. Further studies are required to validate this method in humans. Copyright © 2012 Wiley Periodicals, Inc.

Comparative Effectiveness of Tacrolimus-Based Steroid Sparing versus Steroid Maintenance Regimens in Kidney Transplantation: Results from Discrete Event Simulation.

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Desai, Vibha C A; Ferrand, Yann; Cavanaugh, Teresa M; Kelton, Christina M L; Caro, J Jaime; Goebel, Jens; Heaton, Pamela C

2017-10-01

Corticosteroids used as immunosuppressants to prevent acute rejection (AR) and graft loss (GL) following kidney transplantation are associated with serious cardiovascular and other adverse events. Evidence from short-term randomized controlled trials suggests that many patients on a tacrolimus-based immunosuppressant regimen can withdraw from steroids without increased AR or GL risk. To measure the long-term tradeoff between GL and adverse events for a heterogeneous-risk population and determine the optimal timing of steroid withdrawal. A discrete event simulation was developed including, as events, AR, GL, myocardial infarction (MI), stroke, cytomegalovirus, and new onset diabetes mellitus (NODM), among others. Data from the United States Renal Data System were used to estimate event-specific parametric regressions, which accounted for steroid-sparing regimen (avoidance, early 7-d withdrawal, 6-mo withdrawal, 12-mo withdrawal, and maintenance) as well as patients' demographics, immunologic risks, and comorbidities. Regression-equation results were used to derive individual time-to-event Weibull distributions, used, in turn, to simulate the course of patients over 20 y. Patients on steroid avoidance or an early-withdrawal regimen were more likely to experience AR (45.9% to 55.0% v. 33.6%, P events and other outcomes with no worsening of AR or GL rates compared with steroid maintenance.

Selection of Parasites with Diminished Drug Sensitivity by Amodiaquine-Containing Antimalarial Regimens in Uganda

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Nawaz, Fatima; Nsobya, Samuel L.; Kiggundu, Moses; Joloba, Moses; Rosenthal, Philip J.

2009-01-01

Background Amodiaquine (AQ) is paired with artesunate (AS) or sulfadoxine-pyrimethamine (SP) in recommended antimalarial regimens. It is unclear how readily AQ resistance will be selected with combination chemotherapy. Methods We collected 61 Plasmodium falciparum samples from a cohort of Ugandan children randomized to treatment with AQ/SP, AS/AQ, or artemether-lumefantrine (AL) for uncomplicated malaria. In vitro sensitivity to monodesethylamodiaquine (MDAQ) was measured with a histidine rich protein-2-based ELISA, and potential resistance-mediating polymorphisms pfmdr-1were evaluated. Results Parasites from subjects previously treated with AQ/SP or AS/AQ within 12 weeks were less sensitive to MDAQ (n=18; mean IC50 62.9 nM; range 12.7–158.3 nM) than parasites from those not treated within 12 weeks (n=43; mean IC50 37.5 nM; range 6.3–184.7 nM; p=0.0085) or only those in the treatment arm that did not contain AQ (n=20; mean IC50 28.8 nM; range 6.3–121.8 nM; p=0.0042). The proportion of strains with polymorphisms expected to mediate diminished response to AQ (pfmdr-1 86Y and 1246Y) increased after prior AQ therapy, although differences were not significant. Conclusions Prior therapy selected for diminished response to MDAQ, suggesting that AQ-containing regimens may rapidly lose efficacy in Africa. The mechanism of diminished MDAQ response is not fully explained by known mutations in pfmdr-1. PMID:19905933

Nanoparticles and direct immunosuppression

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Ngobili, Terrika A

2016-01-01

Targeting the immune system with nanomaterials is an intensely active area of research. Specifically, the capability to induce immunosuppression is a promising complement for drug delivery and regenerative medicine therapies. Many novel strategies for immunosuppression rely on nanoparticles as delivery vehicles for small-molecule immunosuppressive compounds. As a consequence, efforts in understanding the mechanisms in which nanoparticles directly interact with the immune system have been overshadowed. The immunological activity of nanoparticles is dependent on the physiochemical properties of the nanoparticles and its subsequent cellular internalization. As the underlying factors for these reactions are elucidated, more nanoparticles may be engineered and evaluated for inducing immunosuppression and complementing immunosuppressive drugs. This review will briefly summarize the state-of-the-art and developments in understanding how nanoparticles induce immunosuppressive responses, compare the inherent properties of nanomaterials which induce these immunological reactions, and comment on the potential for using nanomaterials to modulate and control the immune system. PMID:27229901

Pseudoneutropenia in lymphangioleiomyomatosis (LAM) patients receiving sirolimus: evaluation in a 100 patient cohort.

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Gopalakrishnan, Vissagan; Jones, Amanda M; Julien-Williams, Patricia; Machado, Tania; Danner, Robert L; Swigris, Jeffrey J; Paine, Robert; Lozier, Jay N; Moss, Joel

2018-01-01

In lymphangioleiomyomatosis patients receiving sirolimus treatment, transient leukopenia in the morning may be due to circadian rhythm, with leukocyte counts recovering later in the day, indicating that a decrease in drug dose may not be warranted http://ow.ly/jPFz30iysgV.

Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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Seyed Amir Dadkhahi

2017-05-01

Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen

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Salacz ME

2016-04-01

Full Text Available Michael E Salacz,1,2 Richard E Kast,3 Najmaldin Saki,4 Ansgar Brüning,5 Georg Karpel-Massler,6 Marc-Eric Halatsch6 1Department of Internal Medicine, 2Department of Neurosurgery, University of Kansas, Kansas City, KS, USA; 3IIAIGC Study Center, Burlington, VT, USA; 4Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; 5Molecular Biology Laboratory, University Hospital Munich, Munich, Germany; 6Department of Neurosurgery, University of Ulm, Ulm, Germany Abstract: To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs (monocyte, macrophage, microglia, dendritic cells that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%–30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic – minocycline, an antihypertensive drug – telmisartan, and a bisphosphonate – zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid – the MTZ Regimen – have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low

Factors that determine self-reported immunosuppressant adherence in kidney transplant recipients: a correlational study.

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Weng, Li-Chueh; Yang, Ya-Chen; Huang, Hsiu-Li; Chiang, Yang-Jen; Tsai, Yu-Hsia

2017-01-01

To determine the factors related to immunosuppressant therapy adherence in kidney transplant recipients in Taiwan. Adherence to immunosuppressant treatment is critical after kidney transplantation. Thus, the factors associated with self-reported medication adherence in kidney transplant recipients warrant investigation. The study used a cross-sectional and correlation design. A convenience sample of 145 kidney transplant recipients was included. Structured questionnaires were used to collect data during 2012-2013. Multivariate linear regression was used to examine the factors related to immunosuppressant therapy adherence. Over half of the participants were female (54·5%), mean age was 45·5 years, and mean year after transplant was 7·4. The mean score for medication adherence was 29·73 (possible score range 7-35). The results of the multivariate linear regression analysis showed that gender (male), low income with a high school or college education, years after transplantation and concerns about medication taking were negatively associated with adherence. Medication self-efficacy was positively associated with adherence. Therapy-related factors, partnerships with healthcare professionals and having private healthcare insurance did not significantly relate to immunosuppressant therapy adherence. Kidney transplant recipients demonstrated a high level of adherence. Strategies to enhance patients' self-efficacy and alleviate concerns about medication may promote medication adherence. Male patients, those with a lower income and those with a higher education level, should be a focus of efforts to maintain adherence to the medication regimen. © 2016 John Wiley & Sons Ltd.

The Effect of Different Dosing Schedules of Intravitreal Sirolimus, a Mammalian Target of Rapamycin (mTOR) Inhibitor, in the Treatment of Non-Infectious Uveitis (An American Ophthalmological Society Thesis).

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Nguyen, Quan Dong; Sadiq, Mohammad Ali; Soliman, Mohamed Kamel; Agarwal, Aniruddha; Do, Diana V; Sepah, Yasir J

2016-08-01

To determine if two different doses of intravitreal sirolimus, an mTOR inhibitor, can decrease inflammation and is safe in eyes with non-infectious posterior, intermediate, or panuveitis in the Sirolimus as a Therapeutic Approach UVEitis: Protocol-2 (SAVE-2) Study. SAVE-2 is a prospective randomized, phase II, open-label interventional clinical trial conducted at 4 clinical centers in the United States. Eligible subjects were randomized into one of two treatments. Group 1 received 440µg of intravitreal sirolimus in study eyes on days 0, 30, 60, 90, 120, and 150; group 2 received 880µg of intravitreal sirolimus on days 0, 60, and 120. Fellow eyes were also eligible to receive sirolimus (of opposite dose to that of study eye). Primary endpoint of the study was at month 6 (M6). 24 subjects have been randomized in SAVE-2 and are included in the analysis. Vitreous haze decreased by ≥2 steps in 63.6% and 50% of patients in groups 1 and 2, respectively at M6 (p=0.695). Mean change in best-corrected visual acuity for subjects was +3.66 and -2.91 ETDRS letters in group 1 and 2, respectively. Among subjects with macular edema at baseline (n=13), the mean change in foveal thickness was -89.42µm in group 1 and +81.5µm in group 2 at M6. Both low and high doses of intravitreal sirolimus were found to decrease vitreous haze in eyes with non-infectious uveitis. Low dose (440µg) sirolimus administered monthly may be more efficacious in reducing uveitic macular edema than high dose (880µg) administered every 2 months.

Patient survey to identify reasons for non-adherence and elicitation of quality of life concepts associated with immunosuppressant therapy in kidney transplant recipients.

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Muduma, Gorden; Shupo, Francis C; Dam, Sophie; Hawken, Natalia A; Aballéa, Samuel; Odeyemi, Isaac; Toumi, Mondher

2016-01-01

Renal transplantation (RT) is considered the treatment of choice for end-stage renal disease compared to dialysis, offering better health-related quality of life (HRQoL) and higher survival rates. However, immunosuppressants are essential for the long-term survival of kidney grafts and patients' non-adherence to their medication leads to poor outcomes. Immunosuppressants can also significantly alter patients' HRQoL because of their side effects and the complex chronic medication regimen they represent. To elicit key concepts related to adherence to immunosuppressant therapy (IT) and reasons for non-adherence in terms of patient reported outcomes, side effects, and the impact of the medication on HRQoL in RT population, including patient preference of once daily over twice-daily immunosuppressive regimen. Results were used to develop an IT-specific conceptual framework and provide suggestions for improving patients' adherence to IT. Interviews were conducted with three clinical experts to determine key concepts related to RT and immunosuppressants. Thirty-seven participants in four focus groups were asked to cite important concepts related to adherence and impact of IT on HRQoL and to rate them. Qualitative analysis was conducted to code participants' responses. Non-adherence among participants where admitted was unintentional. The reason for this included forgetfulness, interference with lifestyle, being asleep at the time the medication should be taken, change in routine, and impact of side effects. Overall, participants reported that the evening dose was more problematic to remember and that the exclusion of this dose could make them more adherent. Participants also reported that IT impacted on their HRQoL in a number of ways including: placing restrictions on their lifestyle, causing anxiety, or impairing their ability to work. This study provides qualitative evidence about the barriers to IT adherence and the components of HRQoL that are important from the

Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.

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Tiberi, Simon; Sotgiu, Giovanni; D'Ambrosio, Lia; Centis, Rosella; Abdo Arbex, Marcos; Alarcon Arrascue, Edith; Alffenaar, Jan Willem; Caminero, Jose A; Gaga, Mina; Gualano, Gina; Skrahina, Alena; Solovic, Ivan; Sulis, Giorgia; Tadolini, Marina; Alarcon Guizado, Valentina; De Lorenzo, Saverio; Roby Arias, Aurora Jazmín; Scardigli, Anna; Akkerman, Onno W; Aleksa, Alena; Artsukevich, Janina; Auchynka, Vera; Bonini, Eduardo Henrique; Chong Marín, Félix Antonio; Collahuazo López, Lorena; de Vries, Gerard; Dore, Simone; Kunst, Heinke; Matteelli, Alberto; Moschos, Charalampos; Palmieri, Fabrizio; Papavasileiou, Apostolos; Payen, Marie-Christine; Piana, Andrea; Spanevello, Antonio; Vargas Vasquez, Dante; Viggiani, Pietro; White, Veronica; Zumla, Alimuddin; Migliori, Giovanni Battista

2016-06-01

No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanate versus meropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanate versus meropenem/clavulanate added to background regimens to treat MDR- and XDR-TB cases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8 versus 8) but more fluoroquinolone resistance (79.0% versus 48.9%, pimipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428) versus 85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7% versus 94.8%, p=0.02 and 71.9% versus 94.8%, pimipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating MDR/XDR-TB patients. Copyright ©ERS 2016.

A longitudinal assessment of adherence with immunosuppressive therapy following kidney transplantation from the Mycophenolic Acid Observational REnal Transplant (MORE) study.

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Tsapepas, Demetra; Langone, Anthony; Chan, Laurence; Wiland, Anne; McCague, Kevin; Chisholm-Burns, Marie

2014-04-17

Nonadherence with immunosuppressive therapy after renal transplantation is a major clinical concern, but longitudinal data are sparse. Adherence data were recorded during the Mycophenolic Acid Observational REnal Transplant (MORE) study to help inform compliance management decisions. Prospective data were analyzed from the four-year, observational MORE study of de novo adult renal transplant recipients receiving mycophenolic acid (MPA) as enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at 40 US sites under routine management. Adherence was assessed using the Immunosuppressant Therapy Adherence Scale (ITAS): total score 0-12 (12, adherence; adherent recipients (p=0.59); graft loss was 4.7% (19/402) vs. 3.0% (12/406) (p=0.20); death was 1.5% (6/402) vs. 4.7% (19/406) (p=0.013). Adherence to the immunosuppressive regimen decreases over time, highlighting the need to monitor and encourage adherence even in long-term maintenance kidney transplant patients. Other than African American race, demographic factors may be of limited value in predicting nonadherence.

Place of mTOR inhibitors in management of BKV infection after kidney transplantation.

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Jouve, Thomas; Rostaing, Lionel; Malvezzi, Paolo

2016-01-01

BK virus (BKV) viremia and BKV-associated nephropathy (BKVAN) have become a serious nuisance to kidney transplant (KT) patients since the mid-nineties, when the incidence of this disease has increased significantly. Directory of open access journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science have been searched. Many hypothesis have been made as to why this phenomenon has developed; it is of general opinion that a more potent immunosuppression is at the core of the problem. The use of the association of tacrolimus (TAC) with mycophenolic acid (MPA) has gained momentum in the same years as the increase in BKV viremia incidence making it seem to be the most likely culprit. m-TOR inhibitors (m-TORIs) have been shown to have antiviral properties in vitro and this fact has encouraged different transplant teams to use these agents when confronted with BKV infection (viremia or nephropathy). However, the results are mitigated. There had been conflicting results for example when converting from TAC-to sirolimus-based immunosuppression in the setting of established BKVAN. In order to prevent BKV infection we have to minimize to some extent immunosuppression, but it is not always possible, e.g. in high immunological risk patients. Conversely, we could use m-TORIs associated with low-dose calcineurin inhibitors (CNIs). This could be actually the key to a safe immunosuppression regimen both from the immunological stand point and from the viral one.

Immunosuppressants

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... Brain Death HIV and Kidney Transplantation/Donation Incompatible Blood Types and Paired Exchange Programs Knowing Your Immunosuppressive (anti-rejection) Medications Organ and Tissue Donation The National Kidney ...

Metallic Limus-Eluting Stents Abluminally Coated with Biodegradable Polymers: Angiographic and Clinical Comparison of a Novel Ultra-Thin Sirolimus Stent Versus Biolimus Stent in the DESTINY Randomized Trial.

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Lemos, Pedro A; Abizaid, Alexandre A C; Meireles, George C; Sarmento-Leite, Rogério; Prudente, Mauricio; Cantarelli, Marcelo; Dourado, Adriano D; Mariani, Jose; Perin, Marco A; Costantini, Costantino; Costa, Ricardo A; Costa, José Ribamar; Chamie, Daniel; Campos, Carlos A; Ribeiro, Expedito

2015-12-01

To evaluate the outcomes of patients treated with a new drug-eluting stent formulation with low doses of sirolimus, built in an ultra-thin-strut platform coated with biodegradable abluminal coating. This study is a randomized trial that tested the main hypothesis that the angiographic late lumen loss of the novel sirolimus-eluting stent is noninferior compared with commercially available biolimus-eluting stent. A final study population comprising 170 patients with one or two de novo lesions was randomized in the ratio 2:1 for sirolimus-eluting stent or biolimus-eluting stent, respectively. The primary endpoint was 9-month angiographic in-stent late lumen loss. Adverse clinical events were prospectively collected for 1 year. After 9 months, the novel sirolimus-eluting stent was shown noninferior compared with the biolimus stent for the primary endpoint (angiographic in-stent late lumen loss: 0.20 ± 0.29 mm vs. 0.15 ± 0.20 mm, respectively; P value for noninferiority <0.001). The 1-year incidence of death, myocardial infarction, repeat revascularization, and stent thrombosis remained low and not significantly different between the groups. The present randomized trial demonstrates that the tested novel sirolimus-eluting stent was angiographically noninferior in comparison with a last-generation biolimus-eluting stent. © 2015 John Wiley & Sons Ltd.

Successful Treatment of Disseminated Bacillus Calmette-Guérin Disease in an HIV-Infected Child with a Linezolid-Containing Regimen

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Srđan Roglić

2016-01-01

Full Text Available Upon HIV infection diagnosis, an 8-month-old boy was transferred for evaluation of worsening respiratory distress requiring mechanical ventilation. Pneumocystis jirovecii pneumonia (PCP was diagnosed; the boy also had a nonhealing ulcer at the site of vaccination with Statens Serum Institut (Danish strain Bacillus Calmette-Guérin (BCG vaccine and associated axillary lymphadenopathy. PCP treatment resulted in weaning from mechanical ventilation. Antimycobacterial treatment was immediately attempted but was discontinued because of hepatotoxicity. Over several months, he developed splenic lesions and then disseminated skin and cystic bone lesions. M. bovis was repeatedly cultured from both skin and bone lesions despite various multidrug antimycobacterial regimens which included linezolid. Eventually, treatment with a regimen of rifabutin, isoniazid, ethambutol, and linezolid led to definitive cure. Clinicians should consider a linezolid-containing regimen for treatment of severe disseminated BCG infection, especially if other drug regimens have failed. Although drug toxicity is a particular concern for young children, this patient received linezolid for 13 months without serious toxicity. This case also highlights the need for universal screening among pregnant women to prevent vertical transmission of HIV. Finally, routine immunization with BCG vaccine at birth should be questioned in countries with low and declining burden of tuberculosis.

Advantages of novel BioMimeTM Sirolimus Eluting Coronary Stent system. Moving towards biomimicry.

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Upendra, K; Sanjeev, B

2012-02-01

Since the first reported use of percutaneous transluminal coronary angioplasty (PTCA), advancements in interventional cardiology arena have been fast paced. Within the last ten years, these developments have been exponential. Developers & clinicians are fast adapting from the learning curve awarded by the time course of DES evolution. In that light BioMimeTM Sirolimus Eluting Coronary Stent comes as a fresh thought in taking stents towards a biomimicry concept. The stent is built on an ultra-low strut thickness (65 µm) cobalt chromium stent platform, using an intelligent hybrid of close and open cells allowing for morphology mediated expansion, employs a well known anti-proliferative - Sirolimus that elutes from a biodegradable co-polymer formulation in 30 days and ensures high coating integrity and low coating thickness of 2 µm. The resultant stent demonstrates almost 100% endothelialization at 30 days in preclinical model and zero percent MACE >18 months in the primary efficacy and safety clinical study.

Bioabsorbable polymer-coated sirolimus-eluting stent implantation preserves coronary vasomotion: A DESSOLVE II trial sub-study.

Science.gov (United States)

Rusinaru, Dan; Vrolix, Mathias; Verheye, Stefan; Chowdhary, Saqib; Schoors, Danny; Di Mario, Carlo; Desmet, Walter; Donohoe, Dennis J; Ormiston, John A; Knape, Charlene; Bezerra, Hiram; Lansky, Alexandra; Wijns, William

2015-12-01

We studied coronary vasomotion in patients treated with the Mistent(®) absorbable polymer sirolimus-eluting stent (APSES) and in patients implanted with the Endeavor(®) zotarolimus-eluting stent (ZES). First generation (1st-gen) drug-eluting stents (DES) induce persistent vasomotor dysfunction in the treated coronary artery. It is unknown whether and to what extent the implantation of an absorbable polymer DES impairs coronary vasomotion. This sub-study of the DESSOLVE II trial included 19 APSES Mistent(®) and 10 ZES Endeavor(®) patients. Incremental atrial pacing and quantitative coronary angiography were used to assess vasomotion proximal and distal to the stent and in a reference segment at 9 months after implantation. Percent changes in vessel diameter with pacing versus baseline were calculated and compared. Vasomotor response of the APSES group was also compared with changes observed in a historical group of 17 patients implanted with a 1st-gen sirolimus-eluting stent (SES). Normal vasomotion (vasodilatation) was preserved and of comparable magnitude in the APSES and in the ZES group both proximally (P = 0.34) and distally (P = 0.38) to the stent. This finding was not observed in the 1st-gen SES group showing marked pacing-induced vasoconstriction at both stent edges (P absorbable polymer sirolimus-eluting stent is associated with preserved coronary vasomotion, comparable to that observed after implantation of the Endeavor(®) ZES, and distinct from 1st-gen SES which induce coronary vasomotor dysfunction. © 2015 Wiley Periodicals, Inc.

Application of Response Surface Methodology in Development of Sirolimus Liposomes Prepared by Thin Film Hydration Technique

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Saeed Ghanbarzadeh

2013-04-01

Full Text Available Introduction: The present investigation was aimed to optimize the formulating process of sirolimus liposomes by thin film hydration method. Methods: In this study, a 32 factorial design method was used to investigate the influence of two independent variables in the preparation of sirolimus liposomes. The dipalmitoylphosphatidylcholine (DPPC /Cholesterol (Chol and dioleoyl phosphoethanolamine(DOPE /DPPC molar ratios were selected as the independent variables. Particle size (PS and Encapsulation Efficiency (EE % were selected as the dependent variables. To separate the un-encapsulated drug, dialysis method was used. Drug analysis was performed with a validated RP-HPLC method. Results: Using response surface methodology and based on the coefficient values obtained for independent variables in the regression equations, it was clear that the DPPC/Chol molar ratio was the major contributing variable in particle size and EE %. The use of a statistical approach allowed us to see individual and/or interaction effects of influencing parameters in order to obtain liposomes with desired properties and to determine the optimum experimental conditions that lead to the enhancement of characteristics. In the prediction of PS and EE % values, the average percent errors are found to be as 3.59 and 4.09%. This value is sufficiently low to confirm the high predictive power of model. Conclusion: Experimental results show that the observed responses were in close agreement with the predicted values and this demonstrates the reliability of the optimization procedure in prediction of PS and EE % in sirolimus liposomes preparation.

HIV-2 integrase polymorphisms and longitudinal genotypic analysis of HIV-2 infected patients failing a raltegravir-containing regimen.

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Cavaco-Silva, Joana; Abecasis, Ana; Miranda, Ana Cláudia; Poças, José; Narciso, Jorge; Águas, Maria João; Maltez, Fernando; Almeida, Isabel; Germano, Isabel; Diniz, António; Gonçalves, Maria de Fátima; Gomes, Perpétua; Cunha, Celso; Camacho, Ricardo Jorge

2014-01-01

To characterize the HIV-2 integrase gene polymorphisms and the pathways to resistance of HIV-2 patients failing a raltegravir-containing regimen, we studied 63 integrase strand transfer inhibitors (INSTI)-naïve patients, and 10 heavily pretreated patients exhibiting virological failure while receiving a salvage raltegravir-containing regimen. All patients were infected by HIV-2 group A. 61.4% of the integrase residues were conserved, including the catalytic motif residues. No INSTI-major resistance mutations were detected in the virus population from naïve patients, but two amino acids that are secondary resistance mutations to INSTIs in HIV-1 were observed. The 10 raltegravir-experienced patients exhibited resistance mutations via three main genetic pathways: N155H, Q148R, and eventually E92Q - T97A. The 155 pathway was preferentially used (7/10 patients). Other mutations associated to raltegravir resistance in HIV-1 were also observed in our HIV-2 population (V151I and D232N), along with several novel mutations previously unreported. Data retrieved from this study should help build a more robust HIV-2-specific algorithm for the genotypic interpretation of raltegravir resistance, and contribute to improve the clinical monitoring of HIV-2-infected patients.

Post-Renal Transplant Diabetes Mellitus in Korean Subjects: Superimposition of Transplant-Related Immunosuppressant Factors on Genetic and Type 2 Diabetic Risk Factors

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Hyun Chul Lee

2012-06-01

Full Text Available Postrenal transplantation diabetes mellitus (PTDM, or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced β-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors.

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques.

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Meyer, C; Walker, J; Dewane, J; Engelmann, F; Laub, W; Pillai, S; Thomas, Charles R; Messaoudi, I

2015-09-01

In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show that the administration of cyclosporin A or tacrolimus without radiotherapy did not result in lymphopenia. The addition of TBI to the regimen resulted in lymphopenia as well as alterations in the memory/naive ratio following reconstitution of lymphocyte populations. Dendritic cell (DC) numbers in whole blood were largely unaffected, while the monocyte population was altered by immunosuppressive treatment. Irradiation also resulted in increased levels of circulating cytokines and chemokines that correlated with T cell proliferative bursts and with the shift towards memory T cells. We also report that anti-thymocyte globulin (ATG) treatment and CD3 immunotoxin administration resulted in a selective and rapid depletion of naive CD4 and CD8 T cells and increased frequency of memory T cells. We also examined the impact of these treatments on reactivation of latent simian varicella virus (SVV) infection as a model of varicella zoster virus (VZV) infection of humans. None of the treatments resulted in overt SVV reactivation; however, select animals had transient increases in SVV-specific T cell responses following immunosuppression, suggestive of subclinical reactivation. Overall, we provide detailed observations into immune modulation by TBI and chemotherapeutic agents in rhesus macaques, an important research model of human disease. © 2015 British Society for Immunology.

Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in “Omics” Medicine

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Gianluigi Zaza

2015-02-01

Full Text Available Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients’ quality of life. Significant improvements in one-year renal allograft and patients’ survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%–5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, “omics” techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient’s genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies.

Induction of immunological tolerance in the pig-to-baboon xenotransplantation model : studies aimed at achieving mixed hematopoietic chimerism and preventing associated thrombotic complications

NARCIS (Netherlands)

I.P.J. Alwayn (Ian)

2001-01-01

textabstractThe outcome of clinical organ transplantation has dramatically improved since the introduction of cyclosporine (CyA) in 1979 and of other, more recently introduced, immunosuppressive agents such as azathioprine, mycophenolate mofetil, tacrolimus and sirolimus. Furthermore, due to more

Randomized phase II trial evaluating two paclitaxel and cisplatin-containing chemoradiation regimens as adjuvant therapy in resected gastric cancer (RTOG-0114).

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Schwartz, Gary K; Winter, Kathryn; Minsky, Bruce D; Crane, Christopher; Thomson, P John; Anne, Pramila; Gross, Howard; Willett, Christopher; Kelsen, David

2009-04-20

The investigational arm of INT0116, a fluorouracil (FU) and leucovorin-containing chemoradiotherapy regimen, is a standard treatment for patients with resected gastric cancer with a 2-year disease-free survival rate (DFS) of 52%. Toxicity is also significant. More beneficial and safer regimens are needed. We performed a randomized phase II study among 39 cancer centers to evaluate two paclitaxel and cisplatin-containing regimens, one with FU (PCF) and the other without (PC) in patients with resected gastric cancer. Patients received two cycles of postoperative chemotherapy followed by 45 Gy of radiation with either concurrent FU and paclitaxel or paclitaxel and cisplatin. The primary objective was to show an improvement in 2-year DFS to 67% as compared with INT 0116. From May 2001 to February 2004 (study closure), 78 patients entered this study, and 73 were evaluable. At the planned interim analysis of 22 patients on PCF, grade 3 or higher GI toxicity was 59%. This was significantly worse than INT0116, and this arm was closed. Accrual continued on PC. The median DFS was 14.6 months for PCF and has not been reached for PC. For PC the 2-year DFS is 52% (95% CI, 36% to 68%). Though PC appears to be safe and the median DFS favorable, the DFS failed to exceed the lower bound of 52.9% for the targeted 67% DFS at 2 years and can not be recommended as the adjuvant arm for future randomized trials.

A sirolimus-eluting bioabsorbable polymer-coated stent (MiStent) versus an everolimus-eluting durable polymer stent (Xience) after percutaneous coronary intervention (DESSOLVE III): a randomised, single-blind, multicentre, non-inferiority, phase 3 trial.

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de Winter, Robbert J; Katagiri, Yuki; Asano, Taku; Milewski, Krzysztof P; Lurz, Philipp; Buszman, Pawel; Jessurun, Gillian A J; Koch, Karel T; Troquay, Roland P T; Hamer, Bas J B; Ophuis, Ton Oude; Wöhrle, Jochen; Wyderka, Rafał; Cayla, Guillaume; Hofma, Sjoerd H; Levesque, Sébastien; Żurakowski, Aleksander; Fischer, Dieter; Kośmider, Maciej; Goube, Pascal; Arkenbout, E Karin; Noutsias, Michel; Ferrari, Markus W; Onuma, Yoshinobu; Wijns, William; Serruys, Patrick W

2018-02-03

MiStent is a drug-eluting stent with a fully absorbable polymer coating containing and embedding a microcrystalline form of sirolimus into the vessel wall. It was developed to overcome the limitation of current durable polymer drug-eluting stents eluting amorphous sirolimus. The clinical effect of MiStent sirolimus-eluting stent compared with a durable polymer drug-eluting stents has not been investigated in a large randomised trial in an all-comer population. We did a randomised, single-blind, multicentre, phase 3 study (DESSOLVE III) at 20 hospitals in Germany, France, Netherlands, and Poland. Eligible participants were any patients aged at least 18 years who underwent percutaneous coronary intervention in a lesion and had a reference vessel diameter of 2·50-3·75 mm. We randomly assigned patients (1:1) to implantation of either a sirolimus-eluting bioresorbable polymer stent (MiStent) or an everolimus-eluting durable polymer stent (Xience). Randomisation was done by local investigators via web-based software with random blocks according to centre. The primary endpoint was a non-inferiority comparison of a device-oriented composite endpoint (DOCE)-cardiac death, target-vessel myocardial infarction, or clinically indicated target lesion revascularisation-between the groups at 12 months after the procedure assessed by intention-to-treat. A margin of 4·0% was defined for non-inferiority of the MiStent group compared with the Xience group. All participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02385279. Between March 20, and Dec 3, 2015, we randomly assigned 1398 patients with 2030 lesions; 703 patients with 1037 lesions were assigned to MiStent, of whom 697 received the index procedure, and 695 patients with 993 lesions were asssigned to Xience, of whom 690 received the index procedure. At 12 months, the primary endpoint had occurred in 40 patients (5·8%) in the sirolimus-eluting stent group and in 45

Immunosuppression in Graves' ophthalmopathy

International Nuclear Information System (INIS)

Tian Rong; Kuang Anren; Qin Weishi; Zhang Huimin

2000-01-01

Objective: Graves' ophthalmopathy (GO) is a disease that seriously threatens the health of patients. But up to now, no optimal therapies have been established. Immunosuppressive treatment is usually used in the management of GO, but they may cause side effects. Recently, 99 Tc-MDP, commercially named 'Yun Ke', is used in the management of autoimmune disease. Therefore, a randomized trial was done to compare the values in the treatment of GO with between Yun Ke and immunosuppression. Methods: 42 consecutive patients with moderate or severe GO were randomly assigned to receive either Yun Ke therapy or immunosuppressive therapy. The degree of ocular involvement and responses to the treatment were evaluated by numerical scoring (ophthalmopathy index, OI) and clinical assessment. Therapy outcome was assessed 4 months after the start of treatment by the change in the highest NOSPECS class and OI. Data analysis was performed with the SPASS statistic software. Chi-square test was used to compare percentages, logistic regression was performed to identify which variables might correlated with the treatment outcome. Results: The remarkably effective outcome was observed in 14 (67%) cases in immunosuppression treated group and 13 (62%) cases in Yun Ke treated group. There were no significant differences in the degree of improvements in ocular involvements. There was a marked decrease of thyroid antibody titres in both groups. The variables found to correlated significantly with treatment outcome were thyroid antibody titres and GO activity. Side effects were more frequent and severe during immunosuppressive therapy. No side effects were found during Yun Ke treatment. Conclusion: Yun Ke and immunosuppression appeared to be equally effective in the management of GO, but Yun Ke is safer for patients during treatment

Differential Effects of Tacrolimus versus Sirolimus on the Proliferation, Activation and Differentiation of Human B Cells.

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Opas Traitanon

Full Text Available The direct effect of immunosuppressive drugs calcineurin inhibitor (Tacrolimus, TAC and mTOR inhibitor (Sirolimus, SRL on B cell activation, differentiation and proliferation is not well documented. Purified human B cells from healthy volunteers were stimulated through the B Cell Receptor with Anti-IgM + anti-CD40 + IL21 in the absence / presence of TAC or SRL. A variety of parameters of B cell activity including activation, differentiation, cytokine productions and proliferation were monitored by flow cytometry. SRL at clinically relevant concentrations (6 ng/ml profoundly inhibited CD19(+ B cell proliferation compared to controls whereas TAC at similar concentrations had a minimal effect. CD27(+ memory B cells were affected more by SRL than naïve CD27- B cells. SRL effectively blocked B cell differentiation into plasma cells (CD19(+CD138(+ and Blimp1(+/Pax5(low cells even at low dose (2 ng/ml, and totally eliminated them at 6 ng/ml. SRL decreased absolute B cell counts, but the residual responding cells acquired an activated phenotype (CD25(+/CD69(+ and increased the expression of HLA-DR. SRL-treated stimulated B cells on a per cell basis were able to enhance the proliferation of allogeneic CD4(+CD25(- T cells and induce a shift toward the Th1 phenotype. Thus, SRL and TAC have different effects on B lymphocytes. These data may provide insights into the clinical use of these two agents in recipients of solid organ transplants.

Immunosuppressant-Associated Neurotoxicity Responding to Olanzapine

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James A. Bourgeois

2014-01-01

Full Text Available Immunosuppressants, particularly tacrolimus, can induce neurotoxicity in solid organ transplantation cases. A lower clinical threshold to switch from tacrolimus to another immunosuppressant agent has been a common approach to reverse this neurotoxicity. However, immunosuppressant switch may place the graft at risk, and, in some cases, continuation of the same treatment protocol may be necessary. We report a case of immunosuppressant-associated neurotoxicity with prominent neuropsychiatric manifestation and describe psychiatric intervention with olanzapine that led to clinical improvement while continuing tacrolimus maintenance.

Efficacy of interventions for adherence to the immunosuppressive therapy in kidney transplant recipients: a meta-analysis and systematic review.

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Zhu, Yichen; Zhou, Yifan; Zhang, Lei; Zhang, Jian; Lin, Jun

2017-10-01

Immunosuppressive treatment regimens are complex and require ongoing self-management. Medication adherence can be difficult to achieve for several reasons. The current meta-analysis and systematic review investigated whether adherence interventions improved immunosuppressive treatment adherence in kidney transplant recipients. Medline, Cochrane, EMBASE, and Google Scholar were searched until October 17, 2016 using the following search terms: kidney transplantation, compliance, adherence, and immunosuppressive therapy. Randomized controlled trials and two-arm prospective, retrospective, and cohort studies were included. The primary outcomes were adherence rate and adherence score. Eight studies were included with a total for 546 patients. Among participants receiving intervention, the adherence rate was significantly higher than the control group (pooled OR=2.366, 95% CI 1.222 to 4.578, p=0.011). Participants in the intervention group had greater adherence scores than those in the control group (pooled standardized difference in means =1.706, 95% CI 0.346 to 3.065, p=0.014). Sensitivity analysis indicated that findings for adherence rate were robust. However, for adherence score, the significance of the association disappeared after removing one of the studies indicating the findings may have been overly influenced by this one study. Intervention programs designed to increase immunosuppressive adherence in patients with kidney transplant improve treatment adherence. Copyright © 2017 American Federation for Medical Research.

Patient survey to identify reasons for non-adherence and elicitation of quality of life concepts associated with immunosuppressant therapy in kidney transplant recipients

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Muduma G

2016-01-01

Full Text Available Gorden Muduma,1 Francis C Shupo,2 Sophie Dam,3 Natalia A Hawken,3 Samuel Aballéa,3 Isaac Odeyemi,1 Mondher Toumi4 1Astellas Pharma Europe Ltd, Chertsey, 2Creativ-Ceutical Ltd, London, UK; 3Creativ-Ceutical Ltd, Paris, 4Public Health (EA 3279, Faculty of Medicine, Aix-Marseille University, Marseille, France Background: Renal transplantation (RT is considered the treatment of choice for end-stage renal disease compared to dialysis, offering better health-related quality of life (HRQoL and higher survival rates. However, immunosuppressants are essential for the long-term survival of kidney grafts and patients’ non-adherence to their medication leads to poor outcomes. Immunosuppressants can also significantly alter patients’ HRQoL because of their side effects and the complex chronic medication regimen they represent. Purpose: To elicit key concepts related to adherence to immunosuppressant therapy (IT and reasons for non-adherence in terms of patient reported outcomes, side effects, and the impact of the medication on HRQoL in RT population, including patient preference of once daily over twice-daily immunosuppressive regimen. Results were used to develop an IT-specific conceptual framework and provide suggestions for improving patients’ adherence to IT. Materials and methods: Interviews were conducted with three clinical experts to determine key concepts related to RT and immunosuppressants. Thirty-seven participants in four focus groups were asked to cite important concepts related to adherence and impact of IT on HRQoL and to rate them. Qualitative analysis was conducted to code participants’ responses. Results: Non-adherence among participants where admitted was unintentional. The reason for this included forgetfulness, interference with lifestyle, being asleep at the time the medication should be taken, change in routine, and impact of side effects. Overall, participants reported that the evening dose was more problematic to remember

Clinical aspects of immunosuppression in poultry.

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Hoerr, Frederic J

2010-03-01

Chickens, turkeys, and other poultry in a production environment can be exposed to stressors and infectious diseases that impair innate and acquired immunity, erode general health and welfare, and diminish genetic and nutritional potential for efficient production. Innate immunity can be affected by stressful physiologic events related to hatching and to environmental factors during the first week of life. Exposure to environmental ammonia, foodborne mycotoxins, and suboptimal nutrition can diminish innate immunity. Infectious bursal disease (IBD), chicken infectious anemia (CIA), and Marek's disease (MD) are major infectious diseases that increase susceptibility to viral, bacterial, and parasitic diseases and interfere with acquired vaccinal immunity. A shared feature is lymphocytolytic infection capable of suppressing both humoral and cell-mediated immune functions. Enteric viral infections can be accompanied by atrophic and depleted lymphoid organs, but the immunosuppressive features are modestly characterized. Some reoviruses cause atrophy of lymphoid organs and replicate in blood monocytes. Enteric parvoviruses of chickens and turkeys merit further study for immunosuppression. Hemorrhagic enteritis of turkeys has immunosuppressive features similar to IBD. Other virulent fowl adenoviruses have immunosuppressive capabilities. Newcastle disease can damage lymphoid tissues and macrophages. Avian pneumovirus infections impair the mucociliary functions of the upper respiratory tract and augment deeper bacterial infections. Recognition of immunosuppression involves detection of specific diseases using diagnostic tests such as serology, etiologic agent detection, and pathology. Broader measurements of immunosuppression by combined noninfectious and infectious causes have not found general application. Microarray technology to detect genetic expression of immunologic mediators and receptors offers potential advances but is currently at the developmental state. Control

Type D personality predicts death or myocardial infarction after bare metal stent or sirolimus-eluting stent implantation

DEFF Research Database (Denmark)

Pedersen, Susanne S.; Lemos, Pedro A; van Vooren, Priya R

2004-01-01

We investigated the effect of Type D personality on the occurrence of adverse events at nine months in patients with ischemic heart disease (IHD) after percutaneous coronary intervention (PCI) with sirolimus-eluting stents (SESs) or bare stents. Type D patients experience increased negative...

Randomized Phase II Trial Evaluating Two Paclitaxel and Cisplatin–Containing Chemoradiation Regimens As Adjuvant Therapy in Resected Gastric Cancer (RTOG-0114)

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Schwartz, Gary K.; Winter, Kathryn; Minsky, Bruce D.; Crane, Christopher; Thomson, P. John; Anne, Pramila; Gross, Howard; Willett, Christopher; Kelsen, David

2009-01-01

Purpose The investigational arm of INT0116, a fluorouracil (FU) and leucovorin–containing chemoradiotherapy regimen, is a standard treatment for patients with resected gastric cancer with a 2-year disease-free survival rate (DFS) of 52%. Toxicity is also significant. More beneficial and safer regimens are needed. Patients and Methods We performed a randomized phase II study among 39 cancer centers to evaluate two paclitaxel and cisplatin–containing regimens, one with FU (PCF) and the other without (PC) in patients with resected gastric cancer. Patients received two cycles of postoperative chemotherapy followed by 45 Gy of radiation with either concurrent FU and paclitaxel or paclitaxel and cisplatin. The primary objective was to show an improvement in 2-year DFS to 67% as compared with INT 0116. Results From May 2001 to February 2004 (study closure), 78 patients entered this study, and 73 were evaluable. At the planned interim analysis of 22 patients on PCF, grade 3 or higher GI toxicity was 59%. This was significantly worse than INT0116, and this arm was closed. Accrual continued on PC. The median DFS was 14.6 months for PCF and has not been reached for PC. For PC the 2-year DFS is 52% (95% CI, 36% to 68%). Conclusion Though PC appears to be safe and the median DFS favorable, the DFS failed to exceed the lower bound of 52.9% for the targeted 67% DFS at 2 years and can not be recommended as the adjuvant arm for future randomized trials. PMID:19273696

Effects of immunosuppressive treatment on protein expression in rat kidney

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Kędzierska K

2014-09-01

Full Text Available Karolina Kędzierska,1 Katarzyna Sporniak-Tutak,2 Krzysztof Sindrewicz,2 Joanna Bober,3 Leszek Domański,1 Mirosław Parafiniuk,4 Elżbieta Urasińska,5 Andrzej Ciechanowicz,6 Maciej Domański,1 Tomasz Smektała,2 Marek Masiuk,5 Wiesław Skrzypczak,6 Małgorzata Ożgo,6 Joanna Kabat-Koperska,1 Kazimierz Ciechanowski1 1Department of Nephrology, Transplantology, and Internal Medicine, 2Department of Dental Surgery, 3Department of Medical Chemistry, 4Department of Forensic Medicine, 5Department of Pathomorphology, Pomeranian Medical University, 6Department of Physiology, Cytobiology, and Proteomics, West Pomeranian University of Technology, Szczecin, Poland Abstract: The structural proteins of renal tubular epithelial cells may become a target for the toxic metabolites of immunosuppressants. These metabolites can modify the properties of the proteins, thereby affecting cell function, which is a possible explanation for the mechanism of immunosuppressive agents' toxicity. In our study, we evaluated the effect of two immunosuppressive strategies on protein expression in the kidneys of Wistar rats. Fragments of the rat kidneys were homogenized after cooling in liquid nitrogen and then dissolved in lysis buffer. The protein concentration in the samples was determined using a protein assay kit, and the proteins were separated by two-dimensional electrophoresis. The obtained gels were then stained with Coomassie Brilliant Blue, and their images were analyzed to evaluate differences in protein expression. Identification of selected proteins was then performed using mass spectrometry. We found that the immunosuppressive drugs used in popular regimens induce a series of changes in protein expression in target organs. The expression of proteins involved in drug, glucose, amino acid, and lipid metabolism was pronounced. However, to a lesser extent, we also observed changes in nuclear, structural, and transport proteins' synthesis. Very slight differences

Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial.

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Petrou, Philip A; Cunningham, Denise; Shimel, Katherine; Harrington, Molly; Hammel, Keri; Cukras, Catherine A; Ferris, Frederick L; Chew, Emily Y; Wong, Wai T

2014-12-18

To investigate the safety and effects of intravitreal sirolimus for the potential treatment of geographic atrophy (GA). The study was a single-center, open-label, phase I/II trial enrolling six participants with bilateral GA treated with intravitreal sirolimus in only one randomly assigned eye, with the fellow eye as control. The primary efficacy outcome measure was the change in total GA area from baseline on color fundus photography (CFP); secondary outcomes included changes in GA area on fundus autofluorescence (FAF), visual acuity, central retinal thickness (CRT), and macular sensitivity from baseline. Although no systemic adverse events were attributed to treatment, two of six participants had ocular adverse events that were possibly associated. The treated eye of one participant developed abnormal paralesional changes on FAF that were associated with accelerated retinal thinning. This accelerated retinal thinning was also seen in the treated eye of a second participant. Because of concern that these events were associated with treatment, treatment was suspended. Comparisons of treated and fellow eyes for change in visual acuity, change in GA area, and change in CRT showed no evidence of treatment benefit and generally favored the untreated fellow eye. While paralesional FAF changes and rapid retinal thinning observed are potentially part of the natural course of GA, they may possibly be related to treatment. No general evidence of anatomical or functional benefit was detected in treated eyes. Further data on intravitreal sirolimus for GA treatment will be available from a larger phase II trial. (ClinicalTrials.gov number, NCT01445548.). Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.

Influence of immunosuppressive drugs on the CD30 molecule in kidney transplanted patients.

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Grenzi, Patricia Cristina; Campos, Érika Fernandes; Tedesco-Silva, Hélio; Felipe, Claudia Rosso; Soares, Maria Fernanda; Medina-Pestana, José; Hansen, Hinrich Peter; Gerbase-DeLima, Maria

2018-04-12

Soluble CD30 (sCD30) is a suggested marker for kidney transplantation outcomes. We investigated whether sCD30 serum levels are influenced by immunosuppression and whether they correlate with findings in protocol biopsies and with CD30 gene expression in peripheral blood mononuclear cells (PBMC). We studied 118 kidney transplant recipients that initially received tacrolimus (TAC) and, at month-3, were converted or not to sirolimus (SRL). sCD30 serum levels gradually declined after transplantation, being the decline more pronounced in the SRL group. CD30 gene expression in PBMC was higher in the SRL group than in the TAC group. Patients with IF/TA ≥ I in the month-24 protocol biopsy had higher sCD30 levels than patients without IF/TA, in the SRL group (P = .03) and in the TAC group (P = .07). CD30 + cells were observed in three out of 10 biopsies with inflammatory infiltrate from the SRL group. In mixed lymphocyte cultures, SRL and TAC diminished the number of CD30 + T cells and the sCD30 levels in the supernatant, but the effect of SRL was stronger. Overall, sCD30 levels are lower in SRL-treated patients, but the association between increased sCD30 levels and IF/TA at month-24 post-transplantation is stronger in SRL than in TAC-treated patients. Copyright © 2018 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Extended follow-up of the CYCLOFA-LUNE trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide or on cyclosporine A.

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Závada, J; Sinikka Pesicková, S; Rysavá, R; Horák, P; Hrncír, Z; Lukác, J; Rovensky, J; Vítová, J; Havrda, M; Rychlík, I; Böhmova, J; Vlasáková, V; Slatinská, J; Zadrazil, J; Olejárová, M; Tegzova, D; Tesar, V

2014-01-01

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0-10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Gender difference on five-year outcomes of EXCEL biodegradable polymer-coated sirolimus-eluting stents implantation: results from the CREATE study.

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Zhang, Lei; Qiao, Bing; Han, Ya-Ling; Li, Yi; Xu, Kai; Zhang, Quan-Yu; Yang, Li-Xia; Liu, Hui-Liang; Xu, Bo; Gao, Run-Lin

2013-03-01

The gender difference on long-term outcome in unselected patients after percutaneous coronary intervention (PCI) has not yet been fully investigated. This study aimed to evaluate the gender difference on five-year outcomes following EXCEL biodegradable polymer-coated sirolimus-eluting stenting in patients with coronary disease. A total of 2077 "all comers", consisting of 1528 (73.6%) men and 549 (26.4%) women, who were exclusively treated with EXCEL coronary stents were enrolled in the prospective CREATE study at 59 centers from four countries. After propensity score matching, the baseline characteristics of the two groups were well matched. Recommended antiplatelet regimen was clopidogrel and aspirin for six months followed by chronic aspirin therapy. The primary outcome that was the rate of major adverse cardiac events (MACE), defined as a composite of cardiac mortality, non-fatal myocardial infarction (MI) and target lesion revascularization (TLR), and stent thrombosis (ST) at five years were compared between the two gender groups. In the two groups, women had higher proportions of clinical risk factors, such as being elderly, diabetes mellitus, hypertension and hyperlipidemia, compared to men. Besides, the mean target vessel number per patient was higher and the mean reference vessel diameter smaller for women. Men had higher risks of cardiac death (3.7% vs. 1.6%, P = 0.021) and MACE (8.4% vs. 4.7%, P = 0.004) at five years compared with women. However, the cumulative hazards of non-fatal MI and TLR were similar between men and women. The incidence of Academic Research Consortium (ARC) definite or probable stent thrombosis was similar between the two groups (1.3% vs. 1.0%, P = 0.639). Prolonged clopidogrel therapy (>6 months) did not reduce the cumulative hazards of ST from six months to five years in both men (χ(2) = 0.098, log rank P = 0.754) and women (χ(2) = 2.043, log rank P = 0.153) patients. Women had a lower MACE and cardiac death rate than men after

Third-line rescue therapy with bismuth-containing quadruple regimen after failure of two treatments (with clarithromycin and levofloxacin) for H. pylori infection.

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Gisbert, J P; Perez-Aisa, A; Rodrigo, L; Molina-Infante, J; Modolell, I; Bermejo, F; Castro-Fernández, M; Antón, R; Sacristán, B; Cosme, A; Barrio, J; Harb, Y; Gonzalez-Barcenas, M; Fernandez-Bermejo, M; Algaba, A; Marín, A C; McNicholl, A G

2014-02-01

Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI), clarithromycin, and amoxicillin fails in >20 % of cases. A rescue therapy with PPI-amoxicillin-levofloxacin still fails in >20 % of patients. To evaluate the efficacy and tolerability of a bismuth-containing quadruple regimen in patients with two consecutive eradication failures. Prospective multicenter study of patients in whom 1st treatment with PPI-clarithromycin-amoxicillin and 2nd with PPI-amoxicillin-levofloxacin had failed. A 3rd eradication regimen with a 7- to 14-day PPI (standard dose b.i.d.), bismuth subcitrate (120 mg q.i.d. or 240 mg b.i.d.), tetracycline (from 250 mg t.i.d. to 500 mg q.i.d.) and metronidazole (from 250 mg t.i.d. to 500 mg q.i.d.). Eradication was confirmed by (13)C-urea-breath-test 4-8 weeks after therapy. Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated by means of a questionnaire. Two hundred patients (mean age 50 years, 55 % females, 20 % peptic ulcer/80 % uninvestigated-functional dyspepsia) were initially included, and two were lost to follow-up. In all, 97 % of patients complied with the protocol. Per-protocol and intention-to-treat eradication rates were 67 % (95 % CI 60-74 %) and 65 % (58-72 %). Adverse effects were reported in 22 % of patients, the most common being nausea (12 %), abdominal pain (11 %), metallic taste (8.5 %), and diarrhea (8 %), none of them severe. A bismuth-containing quadruple regimen is an acceptable third-line strategy and a safe alternative after two previous H. pylori eradication failures with standard clarithromycin- and levofloxacin-containing triple therapies.

Efficacy and safety of early tacrolimus conversion to sirolimus after kidney transplantation: Long-term results of a prospective randomized study

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A E El-Agroudy

2017-01-01

Full Text Available We report a prospective, open-label, randomized study to evaluate the safety and efficacy of converting patients with a stable renal function from tacrolimus (Tac-based regimen to a sirolimus (SRL-based regimen after kidney transplantation. Fifty-eight low-risk renal allograft recipients who receiving Tac 6 months posttransplant, were randomly assigned to continue Tac (n = 29 or convert to SRL (n = 29. We evaluated the 3-year outcomes including patient and graft survival, graft function, and safety profile. Three-year patient and graft survival in SRL and Tac groups were 93.1% versus 100% (P = 0.32, and 89.7% versus 100% (P = 0.11, respectively. However, the SRL group had a significantly better renal function, from the 2nd year posttransplant until the last follow-up. Four (13.8% patients in the SRL group and 3 (10.3% in the Tac group (P = 0.5 developed biopsy-proven acute rejection. Mean urinary protein excretion increased significantly after SRL conversion. Diastolic blood pressure was significantly lower at the end of the study in patients who eliminated Tac (80.4 vs. 75.6 mmHg in Tac and SRL group, respectively (P = 0.03. Mean hemoglobin concentrations decreased after SRL conversion and remained significantly lower from 12 months to 36 months (P = 0.01. The mean serum cholesterol (540 ± 44 mg/dl and triglyceride (177 ± 27 mg/dl increased significantly in the SRL group, compared to Tac group (487 ± 62 mg/dl (P = 0.03 and (141 ± 26 mg/dl (P = 0.04. Our experience demonstrates that conversion to SRL from calcineurin inhibitors-based therapy may result in better renal function and blood pressure control in renal transplant recipients without an increased risk of acute rejection. However, these benefits have not resulted in a growing advantage in graft or patient survival.

Switch from a ZDV/3TC-based regimen to a completely once daily (QD regimen of emtricitabine/tenofovir DF fixed dose combination plus a third QD agent (SONETT

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Arasteh K

2009-05-01

Full Text Available Abstract Objectives To assess the efficacy and safety of a treatment switch from a twice-daily (BID regimen containing zidovudine (ZDV and lamivudine (3TC plus a third agent to a once daily (QD regimen containing the fixed-dose combination of tenofovir DF/emtricitabine (TDF/FTC, Truvada® plus a divergent third QD agent in HIV-1 infected patients. Methods Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA 50 cells/μl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. Results During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs. At week 48, plasma HIV-1 RNA was p Conclusions Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.

Hyperbaric Oxygen Therapy as a Sole Agent Is Not Immunosuppressant in a Highly Immunogenic Mouse Model

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Adam Gassas

2011-01-01

Full Text Available Background. Hyperbaric oxygen (HBO therapy, which is used for many conditions, may also have immunosuppressive effects and could be used for prevention or treatment of graft-versus-host disease (GvHD. If HBO is immunosuppressant, then we hypothesize that HBO therapy will delay the T-cell mediated skin graft rejection. Methods. C57/BL6 black-coated (H2B mice received skin graft from CBA (H2D white-coated mice. Mice were treated with either 19 session of 240 kpa oxygen or 29 session of 300 kpa oxygen, for 90 minutes. Mice were housed either 4 per cage or separately, to prevent friction and mechanical factors that may affect graft survival. Skin grafts were assessed daily. Results. There was no difference in length of graft survival between mice that received either regimens of HBO therapy and mice that did not receive HBO therapy. Conclusions. HBO therapy, as a sole agent, did not delay skin graft rejection in a highly immunogenic mouse model.

Immunosuppressive drugs and fertility.

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Leroy, Clara; Rigot, Jean-Marc; Leroy, Maryse; Decanter, Christine; Le Mapihan, Kristell; Parent, Anne-Sophie; Le Guillou, Anne-Claire; Yakoub-Agha, Ibrahim; Dharancy, Sébastien; Noel, Christian; Vantyghem, Marie-Christine

2015-10-21

Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs.

Immunosuppressive drugs and fertility

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Leroy, Clara; Rigot, Jean-Marc; Leroy, Maryse; Decanter, Christine; Le Mapihan, Kristell; Parent, Anne-Sophie; Le Guillou, Anne-Claire; Yakoub-Agha, Ibrahim; Dharancy, Sébastien; Noel, Christian; Vantyghem, Marie-Christine

2015-01-01

Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior ...

Development and Validation of an HPLC Method for the Analysis of Sirolimus in Drug Products

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Hadi Valizadeh

2012-05-01

Full Text Available Purpose: The aim of this study was to develop a simple, rapid and sensitive reverse phase high performance liquid chromatography (RP-HPLC method for quantification of sirolimus (SRL in pharmaceutical dosage forms. Methods: The chromatographic system employs isocratic elution using a Knauer- C18, 5 mm, 4.6 × 150 mm. Mobile phase consisting of acetonitril and ammonium acetate buffer set at flow rate 1.5 ml/min. The analyte was detected and quantified at 278nm using ultraviolet detector. The method was validated as per ICH guidelines. Results: The standard curve was found to have a linear relationship (r2 > 0.99 over the analytical range of 125–2000ng/ml. For all quality control (QC standards in intraday and interday assay, accuracy and precision range were -0.96 to 6.30 and 0.86 to 13.74 respectively, demonstrating the precision and accuracy over the analytical range. Samples were stable during preparation and analysis procedure. Conclusion: Therefore the rapid and sensitive developed method can be used for the routine analysis of sirolimus such as dissolution and stability assays of pre- and post-marketed dosage forms.

Etoposide-containing conditioning regimen reduces the occurrence of hemophagocytic lymphohistiocytosis after SCT.

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Kobayashi, R; Tanaka, J; Hashino, S; Ota, S; Torimoto, Y; Kakinoki, Y; Yamamoto, S; Kurosawa, M; Hatakeyama, N; Haseyama, Y; Sakai, H; Sato, K; Fukuhara, T

2014-02-01

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease of severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages that secrete high amounts of inflammatory cytokines. HLH occurring after SCT is difficult to diagnose. It is characterized by severe clinical manifestations and high mortality. Despite current therapeutic approaches, outcomes remain poor. We analyzed the incidence and risk factors of HLH after SCT and the response to treatment and prognosis of 554 patients with HLH after SCT. The cumulative incidence of HLH after SCT was 4.3% (24/554). Use of etoposide in the conditioning regimen was only factor that reduced HLH after SCT (P=0.027). All patients who received autologous transplantation were successfully treated. Patients with liver dysfunction (for example, high total bilirubin level, prolonged prothrombin time and high level of fibrinogen degradation products) had a poor response to treatment for HLH. Physicians should be cautious of HLH, while not using etoposide for conditioning regimen.

Immunomodulator, immunosuppression of radiation and immune reconstruction

International Nuclear Information System (INIS)

Mao Jianping; Fang Jing; Zhou Ying; Cui Yufang; Jiang Zhujun; Du Li; Ma Qiong

2010-01-01

There is a refined and complicated regulatory network between immune cells, and between immune cells and secretory factors. The immune system is kept in a homeostasis and equilibrium by positive activation and negative inhibition. In recent years, the mechanisms of immunosuppression in depth for successful allograft transplantation were studied, and many immunosuppressants and immunosuppressive drugs have been developed for clinical use. Most of them are targeting T cell receptors and three kinds of singnal pathways. The receptors of the immunosuppression were either found highly expressed in immune cells after irradiation. To relieve the suppression by regulating the receptors could help the immune reconstruction out of radiation damage. Many new immunoenhancers have been discovered to improve the immune system function for radiation by Toll-like receptors. The search for new immunoenhancers and agents for relieving immunosuppression is of great importance to immune construction for radiation sickness. (authors)

Effects of immunosuppression on circulating adeno-associated virus capsid-specific T cells in humans.

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Parzych, Elizabeth M; Li, Hua; Yin, Xiangfan; Liu, Qin; Wu, Te-Lang; Podsakoff, Gregory M; High, Katherine A; Levine, Matthew H; Ertl, Hildegund C J

2013-04-01

In humans adeno-associated virus (AAV)-mediated gene transfer is followed by expansion of AAV capsid-specific T cells, evidence of cell damage, and loss of transgene product expression, implicating immunological rejection of vector-transduced cells, which may be prevented by immunosuppressive drugs. We undertook this study to assess the effect of immunosuppression (IS) used for organ transplantation on immune responses to AAV capsid antigens. Recipients of liver or kidney transplants were tested before and 4 weeks after induction of IS in comparison with matched samples from healthy human adults and an additional cohort with comorbid conditions similar to those of the transplant patients. Our data show that transplant patients and comorbid control subjects have markedly higher frequencies of circulating AAV capsid-specific T cells compared with healthy adults. On average, IS resulted in a reduction of AAV-specific CD4⁺ T cells, whereas numbers of circulating CD8⁺ effector and central memory T cells tended to increase. Independent of the type of transplant or the IS regimens, the trend of AAV capsid-specific T cell responses after drug treatment varied; in some patients responses were unaffected whereas others showed decreases or even pronounced increases, casting doubt on the usefulness of prophylactic IS for AAV vector recipients.

Stent implantation into the tracheo-bronchial system in rabbits: histopathologic sequelae in bare metal vs. drug-eluting stents.

Science.gov (United States)

Sigler, Matthias; Klötzer, Julia; Quentin, Thomas; Paul, Thomas; Möller, Oliver

2015-12-01

Stent implantation into the tracheo-bronchial system may be life-saving in selected pediatric patients with otherwise intractable stenosis of the upper airways. Following implantation, significant tissue proliferation may occur, requiring re-interventions. We sought to evaluate the effect of immunosuppressive coating of the stents on the extent of tissue proliferation in an animal model. Bare metal and sirolimus-coated stents (Bx Sonic and Cypher Select, Johnson & Johnson, Cordis) were implanted into non-stenotic lower airways of New Zealand white rabbits (weight 3.1 to 4.8 kg). Three stents with sirolimus coating and six bare metal stents could be analyzed by means of histology and immunohistochemistry 12 months after implantation. On a macroscopic evaluation, all stents were partially covered with a considerable amount of whitish tissue. Histologically, these proliferations contained fiber-rich connective tissue and some fibromuscular cells without significant differences between both stent types. The superficial tissue layer was formed by typical respiratory epithelium and polygonal cells. Abundant lymphocyte infiltrations and moderate granulocyte infiltrations were found in both groups correspondingly, whereas foreign-body reaction was more pronounced around sirolimus-eluting stents. After stent implantation in the tracheo-bronchial system of rabbits, we found tissue reactions comparable to those seen after stent implantation into the vascular system. There was no difference between coated and uncoated stents with regard to quality and quantity of tissue proliferation. We found, however, a significantly different inflammatory reaction with a more pronounced foreign-body reaction in sirolimus-coated stents. In our small series, drug-eluting stents did not exhibit any benefit over bare metal stents in an experimental setting.

Randomised study to assess the efficacy and safety of once-daily etravirine-based regimen as a switching strategy in HIV-infected patients receiving a protease inhibitor-containing regimen. Etraswitch study.

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Patricia Echeverría

Full Text Available Etravirine (ETR was approved for patients with virological failure and antiretroviral resistance mutations. It has also shown antiviral efficacy in antiretroviral-naïve patients. However, data on the switching from protease inhibitors (PI to ETR are lacking.HIV-1-infected patients with suppressed viral load (VL during a PI-containing regimen (>12 months and no previous virological failure were randomized to switch from the PI to ETR (400 mg/day, dissolved in water (ETR group, n = 22 or to continue with the same regimen (control group, n = 21. Percentage of patients with VL ≤ 50 copies/mL were assessed at week 48, as well as changes in CD4 T-cell counts and metabolic profile.We included 43 patients [72.9% male, 46.3 (42.2; 50.6 years]. Two patients receiving ETR (grade-1 diarrhea and voluntary discontinuation and another in the control group (simplification discontinued therapy early. No patients presented virological failure (two consecutive VL>50 copies/mL; treatment was successful in 95.2% of the control group and 90.9% of the ETR group (intention-to-treat analysis, missing = failure (p = 0.58. CD4+ T-cell counts did not significantly vary [+49 cells/µL in the ETR group (p = 0.25 and -4 cells/µL in the control group (p = 0.71]. The ETR group showed significant reductions in cholesterol (p<0.001, triglycerides (p = <0.001, and glycemia (p = 0.03 and higher satisfaction (0-10 scale (p = 0.04. Trough plasma concentrations of ETR were similar to observed in studies using ETR twice daily.Switch from a PI-based regimen to a once-daily combination based on ETR maintained undetectable VL during 48 weeks in virologically suppressed HIV-infected patients while lipid profile and patient satisfaction improved significantly.ClinicalTrials.gov NCT01034917.

The SABRE Trial (Sirolimus Angioplasty Balloon for Coronary In-Stent Restenosis)

DEFF Research Database (Denmark)

Verheye, Stefan; Vrolix, Mathias; Kumsars, Indulis

2017-01-01

centers, 50 ISR patients were treated with the Virtue balloon. Angiographic measurements at 6 months are reported, along with 12-month clinical follow-up. RESULTS Procedural success in the intention-to-treat population was 100 The primary safety endpoint was target lesion failure (TLF) (cardiac death...... and 14.3% MACE and for the per-protocol population were 2.8% TLF and 2.8% MACE. CONCLUSIONS This first-in-human study showed excellent procedural success for the Virtue sirolimus-eluting angioplasty balloon, 6-month LLL rates in line with current stent-free ISR treatment options, and clinical outcomes...

A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen

DEFF Research Database (Denmark)

Duijkers, Ingrid J M; Heger-Mahn, Doris; Drouin, Dominique

2015-01-01

OBJECTIVES: Progestogen-only pills (POPs) are safer with respect to cardiovascular risks than contraceptives containing estrogens. Despite the increased contraceptive efficacy of a desogestrel-only pill compared with a traditional POP, POPs are still not widely used due to an unpredictable bleeding...... pattern. A new POP containing 4 mg drospirenone has been developed with a 24/4 intake regimen which may improve the bleeding pattern. The objectives of this study were to investigate ovulation inhibition with the new drospirenone-only pill in comparison with the desogestrel-only pill and, in addition......, to assess the effects on cervical mucus permeability and bleeding. METHODS: Sixty-four healthy volunteers with proven ovulatory cycles were randomised and treated with either the drospirenone-only or the desogestrel-only pill during two 28-day cycles. Follicular diameter, endometrial thickness, and serum...

Generic immunosuppression in transplantation: current evidence and controversial issues.

Science.gov (United States)

El Hajj, Sandra; Kim, Miae; Phillips, Karen; Gabardi, Steven

2015-05-01

The overall success of organ transplantation in the 21st century has been predicated, in part, on the use of newer, more potent, and selective immunosuppressive agents. However, the high cost of lifelong immunosuppression represents a financial burden for many patients. In the past 15 years, regulatory agencies in Europe and America have approved several generic immunosuppressants. One concern is whether the conversion between innovator and generic immunosuppressants will prove to be problematic. This manuscript aims to compare and contrast the bioequivalence requirements among regulatory authorities in the USA, Europe, and Canada, evaluate published studies of generic immunosuppressants in transplant recipients, summarize consensus statements made by transplant organizations and discuss how to engage patients in discussion regarding the choice between innovator and generic immunosuppressants.

Safety and Efficacy of Everolimus- Versus Sirolimus-Eluting Stents

DEFF Research Database (Denmark)

Jensen, Lisette Okkels; Thayssen, Per; Christiansen, Evald Høj

2016-01-01

BACKGROUND: Long-term safety and efficacy for everolimus-eluting stents (EES) versus those of sirolimus-eluting stents (SES) are unknown. OBJECTIVES: This study compared 5-year outcomes for EES with those for SES from the SORT OUT IV (Scandinavian Organization for Randomized Trials with Clinical...... rate was lower with EES (HR: 0.71, 95% CI: 0.55 to 0.90; p = 0.006; p interaction = 0.12). Definite stent thrombosis was lower with EES (0.4%) than with SES (2.0%; HR: 0.18, 95% CI: 0.07 to 0.46), with a lower risk of very late definite stent thrombosis in the EES group (0.2% vs. 1.4%, respectively; HR...... in Non-selected Patients With Coronary Heart Disease [SORT OUT IV]; NCT00552877)....

Chlorphenesin: an antigen-associated immunosuppressant.

Science.gov (United States)

Whang, H Y; Neter, E

1970-07-01

Chlorphenesin (3-p-chlorophenoxy-1,2-propanediol), when injected intravenously together with either of two common bacterial antigens, inhibits the antibody response of the rabbit. The antigens studied are those common to Enterobacteriaceae and to gram-positive bacteria. The immunosuppression is contingent upon incubation of chlorphenesin and antigen in vitro prior to administration, since separate injection of antigen and inhibitor or of mixtures without prior incubation yields undiminished antibody response. Chlorphenesin, as shown by hemagglutination-inhibition tests, does not alter the antigenic determinants, because antibody neutralization occurs in the presence or absence of the drug. The immunosuppressive effect is reversible, since precipitation of chlorphenesin at 4 C substantially restores immunogenicity. Animals immunized with antigen-drug mixtures, which fail to respond with significant antibody production, nonetheless are immunologically primed. It is concluded that chlorphenesin represents another example of antigen-associated immunosuppressants.

Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality.

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Carole D Mitnick

Full Text Available A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort.This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7 drugs. Cure or completion was achieved in 66.1% (442 of patients; death occurred in 20.8% (139. Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89, compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93.The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

The performance of five different dried blood spot cards for the analysis of six immunosuppressants

NARCIS (Netherlands)

Koster, Remco A.; Botma, Rixt; Greijdanus, Ben; Uges, Donald R. A.; Kosterink, Jos G. W.; Touw, Daan J.; Alffenaar, Jan-Willem C.

2015-01-01

Background: The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT

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Lorf Thomas

2010-04-01

Full Text Available Abstract Background Immunosuppression with calcineurin inhibitors (CNI increases the risk of renal dysfunction after orthotopic liver transplantation (OLT. Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods/Design A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate, liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT, treatment failure, (i. e., re-introduction of CNI, incidence of adverse events, and mortality up to one year after OLT. Discussion This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation of this phase III trial. Trial registration number NCT00890253 (clinicaltrials.gov

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

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Gianluigi Zaza

Full Text Available The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined.We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group, and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group.A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05. Flagellar motor switch protein (fliNY and type IV pilus assembly protein pilM (pilM were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity.Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen.

Science.gov (United States)

Zaza, Gianluigi; Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

2017-01-01

The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this objective.

Impact of maintenance immunosuppressive therapy on the fecal microbiome of renal transplant recipients: Comparison between an everolimus- and a standard tacrolimus-based regimen

Science.gov (United States)

Dalla Gassa, Alessandra; Felis, Giovanna; Granata, Simona; Torriani, Sandra; Lupo, Antonio

2017-01-01

Background The gut microbiome is the full set of microbes living in the gastrointestinal tract and is emerging as an important dynamic/fluid system that, if altered by environmental, dietetic or pharmacological factors, could considerably influence drug response. However, the immunosuppressive drug-induced modifications of this system are still poorly defined. Methods We employed an innovative bioinformatics approach to assess differences in the whole-gut microbial metagenomic profile of 20 renal transplant recipients undergoing maintenance treatment with two different immunosuppressive protocols. Nine patients were treated with everolimus plus mycophenolate mofetil (EVE+MMF group), and 11 patients were treated with a standard therapy with tacrolimus plus mycophenolate mofetil (TAC+MMF group). Results A statistical analysis of comparative high-throughput data demonstrated that although similar according to the degree of Shannon diversity (alpha diversity) at the taxonomic level, three functional genes clearly discriminated EVE+MMF versus TAC+MMF (cutoff: log2 fold change≥1, FDR≤0.05). Flagellar motor switch protein (fliNY) and type IV pilus assembly protein pilM (pilM) were significantly enriched in TAC+MMF-treated patients, while macrolide transport system mrsA (msrA) was more abundant in patients treated with EVE+MMF. Finally, PERMANOVA revealed that among the variables analyzed and included in our model, only the consumption of sugar significantly influenced beta diversity. Conclusions Our study, although performed on a relatively small number of patients, showed, for the first time, specific immunosuppressive-related effects on fecal microbiome of renal transplant recipients and it suggested that the analysis of the gut microbes community could represent a new tool to better understand the effects of drugs currently employed in organ transplantations. However, multicenter studies including healthy controls should be undertaken to better address this

A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model.

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Abhiram R Bhashyam

Full Text Available Previously, we have demonstrated that mucociliary clearance (MCC is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation.Fifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls were intraperitoneally injected with three 100 µL doses of phosphate buffered saline and eight mice (immunosuppressed were injected with three 100 µL injections of tacrolimus (1 mg/kg, mycophenolate mofetil (30 mg/kg, and prednisone (2 mg/kg once daily. Then, mice inhaled the radioisotope (99mtechnetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1-1.5 hrs and at 6-6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance.Although there was a slowing of MCC at 1-1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1-1.5 hrs for the two groups of mice. At 6-6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78±5.9% cleared versus 23.01±11.7% cleared, respectively (p = 0.006.These preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery.

Merkel Cell Carcinoma in Immunosuppressed Patients

Energy Technology Data Exchange (ETDEWEB)

Ma, Janice E. [Mayo Clinic College of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (United States); Brewer, Jerry D., E-mail: brewer.jerry@mayo.edu [Department of Dermatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (United States)

2014-06-27

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients.

Merkel Cell Carcinoma in Immunosuppressed Patients

International Nuclear Information System (INIS)

Ma, Janice E.; Brewer, Jerry D.

2014-01-01

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy. The infectivity of Merkel cell polyomavirus (MCPyV), an apparent agent in MCC development, may be exacerbated with impaired immune responses. This paper reviews relevant data regarding the role of immunosuppression in the development of MCC and describes modes of immunodeficient states. Because of the inherently low incidence rate of MCC, several case studies and series are also briefly mentioned to provide a more comprehensive summary of MCC in the setting of immunosuppression. We describe immunosuppressed patients who have experienced excessive UV radiation, organ transplantation, human immunodeficiency virus infection/AIDS, autoimmune diseases, and lymphoproliferative disorders. Iatrogenic forms of immunosuppression are also highlighted. Studies that quantify risks consistently report that individuals with a history of solid organ transplantation, autoimmune diseases, AIDS, and/or lymphoproliferative diseases have a significantly elevated risk of developing MCC. Overall, immunocompromised patients also appear to have an early onset and more aggressive course of MCC, with poorer outcomes. Recommendations for multidisciplinary approaches are proposed to effectively prevent and manage MCC in these patients

Transcultural adaptation and initial validation of Brazilian-Portuguese version of the Basel assessment of adherence to immunosuppressive medications scale (BAASIS) in kidney transplants.

Science.gov (United States)

Marsicano, Elisa de Oliveira; Fernandes, Neimar da Silva; Colugnati, Fernando; Grincenkov, Fabiane Rossi dos Santos; Fernandes, Natalia Maria da Silva; De Geest, Sabina; Sanders-Pinheiro, Helady

2013-05-21

Transplant recipients are expected to adhere to a lifelong immunosuppressant therapeutic regimen. However, nonadherence to treatment is an underestimated problem for which no properly validated measurement tool is available for Portuguese-speaking patients. We aimed to initially validate the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS®) to accurately estimate immunosuppressant nonadherence in Brazilian transplant patients. The BAASIS® (English version) was transculturally adapted and its psychometric properties were assessed. The transcultural adaptation was performed using the Guillemin protocol. Psychometric testing included reliability (intraobserver and interobserver reproducibility, agreement, Kappa coefficient, and the Cronbach's alpha) and validity (content, criterion, and construct validities). The final version of the transculturally adapted BAASIS® was pretested, and no difficulties in understanding its content were found. The intraobserver and interobserver reproducibility variances (0.007 and 0.003, respectively), the Cronbach's alpha (0.7), Kappa coefficient (0.88) and the agreement (95.2%) suggest accuracy, preciseness and reliability. For construct validity, exploratory factorial analysis demonstrated unidimensionality of the first three questions (r = 0.76, r = 0.80, and r = 0.68). For criterion validity, the adapted BAASIS® was correlated with another self-report instrument, the Measure of Adherence to Treatment, and showed good congruence (r = 0.65). The BAASIS® has adequate psychometric properties and may be employed in advance to measure adherence to posttransplant immunosuppressant treatments. This instrument will be the first one validated to use in this specific transplant population and in the Portuguese language.

Hand hygiene regimens for the reduction of risk in food service environments.

Science.gov (United States)

Edmonds, Sarah L; McCormack, Robert R; Zhou, Sifang Steve; Macinga, David R; Fricker, Christopher M

2012-07-01

Pathogenic strains of Escherichia coli and human norovirus are the main etiologic agents of foodborne illness resulting from inadequate hand hygiene practices by food service workers. This study was conducted to evaluate the antibacterial and antiviral efficacy of various hand hygiene product regimens under different soil conditions representative of those in food service settings and assess the impact of product formulation on this efficacy. On hands contaminated with chicken broth containing E. coli, representing a moderate soil load, a regimen combining an antimicrobial hand washing product with a 70% ethanol advanced formula (EtOH AF) gel achieved a 5.22-log reduction, whereas a nonantimicrobial hand washing product alone achieved a 3.10log reduction. When hands were heavily soiled from handling ground beef containing E. coli, a wash-sanitize regimen with a 0.5% chloroxylenol antimicrobial hand washing product and the 70% EtOH AF gel achieved a 4.60-log reduction, whereas a wash-sanitize regimen with a 62% EtOH foam achieved a 4.11-log reduction. Sanitizing with the 70% EtOH AF gel alone was more effective than hand washing with a nonantimicrobial product for reducing murine norovirus (MNV), a surrogate for human norovirus, with 2.60- and 1.79-log reductions, respectively. When combined with hand washing, the 70% EtOH AF gel produced a 3.19-log reduction against MNV. A regimen using the SaniTwice protocol with the 70% EtOH AF gel produced a 4.04-log reduction against MNV. These data suggest that although the process of hand washing helped to remove pathogens from the hands, use of a wash-sanitize regimen was even more effective for reducing organisms. Use of a high-efficacy sanitizer as part of a wash-sanitize regimen further increased the efficacy of the regimen. The use of a well-formulated alcohol-based hand rub as part of a wash-sanitize regimen should be considered as a means to reduce risk of infection transmission in food service facilities.

Virological and immunological response to antiretroviral regimens containing maraviroc in HIV type 1-infected patients in clinical practice: role of different tropism testing results and of concomitant treatments.

Science.gov (United States)

Rossetti, Barbara; Bianco, Claudia; Bellazzi, Lara Ines; Bruzzone, Bianca; Colao, Grazia; Corsi, Paola; Monno, Laura; Pagano, Gabriella; Paolucci, Stefania; Punzi, Grazia; Setti, Maurizio; Zazzi, Maurizio; De Luca, Andrea

2014-01-01

We assessed the immunovirological response to antiretroviral regimens containing maraviroc in HIV-infected viremic patients with viral tropism predicted by different assays. We selected antiretroviral treatment-experienced HIV-1-infected patients initiating regimens containing maraviroc after different phenotypic or genotypic viral tropism assays, with at least one HIV-1 RNA determination during follow-up. Survival analysis was employed to assess the virological response as time to HIV-1 RNA immunological response as time to a CD4 cell count increase of ≥ 100/μl from baseline. Predictors of these outcomes were analyzed by multivariate Cox regression models. In 191 treatments with maraviroc, virological response was achieved in 65.4% and the response was modestly influenced by the baseline viral load and concomitant drug activity but not influenced by the type of tropism assay employed. Immunological response was achieved in 58.1%; independent predictors were baseline HIV-1 RNA (per log10 higher: HR 1.29, 95% CI 1.05-1.60) and concomitant therapy with enfuvirtide (HR 2.05, 0.96-4.39) but not tropism assay results. Of 17 patients with baseline R5-tropic virus and available tropism results while viremic during follow-up on maraviroc, seven (41%) showed a tropism switch to non-R5 virus. A significant proportion of experienced patients treated with regimens containing maraviroc achieved virological response. The tropism test type used was not associated with immunovirological response and concomitant treatment with enfuvirtide increased the chance of immunological response. More than half of virological failures with maraviroc were not accompanied by tropism switch.

Re: Fibrin Glue Injections: A Minimally Invasive and Cost-Effective Treatment for Post-Renal Transplant Lymphoceles and Lymph Fistulas

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Presser N

2016-03-01

Full Text Available In this retrospective study, 46 (2.7% patients out of 1662 kidney transplant recipients had developed symptomatic lymphocele/lymph fistula requiring intervention over an 11-year period. Open surgical drainage (22, laparoscopic surgical drainage (11 and percutaneous fibrin glue injections into the drained lymphocele cavity (13 were used to treat this complication. Besides being effective both on the early and late developed lymphoceles, significantly lower recurrence rates by fibrin glue injections and lower median treatment costs were observed when compared with the other two surgical modalities. It has also the advantage of an outpatient procedure that can be performed using fluoroscopic guidance, under local anesthesia. However, due to era effect, most of the open and laparoscopic surgical recipients were treated with sirolimus, a well-known antiproliferative immunosuppressive agent, which can promote development of lymphoceles and surgical failure. However, the majority of fibrin glue-treated cases were with tacrolimus-based regimens, but this study, in its nature, is far from giving the answer for decreased number of recurrences with fibrin glue

Use of Mishell-Dutton culture for the detection of the immunosuppressive effect of iron-containing compounds

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Ban, M.; Hettich, D.; Cavelier, C. [Institut National de Recherche et de Securite, Vandoeuvre (France)

1995-11-15

Mishell-Dutton culture, known as an in vitro model for the evaluation of the humoral immune response of mice spleen cells to sheep red blood cells (SRBC), was used to study the immunosuppressive effect of iron-containing compounds. This response was indicated by the number of anitbody forming cell (AFC) per million nucleated cells. Ferrous sulfate and ferric citrate (0.1 mM), when continuously present in Mishell-Dutton culture, significantly decreased the SRBC AFC response by approximately 63% and 86% of the control values, respectively. Ferric citrate, preincubated (24h) with spleen cells and followed by lavage, significantly decreased the SRBC AFC response by approximately 54% for the control values. Primary and iron-treated coal, in concentration ranging from 40{mu}g ml{sup -1} to 120{mu}g.m{sup -1}, significantly decreased the SRBC AFC response when continuously present in Mishell-Dutton culture. Iron-treated coal, suppressed this response in dose-dependent amounts, to a greater extent than did the primary coal: 73% versus 54% at 120{mu}g.ml{sup -1}. It was concluded that Mishell-Dutton culture is suitable for studying the immunotoxicity of iron and these results may contribute to explain a decrease of host resistance against parasitic and bacterial infection in workers exposed to iron. 28 refs., 3 tabs.

Serum vitamin D levels in kidney transplant recipients: the importance of an immunosuppression regimen and sun exposure.

Science.gov (United States)

Eyal, Ophir; Aharon, Michal; Safadi, Rifaat; Elhalel, Michal Dranitzki

2013-10-01

Vitamin D deficiency was shown to be prevalent among renal transplant recipients in northern countries, but little is known regarding risk factors. To test vitamin D levels in kidney transplant recipients residing closer to the equator, compare them to levels in liver transplant recipients and hemodialysis patients, and identify possible risk factors. In a cross-sectional study 103 kidney transplant recipients, 27 liver transplant recipients and 50 hemodialysis patients followed at our institute were tested for vitamin D levels. Demographic data, medical history and current treatment were recorded from the medical files. Inadequate vitamin D levels (Vitamin D levels were higher among dialysis patients than transplant recipients, though deficiency rates were similar. No association was found between kidney function and vitamin deficiency. Deficiency was associated with higher prednisone doses, use of mycophenolate sodium, tacrolimus, and iron supplements, or lower doses of vitamin D supplementation. Despite potential higher ultraviolet B exposure, inadequate vitamin D levels were prevalent in our study group. Importantly, some immunosuppressive medications were associated with vitamin D deficiency and high doses of vitamin D were associated with less deficiency.

Targeting Myeloid-Derived Suppressor Cells to Bypass Tumor-Induced Immunosuppression

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Viktor Fleming

2018-03-01

Full Text Available The immune system has many sophisticated mechanisms to balance an extensive immune response. Distinct immunosuppressive cells could protect from excessive tissue damage and autoimmune disorders. Tumor cells take an advantage of those immunosuppressive mechanisms and establish a strongly immunosuppressive tumor microenvironment (TME, which inhibits antitumor immune responses, supporting the disease progression. Myeloid-derived suppressor cells (MDSC play a crucial role in this immunosuppressive TME. Those cells represent a heterogeneous population of immature myeloid cells with a strong immunosuppressive potential. They inhibit an antitumor reactivity of T cells and NK cells. Furthermore, they promote angiogenesis, establish pre-metastatic niches, and recruit other immunosuppressive cells such as regulatory T cells. Accumulating evidences demonstrated that the enrichment and activation of MDSC correlated with tumor progression, recurrence, and negative clinical outcome. In the last few years, various preclinical studies and clinical trials targeting MDSC showed promising results. In this review, we discuss different therapeutic approaches on MDSC targeting to overcome immunosuppressive TME and enhance the efficiency of current tumor immunotherapies.

Engraftment versus immunosuppression: cost-benefit analysis of immunosuppression after intrahepatic murine islet transplantation.

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Marzorati, Simona; Melzi, Raffaella; Citro, Antonio; Cantarelli, Elisa; Mercalli, Alessia; Scavini, Marina; Piemonti, Lorenzo

2014-05-27

Immunosuppression (IS) in islet transplantation (Tx) is a double-edged sword: it prevents immunoreaction but has the potential to impair islet engraftment. The aim of this study was to identify in murine animal models the IS platform with the best balance between these two opposite effects. To study the impact of IS on islet engraftment diabetic C57BL/6 mice were transplanted with 350 syngeneic islets through the portal vein and treated once-daily with either rapamycin (RAPA; 0.1-0.5-1 mg/kg ip), tacrolimus (FK506; 0.1-0.5-1 mg/kg ip), mycophenolate mofetil (MMF; 60-120-300 mg/kg oral) or vehicle for 14 days. Islet function was evaluated by measuring not-fasting glycemia and by performing an IVGTT on days 15 and 30 post-Tx. RAPA ≥0.5 mg/Kg, FK506 ≥0.5 mg/Kg, and MMF ≥120 mg/kg had detrimental effects on islet engraftment but not on the function of islets already engrafted in the liver. The effect on engraftment was irreversible and persisted even after IS withdrawal. The lower dose of IS that did not affect engraftment was tested for preventing rejection in the full mismatch allogeneic Tx BALB/c to C57BL/6 model. RAPA and/or FK506 were inefficient in preventing rejection, even when anti-IL2R mAb was added to the IS regimen. On the other hand, MMF alone or in association with FK506 significantly prolonged the time to islet rejection. IS showed profound dose-dependent deleterious effects on islet cell engraftment. The MMF/FK506 combination proved the best balance with less toxicity at the time of engraftment and more efficacy in controlling graft rejection.

Putative bronchopulmonary flagellated protozoa in immunosuppressed patients.

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Kilimcioglu, Ali Ahmet; Havlucu, Yavuz; Girginkardesler, Nogay; Celik, Pınar; Yereli, Kor; Özbilgin, Ahmet

2014-01-01

Flagellated protozoa that cause bronchopulmonary symptoms in humans are commonly neglected. These protozoal forms which were presumed to be "flagellated protozoa" have been previously identified in immunosuppressed patients in a number of studies, but have not been certainly classified so far. Since no human cases of bronchopulmonary flagellated protozoa were reported from Turkey, we aimed to investigate these putative protozoa in immunosuppressed patients who are particularly at risk of infectious diseases. Bronchoalveolar lavage fluid samples of 110 immunosuppressed adult patients who were admitted to the Department of Chest Diseases, Hafsa Sultan Hospital of Celal Bayar University, Manisa, Turkey, were examined in terms of parasites by light microscopy. Flagellated protozoal forms were detected in nine (8.2%) of 110 cases. Metronidazole (500 mg b.i.d. for 30 days) was given to all positive cases and a second bronchoscopy was performed at the end of the treatment, which revealed no parasites. In conclusion, immunosuppressed patients with bronchopulmonary symptoms should attentively be examined with regard to flagellated protozoa which can easily be misidentified as epithelial cells.

Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.

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Cui, Xin; Morales, Renee-Tyler Tan; Qian, Weiyi; Wang, Haoyu; Gagner, Jean-Pierre; Dolgalev, Igor; Placantonakis, Dimitris; Zagzag, David; Cimmino, Luisa; Snuderl, Matija; Lam, Raymond H W; Chen, Weiqiang

2018-04-01

Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (α v β 3 ) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (α v β 3 )-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (α v β 3 ) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and

No impact of HIV-1 protease minority resistant variants on the virological response to a first-line PI-based regimen containing darunavir or atazanavir.

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Perrier, Marine; Visseaux, Benoit; Landman, Roland; Joly, Véronique; Todesco, Eve; Yazdanpanah, Yazdan; Calvez, Vincent; Marcelin, Anne-Geneviève; Descamps, Diane; Charpentier, Charlotte

2018-01-01

To evaluate, in a clinical cohort of HIV-1-infected patients, the prevalence of PI minority resistant variants (MRV) at ART baseline and their impact on the virological response to a first-line PI-based regimen. In an observational single-centre cohort, we assessed all ART-naive patients initiating a first-line regimen including two NRTI and one boosted PI, darunavir/ritonavir or atazanavir/ritonavir, between January 2012 and March 2015. Ultra-deep sequencing of the pol gene was performed using Illumina® technology. Protease mutations were identified using the WHO transmitted drug resistance list and major PI resistance mutations (IAS-USA drug resistance mutations list). Ninety-four and 16 patients initiating a darunavir/ritonavir-based regimen and an atazanavir/ritonavir-based regimen, respectively, were assessed. Twenty-eight percent of the patients were HIV-1 subtype B, 39% CRF02_AG and 33% other non-B subtypes. Thirteen patients (13.8%) in the darunavir group and three patients (18.8%) in the atazanavir group experienced a virological failure (VF). Overall, 13 (11.8%) subjects had PI MRV at baseline in the median proportion of 1.3% (IQR = 1.1-1.7). The most prevalent PI MRV were G73C (n = 5) and M46I (n = 3). The proportion of patients harbouring baseline PI MRV was similar between those with virological success (10.6%) and those experiencing VF (18.8%) (P = 0.40). No difference was observed in the rate of PI MRV by viral subtype (P = 0.51) or by PI drug (P = 0.40). This study showed a prevalence of 11.8% of PI MRV among 110 ART-naive subjects, without significant impact on the virological response to a first-line PI-based regimen containing darunavir or atazanavir. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

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Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TB...

A single daily dose enhances the adherence to immunosuppressive treatment in kidney transplant recipients: a cross-sectional study.

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Obi, Yoshitsugu; Ichimaru, Naotsugu; Kato, Taigo; Kaimori, Jun-Ya; Okumi, Masayoshi; Yazawa, Koji; Rakugi, Hiromi; Nonomura, Norio; Isaka, Yoshitaka; Takahara, Shiro

2013-04-01

Nonadherence to treatment regimens for immunosuppressive agents is one of the major risk factors for allograft failure in kidney transplant recipients. The aim of this study was to estimate the relative effect of daily dosing on treatment adherence, not to identify how patients are non-adherent, in long-term kidney transplant recipients. In January 2009, a cross-sectional, anonymous, and voluntary questionnaire survey was given to kidney transplant recipients who regularly visited Inoue Hospital. A self-reporting questionnaire underestimates nonadherence, but we reasoned that the effect of the dosing regimen should be estimated with relative accuracy by using the generalized ordered logit/partial proportional hazard odds model given that the distribution patterns in the degree of nonadherence have been shown to be similar with other measures. Of 336 eligible patients, 312 (92.9 %) participated in this study. Two hundred seventy-four patients (87.8 %) were more than 3 years post-transplant. Univariate analysis revealed that a single daily dose was significantly associated with better adherence. After controlling for age, sex, time since transplantation, and the number of prescribed drugs, the effect of a single daily dose still remained significant [odds ratio, 0.40 (95 % confidence interval, 0.19-0.81); p = 0.011]. Several sensitivity analyses yielded similar results. To our knowledge, this is the first report that, in long-term kidney transplant recipients, a single daily regimen-one of few modifiable factors-might improve treatment adherence and allograft survival.

Multi-Center, Double-Blind, Vehicle-Controlled Clinical Trial of an Alpha and Beta Defensin-Containing Anti-Aging Skin Care Regimen With Clinical, Histopathologic, Immunohistochemical, Photographic, and Ultrasound Evaluation.

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Taub, Amy; Bucay, Vivian; Keller, Gregory; Williams, Jay; Mehregan, Darius

2018-04-01

Anti-aging strategies utilizing stem cells are in the forefront. Alpha and beta defensins are natural immune peptides that have been shown to activate an LGR6-positive stem cell locus in the hair follicle, identified as the source of most new epidermal cells during acute wound healing. We investigated the ability of biomimetic alpha and beta defensin molecules, supplemented with supportive cosmetic ingredients, formulated into three skin care products, at improving the structure and function of aging skin. A participant- and investigator -blinded, placebo-controlled, multi-center trial was performed in outpatient settings. Forty-four healthy female subjects, aged 41-71 years, skin types I-V, completed the study with 2/3 receiving full formula and 1/3 receiving the placebo formula. A skin care regimen of 3 products (serum, cream, and mask) containing alpha-defensin 5 and beta-defensin 3, and other cosmetic ingredients, was applied to the face, post-auricular, and neck skin two times per day for 12 weeks in those receiving full formula, whereas the placebo group received the identically packaged regimen without the active ingredients. Methods of evaluation included histopathology and immunohistochemistry (7 subjects), clinical evaluation of pores, superficial and deep wrinkles based on Griffiths scale, and high-resolution photography (all subjects). In addition, a subset of 15 patients were evaluated with the QuantifiCare system (3-dimensional imaging and skin care scores for evenness, pores, oiliness) and Cortex measurements (high-resolution skin ultrasound, TEWL, elasticity, color, and hydration). Data points for evaluation included baseline, 6 weeks, and 12 weeks. All patients used the same sunscreen and cleanser, which was provided to them. The full formula regimen caused a significantly (P equals 0.027) increased thickness of the epidermis as seen in histology, not seen in the placebo group, with no signs of inflammation. No excessive cell proliferation was

Immunosuppressive therapy after solid-organ transplantation: does the INTERMED identify patients at risk of poor adherence?

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Michaud L

2016-12-01

Full Text Available Background: Lack of adherence to medication is a trigger of graft rejection in solid-organ transplant (SOT recipients. Objective: This exploratory study aimed to assess whether a biopsychosocial evaluation using the INTERMED instrument before transplantation could identify SOT recipients at risk of suboptimal post-transplantation adherence to immunosuppressant drugs. We hypothesized that complex patients (INTERMED>20 might have lower medication adherence than noncomplex patients (INTERMED≤20. Methods: Each patient eligible for transplantation at the University Hospital of Lausanne, Switzerland, has to undergo a pre-transplantation psychiatric evaluation. In this context the patient was asked to participate in our study. The INTERMED was completed pre-transplantation, and adherence to immunosuppressive medication was monitored post-transplantation by electronic monitors for 12 months. The main outcome measure was the implementation and persistence to two calcineurin inhibitors, cyclosporine and tacrolimus, according to the dichotomized INTERMED score (>20 or ≤20. Results: Among the 50 SOT recipients who completed the INTERMED, 32 entered the study. The complex (N=11 and noncomplex patients (N=21 were similar in terms of age, sex and transplanted organ. Implementation was 94.2% in noncomplex patients versus 87.8% in complex patients (non-significant p-value. Five patients were lost to follow-up: one was non-persistent, and four refused electronic monitoring. Of the four patients who refused monitoring, two were complex and withdrew early, and two were noncomplex and withdrew later in the study. Conclusion: Patients identified as complex pre-transplant by the INTERMED tended to deviate from their immunosuppressant regimen, but the findings were not statistically significant. Larger studies are needed to evaluate this association further, as well as the appropriateness of using a nonspecific biopsychosocial instrument such as INTERMED in highly

Classifying insulin regimens

DEFF Research Database (Denmark)

Neu, A; Lange, K; Barrett, T

2015-01-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...

African American kidney transplantation survival: the ability of immunosuppression to balance the inherent pre- and post-transplant risk factors.

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Malat, Gregory E; Culkin, Christine; Palya, Aniruddha; Ranganna, Karthik; Kumar, Mysore S Anil

2009-10-22

Among organ transplant recipients, the African American population historically has received special attention. This is because secondary to their disposition to certain disease states, for example hypertension, an African American patient has a propensity to reach end-stage renal disease and require renal replacement earlier than a Caucasian patient. Regardless of the initiative to replace dialysis therapy with organ transplantation, the African American patient has many barriers to kidney transplantation, thus extending their time on dialysis and waiting time on the organ transplant list. These factors are among the many negative causes of decreased kidney graft survival, realized before kidney transplantation. Unfortunately, once the African American recipient receives a kidney graft, the literature documents that many post-transplant barriers exist which limit successful outcomes. The primary post-transplant barrier relates to designing proper immunosuppression protocols. The difficulty in designing protocols revolves around (i) altered genetic metabolism/lower absorption, (ii) increased immuno-active cytokines and (iii) detrimental effects of noncompliance. Based on the literature, dosing of immunosuppression must be aggressive and requires a diligent practitioner. Research has indicated that, despite some success with proven levels of immunosuppression, the African American recipient usually requires a higher 'dose per weight' regimen. However, even with aggressive immunosuppressant dosing, African Americans still have worse outcomes than Caucasian recipients. Additionally, many of the targeted sites of action that immunosuppression exerts its effects on have been found to be amplified in the African American population. Finally, noncompliance is the most discouraging inhibitor of long-term success in organ transplantation. The consequences of noncompliance are biased by ethnicity and affect the African American population more severely. All of these factors

A tacrolimus-related immunosuppressant with reduced toxicity.

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Dumont, F J; Koprak, S; Staruch, M J; Talento, A; Koo, G; DaSilva, C; Sinclair, P J; Wong, F; Woods, J; Barker, J; Pivnichny, J; Singer, I; Sigal, N H; Williamson, A R; Parsons, W H; Wyvratt, M

1998-01-15

Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility. Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity. Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intracellular FK506 binding protein-12 than tacrolimus or ASC. Further evaluation of indolyl-ASC revealed that it is threefold less potent than tacrolimus in inducing hypothermia, a response that may reflect neurotoxicity, and in causing gastrointestinal transit alterations in mice. Moreover, indolyl-ASC was at least twofold less nephrotoxic than tacrolimus upon 3-week oral treatment in rats. Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.

Role of mTOR Inhibitors in Kidney Disease

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Moto Kajiwara

2016-06-01

Full Text Available The first compound that inhibited the mammalian target of rapamycin (mTOR, sirolimus (rapamycin was discovered in the 1970s as a soil bacterium metabolite collected on Easter Island (Rapa Nui. Because sirolimus showed antiproliferative activity, researchers investigated its molecular target and identified the TOR1 and TOR2. The mTOR consists of mTOR complex 1 (mTORC1 and mTORC2. Rapalogues including sirolimus, everolimus, and temsirolimus exert their effect mainly on mTORC1, whereas their inhibitory effect on mTORC2 is mild. To obtain compounds with more potent antiproliferative effects, ATP-competitive inhibitors of mTOR targeting both mTORC1 and mTORC2 have been developed and tested in clinical trials as anticancer drugs. Currently, mTOR inhibitors are used as anticancer drugs against several solid tumors, and immunosuppressive agents for transplantation of various organs. This review discusses the role of mTOR inhibitors in renal disease with a particular focus on renal cancer, diabetic nephropathy, and kidney transplantation.

Differential Antitumoral Properties and Renal-Associated Tissue Damage Induced by Tacrolimus and Mammalian Target of Rapamycin Inhibitors in Hepatocarcinoma: In Vitro and In Vivo Studies.

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Elena Navarro-Villarán

Full Text Available Orthotopic liver transplantation (OLT is the recommended treatment for patients at early stages of hepatocarcinoma (HCC with potential portal hypertension and/or bilirubinemia, but without vascular-associated diseases. The patients are receiving immunosuppressive therapy to reduce graft rejection, but differential side effects have been related to calcineurin and mTOR inhibitor administration regarding tumor recurrence and nephrotoxicity. The in vitro studies showed that Tacrolimus exerted a more potent pro-apoptotic effect than Everolimus (Huh 7>Hep 3B>HepG2, being sirolimus only active in Hep3B cell line. Tacrolimus and Everolimus exerted potent antiproliferative properties in Huh 7 and Hep3B in which cells Sirolimus was inactive. Interestingly, Tacrolimus- and Everolimus-dependent G0/G1 cell accumulation occurred as a consequence of drastic reduction in S, as well as in S and G2+M phases, respectively. The in vivo studies support data on the more effective antitumoral properties of Everolimus, eventual risk of pro-angiogenic tumoral properties and nephrotoxicity of Tacrolimus, and pro-proliferative properties of Sirolimus in tumors developed in nude mice.

Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial

DEFF Research Database (Denmark)

Rasmussen, Klaus; Maeng, Michael; Kaltoft, Anne

2010-01-01

In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery disease who we...

[Clinical views from the forefront of immunosuppressive drugs].

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Kobayashi, Eiji

2005-11-01

Recently, many immunosuppressants have been developed and some of them have already been introduced in clinical organ transplantation. With a new concept of immunoregulation, which focuses on prevention of rejection and over-immunosuppression, the latest protocol has been conducted. Chimeric or humanized antibodies targeting the lymphocyte surface molecule such as CD19, 20, 25, 40, and 52 are administrated in the induction phase, and calcineurin inhibitors (cyclosporin and tacrolimus) are used as key drugs. For tapering the doses of them, the combined application of anti-metabolic agents of azathioprine, mizoribine, or mycophenolate mofetil (MMF) has been proved effective. Lymphocyte forming drugs induce unique immunoregulation, targeting at sphingosine 1-phosphate (SlP) receptors. FTY720 is now in the procedure of clinical trial to compare with MMF. KRP203 is also a candidate for more specific SIP receptor agonist. In this issue, I reviewed the recent immunosuppressive strategy and focused on the advance of novel immunosuppressive drugs.

Immunosuppressive agents are associated with peptic ulcer bleeding.

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Tomizawa, Minoru; Shinozaki, Fuminobu; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

2017-05-01

Peptic ulcer bleeding can be fatal. Non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids and immunosuppressive agents are administered for long-term usage. The present study assessed the association between peptic ulcer bleeding and administration of NSAIDs, corticosteroids and immunosuppressive agents. Furthermore, the efficacy of lowering the risk of peptic ulcer bleeding with proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was evaluated. Medical records were retrospectively analyzed for patients subjected to an upper gastrointestinal (GI) endoscopy performed at the National Hospital Organization Shimoshizu Hospital (Yotsukaido, Japan) from October 2014 to September 2015. During this period, a total of 1,023 patients underwent an upper GI endoscopy. A total of 1,023 patients, including 431 males (age, 68.1±12.9 years) and 592 females (age, 66.4±12.3 years), who had been administered NSAIDs, corticosteroids, immunosuppressive agents, PPIs and H2RAs, were respectively enrolled. Endoscopic findings of the patients were reviewed and their data were statistically analyzed. Logistic regression analysis was used to determine the odds ratio of peptic ulcer bleeding for each medication; immunosuppressive agents had an odds ratio of 5.83, which was larger than that for NSAIDs (4.77). The Wald test was applied to confirm the correlation between immunosuppressive agents and peptic ulcer bleeding. Furthermore, χ 2 tests were applied to the correlation between peptic ulcer bleeding and administration of PPIs or H2RAs. Immunosuppressive agents had the largest χ 2 , and the P-value was 0.03. Administration of PPIs was significantly correlated with non-peptic ulcer bleeding (P=0.02); furthermore, a tendency toward non-peptic ulcer bleeding with administration of H2RA was indicated, but it was not statistically significant (P=0.12). In conclusion, immunosuppressive agents were correlated with peptic ulcer bleeding and PPIs were effective at

Immunosuppressive T-cell antibody induction for heart transplant recipients

DEFF Research Database (Denmark)

Penninga, Luit; Møller, Christian H; Gustafsson, Finn

2013-01-01

Heart transplantation has become a valuable and well-accepted treatment option for end-stage heart failure. Rejection of the transplanted heart by the recipient's body is a risk to the success of the procedure, and life-long immunosuppression is necessary to avoid this. Clear evidence is required...... to identify the best, safest and most effective immunosuppressive treatment strategy for heart transplant recipients. To date, there is no consensus on the use of immunosuppressive antibodies against T-cells for induction after heart transplantation....

Cutaneous toxoplasmosis in an immunosuppressed dog

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T.S. Oliveira

2014-06-01

Full Text Available A seven-year-old female spayed Schnauzer was presented with cutaneous ulcerated nodular lesions shortly after the beginning of an immunosuppressive treatment for immune-mediated hemolytic disease. Cytology was performed and a great number of neutrophils and banana-shaped organisms were observed. Biopsy showed a neutrophilic and histiocytic dermatitis and panniculitis with myriads of intralesional bradyzoites cysts and tachyzoites. PCR analysis was positive for Toxoplasma gondii and negative for Neospora caninum. Immunohistochemistry confirmed intralesional T. gondii antigens. This study reports a rare case of cutaneous toxoplasmosis in an immunosuppressed dog.

Anti-thymocyte serum as part of an immunosuppressive regimen in treating haematological immune-mediated diseases in dogs.

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Cuq, B; Blois, S L; Mathews, K A

2017-06-01

To report the outcomes associated with the use of rabbit anti-dog thymocyte serum in dogs with haematological immune-mediated diseases. Medical records from 2000 to 2016 of patients diagnosed with immune-mediated haemolytic anaemia, immune-mediated thrombocytopenia, pancytopenia and myelofibrosis were reviewed. All dogs had a severe or refractory disease and received rabbit anti-dog thymocyte serum. Lymphocyte counts were used to monitor the immediate anti-thymocyte effect of therapy; long-term patient outcome was recorded. A total of 10 dogs were included. All dogs except one had a notable decrease in their lymphocyte count after rabbit anti-dog thymocyte serum; four of nine had a decrease to less than 10% of the initial lymphocyte count and one dog reached 10·8%. All dogs were discharged from the hospital following their treatment. The dog with no alteration of lymphocyte count following therapy with rabbit anti-dog thymocyte serum had refractory immune mediated haemolytic anemia and was euthanised within two weeks. All other cases achieved clinical remission with immunosuppressive therapy eventually being tapered (3 of 10) or discontinued (6 of 10). Rabbit anti-dog thymocyte serum therapy might be of interest as an adjunctive therapy in refractory immune-mediated diseases and suppressed lymphocyte counts in most dogs. © 2017 British Small Animal Veterinary Association.

Transplantation of co-aggregates of Sertoli cells and islet cells into liver without immunosuppression.

Science.gov (United States)

Takemoto, Naohiro; Liu, Xibao; Takii, Kento; Teramura, Yuji; Iwata, Hiroo

2014-02-15

Transplantation of islets of Langerhans (islets) was used to treat insulin-dependent diabetes mellitus. However, islet grafts must be maintained by administration of immunosuppressive drugs, which can lead to complications in the long term. An approach that avoids immunosuppressive drug use is desirable. Co-aggregates of Sertoli cells and islet cells from BALB/c mice that were prepared by the hanging drop method were transplanted into C57BL/6 mouse liver through the portal vein as in human clinical islet transplantation. The core part of the aggregates contained mainly Sertoli cells, and these cells were surrounded by islet cells. The co-aggregates retained the functions of both Sertoli and islet cells. When 800 co-aggregates were transplanted into seven C57BL/6 mice via the portal vein, six of seven recipient mice demonstrated quasi-normoglycemia for more than 100 days. The hanging drop method is suitable for preparing aggregates of Sertoli and islet cells for transplantation. Notably, transplantation of these allogeneic co-aggregates into mice with chemically induced diabetes via the portal vein resulted in long-term graft survival without systemic immunosuppression.

Immunosuppressive effect of total lymphoid irradiation

International Nuclear Information System (INIS)

Bendel, V.; Medizinische Hochschule Hannover

1981-01-01

Contrary to the immunosuppression by means of wholebody irradiation which is known for a long while but connected with considerable side effects and risks, the total lymphoid irradiation (TLI) is a new possibility of immunosuppression the tolerance of which by man is known by virtue of long-standing experiences with the treatment of malignant lymphatic system diseases. In connexion with organ transplantations, TLI might possibly soon be important for the radiotherapeutist. In the experimentation on animals, the unspecific immunosuppression induced by TLI causes a prolonged survival time of allogeneic skin and organ grafts in certain mammals. Furthermore, a formation of blood chimeras combined with specific, permanent tolerance of organ grafts from the bone marrow donor can be caused by bone marrow transplantation after TLI. First experiences with man have been made. In the German literature, TLI has not been mentioned yet. In the present study, a summary is given on the Anglo-Saxon literature, and the first own experiments with regard to the problem of irradiation dose and transplantation interval are presented. (orig.) [de

Helper-dependent adenovirus achieve more efficient and persistent liver transgene expression in non-human primates under immunosuppression.

Science.gov (United States)

Unzu, C; Melero, I; Hervás-Stubbs, S; Sampedro, A; Mancheño, U; Morales-Kastresana, A; Serrano-Mendioroz, I; de Salamanca, R E; Benito, A; Fontanellas, A

2015-11-01

Helper-dependent adenoviral (HDA) vectors constitute excellent gene therapy tools for metabolic liver diseases. We have previously shown that an HDA vector encoding human porphobilinogen deaminase (PBGD) corrects acute intermittent porphyria mice. Now, six non-human primates were injected in the left hepatic lobe with the PBGD-encoding HDA vector to study levels and persistence of transgene expression. Intrahepatic administration of 5 × 10(12) viral particles kg(-1) (10(10) infective units kg(-1)) of HDA only resulted in transient (≈14 weeks) transgene expression in one out of three individuals. In contrast, a more prolonged 90-day immunosuppressive regimen (tacrolimus, mycophenolate, rituximab and steroids) extended meaningful transgene expression for over 76 weeks in two out of two cases. Transgene expression under immunosuppression (IS) reached maximum levels 6 weeks after HDA administration and gradually declined reaching a stable plateau within the therapeutic range for acute porphyria. The non-injected liver lobes also expressed the transgene because of vector circulation. IS controlled anticapsid T-cell responses and decreased the induction of neutralizing antibodies. Re-administration of HDA-hPBGD at week +78 achieved therapeutically meaningful transgene expression only in those animals receiving IS again at the time of this second vector exposure. Overall, immunity against adenoviral capsids poses serious hurdles for long-term HDA-mediated liver transduction, which can be partially circumvented by pharmacological IS.

Biolimus-eluting biodegradable polymer-coated stent versus durable polymer-coated sirolimus-eluting stent in unselected patients receiving percutaneous coronary intervention (SORT OUT V)

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Christiansen, Evald Høj; Jensen, Lisette Okkels; Thayssen, Per

2013-01-01

Third-generation biodegradable polymer drug-eluting stents might reduce the risk of stent thrombosis compared with first-generation permanent polymer drug-eluting stents. We aimed to further investigate the effects of a biodegradable polymer biolimus-eluting stent compared with a durable polymer......-coated sirolimus-eluting stent in a population-based setting....

Randomized clinical comparison of the dual-therapy CD34 antibody-covered sirolimus-eluting Combo stent with the sirolimus-eluting Orsiro stent in patients treated with percutaneous coronary intervention

DEFF Research Database (Denmark)

Jakobsen, Lars; Christiansen, Evald H; Maeng, Michael

2018-01-01

Background: The Combo stent (OrbusNeich, Hoevelaken, the Netherlands) combining an abluminal, bioabsorbable polymer eluting sirolimus with a luminal CD34+ antibody to capture endothelial progenitor cells has been developed to further improve safety and efficacy of coronary interventions. We have...... designed a large-scale registry-based randomized clinical trial to compare the Combo stent to the Orsiro stent (Biotronik, Bülach, Switzerland) in patients undergoing percutaneous coronary intervention. Methods: The SORT OUT X study will randomly assign 3,140 patients to treatment with Combo or Orsiro...... stents at 3 sites in Western Denmark. Patients are eligible if they are ≥18 years old, have chronic stable coronary artery disease or acute coronary syndromes, and have ≥1 coronary lesion with >50% diameter stenosis requiring treatment with a drug-eluting stent. The primary end point target lesion...

ATG-Fresenius S combined with cyclosporine a: an effective immunosuppressive therapy for children with aplastic anemia.

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Luo, Cheng-Juan; Gao, Yi-Jin; Tang, Jing-Yan; Zhu, Xiao-Hua; Xue, Hui-Liang; Lu, Feng-Juan; Pan, Ci; Jiang, Hua; Luo, Chang-Ying; Ye, Qi-Dong; Zhou, Min; Chen, Jing

2014-07-01

For the first time, we conducted a 2-center retrospective study to show the efficacy of antithymocyte globulin (ATG)-Fresenius S plus cyclosporine treatment of children with severe aplastic anemia. From March 1997 to May 2011, a total of 124 patients (median age, 7.5 y; range, 1.5 to 16 y) from 2 centers with acquired AA treated with an immunosuppressive therapy (IST) regimen, consisting of ATG-Fresenius S (5 mg/kg per day for 5 d) and cyclosporine, were enrolled. The response rate was 55.6%. The median time between IST and response was 6 (0.5 to 18) months. After a median follow-up time of 29 (6 to 153) months, the rates of relapse and clonal evolution were 3.2% and 0.8%, respectively. Overall, 17 patients (13.7%) died in this study: 14 resulted from sepsis, 1 resulted from intracranial hemorrhage, 1 occurred after hematopoietic stem cell transplantation, and 1 resulted from clonal disease progression. The 5-year overall survival rate for the entire cohort was 74.7%. IST responders had a better survival rate (100%) than nonresponders (70.7%). The use of ATG-Fresenius S plus cyclosporine as a first-line immunosuppressive treatment appeared to be effective for children with severe aplastic anemia in our study. ATG-Fresenius S could be another option in the treatment arsenal, especially in countries where the other ATG products are harder to acquire.

A prospective, multicenter, post marketing surveillance study to evaluate the safety and effectiveness of the Superia-Sirolimus Eluting Coronary Stent System (SSECSS) implanted during routine clinical practice in India.

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Chandra, Praveen; Kumar, Tarun

2014-01-01

A prospective, multicenter, post marketing surveillance study to evaluate the safety and effectiveness of the Superia-Sirolimus Eluting Coronary Stent System (SSECSS) implanted during routine clinical practice in India. 1. To study the MACE and in stent and In-segment Loss at Six Months (in a pre selected group of 50 patients). 1. Clinical and procedural success. This is a prospective, open label, single-arm, multicenter (16 sites), post marketing observational study enrolling patients implanted with Superia-Sirolimus Eluting Coronary Stent (SSECS) in routine clinical practice in India. A total of 200 Patients of coronary Artery Disease (CAD) implanted with Superia-Sirolimus Eluting Coronary Stent (SSECS) were enrolled. Clinical assessments were done at 30 days, 180 days and at 1, 2 years either telephonically or office visit. A cohort of 50 pre-selected patients were followed up for angiographic evaluation at 180 days. MACE at 12 month of follow up was 1.71%.Late lumen loss, in segment was 0.14 and in stent was 0.10 mm at 6 month of follow-up. TLR was required only in 2 patients. Superia stent is as safe as other biodegradable polymer stent in the market and time has come for biodegradable polymer stent with thin struts. Copyright © 2014 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

免疫抑制剂对移植术后血脂异常的研究%Research of immunosuppressant on dyslipidemia after organ transplantation

Institute of Scientific and Technical Information of China (English)

应亮; 邱丰

2012-01-01

Cardiovascular and cerebrovascular complications is one of the major causes of transplanted organ death for the long-term survival patients with organ transplantation. In many factors of the resulting cardiac cerebral arteriosclerosis, hy-perlipidemia is one of the most important reasons. The immunosuppressive effects on serum lipids were reviewed in detail in this paper, including Corticosteroids, Cyclosporine, Tacrolimus, Sirolimus, Mycophenolate Mofetil, Azathioprine, and ultimately Mycophenolate Mofetil is one of the drugs which has minimal impact on blood lipids.%心脑血管合并症是导致长期存活器官移植患者移植器官功能死亡的主要原因之一.在导致心脑动脉硬化的诸多因素中,高脂血症是其中最重要的原因.文章详细地论述了不同免疫抑制剂对血脂的影响,包括皮质类固醇激素、环孢霉素、他克莫司、西罗莫司、吗替麦考酚酯、硫唑嘌呤等,最终发现吗替麦考酚酯是对血脂影响最小的药物之一.

Awareness of memory impairment increases the adherence to immunosuppressants in kidney transplant recipients.

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Cheng, C-Y; Lin, B Y-J; Chang, K-H; Shu, K-H; Wu, M-J

2012-04-01

Nonadherence to immunosuppressive drugs is a concern among kidney transplantation recipients (KTRs). The adverse effects of immunosuppressive drugs can trigger nonadherence and lead to a great impact on the allograft survival. The aim of this prospective controlled study is to determine the major adverse effects of immunosuppressive drugs and their correlation with the nonadherence in kidney transplantation recipients. All data were collected from medical and pharmacy records. We use modified Immunosuppressant Therapy Adherence Scale combined with Modified Transplant Symptom Occurrence and Symptom Distress scale to explore the relationship between symptom experience related to side effects of immunosuppressants and adherence. The risk of nonadherence was estimated by stepwise logistic regression while controlling for age, gender, education, and immunosuppressive medications. Multivariable analysis was performed using a single random effect of P adherence increased in patients with awareness of memory impairment (odds ratio 2.320, 95% confidence interval: 1.259-4.274, P = .007). There was no significant difference in the incidence of acute rejection, gender, age, and education between adherent and nonadherent patients. In summary, these results indicate a significant prevalence of nonadherence to immunosuppressive drugs in kidney transplantation recipients. Awareness of memory impairment significantly affected adherence to immunosuppressive drugs. Copyright © 2012 Elsevier Inc. All rights reserved.

Primer trasplante de intestino en Chile: Caso clínico

OpenAIRE

Buckel G,Erwin; Ferrario B,Mario; Uribe M,Mario; González G,Gloria; Godoy L,Jorge; Fluxá G,Fernando; Quera P,Rodrigo; Codoceo R,Verner; Morales B,Jorge; Benavente M,David; Santander D,María Teresa; Herzog O,Cristina

2009-01-01

Small bowel transplantation is associated with a patient survival at one and five years, of 80% and 63%, respectively. We repon a 36 year-old female with short bowel syndrome, subjected to the first small bowel transplantation performed in Chile. A cadaveric gran was used. Immunosuppression was achieved by means of alemtuzumab, tacrolimus, sirolimus, micofenolate mofetil and steroids. Serial endoscopies and biopsies were performed during seven months after transplantation. The most important ...

Intimal hyperplasia and vascular remodeling after everolimus-eluting and sirolimus-eluting stent implantation in diabetic patients the randomized diabetes and drug-eluting stent (DiabeDES) IV intravascular ultrasound trial

DEFF Research Database (Denmark)

Antonsen, Lisbeth; Maeng, Michael; Thayssen, Per

2013-01-01

OBJECTIVE: To evaluate the effects of the everolimus-eluting Xience™/Promus™ stent (EES) and the sirolimus-eluting Cypher™ stent (SES) on intimal hyperplasia (IH) in diabetic patients. BACKGROUND: Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent...... implantation due to intimal hyperplasia (IH). METHODS: In a sub study of the Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated with Percutaneous Coronary Intervention (SORT OUT IV trial), serial intravascular ultrasound (IVUS) 10-month follow-up data were available...... in 88 patients, including 48 EES and 40 SES treated patients. IVUS endpoints included IH volume, in-stent % volume obstruction and changes in external elastic membrane (EEM) volume. RESULTS: Compared with the SES group, IH volume was increased in the EES group [median (interquartile range): 2.8 mm(3) (0...

Real-World Assessment of Renal and Bone Safety among Patients with HIV Infection Exposed to Tenofovir Disoproxil Fumarate-Containing Single-Tablet Regimens.

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Nkhoma, Ella T; Rosenblatt, Lisa; Myers, Joel; Villasis-Keever, Angelina; Coumbis, John

2016-01-01

Tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens have been associated with an increased incidence of renal and bone adverse outcomes. Here, we estimated the real-world incidence of renal and bone adverse outcomes among patients with HIV infection receiving different TDF-containing single-tablet regimens (STRs). This cohort study used US health insurance data spanning the years 2008-2014. We identified HIV-infected patients aged ≥18 years (all HIV patients) and those with ≥6 months of continuous enrollment prior to initiating efavirenz/emtricitabine/TDF (EFV/FTC/TDF), rilpivirine/FTC/TDF (RPV/FTC/TDF) or elvitegravir/cobicistat/FTC/TDF (EVG/COBI/FTC/TDF). Renal adverse outcomes were identified using renal International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes. Bone adverse outcomes were identified using ICD-9-CM diagnosis codes for fracture. Incidence rates (IRs) and associated 95% confidence intervals (CIs) were estimated assuming a Poisson distribution, and outcomes between STRs were compared using IR ratios (IRRs) and IR differences (IRDs). We identified 9876 and 10,383 eligible patients for the renal and fracture analyses, respectively. Observed IRs for renal adverse outcomes were 9.7, 10.5, 13.6, and 18.0 per 1000 person-years among those receiving EFV/FTC/TDF, RPV/FTC/TDF, or EVG/COBI/FTC/TDF, or all HIV patients, respectively. Corresponding values for IRs of fracture were 3.4, 3.6, 7.2, and 4.4 per 1000 person-years, respectively. Renal adverse outcomes with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRD -3.96; 95% CI: -7.31, -1.06). No IRR differences were identified for the renal analysis. Fractures with EFV/FTC/TDF were significantly less frequent than with EVG/COBI/FTC/TDF (IRR 0.47; 95% CI: 0.27, 0.81 and IRD -3.85; 95% CI: -5.02, -2.78). In this large real-world database, observed IRs for renal adverse outcomes with TDF-containing STRs were lower

Generic maintenance immunosuppression in solid organ transplant recipients.

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Ensor, Christopher R; Trofe-Clark, Jennifer; Gabardi, Steven; McDevitt-Potter, Lisa M; Shullo, Michael A

2011-11-01

Survival after solid organ transplantation has increased in the era of tacrolimus and mycophenolate. This increased survival could be due in part to the broad clinical use of these potent and specific agents for maintenance immunosuppression. These drugs have enhanced specificity and potency for T and B lymphocytes compared with their predecessors, cyclosporine and azathioprine. Between 2008 and 2010, the United States Food and Drug Administration approved several generic formulations of both tacrolimus and mycophenolate mofetil. Deciding whether generic products can be safely substituted for the innovator product is a clinical dilemma similar to that which occurred when generic formulations of cyclosporine became available. We describe the concerns regarding generic immunosuppression use, summarize expert opinion and consensus statements in transplantation, analyze the potential impact of generic substitution, and provide estimates of populations affected based on generic drug market penetration. Formulary considerations such as cost, availability, and potential drug ordering and drug selection errors are described, and transplant coordinator and patient perspectives are reviewed. Finally, general recommendations about the use of generic maintenance immunosuppression in solid organ transplant recipients are provided. Although more research is needed to confirm clinical and therapeutic equivalence and pharmacoeconomic benefit, generic immunosuppressants can be safely substituted for innovator products as long as patients consistently receive the same product, patients and clinicians are aware of when substitutions occur, and enhanced therapeutic drug monitoring is provided during the transition.

Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide.

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Kanakry, Christopher G; Bolaños-Meade, Javier; Kasamon, Yvette L; Zahurak, Marianna; Durakovic, Nadira; Furlong, Terry; Mielcarek, Marco; Medeot, Marta; Gojo, Ivana; Smith, B Douglas; Kanakry, Jennifer A; Borrello, Ivan M; Brodsky, Robert A; Gladstone, Douglas E; Huff, Carol Ann; Matsui, William H; Swinnen, Lode J; Cooke, Kenneth R; Ambinder, Richard F; Fuchs, Ephraim J; de Lima, Marcos J; Andersson, Borje S; Varadhan, Ravi; O'Donnell, Paul V; Jones, Richard J; Luznik, Leo

2017-03-09

The intensive and prolonged immunosuppressive therapy required to prevent or treat graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT) puts patients at substantial risk for life-threatening infections, organ toxicity, and disease relapse. Posttransplantation cyclophosphamide (PTCy) can function as single-agent GVHD prophylaxis after myeloablative, HLA-matched related (MRD), or HLA-matched unrelated (MUD) donor T-cell-replete bone marrow allografting, obviating the need for additional prophylactic immunosuppression. However, patients who develop GVHD require supplemental treatment. We assessed the longitudinal requirement for immunosuppressive therapy in 339 patients treated with this transplantation platform: 247 receiving busulfan/cyclophosphamide (BuCy) conditioning (data collected retrospectively) and 92 receiving busulfan/fludarabine (BuFlu) conditioning (data collected prospectively). Approximately 50% of MRD patients and 30% of MUD patients never required immunosuppression beyond PTCy. In patients requiring further immunosuppression, typically only 1 to 2 agents were required, and the median durations of systemic pharmacologic immunosuppression for the BuCy MRD, BuFlu MRD, BuCy MUD, and BuFlu MUD groups all were 4.5 to 5 months. For these 4 groups, 1-year probabilities of being alive and off all systemic immunosuppression were 61%, 53%, 53%, and 51% and 3-year probabilities were 53%, 48%, 49%, and 56%, respectively. These data suggest that PTCy minimizes the global immunosuppressive burden experienced by patients undergoing HLA-matched alloBMT.

Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen

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Colebunders Robert

2010-11-01

Full Text Available Abstract Background Vitamin D is an important determinant of bone health and also plays a major role in the regulation of the immune system. Interestingly, vitamin D status before the start of highly active antiretroviral therapy (HAART has been recently associated with HIV disease progression and overall mortality in HIV-positive pregnant women. We prospectively studied vitamin D status in HIV individuals on HAART in Belgium. We selected samples from HIV-positive adults starting HAART with a pre-HAART CD4 T-cell count >100 cells/mm3 followed up for at least 12 months without a treatment change. We compared 25-hydroxyvitamin D plasma [25-(OHD] concentration in paired samples before and after 12 months of HAART. 25-(OHD levels are presented using two different cut-offs: Results Vitamin D deficiency was common before HAART, the frequency of plasma 25-(OHD concentrations below 20 ng/ml and 30 below ng/ml was 43.7% and 70.1% respectively. After 12 months on HAART, the frequency increased to 47.1% and 81.6%. HAART for 12 months was associated with a significant decrease of plasma 25-(OHD concentration (p = 0.001. Decreasing plasma 25-(OHD concentration on HAART was associated in the multivariate model with NNRTI-based regimen (p = 0.001 and lower body weight (p = 0.008. Plasma 25-(OHD concentrations decreased significantly in both nevirapine and efavirenz-containing regimens but not in PI-treated patients. Conclusions Vitamin D deficiency is frequent in HIV-positive individuals and NNRTI therapy further decreases 25-(OHD concentrations. Consequently, vitamin D status need to be checked regularly in all HIV-infected patients and vitamin D supplementation should be given when needed.

Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

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Prinitha Pillay

Full Text Available There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI efavirenz (EFV and nevirapine (NVP in first-line antiretroviral therapy (ART.We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2 statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2 = 0% and observational studies (RR 0.65 [0.59-0.71] I(2 = 54%. EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2 = 0% and observational studies (RR 1.06 [1.00-1.12] I(2 = 68%.EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

Favorable Outcomes after Implantation of Biodegradable Polymer Coated Sirolimus-Eluting Stents in Diabetic Population: Results from INDOLIMUS-G Diabetic Registry

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Anurag Polavarapu

2015-01-01

Full Text Available Objective. The main aim is to evaluate safety, efficacy, and clinical performance of the Indolimus (Sahajanand Medical Technologies Pvt. Ltd., Surat, India sirolimus-eluting stent in high-risk diabetic population with complex lesions. Methods. It was a multicentre, retrospective, non-randomized, single-arm study, which enrolled 372 diabetic patients treated with Indolimus. The primary endpoint of the study was major adverse cardiac events (MACE, which is a composite of cardiac death, target lesion revascularization (TLR, target vessel revascularization (TVR, myocardial infarction (MI, and stent thrombosis (ST. The clinical follow-ups were scheduled at 30 days, 6 months, and 9 months. Results. The mean age of the enrolled patients was 53.4 ± 10.2 years. A total of 437 lesions were intervened successfully with 483 stents (1.1 ± 0.3 per lesion. There were 256 (68.8% male patients. Hypertension and totally occluded lesions were found in 202 (54.3% and 45 (10.3% patients, respectively. The incidence of MACE at 30 days, 6 months and 9 months was 0 (0%, 6 (1.6%, and 8 (2.2%, respectively. The event-free survival at 9-month follow-up by Kaplan Meier method was found to be 97.8%. Conclusion. The use of biodegradable polymer coated sirolimus-eluting stent is associated with favorable outcomes. The results demonstrated in our study depict its safety and efficacy in diabetic population.

Immunity and immunosuppression in experimental visceral leishmaniasis

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Goto H.

2004-01-01

Full Text Available Leishmaniasis is a disease caused by protozoa of the genus Leishmania, and visceral leishmaniasis is a form in which the inner organs are affected. Since knowledge about immunity in experimental visceral leishmaniasis is poor, we present here a review on immunity and immunosuppression in experimental visceral leishmaniasis in mouse and hamster models. We show the complexity of the mechanisms involved and differences when compared with the cutaneous form of leishmaniasis. Resistance in visceral leishmaniasis involves both CD4+ and CD8+ T cells, and interleukin (IL-2, interferon (IFN- gamma, and IL-12, the latter in a mechanism independent of IFN- gamma and linked to transforming growth factor (TGF-ß production. Susceptibility involves IL-10 but not IL-4, and B cells. In immune animals, upon re-infection, the elements involved in resistance are different, i.e., CD8+ T cells and IL-2. Since one of the immunopathological consequences of active visceral leishmaniasis in humans is suppression of T-cell responses, many studies have been conducted using experimental models. Immunosuppression is mainly Leishmania antigen specific, and T cells, Th2 cells and adherent antigen-presenting cells have been shown to be involved. Interactions of the co-stimulatory molecule family B7-CTLA-4 leading to increased level of TGF-ß as well as apoptosis of CD4+ T cells and inhibition of macrophage apoptosis by Leishmania infection are other components participating in immunosuppression. A better understanding of this complex immune response and the mechanisms of immunosuppression in experimental visceral leishmaniasis will contribute to the study of human disease and to vaccine development.

Conversion from calcineurin inhibitors to sirolimus of recipients with chronic kidney graft disease grade iii for a period 2003-2011

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Ignjatović Ljiljana

2013-01-01

Full Text Available Background/Aim. Tremendous breakthrough in solid organ transplantation was made with the introduction of calcineurin inhibitors (CNI. At the same time, they are potentially nephrotoxic drugs with influence on onset and progression of renal graft failure. The aim of this study was to evaluate the outcome of a conversion from CNIbased immunosuppressive protocol to sirolimus (SRL in recipients with graft in chronic kidney disease (CKD grade III and proteinuria below 500 mg/day. Methods. In the period 2003-2011 24 patients (6 famale and 18 male, mean age 41 ± 12.2 years, on triple immunosuppressive therapy: steroids, antiproliferative drug [mycophenolate mofetil (MMF or azathiopirine (AZA] and CNI were switched from CNI to SRL and followe-up for 76 ± 13 months. Nine patients (the group I had early postransplant conversion after 4 ± 3 months and 15 patients (the group II late conversion after 46 ± 29 months. During the regular outpatient controls we followed graft function through the serum creatinine and glomerular filtration rate (GFR, proteinuria, lipidemia and side effects. Results. Thirty days after conversion, in all the patients GFR, proteinuria and lipidemia were insignificantly increased. In the first two post-conversion months all the patients had at least one urinary or respiratory infection, and 10 patients reactivated cytomegalovirus (CMV infection or disease, and they were successfully treated with standard therapy. After 21 ± 11 months 15 patients from both groups discontinued SRL therapy due to reconversion to CNI (10 patients and double immunosuppressive therapy (3 patients, return to hemodialysis (1 patient and death (1 patient. Nine patients were still on SRL therapy. By the end of the follow-up they significantly improved GFR (from 53.2 ± 12.7 to 69 ± 15 mL/min, while the increase in proteinuria (from 265 ± 239 to 530.6 ± 416.7 mg/day and lipidemia (cholesterol from 4.71 ± 0.98 to 5.61 ± 1.6 mmol/L and triglycerides

Impact of adverse events of antiretroviral treatment on regimen change and mortality in Ugandan children

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Ntambwe Malangu

2010-06-01

Objectives: The purpose of this study was to determine the prevalence of the adverse events of antiretroviral treatment, their impact on mortality and the change in regimens prescribed to children treated at Mildway Centre in Uganda. Method: A retrospective chart review was performed for children younger than 6 years, treated since the Mildway Centre was opened in 1999. In order to achieve a larger sample, the records of children treated from January 2000 to July 2005 were included in the study. A pre-tested data collection form was used to collate socio-demographic and clinical data of the patients. These included the documented adverse events, causes of death, stage of infection, duration of treatment, regimen prescribed, year of enrolment into the treatment program, as well as whether or not they were still alive. Descriptive statistics were used in the analysis of data. Results: Of the 179 children, the majority were males and had a median age of 4 years. The majority (58.8% of children had suffered from severe immune depression since they met the WHO clinical stage III and IV, 73.8% had a baseline CD4T of less than 15%. Four regimens were prescribed to the children. The most common was a regimen containing zidovudine, lamivudine, and nevirapine (34.6%, followed by a regimen containing stavudine, lamivudine, and nevirapine (27.9%. Eleven children (6.1% had their regimen changed, of which six (54.5% were due to adverse events. The prevalence of adverse events was 8%; of the 14 documented adverse events, the most common were severe anaemia (3, vomiting (3, and skin rashes (3. After 12 months on treatment, 8% of the patients had died. The most common causes of death were infectious diseases (28.6%, severe anaemia (21.4%, and severe dehydration (21.4%. Conclusion: The prevalence of adverse events was 8%; they were responsible for 54.5% of regimen changes and 21.4% of deaths in children treated at the study site. These findings suggest the need for incorporating

New Immunosuppressive Therapies in Uveitis Treatment

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Salvador Mérida

2015-08-01

Full Text Available Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines.

New Immunosuppressive Therapies in Uveitis Treatment

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Mérida, Salvador; Palacios, Elena; Navea, Amparo; Bosch-Morell, Francisco

2015-01-01

Uveitis is an inflammatory process that initially starts in the uvea, but can also affect other adjacent eye structures, and is currently the fourth cause of blindness in developed countries. Corticoids are probably the most widespread treatment, but resorting to other immunosuppressive treatments is a frequent practice. Since the implication of different cytokines in uveitis has been well demonstrated, the majority of recent treatments for this disease include inhibitors or antibodies against these. Nevertheless, adequate treatment for each uveitis type entails a difficult therapeutic decision as no clear recommendations are found in the literature, despite the few protocolized clinical assays and many case-control studies done. This review aims to present, in order, the mechanisms and main indications of the most modern immunosuppressive drugs against cytokines. PMID:26270662

Symptom Experience Associated With Immunosuppressive Medications in Chinese Kidney Transplant Recipients.

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Teng, Sha; Zhang, Shuping; Zhang, Wenxin; Lin, Xiaohong; Shang, Yabin; Peng, Xiao; Liu, Hongxia

2015-09-01

Kidney transplant recipients require lifelong treatment with immunosuppressive medications to avoid graft rejection and graft loss. Symptoms experienced may influence recipients' perceived quality of life and medication adherence. The purpose of this study was to evaluate the symptom experience associated with immunosuppressive medications in adult kidney transplant recipients and to explore the association between the symptom experience and adherence to immunosuppressive medications. A cross-sectional design was used. The study was conducted in a general hospital in China from October 2013 to September 2014. A total of 231 recipients with a follow-up of at least 1 year after kidney transplantation were included. Symptom experience associated with immunosuppressive medications was measured by the 13-item Symptom Experience of Immunosuppressive-related Side Effects Scale. Self-reported adherence to immunosuppressive medications was assessed using the Adherence with Immunosuppressive Medication Scale. Ridit analysis was used to rank symptom distress items. A proportion of 60.6% of recipients were male; the time after kidney transplantation was arbitrarily divided into a short-term cohort (1-4 years) and a long-term cohort (4-16 years) according to the median duration of follow-up (4 years). High blood pressure, hair loss, and tiredness were the three most distressing symptoms over all items of the whole sample. High blood pressure was the most distressing symptom for the 1- to 4-year cohort and the 4- to 16-year cohort. For men high blood pressure was the most distressing symptom, whereas for women hair loss was the most distressing symptom. Recipients in the 4- to 16-year cohort perceived a higher level of symptom distress compared with those in the 1- to 4-year cohort, especially in excess hair growth and difficulty sleeping. A negative relationship was found between symptom distress and adherence to immunosuppressive medications (r = -.541, p = .000). Recipients

Rationale and Design of a Randomized Clinical Comparison of Everolimus-Eluting (Xience V/Promus) and Sirolimus-Eluting (Cypher Select+) Coronary Stents in Unselected Patients with Coronary Heart Disease

DEFF Research Database (Denmark)

Jensen, Lisette Okkels; Thayssen, Per; Tilsted, Hans Henrik

2010-01-01

with Clinical Outcome (SORT OUT) IV trial was designed as a prospective, multi-center, open-label, all-comer, two-arm, randomized, non-inferiority study comparing the everolimus-eluting stent with the sirolimus-eluting stent in the treatment of atherosclerotic coronary artery lesions. Based on a non...

Outcomes of immunosuppressive therapy in chronic hypersensitivity pneumonitis

Directory of Open Access Journals (Sweden)

Ayodeji Adegunsoye

2017-08-01

Full Text Available In chronic hypersensitivity pneumonitis (CHP, lack of improvement or declining lung function may prompt use of immunosuppressive therapy. We hypothesised that use of azathioprine or mycophenolate mofetil with prednisone reduces adverse events and lung function decline, and improves transplant-free survival. Patients with CHP were identified. Demographic features, pulmonary function tests, incidence of treatment-emergent adverse events (TEAEs and transplant-free survival were characterised, compared and analysed between patients stratified by immunosuppressive therapy. A multicentre comparison was performed across four independent tertiary medical centres. Among 131 CHP patients at the University of Chicago medical centre (Chicago, IL, USA, 93 (71% received immunosuppressive therapy, and had worse baseline forced vital capacity (FVC and diffusing capacity, and increased mortality compared with those who did not. Compared to patients treated with prednisone alone, TEAEs were 54% less frequent with azathioprine therapy (p=0.04 and 66% less frequent with mycophenolate mofetil (p=0.002. FVC decline and survival were similar between treatment groups. Analyses of datasets from four external tertiary medical centres confirmed these findings. CHP patients who did not receive immunosuppressive therapy had better survival than those who did. Use of mycophenolate mofetil or azathioprine was associated with a decreased incidence of TEAEs, and no difference in lung function decline or survival when compared with prednisone alone. Early transition to mycophenolate mofetil or azathioprine may be an appropriate therapeutic approach in CHP, but more studies are needed.

Induction of MHC-mismatched Mouse Lung Allograft Acceptance with Combined Donor Bone Marrow: Lung Transplant using a 12-Hour Nonmyeloablative Conditioning Regimen

Science.gov (United States)

Vulic, Ante; Panoskaltsis-Mortari, Angela; McDyer, John F.; Luznik, Leo

2016-01-01

Background Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Methods Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low dose total body irradiation and posttransplant (donor) bone marrow and splenocyte infusion followed by posttransplantation cyclophosphamide (PTTT-PTB/PTCy). Results Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3+ T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of PTTT-PTB/PTCy following a chimerism-ablating secondary recipient lymphocyte infusion. Conclusion Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation (BMT) using a short-duration nonmyeloablative conditioning regimen and PTCy. PMID:27861294

Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of different immunosuppressive regimens.

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Weimer, R; Süsal, C; Yildiz, S; Staak, A; Pelzl, S; Renner, F; Dietrich, H; Daniel, V; Kamali-Ernst, S; Ernst, W; Padberg, W; Opelz, G

2006-08-01

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year follow-up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p sCD30 could not be attributed to enhanced Th2-type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage in patients with elevated sCD30 or neopterin.

The immune-enhancing activity of Cervus nippon mantchuricus extract (NGE) in RAW264.7 macrophage cells and immunosuppressed mice.

Science.gov (United States)

Hong, Se Hyang; Ku, Jin Mo; In Kim, Hyo; Ahn, Chang-Won; Park, Soo-Hyun; Seo, Hye Sook; Shin, Yong Cheol; Ko, Seong-Gyu

2017-09-01

Chemotherapeutics are often used to inhibit the proliferation of cancer cells. However, they can also harm healthy cells and cause side effects such as immunosuppression. Especially traditional oriental medicines long used in Asia, may be beneficial candidates for the alleviation of immune diseases. Cervus nippon mantchuricus extract (NGE) is currently sold in the market as coffee and health drinks. However, NGE was not widely investigated and efficacy remain unclear and essentially nothing is known about their potential immune-regulatory properties. As a result, NGE induced the differentiation of RAW264.7 macrophage cells. NGE-stimulated RAW264.7 macrophage cells elevated cytokines levels and NO production. NGE-stimulated RAW264.7 macrophage cells activated MAPKs and NF-κB signaling pathways. NGE encouraged the immuno-enhancing effects in immunosuppressed short-term treated with NGE mice model. NGE or Red ginseng encouraged the immuno-enhancing effects in immunosuppressed long-term treated with NGE mice model. Our data clearly show that NGE contains immune-enhancing activity and can be used to treat immunodeficiency. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pancreatic islet allograft in spleen with immunosuppression with cyclosporine. Experimental model in dogs.

Science.gov (United States)

Waisberg, Jaques; Neff, Charles Benjamin; Waisberg, Daniel Reis; Germini, Demetrius; Gonçalves, José Eduardo; Zanotto, Arnaldo; Speranzini, Manlio Basilio

2011-01-01

To study the functional behavior of the allograft with immunosuppression of pancreatic islets in the spleen. Five groups of 10 Mongrel dogs were used: Group A (control) underwent biochemical tests; Group B underwent total pancreatectomy; Group C underwent total pancreatectomy and pancreatic islet autotransplant in the spleen; Group D underwent pancreatic islet allograft in the spleen without immunosuppressive therapy; Group E underwent pancreatic islet allograft in the spleen and immunosuppression with cyclosporine. All of the animals with grafts received pancreatic islets prepared by the mechanical-enzymatic method - stationary collagenase digestion and purification with dextran discontinuous density gradient, implanted in the spleen. The animals with autotransplant and those with allografts with immunosuppression that became normoglycemic showed altered results of intravenous tolerance glucose (p < 0.001) and peripheral and splenic vein plasmatic insulin levels were significantly lower (p < 0.001) in animals that had allografts with immunosuppression than in those with just autotransplants. In the animals with immunosuppression with cyclosporine subjected to allograft of pancreatic islets prepared with the mechanical-enzymatic preparation method (stationary collagenase digestion and purification with dextran discontinuous density gradient), the production of insulin is decreased and the response to intravenous glucose is altered.

Immunosuppression in the elderly renal allograft recipient

DEFF Research Database (Denmark)

Montero, Nuria; Pérez-Sáez, María José; Pascual, Julio

2016-01-01

BACKGROUND: The Elderly are the fastest growing part of kidney transplant recipients. The best immunosuppressive strategy is unknown. METHODS: We performed a systematic search of randomized controlled trials and observational studies focused on safety and efficacy of different immunosuppression...... strategies in elderly kidney recipients. Data extraction and risk of bias evaluation were systematically performed. RESULTS: Ten studies were included: 2 randomized clinical trials and 8 observational. A marginal benefit was found for early renal function with delayed tacrolimus or complete tacrolimus...... receptor antibody induction, calcineurin-inhibitor minimization with MMF and steroid minimization is advisable in the low immunologic risk elderly recipient, considering the increased risk of toxicities, infection and malignancies. In the high immunologic risk elderly recipient, taking into account...

CCL2 is critical for immunosuppression to promote cancer metastasis.

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Kudo-Saito, Chie; Shirako, Hiromi; Ohike, Misa; Tsukamoto, Nobuo; Kawakami, Yutaka

2013-04-01

We previously found that cancer metastasis is accelerated by immunosuppression during Snail-induced epithelial-to-mesenchymal transition (EMT). However, the molecular mechanism still remained unclear. Here, we demonstrate that CCL2 is a critical determinant for both tumor metastasis and immunosuppression induced by Snail(+) tumor cells. CCL2 is significantly upregulated in various human tumor cells accompanied by Snail expression induced by snail transduction or TGFβ treatment. The Snail(+) tumor-derived CCL2 amplifies EMT events in other cells including Snail(-) tumor cells and epithelial cells within tumor microenvironment. CCL2 secondarily induces Lipocalin 2 (LCN2) in the Snail(+) tumor cells in an autocrine manner. CCL2 and LCN2 cooperatively generate immunoregulatory dendritic cells (DCreg) having suppressive activity accompanied by lowered expression of costimulatory molecules such as HLA-DR but increased expression of immunosuppressive molecules such as PD-L1 in human PBMCs. The CCL2/LCN2-induced DCreg cells subsequently induce immunosuppressive CD4(+)FOXP3(+) Treg cells, and finally impair tumor-specific CTL induction. In murine established tumor model, however, CCL2 blockade utilizing the specific siRNA or neutralizing mAb significantly inhibits Snail(+) tumor growth and metastasis following systemic induction of anti-tumor immune responses in host. These results suggest that CCL2 is more than a chemoattractant factor that is the significant effector molecule responsible for immune evasion of Snail(+) tumor cells. CCL2 would be an attractive target for treatment to eliminate cancer cells via amelioration of tumor metastasis and immunosuppression.

UVB-induced systemic immunosuppression: role of mast cells and histamine

International Nuclear Information System (INIS)

Hart, P.H.; Grimbaldeston, M.A.; Finlay-Jones, J.J.

1999-01-01

Full text: UVB radiation (290-320 nm) is immunosuppressive by multiple mechanisms allowing the outgrowth of UV-induced tumours in both mouse and man. Furthermore, patients with non-melanoma skin cancers have a higher risk of death from other cancers which could be explained by UV-induced immunomodulation. The mechanism(s) of suppression by UVB depend on whether the sensitising antigen is applied to the irradiated site ('local') or to non-irradiated sites ('systemic'). In the former, the activity of UV-induced TNFα is important as it affects the migration of Langerhans cells to draining lymph nodes. In contrast, histamine from dermal mast cells is critical to the early events by which UVB can suppress systemic immune responses. The prevalence of dermal mast cells in 7 strains and substrains of mice correlates directly with their susceptibility to UVB-induced systemic immunosuppression. Furthermore, mast cell depleted mice (Wf/Wf) are resistant to UVB-induced systemic immunomodulation. However, they become susceptible after reconstitution of the site to be irradiated with bone marrow derived mast cell precursors. The mice also gain susceptibility to cis-urocanic acid-induced systemic immunomodulation. There is considerable evidence that histamine is the mast cell product critical to downstream immunosuppressive events. Firstly, physiological concentrations of histamine suppress contact hypersensitivity responses. Secondly, histamine receptor antagonists halve UVB-induced systemic immunosuppression. Thirdly, mice with different UVB-susceptibilities are equally susceptible to histamine-induced immunosuppression, and finally, histamine can suppress contact hypersensitivity responses in Wf/Wf mice. We suggest that histamine may be immunomodulatory by multiple pathways. Histamine can induce the production of immunosuppressive prostanoids from keratinocytes. A lymphocyte-derived, histamine-induced suppressor factor was reported in the 1970's. More recently histamine has

Prevention and treatment of Encephalitozoon cuniculi infection in immunosuppressed rabbits with fenbendazole.

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Abu-Akkada, S S; Oda, S S

2016-01-01

This study was conducted to evaluate the efficacy of oral administration of fenbendazole (20 mg/kg body weight) prior to and after experimental infection of immunosuppressed rabbits with Encephalitozoon cuniculi . A total of thirty rabbits were divided into five groups: NN (non-immunosuppressed; non-infected), IN (immunosuppressed; non-infected), IPI (immunosuppressed; protected-infected), ITI (immunosuppressed; treated-infected), and II (immunosuppressed; infected) groups. Fenbendazole was administered as a prophylactic for seven successive days before infection with E. cuniculi and as a treatment for four weeks initiated on the 28th day post-challenge (PC). Experimental rabbits were infected with intraperitoneal injection of 2 × 10 5 E. cuniculi spores. Parameters evaluated were body weight, detection of spores in urine, serum antibody assay, hematological, biochemical and histopathological changes. The IPI and ITI groups showed a significant better final bwt than the II group. Spores were detected in urine of all infected rabbits from the 28th day PC until the end of the study. The IPI group showed the least values of antibodies (IgG) compared to the ITI and II groups. Concerning histopathological changes, the intensity of the lesions was marked particularly in the II rabbits and to a lesser extent in the ITI rabbits. Noticeable improvement was found in the IPI rabbits. It could be concluded that fenbendazole was effective to some extent in protection of rabbits against E. cuniculi infection, while when administered as a therapeutic no significant effects were observed.

Treatment of patients with severe autoimmune hepatitis

DEFF Research Database (Denmark)

Larsen, Finn Stolze

2008-01-01

Autoimmune hepatitis (AIH) is a progressive inflammatory diseases of unknown origin that is characterised by a necro-inflammatory and fibrotic process and may result in liver failure or uncompensated liver cirrhosis. Normally AIH is responsive to immunosuppressive therapy, and treatment aims...... and tacrolimus) might salvage patients from transplantation. Mycophenolate mofetil may also improve liver tests and reduce the requirement for corticosteroids. Besides, sirolimus is effective for treatment of de novo autoimmune hepatitis that sometimes develops after liver transplantation. Initial experience...

AChR-specific immunosuppressive therapy of myasthenia gravis.

Science.gov (United States)

Luo, Jie; Lindstrom, Jon

2015-10-15

Myasthenia gravis (MG) is an organ-specific autoimmune disease characterized by muscle fatigability. In most cases, it is mediated by autoantibodies targeting muscle nicotinic acetylcholine receptors (AChRs) at the neuromuscular junction. Experimental autoimmune myasthenia gravis (EAMG) is an animal model for MG, which is usually induced by immunization with AChR purified from fish electric organ. Pathological autoantibodies to AChRs are directed at the extracellular surface, especially the main immunogenic region (MIR). Current treatments for MG can help many but not all patients. Antigen-specific immunosuppressive therapy for MG that specifically suppresses the autoimmune response without affecting the entire immune system and avoids side effects of general immunosuppression is currently unavailable. Early attempts at antigen-specific immunosuppression for EAMG using AChR extracellular domain sequences that form epitopes for pathological autoantibodies risked provoking autoimmunity rather than suppressing it. We discovered a novel approach to specific immunosuppression of EAMG with a therapeutic vaccine consisting of bacterially-expressed human AChR cytoplasmic domains, which has the potential to specifically suppress MG without danger of causing exacerbation. This approach prevents development of chronic EAMG when initiated immediately after the acute phase of EAMG, and rapidly reverses established chronic EAMG when started during the chronic phase of EAMG. Successfully treated rats exhibited long-term resistance to re-induction of EAMG. In this review we also discuss the current understanding of the mechanisms by which the therapy works. Vaccination with AChR cytoplasmic domains in adjuvant is promising as a safe, antigen-specific, potent, effective, rapidly acting, and long lasting approach to therapy of MG. Copyright © 2015 Elsevier Inc. All rights reserved.

Prevention of Intraabdominal Adhesions by Local and Systemic Administration of Immunosuppressive Drugs

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Peker, Kemal; Inal, Abdullah; Sayar, Ilyas; Sahin, Murat; Gullu, Huriye; Inal, Duriye Gul; Isik, Arda

2013-01-01

Background: Intraperitoneal adhesion formation is a serious postsurgical issue. Adhesions develop after damage to the peritoneum by surgery, irradiation, infection or trauma. Objectives: Using a rat model, we compared the effectiveness of systemic and intraperitoneally administered common immunosuppressive drugs for prevention of postoperative intraperitoneal adhesions. Materials and Methods: Peritoneal adhesions were induced in 98 female Wistar-Albino rats by cecal abrasion and peritoneal excision. Rats were randomly separated into seven groups, each containing fourteen rats, and the standard experimental model was applied to all of rats. 14 days later, rats were euthanized, intraperitoneal adhesions were scored and tissues were examined histologically using hematoxylin/eosin and Masson’s trichrome staining. Results: Throughout the investigation, no animal died during or after surgery. In all of experimental groups, decrease in fibrosis was statistically significant. Decrease in fibrosis was most prominently in intraperitoneal tacrolimus group (P = 0.000), and decrease was least in intraperitoneal cyclosporine group (P = 0.022). Vascular proliferation was significantly decreased in all experimental groups (P < 0.05) except for systemic tacrolimus group (P = 0.139). Most prominent reduction in vascular proliferation was in intraperitoneal tacrolimus group (P = 0.000). Conclusions: Administration of immunosuppressive drugs is effective for prevention of intraperitoneal adhesions. PMID:24693396

A Danish nationwide questionnaire study of hepatitis B virus screening before immunosuppressive therapy

DEFF Research Database (Denmark)

Bunyoz, Kristine Ifigenia; Krarup, Henrik; Weis, Nina

2017-01-01

INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation of immunos......INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation...... of immunosuppressive therapy and to explore HBV treatment strategies. METHODS: All Danish units of haematology, oncology, dermatology, rheumatology and gastroenterology using immunosuppressive agents were invited to fill out a questionnaire for The Danish Database for Hepatitis B and C. RESULTS: A total of 28 (53...

Immunosuppression and tolerance after total lymphoid irradiation (TLI)

International Nuclear Information System (INIS)

Strober, S.; Gottlieb, M.; Slavin, S.; King, D.P.; Hoppe, R.T.; Fuks, Z.; Bieber, C.P.; Kaplan, H.S.

1980-01-01

The immunosuppressive effects of total lymphoid irradiation (TLI) in humans and in several species of inbred and outbred laboratory animals have been investigated. A unique property of TLI, the prevention of the graft vs. host disease, was used to induce transplantation tolerance in order to study the mechanism of altered immunity when the celluar basis of the TLI-induced immunosuppression was examined by means of the mixed lymphocyte response (MLR), no suppression of the MLR was observed when spleen cells from unirradiated or whole body-irradiated donors were used instead of donors given TLI. These results indicated that TLI induces a population of cells in the spleen that can nonspecifically suppress the MLR

Immunosuppressive Treatment of Non-infectious Uveitis: History and Current Choices.

Science.gov (United States)

Zhao, Chan; Zhang, Meifen

2017-04-10

Non-infectious uveitis is one of the leading causes of preventable blindness worldwide. Long-term immunosuppressive treatment is generally required to achieve durable control of inflammation in posterior and panuveitis. Although systemic corticosteroids have been the gold standard of immunosup- pressive treatment for uveitis since first introduced in 1950s, its side effects of long-term use often warrant an adjuvant treatment to reduce the dosage/duration of corticosteroids needed to maintain disease control. Conventional immunosuppressive drugs, classified into alkylating agent, antimetabolites and T cell inhibitors, have been widely used as corticosteroid-sparing agents, each with characteristic safety/tolerance profiles on different uveitis entities. Recently, biologic agents, which target specific molecules in immunopathogenesis of uveitis, have gained great interest as alternative treatments for refractory uveitis based on their favorable safety and effectiveness in a variety of uveitis entities. However, lack of large randomized controlled clinical trials, concerns about efficacy and safety of long-term usage, and economic burden are limiting the use of biologics in non-infectious uveitis. Local administration of immunosuppressive drugs (from corticosteroids to biologics) through intraocular drug delivery systems represent another direction for drug development and is now under intense investigation, but more evidences are needed to support their use as regular alternative treatments for uveitis. With the numerous choices belonging to different treatment modalities (conventional immunosuppressive agents, biologics and local drug delivery systems) on hand, the practice patterns have been reported to vary greatly from center to center. Factors influence uveitis specialists' choices of immunosuppressive agents may be complex and may include personal familiarity, treatment availability, safety/tolerability, effectiveness, patient compliance, cost concerns and

The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study

NARCIS (Netherlands)

Collaboration, H.-C.; Koopmans †, P.P.; Brouwer, A.M.; Dofferhoff, A.S.M.; Flier, M. van der; Groot, R. de; Hofstede, H.J.M. ter; Keuter, M.; Ven, A.J.A.M. van der; et al.,

2012-01-01

OBJECTIVE: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. DESIGN: Prospective

A Danish nationwide questionnaire study of hepatitis B virus screening before immunosuppressive therapy

DEFF Research Database (Denmark)

Bunyoz, Kristine Ifigenia; Krarup, Henrik; Weis, Nina

2017-01-01

INTRODUCTION: Difficulty in identifying patients who are at risk for hepatitis B virus (HBV) reactivation makes it import-ant to screen for HBV before initiating immunosuppressive therapy. The aim of this study was to investigate screening procedures for HBV infection before initiation...... of immunosuppressive therapy and to explore HBV treatment strategies. METHODS: All Danish units of haematology, oncology, dermatology, rheumatology and gastroenterology using immunosuppressive agents were invited to fill out a questionnaire for The Danish Database for Hepatitis B and C. RESULTS: A total of 28 (53......%) of the 53 included units answered the questionnaire, of which 25 (89.3%) had a guideline regarding screening for HBV serological markers prior to immunosuppressive therapy, but only ten (37%) had a guideline that is in line with the joint guidelines from the national Danish Societies of Infectious Diseases...

Safety of lornoxicam in the treatment of postoperative pain: a post-marketing study of analgesic regimens containing lornoxicam compared with standard analgesic treatment in 3752 day-case surgery patients.

Science.gov (United States)

Rawal, Narinder; Krøner, Karsten; Simin-Geertsen, Marija; Hejl, Charlotte; Likar, Rudolf

2010-01-01

Post-marketing surveillance studies can provide supplemental data on the safety of medications in the general population. This study aimed to evaluate the safety of analgesic regimens including the NSAID lornoxicam in the short-term treatment of postoperative pain in a clinically relevant population. Randomized, open-label, multicentre, multinational, observational cohort study of 4 days' duration. In-hospital postoperative setting, with discharge to home treatment within 24 hours of surgery. Adults aged > or =18 years expected to be in need of analgesic treatment after day-case surgery. Analgesic regimens containing lornoxicam were compared with a standard analgesic treatment, which was defined as the treatment that the patient would normally receive at the centre. Following day-case surgery, patients were provided with appropriate analgesic medication, and adverse events (AEs; defined as all recorded events with symptoms) were recorded by the investigator during the in-hospital stay and by the patient for the next 3 days using entries recorded morning and evening in a patient diary. Statistical analyses tested for between-treatment differences in AEs, adverse drug reactions (ADRs; defined as events probably, possibly or unlikely to be related to treatment) and gastrointestinal AEs (GI-AEs). A total of 4152 patients were randomized to treatment. Since 400 patients did not take any analgesic, the safety population consisted of 1838 patients for lornoxicam and 1914 patients for standard analgesic treatment. Demographic and disease characteristics were similar between the two treatment groups, as were the type of surgery and the anaesthesia used in surgery. In the safety population, 16.9% of patients received no analgesic in hospital, and when analgesics were provided they were often administered in combination. Similarly, approximately 17% of patients did not take any analgesics at home. AEs were reported in 27.1% and 29.4% of patients in the lornoxicam and standard

The targeting of immunosuppressive mechanisms in hematological malignancies

DEFF Research Database (Denmark)

Andersen, M H

2014-01-01

enzymes such as indoeamine-2,3-dioxygenase (IDO). The possible therapeutic targeting of these pathways is also discussed. Exciting new strategies that might affect future antileukemia immunotherapy include monoclonal antibodies that block inhibitory T-cell pathways (PD-1/PD-L1) and the prevention...... of tryptophan depletion by IDO inhibitors. Furthermore, the clinical effect of several chemotherapeutic drugs may arise from the targeting of immunosuppressive cells. Evidence for a new feedback mechanism to suppress the function of regulatory immune cells was recently provided by the identification...... and characterization of spontaneous cytotoxic T lymphocyte (CTL) responses against regulatory immune cells. Such specific CTLs may be immensely useful in anticancer immunotherapy (for example, by anticancer vaccination). The targeting of one or more immunosuppressive pathways may be especially interesting...

Neurologic emergencies in HIV-negative immunosuppressed patients.

Science.gov (United States)

Guzmán-De-Villoria, J A; Fernández-García, P; Borrego-Ruiz, P J

HIV-negative immunosuppressed patients comprise a heterogeneous group including transplant patients, patients undergoing treatment with immunosuppressors, uremic patients, alcoholics, undernourished patients, diabetics, patients on dialysis, elderly patients, and those diagnosed with severe or neoplastic processes. Epileptic seizures, focal neurologic signs, and meningoencephalitis are neurologic syndromes that require urgent action. In most of these situations, neuroimaging tests are necessary, but the findings can be different from those observed in immunocompetent patients in function of the inflammatory response. Infectious disease is the first diagnostic suspicion, and the identification of an opportunistic pathogen should be oriented in function of the type and degree of immunosuppression. Other neurologic emergencies include ischemic stroke, cerebral hemorrhage, neoplastic processes, and pharmacological neurotoxicity. This article reviews the role of neuroimaging in HIV-negative immunodepressed patients with a neurologic complication that requires urgent management. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

PROPOSAL OF ANTI-TUBERCULOSIS REGIMENS BASED ON SUSCEPTIBILITY TO ISONIAZID AND RIFAMPICIN

Science.gov (United States)

Mendoza-Ticona, Alberto; Moore, David AJ; Alarcón, Valentina; Samalvides, Frine; Seas, Carlos

2014-01-01

Objective To elaborate optimal anti-tuberculosis regimens following drug susceptibility testing (DST) to isoniazid (H) and rifampicin (R). Design 12 311 M. tuberculosis strains (National Health Institute of Peru 2007-2009) were classified in four groups according H and R resistance. In each group the sensitivity to ethambutol (E), pirazinamide (Z), streptomycin (S), kanamycin (Km), capreomycin (Cm), ciprofloxacin (Cfx), ethionamide (Eto), cicloserine (Cs) and p-amino salicilic acid (PAS) was determined. Based on resistance profiles, domestic costs, and following WHO guidelines, we elaborated and selected optimal putative regimens for each group. The potential efficacy (PE) variable was defined as the proportion of strains sensitive to at least three or four drugs for each regimen evaluated. Results Selected regimes with the lowest cost, and highest PE of containing 3 and 4 effective drugs for TB sensitive to H and R were: HRZ (99,5%) and HREZ (99,1%), respectively; RZECfx (PE=98,9%) and RZECfxKm (PE=97,7%) for TB resistant to H; HZECfx (96,8%) and HZECfxKm (95,4%) for TB resistant to R; and EZCfxKmEtoCs (82.9%) for MDR-TB. Conclusion Based on resistance to H and R it was possible to select anti-tuberculosis regimens with high probability of success. This proposal is a feasible alternative to tackle tuberculosis in Peru where the access to rapid DST to H and R is improving progressively. PMID:23949502

Immunosuppressive potential of bardoxolone methyl using a modified murine local lymph node assay (LLNA).

Science.gov (United States)

Kitsukawa, Mika; Tsuchiyama, Hiromi; Maeda, Akihisa; Oshida, Keiyu; Miyamoto, Yohei

2014-08-01

2-Cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid methyl ester (CDDO-Me; bardoxolone methyl) is one of the synthetic oleanane triterpenoids (SOs). It is known that it is the strongest Nrf2/ARE signaling inducer of SOs and slightly inhibits immune response. Little was known about the immunomodulatory action of CDDO-Me in vivo. We assessed its immunosuppressive potential by using the modified mouse lymph node assay (LLNA) including immunosuppression-related gene expression analysis. In the modified LLNA, CDDO-Me showed a significant decrease in lymph node weight and changes in expressions of the immunosuppression-related genes, Zfp459 and Fmo2. It has been already reported that a decrease in lymph node weight was induced by several types of immunosuppressive chemicals such as calcineurin inhibitors, antimetabolites, steroids, and alkylators. In addition, changes in Zfp459 and Fmo2 expression was reported in response after only treatment of antimetabolites. From these results, CDDO-Me is considered to have an immunosuppressive action and similar mechanism to antimetabolites.

Differences in Attitudes Toward Immunosuppressant Therapy in a Multi-ethnic Sample of Kidney Transplant Recipients.

Science.gov (United States)

Constantiner, Melissa; Rosenthal-Asher, Deborah; Tedla, Fasika; Salifu, Moro; Cukor, Judith; Wyka, Katarzyna; Hartono, Choli; Serur, David; de Boccardo, Graciela; Cukor, Daniel

2018-03-01

Barriers for renal transplant patients to immunosuppressant medication adherence are poorly understood, despite the high rate and toll of non-adherence. We sought to assess factors that contribute to barriers to immunosuppressive medication adherence in an ethnically diverse sample of 312 renal transplant patients recruited from three transplant centers across New York City. Transplant patients who were at least 6 months post-transplant completed questionnaires while waiting for their medical appointment. Ethnic differences were observed on barriers to immunosuppressant adherence. Black and Hispanic participants reported significantly more barriers to adherence compared to Caucasian participants. Differences in perception about the potential harm and necessity of immunosuppressant medications also were present. Using hierarchical multiple regression, age and income were significant predictors of reported barriers to adherence, even while controlling for ethnicity. The most robust predictor of reported barriers was the perception of the medication cost-benefit differential, i.e., the balance between concerns about immunosuppressant medications and their perceived helpfulness (B = - 0.5, p adherence. Future interventions targeting non-adherence should aim to reduce the barriers to adherence by addressing perceived risks and benefits of taking immunosuppressant medication.

Cutaneous lymphoproliferative disorder complicating infectious mononucleosis in an immunosuppressed patient.

Science.gov (United States)

Owen, Cindy England; Callen, Jeffrey P; Bahrami, Soon

2011-01-01

Infectious mononucleosis is the syndrome produced by primary infection with Epstein-Barr virus during adolescence or early adulthood. In immunosuppressed individuals, depressed T-cell function allows the Epstein-Barr virus-driven B-cell proliferation to continue unabated, potentially leading to a lymphoproliferative disorder. A 15-year-old girl with a history of ulcerative colitis treated with 6-mercaptopurine and mesalamine presented with the acute onset of a rapidly enlarging, ulcerative nodule on her left lower eyelid 4 weeks following recovery from infectious mononucleosis. The biopsy revealed an Epstein-Barr virus-positive lymphoproliferative disorder. Systemic disease was absent. Following discontinuation of 6-mercaptopurine, the patient was treated with two courses of intravenous cyclophosphamide. The lesion resolved completely and she remains disease free at 14 months following diagnosis. We report a solitary cutaneous lesion of an immunosuppression-related lymphoproliferative disorder (IR-LPD) occurring as a complication of infectious mononucleosis, and review the pathogenesis and reported cases of Epstein-Barr virus-related immunosuppression-related lymphoproliferative disorder arising in the setting of inflammatory bowel disease. It is important for dermatologists and dermatopathologists to be aware of the occurrence of IR-LPD in patients being treated for inflammatory conditions, including inflammatory bowel disease. Given the role of primary infection with Epstein-Barr virus in the development of IR-LPD, consideration may be given to assessing Epstein-Barr virus status prior to initiating immunosuppressive therapy in young patients. © 2010 Wiley Periodicals, Inc.

Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis.

Science.gov (United States)

Kumari, P; Nigam, R; Singh, A; Nakade, U P; Sharma, A; Garg, S K; Singh, S K

2017-09-01

Demodex canis infestation in dogs remains one of the main challenges in veterinary dermatology. The exact pathogenesis of canine demodicosis is unknown but an aberration in immune status is considered very significant. No studies have underpinned the nexus between induction of demodicosis and neural immunosuppressive pathways so far. We have evaluated the involvement of cholinergic pathways in association with cytokines regulation as an insight into the immuno-pathogenesis of canine demodicosis in the present study. Remarkable elevations in circulatory immunosuppressive cytokine interleukin-10 and cholinesterase activity were observed in dogs with demodicosis. Simultaneously, remarkable reduction in circulatory pro-inflammatory cytokine tumour necrosis factor-alpha level was observed in dogs with demodicosis. Findings of the present study evidently suggest that Demodex mites might be affecting the cholinergic pathways to induce immunosuppression in their host and then proliferate incessantly in skin microenvironment to cause demodicosis.

Persistent Hypotony Associated with Immunosuppressive Therapy in Glaucoma Drainage Implant Surgery

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Susana Duch

2016-09-01

Full Text Available Purpose: To describe the histopathology of non-valved implant capsules in three cases of persistent postoperative hypotony after the restrictive tube ligature was released in patients receiving immunosuppressive therapy. Observations: The macroscopic appearance of the capsules 3 and 4 months postoperatively was immature and loose. Microscopic examination disclosed extremely irregular thin tissue, with thicknesses ranging from 0.02 to 0.6 mm, depending on the capsular location studied. Withdrawal of immunosuppressive therapy did not facilitate rebuilding of new capsules. Replacement with a valved implant device was necessary in two cases; the third case recovered with tapering of prednisone. Conclusions and Importance: The use of chronic systemic immunosuppressive therapy might interfere with capsular formation around the plates of drainage devices inducing persistent hypotony. In these cases, the use of valved implants might be safer.

Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides.

Science.gov (United States)

Di Biagio, Antonio; Riccardi, Niccolò; Taramasso, Lucia; Capetti, Amedeo; Cenderello, Giovanni; Signori, Alessio; Vitiello, Paola; Guerra, Michele; de Socio, Giuseppe Vittorio; Cassola, Giovanni; Quirino, Tiziano; Viscoli, Claudio

2016-11-01

This study aimed to evaluate the efficacy, tolerability and potential savings of combined antiretroviral therapy (cART) simplification from an unboosted protease inhibitor (PI) regimen with atazanavir or fosamprenavir to a single-tablet regimen (STR) based on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) among HIV-1-infected patients with HIV-1 RNA triglycerides, bilirubin, glycaemia, creatinine and physical examination were performed at baseline and at scheduled follow-up. All patient costs were calculated and were estimated for 52 weeks of therapy. Fifty-one patients were enrolled [28 male (54.9%)]. At baseline, 30 patients (58.8%) were treated with FTC/TDF, 20 (39.2%) with abacavir/lamivudine and 1 (2.0%) with lamivudine/zidovudine. Thirty-three patients (64.7%) received atazanavir. All patients maintained HIV-RNA triglycerides decreased from 124 mg/dL (range, 39-625) at enrolment to 108.7 mg/dL (range, 39-561) at study end (P = 0.25). At baseline, mean cholesterol was 172.8 ± 38.1 mg/dL and decreased to 161.9 ± 38.6 mg/dL (P = 0.038); likewise, median total bilirubin decreased from 1.07 mg/dL (range, 0.2-4.7) to 0.6 mg/dL (range, 0.13-3.1) (P triglycerides, cholesterol and cART-related costs. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Viro-immunological response of drug-naive HIV-1-infected patients starting a first-line regimen with viraemia >500,000 copies/ml in clinical practice.

Science.gov (United States)

Santoro, Maria Mercedes; Di Carlo, Domenico; Armenia, Daniele; Zaccarelli, Mauro; Pinnetti, Carmela; Colafigli, Manuela; Prati, Francesca; Boschi, Andrea; Antoni, Anna Maria Degli; Lagi, Filippo; Sighinolfi, Laura; Gervasoni, Cristina; Andreoni, Massimo; Antinori, Andrea; Mussini, Cristina; Perno, Carlo Federico; Borghi, Vanni; Sterrantino, Gaetana

2017-09-22

Virological success (VS) and immunological reconstitution (IR) of antiretroviral-naive HIV-1-infected patients with pre-therapy viral load (VL) >500,000 copies/ml was assessed after 12 months of treatment according to initial drug-class regimens. An observational multicentre retrospective study was performed. VS was defined as the first VL 500,000 copies/ml who start a first-line regimen containing PI+INI or NNRTI yield a better VS compared to those receiving a PI-based regimen.

96 Week Follow-Up of HIV-Infected Patients in Rescue with Raltegravir Plus Optimized Backbone Regimens: A Multicentre Italian Experience

OpenAIRE

Capetti, Amedeo; Landonio, Simona; Meraviglia, Paola; Di Biagio, Antonio; Lo Caputo, Sergio; Sterrantino, Gaetana; Ammassari, Adriana; Menzaghi, Barbara; Franzetti, Marco; De Socio, Giuseppe Vittorio; Pellicanò, Giovanni; Mazzotta, Elena; Soria, Alessandro; Meschiari, Marianna; Trezzi, Michele

2012-01-01

BACKGROUND: Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. METHODS: Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. R...

IMMUNOSUPPRESSIVE EFFECTS OF ARGININE DEIMINASE FROM STREPTOCOCCUS PYOGENES

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E. A. Starikova

2015-01-01

Full Text Available Many pathogens use metabolic pathway of arginine for successful dissemination. Bacterial arginine deiminase hydrolyzes arginine to form one molecule of ammonia and two molecules of ATP. The activity of the enzyme contributes to the improvement of survival of pathogenic bacteria in conditions of low pH at the site of infection or in phagolysosome, as well as in anaerobic conditions, and also leads to deficiency of arginine. Metabolism of arginine plays an important role in regulating the functions of immune system cells in mammals. Arginine is a substrate of enzymes NOS and arginase. Arginine depletion, potentially contributs to immunosuppression. The review analyzed the literature data on the effect of streptococcal arginine deiminase on the metabolism of arginine eukaryotic cells, and discusses immunosuppressive action of the enzyme.

Immunosuppression by non-ionising and ionising radiation - are there similarities?

International Nuclear Information System (INIS)

Reeves, V.

2003-01-01

Solar UV radiation, the ubiqitous environmental non-ionising radiation, initiates its immunomodulating effects almost entirely in the skin. In direct contrast, ionising radiation penetrates much more efficiently, and has a multitude of internal targets throughout the body. As a consequence, the mechanisms underlying UV-induced immunosuppression have been more readily characterised, whereas surprisingly little is known about immunosuppression resulting from ionising radiation. Photoimmunological studies in mice during the past 20-30 years have established the action spectrum for UV-induced immunosuppression, implicating the UVB waveband, 290-320 nm. Controversy rages over the immunosuppressive potential of the UVA waveband, 320-400 nm, but we demonstrate that environmentally relevant doses of UVA not only are immunologically innocuous, but provide protection against UVB-immunosuppression. Increasingly larger UVA exposures increasingly immunosuppress mice. The UVA immunoprotective effect is strongly dependent on the induction of a cutaneous redox-regulated enzyme, haem oxygenase (heat shock protein 32) that is known to protect cells from oxidative stress, and it is consistent that a number of exogenous antioxidants (vitamin E, vitamin C, green tea polyphenols, isoflavones) can protect effectively from photoimmuno-suppression. Thus the UV-immunosuppressed state is promoted by oxidative damage and depletion of endogenous antioxidant molecules. It is also associated with cutaneous cytokine derangements, such that Th-2 cytokines (IL-4, IL-10) are increased at the expense of Th-1 cytokines (IFN-gamma, IL-12), and with histamine and inflammatory prostaglandin activity. In contrast, immunoprotective UVA irradiation protects the cutaneous cytokine array, inhibits IL-10 upregulation and increases IFN-gamma and IL-12 expression. On the other hand, while ionising radiation is known to cause immunosuppression, large doses target the bone marrow and haemopoiesis lethally and

Estudo Pré-Clínico de Stent com Polímero Biodegradável e Liberação Abluminal de Sirolimus

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Celso Kiyochi Takimura

2014-06-01

Full Text Available Fundamento: Stents recobertos com polímeros bioabsorvíveis e fármacos apenas na face abluminal podem ser mais seguros que stents farmacológicos com polímeros permanentes. Objetivo: Relatar os resultados experimentais com o stent Inspiron(r, um stent recoberto com polímero bioabsorvível e com liberação de sirolimus apenas da face abluminal, recentemente aprovado para uso clínico. Métodos: Foram implantados 45 stents nas artérias coronárias de 15 porcos e, no 28° dia pós-implante, foram obtidos os resultados angiográficos, de ultrassonografia intracoronária e de histomorfologia. Cinco grupos foram avaliados: Grupo I (nove stents sem recobrimento; Grupo II (nove stents com polímero bioabsorvível nas faces luminal e abluminal; Grupo III (oito stents com polímero bioabsorvível na face abluminal; Grupo IV (nove stents com polímero bioabsorvível e sirolimus nas faces luminal e abluminal; e Grupo V (dez stents com polímero bioabsorvível e sirolimus na face abluminal exclusivamente. Resultados: Observamos, para os Grupos I, II, III, IV e V respectivamente: porcentual de estenose de 29 ± 20; 36 ± 14; 33 ± 19; 22 ± 13 e 26 ± 15 (p = 0,443; perda luminal tardia (em mm de 1,02 ± 0,60; 1,24 ± 0,48; 1,11 ± 0,54; 0,72 ± 0,44 e 0,78 ± 0,39 (p = 0,253; área neointimal (em mm2 de 2,60 ± 1,99; 2,74 ± 1,51; 2,74 ± 1,30; 1,30 ± 1,14 e 0,97 ± 0,84 (p = 0,001; Grupos IV e V versus Grupos I, II e III e porcentual de área neointimal de 35 ± 25; 38 ± 18; 39 ± 19; 19 ± 18 e 15 ± 12 (p = 0,001; Grupo IV e V versus Grupo I, II e III. Os escores de injúria e inflamação foram baixos e sem diferenças entre os grupos. Conclusão: O stent Inspiron(r foi seguro e inibiu significativamente a hiperplasia neointimal observada no 28° dia pós-implante em artérias coronárias porcinas.

Sustainability of first-line antiretroviral regimens: findings from a large HIV treatment program in western Kenya.

Science.gov (United States)

Braitstein, Paula; Ayuo, Paul; Mwangi, Ann; Wools-Kaloustian, Kara; Musick, Beverly; Siika, Abraham; Kimaiyo, Sylvester

2010-02-01

To describe first change or discontinuation in combination antiretroviral treatment (cART) among previously treatment naive, HIV-infected adults in a resource-constrained setting. The United States Agency for International Development-Academic Model Providing Access to Healthcare Partnership has enrolled >90,000 HIV-infected patients at 18 clinics throughout western Kenya. Patients in this analysis were aged > or =18 years, previously antiretroviral treatment naive, and initiated to cART between January 2006 and November 2007, with at least 1 follow-up visit. A treatment change or discontinuation was defined as change of regimen including single drug substitutions or a complete halting of cART. There were 14,162 patients eligible for analysis and 10,313 person-years of follow-up, of whom 1376 changed or stopped their cART. Among these, 859 (62%) changed their regimen (including 514 patients who had a single drug substitution) and 517 (38%) completely discontinued cART. The overall incidence rate (IR) of cART changes or stops per 100 person-years was 13.3 [95% confidence interval (CI): 12.7-14.1]. The incidence was much higher in the first year of post-cART initiation (IR: 25.0, 95% CI: 23.6-26.3) compared with the second year (IR: 2.4, 95% CI: 2.0-2.8). The most commonly cited reason was toxicity (46%). In multivariate regression, individuals were more likely to discontinue cART if they were World Health Organization stage III/IV [adjusted hazard ratio (AHR): 1.37, 95% CI: 1.11-1.69] or were receiving a zidovudine-containing regimen (AHR: 4.44, 95% CI: 3.35-5.88). Individuals were more likely to change their regimen if they were aged > or =38 years (AHR: 1.44, 95% CI: 1.23-1.69), had to travel more than 1 hour to clinic (AHR: 1.34, 95% CI: 1.15-1.57), had a CD4 at cART initiation < or =111 cells/mm3 (AHR: 1.51, 95% CI: 1.29-1.77), or had been receiving a zidovudine-containing regimen (AHR: 3.73, 95% CI: 2.81-4.95). Those attending urban clinics and those receiving

Pulmonary tuberculosis in a patient with rheumatoid arthritis undergoig immunosuppressive treatment: case report

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Sandro Ceratti

2014-02-01

Full Text Available Rheumatoid arthritis is a disease which characteristically affects the joints. Because it is an autoimmune disease, immunosuppressive drugs are widely used in its treatment. The present case report illustrates the association of immunosuppressive treatment with the development of opportunistic infections in a 64-year-old patient.

A systematic checklist approach to immunosuppression risk management: An audit of practice at two clinical neuroimmunology centers.

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Mori, Amelia M; Agarwal, Smriti; Lee, Monique W M; Rafferty, Martina; Hardy, Todd A; Coles, Alasdair; Reddel, Stephen W; Riminton, D Sean

2017-11-15

There is no consensus approach to safety screening for immune intervention in clinical neuroimmunology. An immunosuppression risk evaluation checklist was used as an audit tool to assess real-world immunosuppression risk management and formulate recommendations for quality improvements in patient safety. Ninety-nine patients from two centres with 27 non-MS diagnoses were included. An average of 1.9 comorbidities with the potential to adversely impact morbidity and mortality associated with immunosuppression were identified. Diabetes and smoking were the most common, however a range of rarer but potentially life-threatening co-morbid disorders in the context of immunosuppression were identified. Inadequate documentation of risk mitigation tasks was common at 40.1% of total tasks across both cohorts. A routine, systematic immunosuppression checklist approach should be considered to improve immunosuppression risk management in clinical neuroimmunology practice. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparison of single and boosted protease inhibitor versus nonnucleoside reverse transcriptase inhibitor-containing cART regimens in antiretroviral-naïve patients starting cART after January 1, 2000

DEFF Research Database (Denmark)

Mocroft, A; Horban, A; Clumeck, N

2006-01-01

increase) response in antiretroviral-naïve patients starting either a single protease inhibitor (PI; n = 183), a ritonavir-boosted PI regimen (n = 197), or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based cART regimen (n = 447) after January 1, 2000, and the odds of lack of virologic...... or immunologic response at 3 years after starting cART. METHOD: Cox proportional hazards models and logistic regression. RESULTS: After adjustment, compared to patients taking an NNRTI-regimen, patients taking a single-PI regimen were significantly less likely to achieve a viral load (VL)

Immunosuppression prior to marrow transplantation for sensitized aplastic anemia patients: comparison of TLI with TBI

International Nuclear Information System (INIS)

Shank, B.; Brochstein, J.A.; Castro-Malaspina, H.; Yahalom, J.; Bonfiglio, P.; O'Reilly, R.J.

1988-01-01

From May 1980 through July 1986, 26 patients with severe aplastic anemia, sensitized with multiple transfusions of blood products, were treated on either of two immunosuppressive regimens in preparation for bone marrow transplantation from a matched donor. There were 10 patients treated with total body irradiation (TBI), 200 cGy/fraction X 4 daily fractions (800 cGy total dose), followed by cyclophosphamide, 60 mg/kg/d X 2 d. An additional 16 patients were treated with total lymphoid irradiation (TLI) [or, if they were infants, a modified TLI or thoracoabdominal irradiation (TAI)], 100 cGy/fraction, 3 fractions/d X 2 d (600 cGy total dose), followed by cyclophosphamide, 40 mg/kg/d X 4 d. The extent of immunosuppression was similar in both groups as measured by peripheral blood lymphocyte depression at the completion of the course of irradiation (5% of initial concentration for TBI and 24% for TLI), neutrophil engraftment (10/10 for TBI and 15/16 for TLI), and time to neutrophil engraftment (median of 22 d for TBI and 17 d for TLI). Marrow and peripheral blood cytogenetic analysis for assessment of percent donor cells was also compared in those patients in whom it was available. 2/2 patients studied with TBI had 100% donor cells, whereas 6/11 with TLI had 100% donor cells. Of the five who did not, three were stable mixed chimeras with greater than or equal to 70% donor cells, one became a mixed chimera with about 50% donor cells, but became aplastic again after Cyclosporine A cessation 5 mo post-transplant, and the fifth reverted to all host cells by d. 18 post-transplant. Overall actuarial survival at 2 years was 56% in the TLI group compared with 30% in the TBI group although this was not statistically significant. No survival decrement has been seen after 2 years in either group

Varicella-zoster virus immunity in dermatological patients on systemic immunosuppressant treatment.

LENUS (Irish Health Repository)

Hackett, C B

2012-02-01

BACKGROUND: Primary varicella infection is caused by varicella-zoster virus (VZV). It is a common childhood infection, which is usually benign but can occasionally cause morbidity and mortality. In immunosuppressed adults, atypical presentation and disseminated disease can occur with significant morbidity and mortality. A VZV vaccine is available. OBJECTIVES: This study was designed to measure the prevalence of immunity to VZV and to determine the predictive value of a self-reported history of varicella infection in a population of dermatological patients receiving systemic immunosuppressant therapy. We sought to assess the need for routine serological testing for varicella-zoster immunity in this cohort. METHODS: Serological testing for VZV immunity was done on 228 patients receiving systemic immunosuppressive treatment for a dermatological condition. Information regarding a history of previous primary VZV infection was obtained from each patient. RESULTS: Two hundred and twenty-eight patients had VZV serology performed. The mean age of the patients was 49.6 years. The prevalence of VZV seropositivity in this cohort was 98.7%. One hundred and two patients (44.7%) reported having a definite history of primary VZV. The sensitivity of a self-reported history of VZV infection was 45.3% with a specificity of 100%. The positive and negative predictive values of a self-reported history of VZV for serologically confirmed immunity were 100% and 2.3%, respectively. CONCLUSIONS: The prevalence of VZV IgG antibodies in our cohort of Irish dermatology patients receiving immunosuppressive therapy is 98.7%. A recalled history of varicella infection is a good predictor of serological immunity. This study has shown that there are VZV-susceptible individuals within our cohort. These patients did not have a clear history of previous infection. We recommend serological testing of patients without a clear history of infection prior to the commencement of immunosuppressive therapy and

Once-daily dose regimen of ribavirin is interchangeable with a twice-daily dose regimen: randomized open clinical trial

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Balk JM

2015-08-01

Full Text Available Jiska M Balk,1 Guido RMM Haenen,1 Özgür M Koc,2 Ron Peters,3 Aalt Bast,1 Wim JF van der Vijgh,1 Ger H Koek,4 1Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 2Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, 3DSM Resolve, Geleen, 4Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands Background: The combination of ribavirin (RBV and pegylated interferon (PEG-IFN is effective in the treatment of chronic hepatitis C infection. Reducing the frequency of RBV intake from twice to once a day will improve compliance and opens up the opportunity to combine RBV with new and more specific direct-acting agents in one pill. Therefore, the purpose of this study was to evaluate the pharmacokinetic profile of RBV in a once-daily to twice-daily regimen. The secondary aim was to determine tolerability as well as the severity and differences in side effects of both treatment regimens. Methods: In this randomized open-label crossover study, twelve patients with chronic type 1 hepatitis C infection and weighing more than 75 kg were treated with 180 µg of PEG-IFN weekly and 1,200 mg RBV daily for 24 weeks. The patients received RBV dosed as 1,200 mg once-daily for 12 weeks followed by RBV dosed as 600 mg twice-daily for 12 weeks, or vice versa. In addition to the pharmacokinetic profile, the hematological profile and side effects were recorded. The RBV concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Results: Eight of twelve patients completed the study. Neither the time taken for RBV to reach peak plasma concentration nor the AUC0-last (adjusted for difference in dose was significantly different between the two groups (P>0.05. Furthermore, the once-daily regimen did not give more side effects than the twice-daily regimen (P>0

Hair Follicle Dermal Sheath Derived Cells Improve Islet Allograft Survival without Systemic Immunosuppression

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Xiaojie Wang

2015-01-01

Full Text Available Immunosuppressive drugs successfully prevent rejection of islet allografts in the treatment of type I diabetes. However, the drugs also suppress systemic immunity increasing the risk of opportunistic infection and cancer development in allograft recipients. In this study, we investigated a new treatment for autoimmune diabetes using naturally immune privileged, hair follicle derived, autologous cells to provide localized immune protection of islet allotransplants. Islets from Balb/c mouse donors were cotransplanted with syngeneic hair follicle dermal sheath cup cells (DSCC, group 1 or fibroblasts (FB, group 2 under the kidney capsule of immune-competent, streptozotocin induced, diabetic C57BL/6 recipients. Group 1 allografts survived significantly longer than group 2 (32.2 ± 12.2 versus 14.1 ± 3.3 days, P<0.001 without administration of any systemic immunosuppressive agents. DSCC reduced T cell activation in the renal lymph node, prevented graft infiltrates, modulated inflammatory chemokine and cytokine profiles, and preserved better beta cell function in the islet allografts, but no systemic immunosuppression was observed. In summary, DSCC prolong islet allograft survival without systemic immunosuppression by local modulation of alloimmune responses, enhancing of beta cell survival, and promoting of graft revascularization. This novel finding demonstrates the capacity of easily accessible hair follicle cells to be used as local immunosuppression agents in islet transplantation.

A Rationale for Age-Adapted Immunosuppression in Organ Transplantation.

Science.gov (United States)

Krenzien, Felix; ElKhal, Abdallah; Quante, Markus; Rodriguez Cetina Biefer, Hector; Hirofumi, Uehara; Gabardi, Steven; Tullius, Stefan G

2015-11-01

Demographic changes are associated with a steady increase of older patients with end-stage organ failure in need for transplantation. As a result, the majority of transplant recipients are currently older than 50 years, and organs from elderly donors are more frequently used. Nevertheless, the benefit of transplantation in older patients is well recognized, whereas the most frequent causes of death among older recipients are potentially linked to side effects of their immunosuppressants.Immunosenescence is a physiological part of aging linked to higher rates of diabetes, bacterial infections, and malignancies representing the major causes of death in older patients. These age-related changes impact older transplant candidates and may have significant implications for an age-adapted immunosuppression. For instance, immunosenescence is linked to lower rates of acute rejections in older recipients, whereas the engraftment of older organs has been associated with higher rejection rates. Moreover, new-onset diabetes mellitus after transplantation is more frequent in the elderly, potentially related to corticosteroids, calcineurin inhibitors, and mechanistic target of rapamycin inhibitors.This review presents current knowledge for an age-adapted immunosuppression based on both, experimental and clinical studies in and beyond transplantation. Recommendations of maintenance and induction therapy may help to improve graft function and to design future clinical trials in the elderly.

High immunosuppressive burden in advanced hepatocellular carcinoma patients: Can effector functions be restored?

Science.gov (United States)

Lugade, Amit A; Kalathil, Suresh; Miller, Austin; Iyer, Renuka; Thanavala, Yasmin

2013-07-01

The accumulation of immunosuppressive cells and exhausted effector T cells highlight an important immune dysfunction in advanced stage hepatocellular carcinoma (HCC) patients. These cells significantly hamper the efficacy immunotherapies and facilitate HCC progression. We have recently demonstrated that the multipronged depletion of immunosuppressive cells potentially restores effector T-cell function in HCC.

Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.

Science.gov (United States)

Vargas-Hitos, J A; Sabio, J M; Navarrete-Navarrete, N; Arenas-Miras, M del M; Zamora-Pasadas, M; Jiménez-Alonso, J

2016-03-01

Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant. © The Author(s) 2015.

Does Pre-Operative Multiple Immunosuppressive Therapy Associate with Surgical Site Infection in Surgery for Ulcerative Colitis.

Science.gov (United States)

Uchino, Motoi; Ikeuchi, Hiroki; Bando, Toshihiro; Hirose, Kei; Hirata, Akihiro; Chohno, Teruhiro; Sasaki, Hirofumi; Takahashi, Yoshiko; Takesue, Yoshio; Hida, Nobuyuki; Hori, Kazutoshi; Nakamura, Shiro

2015-01-01

Almost all surgeries for ulcerative colitis (UC) are performed under immunosuppressive conditions. Immunomodulators or biologics, with the exception of corticosteroids, do not appear to be risk factors for post-operative infectious complications. However, many patients are on multiagent immunosuppressive therapy at the time of surgery. Therefore, we evaluated the influence of pre-operative multiple immunosuppressives on the occurrence of surgical site infection (SSI) in UC. We reviewed surveillance data from 181 patients who underwent restorative proctocolectomy between January 2012 and March 2014. The incidences of SSI and the possible risk factors among patients receiving different immunosuppressive therapies were compared and analyzed. The incidence of incisional (INC) SSI was 13.3% and that of organ/space (O/S) SSI was 7.2%. The number of immunosuppressives did not significantly correlate with each incidence. Total prednisolone administration ≥12,000 mg (OR 2.6) and an American Society of Anesthesiologists score ≥3 (OR 2.8) were shown to be independent risk factors for overall SSI, whereas corticosteroid use in INC SSI (OR 17.4) and severe disease (OR 5.2) and a large amount of blood loss (OR 3.9) in O/S SSI were identified as risk factors. Although a correlation between multiple immunosuppressive therapy and SSIs was not found, it is not recommended that all patients be treated with multiple immunosuppressive therapy. Treatment strategy should be applied based on the patient's condition. © 2015 S. Karger AG, Basel.

Contribution of different antiretroviral regimens containing zidovudine, lamivudine and ritonavir-boosted lopinavir on HIV viral load reduction during pregnancy.

Science.gov (United States)

Sripan, Patumrat; Le Coeur, Sophie; Ingsrisawang, Lily; Cressey, Tim R; Bouazza, Naïm; Foissac, Frantz; Ngo-Giang-Huong, Nicole; Traisathit, Patrinee; Srirompotong, Ussanee; Ayudhaya, Orada Patamasingh Na; Puangsombat, Achara; Jungpipun, Jantana; Jittayanun, Kanokwan; Tréluyer, Jean-Marc; Jourdain, Gonzague; Lallemant, Marc; Urien, Saïk

2016-01-01

Antiretroviral (ARV) regimens used for the prevention of mother-to-child transmission of HIV have evolved over time. We evaluated the contribution of different ARV regimens on the reduction of the plasma HIV RNA viral load (VL) during pregnancy. A total of 1,833 VL measurements from ARV-naive pregnant women participating in perinatal prevention trials in Thailand were included. Women received either zidovudine (ZDV) monotherapy, ZDV plus lopinavir/ritonavir (LPV/r), or ZDV plus lamivudine (3TC) plus LPV/r. VL time-course during pregnancy was described as a function of pretreatment VL and treatment duration using an Emax non-linear mixed-effect model. VL reduction and median time to achieve a VL<50 copies/ml were estimated for each regimen. Among 745 women, 279 (37%), 145 (20%) and 321 (43%) received ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. The predicted VL reduction from baseline to delivery after a median of 10 weeks of treatment were 0.5, 2.7 and 2.9 log10 copies/ml with ZDV monotherapy, ZDV+LPV/r and ZDV+3TC+LPV/r, respectively. At delivery, 1%, 57% and 63% of women receiving ZDV monotherapy, ZDV+LPV/r or ZDV+3TC+LPV/r had a VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r reduced the time to achieve a VL<50 copies/ml and the higher the pretreatment VL, the larger the effect 3TC had on reducing the time to VL<50 copies/ml. The addition of 3TC to ZDV+LPV/r was associated with a slight further VL reduction but the time to reach a VL<50 copies/ml was shorter. This beneficial effect of 3TC is crucial for prevention of mother-to-child transmission in women who receive ARVs late and with high pretreatment VL.

T cell costimulation blockade promotes transplantation tolerance in combination with sirolimus and post-transplantation cyclophosphamide for haploidentical transplantation in children with severe aplastic anemia.

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Jaiswal, Sarita Rani; Bhakuni, Prakash; Zaman, Shamsuz; Bansal, Satish; Bharadwaj, Priyanka; Bhargava, Sneh; Chakrabarti, Suparno

2017-08-01

We conducted a pilot study employing extended T cell costimulation blockade (COSBL) with Abatacept along with sirolimus and post-transplantation cyclophosphamide (PTCy) in 10 patients (median age 12) with severe aplastic anemia (SAA). Nine patients engrafted in the COSBL group, compared to all 10 patients (median 14 vs 13days) treated on PTCy protocols without abatacept (CONTROL group). The incidence of acute graft-versus-host disease (GVHD) was 10.5% in the COSBL group compared to 50% in the CONTROL group (p=0.04). Chronic GVHD (12.5% vs 56%, p=0.02) and CMV reactivation (30% vs 80%, p=0.03) were also reduced in the COSBL group. T and NK cell subset analysis revealed higher CD56 bright CD16 - NK cells in the CONTROL group (p=0.004), but similar CD56 dim CD16 + NK cells in both groups at day+30. Tregs (CD4 + CD25 + CD127 dim/- FoxP3+) were markedly higher in the COSBL group at day+30 (8.4% vs 1.1%) and the trend was maintained through day+90 (p<0.01). The GVHD and Disease-free survival at one year in the COSBL group was 80% vs. 30% in the CONTROL group (p=0.05). Our preliminary findings suggest that COSBL in combination with PTCy and sirolimus might augment transplantation tolerance in children with SAA, probably due to synergistic effect on early recovery of Tregs. Copyright © 2017 Elsevier B.V. All rights reserved.

Minimally-Myelosuppressive Asparaginase-Containing Induction Regimen for Treatment of a Jehovah’s Witness with mutant IDH1/NPM1/NRAS Acute Myeloid Leukemia

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Ashkan Emadi

2016-03-01

Full Text Available Treatment of patients with acute myeloid leukemia (AML who do not wish to accept blood product transfusion, including Jehovah’s Witnesses, is extremely challenging. The use of conventional chemotherapy for induction of complete remission (CR results in profound anemia and thrombocytopenia requiring frequent transfusions of blood products, without which such treatment will be life-threatening. Finding a well tolerable, minimally myelosuppressive induction regimen for such patients with AML is a clear example of area of unmet medical need. Here, we report a successful treatment of a 52-year-old Jehovah’s Witness with newly diagnosed AML with peg-asparaginase, vincristine and methylprednisolone. The AML was characterized with normal karyotype, and mutations in isocitrate dehydrogenase 1 (IDH1-Arg132Ser, nucleophosmin 1 (NPM1-Trp289Cysfs*12 and neuroblastoma RAS viral oncogene homolog (NRAS-G1y12Va1. After one 28-day cycle of treatment, the patient achieved complete remission with incomplete count recovery (CRi and after the second cycle, he achieved CR with full blood count recovery. The patient has never received any blood products. Notwithstanding that myeloperoxidase-induced oxidative degradation of vincristine results in its lack of activity as monotherapy in AML, its combination with corticosteroid and asparaginase has resulted in a robust remission in this patient. Diminished steroid clearance by asparaginase activity as well as reduction in serum glutamine level induced by glutaminase enzymatic activity of asparaginase may have contributed to effective killing of the myeloblasts that carry IDH1/NPM1/NRAS mutations. In conclusion, asparaginase-containing regimens, which are approved for treatment of acute lymphoblastic leukemia (ALL but not AML, can be used to treat patients with AML who do not accept blood transfusion.

HMB-45 negative multifocal malignant perivascular epithelioid cell tumor of the soft tissue responding to sirolimus: First case report from India.

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Kapoor, Akhil; Beniwal, Surender; Singhal, Mukesh Kumar; Kumar, Narender; Kumar, Vanita; Kumar, Harvindra Singh

2015-01-01

Perivascular epithelioid cell tumor (PEComa) is a group of sarcomas that exhibit a myomelanocytic phenotype and possess a unique cell type in the perivascular epithelioid cell. Traditionally HMB-45 immunoreactivity is the first criteria required to consider a tumor to be PEComa. We report a case of multifocal PEComa with negative HMB-45 marker. The patient presented with three big ulceroproliferative lesions; two over right thigh and one over the scalp in the right frontal region. The patient was prescribed with oral sirolimus to which good response was seen. To the best of our knowledge, this is the first case of HMB-45 negative multifocal malignant PEComa from India.

Characterization of Remitting and Relapsing Hyperglycemia in Post-Renal-Transplant Recipients.

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Alireza Boloori

Full Text Available Hyperglycemia following solid organ transplant is common among patients without pre-existing diabetes mellitus (DM. Post-transplant hyperglycemia can occur once or multiple times, which if continued, causes new-onset diabetes after transplantation (NODAT.To study if the first and recurrent incidence of hyperglycemia are affected differently by immunosuppressive regimens, demographic and medical-related risk factors, and inpatient hyperglycemic conditions (i.e., an emphasis on the time course of post-transplant complications.We conducted a retrospective analysis of 407 patients who underwent kidney transplantation at Mayo Clinic Arizona. Among these, there were 292 patients with no signs of DM prior to transplant. For this category of patients, we evaluated the impact of (1 immunosuppressive drugs (e.g., tacrolimus, sirolimus, and steroid, (2 demographic and medical-related risk factors, and (3 inpatient hyperglycemic conditions on the first and recurrent incidence of hyperglycemia in one year post-transplant. We employed two versions of Cox regression analyses: (1 a time-dependent model to analyze the recurrent cases of hyperglycemia and (2 a time-independent model to analyze the first incidence of hyperglycemia.Age (P = 0.018, HDL cholesterol (P = 0.010, and the average trough level of tacrolimus (P<0.0001 are significant risk factors associated with the first incidence of hyperglycemia, while age (P<0.0001, non-White race (P = 0.002, BMI (P = 0.002, HDL cholesterol (P = 0.003, uric acid (P = 0.012, and using steroid (P = 0.007 are the significant risk factors for the recurrent cases of hyperglycemia.This study draws attention to the importance of analyzing the risk factors associated with a disease (specially a chronic one with respect to both its first and recurrent incidence, as well as carefully differentiating these two perspectives: a fact that is currently overlooked in the literature.

Psychosocial Variables Associated with Immunosuppressive Medication Non-Adherence after Renal Transplantation

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Jennifer Felicia Scheel

2018-02-01

Full Text Available IntroductionNon-adherence to immunosuppressive medication is regarded as an important factor for graft rejection and loss after successful renal transplantation. Yet, results on prevalence and relationship with psychosocial parameters are heterogeneous. The main aim of this study was to investigate the association of immunosuppressive medication non-adherence and psychosocial factors.MethodsIn 330 adult renal transplant recipients (≥12 months posttransplantation, health-related quality of life, depression, anxiety, social support, and subjective medication experiences were assessed, and their associations with patient-reported non-adherence was evaluated.Results33.6% of the patients admitted to be partially non-adherent. Non-adherence was associated with younger age, poorer social support, lower mental, but higher physical health-related quality of life. There was no association with depression and anxiety. However, high proportions of clinically relevant depression and anxiety symptoms were apparent in both adherent and non-adherent patients.ConclusionIn the posttransplant follow-up, kidney recipients with lower perceived social support, lower mental and higher physical health-related quality of life, and younger age can be regarded as a risk group for immunosuppressive medication non-adherence. In follow-up contacts with kidney transplant patients, physicians may pay attention to these factors. Furthermore, psychosocial interventions to optimize immunosuppressive medication adherence can be designed on the basis of this information, especially including subjectively perceived physical health-related quality of life and fostering social support seems to be of importance.

Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors.

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Gabardi, Steven

2013-03-01

To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements. Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated. REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations. The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the

Incidence of adverse cardiac events 5 years after polymer-free sirolimus eluting stent implantation: Results from the prospective Bad Berka Yukon Choice™ registry.

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Ohlow, Marc-Alexander; von Korn, Hubertus; Gunkel, Oliver; Farah, Ahmed; Fuhrmann, Joerg T; Lauer, Bernward

2014-12-01

Drug-eluting stents (DES) constitute a major achievement in preventing re-stenosis, concerns remain regarding the increased inflammatory responses associated with the polymers used. This analysis focuses on outcomes in patients receiving the polymer-free sirolimus-eluting stent system YUKON-Choice (Yukon-DES, Translumina, Germany). From 01/2006-09/2008 all patients receiving Yukon-DES (≥2.5 mm diameter) were prospectively enrolled in our registry. The primary endpoint was long-term major adverse cardiac events (MACE). 701 patients were included in our registry. Mean age was 65.7 ± 10 years (73% male gender, 35.5% diabetes, and 32.2% acute coronary syndrome). 76% of the lesions were of Type B2/C. Lesion length was 24.6 ± 5.2 mm and mean stent diameter was 2.8 ± 0.4 mm. A total of 511 pts (72%) underwent 6-months angiographic follow-up, target vessel revascularization was noted in 23.5%. At 5 years clinical outcomes were: cardiac death 5.8%; myocardial infarction 3.4%; and TVR 24.6%. The incidence of MACE differed significantly between "on-label" and "off-label" indications (14.8% vs. 40.8% MACE; P 1 year) ST occurred in 0.29%. Our data suggests that the implantation of the sirolimus-coated polymer-free YUKON-DES is safe and feasible with a very low incidence of ST in this real world patient cohort with high percentage of diabetes and small vessels. © 2013 Wiley Periodicals, Inc.

Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein [version 1; referees: 2 approved

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Bryony Jenkins

2016-12-01

Full Text Available To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II, and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

Antigenicity of peptides comprising the immunosuppressive domain of the retroviral envelope glycoprotein [version 2; referees: 2 approved

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Bryony Jenkins

2017-02-01

Full Text Available To achieve persistent infection of the host, viruses often subvert or suppress host immunity through mechanisms that are not entirely understood. The envelope glycoprotein of several retroviruses is thought to possess potent immunosuppressive activity, mapped to a 17-amino acid residue conserved domain. Synthetic peptides corresponding to this immunosuppressive domain can inhibit lymphocyte activation, whereas mutation of key domain residues can increase the lymphocyte response to linked antigenic epitopes. Using three T cell receptors (TCRs of defined specificity, we examine the effect of the immunosuppressive domain on the T cell response to their respective antigenic peptides. We find that fusion of a T cell epitope to the immunosuppressive domain can greatly modulate its potency. However, the effects heavily depend on the particular combination of TCR and peptide-major histocompatibility complex class II (pMHC II, and are mimicked by sequence-scrambled peptides of similar length, suggesting they operate at the level of pMHC formation or TCR-pMHC interaction. These results offer an alternative explanation for the immunogenicity of T cell epitopes comprising the putative immunosuppressive domain, which is more consistent with an effect on peptide antigenicity than true immunosuppressive activity.

First-in-human evaluation of a bioabsorbable polymer-coated sirolimus-eluting stent: imaging and clinical results of the DESSOLVE I Trial (DES with sirolimus and a bioabsorbable polymer for the treatment of patients with de novo lesion in the native coronary arteries).

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Ormiston, John; Webster, Mark; Stewart, James; Vrolix, Mathias; Whitbourn, Robert; Donohoe, Dennis; Knape, Charlene; Lansky, Alexandra; Attizzani, Guilherme F; Fitzgerald, Peter; Kandzari, David E; Wijns, William

2013-10-01

This first-in-human multicenter study sought to examine prospectively the safety and efficacy of a new, cobalt chromium thin-strut, coronary absorbable polymer-coated, sirolimus-eluting stent. Bioabsorbable polymers on drug-eluting stents may lower the long-term risks of inflammation, delayed healing, and adverse events. We enrolled patients with symptomatic coronary artery disease with stable or unstable angina pectoris and >50% diameter stenosis, amenable to coverage with a ≤23-mm long stent in a vessel 2.5 to 3.5 mm in diameter. All patients received dual antiplatelet therapy after implantation. Patients, in groups of 10, underwent repeat angiography, intravascular ultrasound, and optical coherence tomography at 4, 6, or 8 months, and all patients were seen or contacted at 18 months of follow-up. The median (range) in-stent late lumen loss (LLL) was 0.03 mm (-0.22 to 0.21 mm), 0.10 mm (-0.03 to 1.2 mm), and 0.08 mm (-0.01 to 0.28 mm), at 4, 6, and 8 months, respectively. At 18 months, the median in-stent LLL was 0.08 mm (-0.30 to 0.46 mm). On optical coherence tomography, the proportion of uncovered stent struts decreased from a median of 7.3% (range 0.4% to 46.3%) at 4 months to 0% (range: 0% to 3.4%) at 18 months. The percentage of neointimal volume obstruction by intravascular ultrasound increased from a median of 5.3% to 9.1% between 4 and 6 months and remained nearly unchanged thereafter through 18 months of follow-up. The only recorded major adverse cardiac event was a myocardial infarction. At 18 months of follow-up, this absorbable polymer-coated, cobalt chromium sirolimus-eluting stent was associated with a low and stable in-stent LLL, complete strut coverage, and no stent thrombosis. (First-In-Human Trial of the MiStent Drug-Eluting Stent [DES] in Coronary Artery Disease [DESSOLVE-I]; NCT01247428). Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial.

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Gaber, A Osama; Kahan, Barry D; Van Buren, Charles; Schulman, Seth L; Scarola, Joseph; Neylan, John F

2008-11-15

The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients. Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies. Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI -10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients. This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

Efficacy of three-week oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi.

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Bah, Germanus S; Ward, Emma L; Srivastava, Abhishek; Trees, Alexander J; Tanya, Vincent N; Makepeace, Benjamin L

2014-01-01

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont (Wolbachia), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus (Onchocerca ochengi) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved >2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for >24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations.

From Leflunomide to Teriflunomide: Drug Development and Immunosuppressive Oral Drugs in the Treatment of Multiple Sclerosis.

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Aly, Lilian; Hemmer, Bernhard; Korn, Thomas

2017-01-01

Immunosuppressive drugs have been used in the treatment of multiple sclerosis (MS) for a long time. Today, orally available second generation immunosuppressive agents have been approved or are filed for licensing as MS therapeutics. Due to semi-selective targeting of cellular processes, these second-generation immunosuppressive compounds might rather be immunomodulatory. For example, Teriflunomide inhibits the de novo pyrimidine synthesis and thus only targets rapidly proliferating cells, including lymphocytes. It is used as first line disease modifying therapy (DMT) in relapsing-remitting MS (RRMS). Review of online content related to oral immunosuppressants in MS with an emphasis on Teriflunomide. Teriflunomide and Cladribine are second-generation immunosuppressants that are efficient in the treatment of MS patients. For Teriflunomide, a daily dose of 14 mg reduces the annualized relapse rate (ARR) by more than 30% and disability progression by 30% compared to placebo. Cladribine reduces the ARR by about 50% compared to placebo but has not yet been licensed due to unresolved safety concerns. We also discuss the significance of older immunosuppressive compounds including Azathioprine, Mycophenolate mofetile, and Cyclophosphamide in current MS therapy. Teriflunomide has shown a favorable safety and efficacy profile in RRMS and is a therapeutic option for a distinct group of adult patients with RRMS. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Variation in training regimens in professional showjumping yards

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Lönnell, A C; Bröjer, J; Nostell, K; Hernlund, E; Roepstorff, L; Tranquille, C A; Murray, R C; Oomen, A; van Weeren, René; Bitschnau, C; Montavon, S; Weishaupt, M A; Egenvall, A

2014-01-01

REASONS FOR PERFORMING STUDY: Training regimens of showjumping horses under field conditions are largely undocumented. OBJECTIVES: The aims of this study were to quantify and compare training regimens used in professional-level showjumping yards, with respect to time exercised and type of activity.

Risk of high-grade cervical dysplasia and cervical cancer in women with systemic lupus erythematosus receiving immunosuppressive drugs.

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Feldman, C H; Liu, J; Feldman, S; Solomon, D H; Kim, S C

2017-06-01

Objective Prior studies suggest an increased risk of cervical cancer among women with systemic lupus erythematosus. However, the relationship with immunosuppressive drugs is not well studied in US nationwide cohorts. We compared the risk of high-grade cervical dysplasia and cervical cancer among women with systemic lupus erythematosus who started immunosuppressive drugs versus hydroxychloroquine. Methods We identified systemic lupus erythematosus patients initiating immunosuppressive drugs or hydroxychloroquine using claims data from two US commercial health plans and Medicaid (2000-2012). We used a validated claims-based algorithm to identify high-grade cervical dysplasia or cervical cancer. To account for potential confounders, including demographic factors, comorbidities, medication use, HPV vaccination status, and health care utilization, immunosuppressive drugs and hydroxychloroquine initiators were 1:1 matched on the propensity score. We used inverse variance-weighted, fixed effect models to pool hazard ratios from the propensity score-matched Medicaid and commercial cohorts. Results We included 2451 matched pairs of immunosuppressive drugs and hydroxychloroquine new users in the commercial cohort and 7690 matched pairs in Medicaid. In the commercial cohort, there were 14 cases of cervical dysplasia or cervical cancer among immunosuppressive drugs users and five cases among hydroxychloroquine users (hazard ratio 2.47, 95% CI 0.89-6.85, hydroxychloroquine = ref). In Medicaid, there were 46 cases among immunosuppressive drugs users and 29 cases in hydroxychloroquine users (hazard ratio 1.24, 95% CI 0.78-1.98, hydroxychloroquine = ref). The pooled hazard ratio of immunosuppressive drugs was 1.40 (95% CI 0.92-2.12). Conclusion Among women with systemic lupus erythematosus, immunosuppressive drugs may be associated with a greater, albeit not statistically significant, risk of high-grade cervical dysplasia and cervical cancer compared to patients receiving

Superior Efficacy and Improved Renal and Bone Safety After Switching from a Tenofovir Disoproxil Fumarate- to a Tenofovir Alafenamide-Based Regimen Through 96 Weeks of Treatment.

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DeJesus, Edwin; Haas, Bernard; Segal-Maurer, Sorana; Ramgopal, Moti N; Mills, Anthony; Margot, Nicolas; Liu, Ya-Pei; Makadzange, Tariro; McCallister, Scott

2018-04-01

We previously demonstrated superior efficacy and safety advantages in HIV-infected, virologically suppressed adults switched to a regimen containing tenofovir alafenamide (TAF) as compared with those remaining on a tenofovir disoproxil fumarate (TDF) regimen through week 48. We now report long-term data through week 96. In this randomized, active-controlled, multicenter, open-label, noninferiority trial (ClinicalTrials.gov No. NCT01815736), we randomized virologically suppressed (HIV-1 RNA TAF group or to continue one of four TDF-containing regimens (TDF group) for 96 weeks. We evaluated efficacy (HIV-1 RNA TAF n = 959, TDF n = 477). At week 96, TAF was superior to TDF in virologic efficacy, with 93% on TAF and 89% on TDF having HIV-1 RNA TAF versus TDF continued through week 96 (p TAF group versus TDF through week 96 (p TAF group as compared with one case in the TDF group. Switching to EVG/COBI/FTC/TAF (E/C/F/TAF) was associated with statistically significant efficacy and safety advantages over remaining on a standard-of-care TDF-based regimen.

Differential clinical outcomes after 1 year versus 5 years in a randomised comparison of zotarolimus-eluting and sirolimus-eluting coronary stents (the SORT OUT III study)

DEFF Research Database (Denmark)

Maeng, Michael; Tilsted, Hans Henrik; Jensen, Lisette Okkels

2014-01-01

received two different types of drug-eluting stents. METHODS: We undertook this multicentre, open-label, randomised superiority trial at five percutaneous coronary intervention centres in Denmark. We randomly allocated 2332 eligible adult patients (≥18 years of age) with an indication for drug......-eluting stent implantation to the zotarolimus-eluting Endeavor Sprint stent (Medtronic, Santa Rosa, CA, USA) or the sirolimus-eluting Cypher Select Plus stent (Cordis, Johnson & Johnson, Warren, NJ, USA). Randomisation of participants was achieved by computer-generated block randomisation and a telephone...

Nonadherence to immunosuppression: challenges and solutions

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Moreso F

2015-06-01

Full Text Available Francesc Moreso,1 Irina B Torres,1 Gemma Costa-Requena,2 Daniel Serón1 1Nephrology Department, 2Psychiatry Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, Barcelona, Spain Abstract: Nonadherence to immunosuppressant treatment is common after renal transplantation involving >20% of patients. It is associated with cellular rejection, appearance of donor-specific antibodies, and chronic rejection. It has been estimated that nonadherence can be detected in approximately 50% of failing grafts. Since the evaluation of sociodemographic factors do not allow characterizing the target population, it is necessary to combine different measures of adherence (self-reporting and collateral reporting, pill counts, biological monitoring of blood samples, or others to increase its diagnostic accuracy. During the last decade, it has been shown that the implementation of a multidimensional intervention including information, motivation, and behavioral interventions may lead to an improvement of adherence to treatment. On the other hand, it has been shown that one-off feedback from a nurse, simplification of treatment, or financial assistance programs offered little improvement. Thus, increasing the effectiveness of adherence interventions might have a far greater impact on the long-term outcome of renal transplants than any improvement in specific medical treatments. This will require coordinated action from health professionals, researchers, health planners, and policy makers. Keywords: renal transplantation, nonadherence, immunosuppressive treatment

Ocular toxoplasmosis in immunosuppressed nonhuman primates

International Nuclear Information System (INIS)

Holland, G.N.; O'Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

1988-01-01

To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease

Ocular toxoplasmosis in immunosuppressed nonhuman primates

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Holland, G.N.; O' Connor, G.R.; Diaz, R.F.; Minasi, P.; Wara, W.M.

1988-06-01

To investigate the role of cellular immunodeficiency in recurrent toxoplasmic retinochoroiditis, six Cynomolgus monkeys (Macaca fascicularis) with healed toxoplasmic lesions of the retina were immunosuppressed by total lymphoid irradiation. Three months prior to irradiation 30,000 Toxoplasma gondii organisms of the Beverley strain had been inoculated onto the macula of eye in each monkey via a pars plana approach. Toxoplasmic retinochoroiditis developed in each animal, and lesions were allowed to heal without treatment. During total lymphoid irradiation animals received 2000 centigrays (cGy) over a 7-week period. Irradiation resulted in an immediate drop in total lymphocyte counts and decreased ability to stimulate lymphocytes by phytohemagglutinin. Weekly ophthalmoscopic examinations following irradiation failed to show evidence of recurrent ocular disease despite persistent immunodeficiency. Four months after irradiation live organisms were reinoculated onto the nasal retina of the same eye in each animal. Retinochoroidal lesions identical to those seen in primary disease developed in five of six animals. Toxoplasma organisms therefore were able to proliferate in ocular tissue following the administration of immunosuppressive therapy. This study fails to support the hypothesis that cellular immunodeficiency alone will initiate recurrent toxoplasmic retinochoroiditis. Results suggest that reactivation of disease from encysted organisms involves factors other than suppression of Toxoplasma proliferation. If reactivation occurs by other mechanisms, however, cellular immunodeficiency then may allow development of extensive disease.

Hypofractionation Regimens for Stereotactic Radiotherapy for Large Brain Tumors

International Nuclear Information System (INIS)

Yuan Jiankui; Wang, Jian Z.; Lo, Simon; Grecula, John C.; Ammirati, Mario; Montebello, Joseph F.; Zhang Hualin; Gupta, Nilendu; Yuh, William T.C.; Mayr, Nina A.

2008-01-01

Purpose: To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. Methods and Materials: The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The α/β ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach, which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach, which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. Results: A plausible α/β ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. Conclusions: The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens

Malaria in immuno-suppressed individuals on antiretroviral therapy ...

African Journals Online (AJOL)

Malaria in immuno-suppressed individuals on antiretroviral therapy (ART) in north-central Nigeria. C.R. Pam, B.T. Abubakar, G.O. Inwang, G.A. Amuga. Abstract. The immune deficiency caused by HIV infection reduces the immune response to malaria parasitaemia and therefore leads to an increased frequency of clinical ...

Inappropriate Tuberculosis Treatment Regimens in Chinese Tuberculosis Hospitals

NARCIS (Netherlands)

Xue He, Guang; van den Hof, Susan; van der Werf, Marieke J.; Guo, Hui; Hu, Yuan Lian; Fan, Ji Huan; Zhang, Wei Min; Tostado, Christopher P.; Borgdorff, Martien W.

2011-01-01

This investigation of tuberculosis (TB) treatment regimens in 6 TB hospitals in China showed that only 18% of patients with new cases and 9% of patients with retreatment cases were prescribed standard TB treatment regimens. Adherence to treatment guidelines needs to be improved in TB hospitals to

Identification of patients at risk of acute rejection by pretransplantation and posttransplantation monitoring of soluble CD30 levels in kidney transplantation.

Science.gov (United States)

Sengul, Sule; Keven, Kenan; Gormez, Ulku; Kutlay, Sim; Erturk, Sehsuvar; Erbay, Bulent

2006-04-27

In this study, we investigated the impact of pre- and posttransplantation sCD30 monitoring on early (acute rejection (AR) risk and analyzed the effect of different immunosuppressive regimens on posttransplantation sCD30 levels in kidney recipients. Fifty patients receiving kidney allograft and 10 healthy donors were included in this retrospective cohort study. Eight patients developed biopsy-proven AR (19%). In pretransplantation samples, patients showed a significantly higher sCD30 than healthy controls. The pretransplantation and posttransplantation (day-15) sCD30 levels were significantly elevated in rejecting patients compared to non-rejecting patients. No significant differences among immunosuppressive regimens were found in posttransplantation sCD30 levels. High pretransplantation and posttransplantation (day 15) sCD30 levels are associated with increased risk of early AR, and sCD30 can be another tool to evaluate immunological risk prior to kidney transplantation. There was no difference in immunosuppressive regimens used in this study on posttransplantation sCD30 levels at the first month.

Prophylactic antibiotic regimens in tumour surgery (PARITY)

DEFF Research Database (Denmark)

Petersen, Michael Mørk; Hettwer, Werner H; Grum-Schwensen, Tomas

2015-01-01

-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. METHODS: We performed a pilot international multi-centre RCT. We used central randomisation...... to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. RESULTS: We screened 96 patients and enrolled 60 participants......% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all post-operative doses were administered per protocol. CONCLUSIONS: It is feasible to conduct a definitive multi-centre RCT of post...

Natural history and epidemiology of post transplantation diabetes ...

African Journals Online (AJOL)

PRACTICE POINTS - Natural history and epidemiology of post transplantation diabetes mellitus. ... Conclusions: The most important risk factor predisposing to the development of PTD is the immunosuppressive drugs. The selection of immunosuppressive regimen should take into account individuals diabetes risk profile ...

Generation of Human Immunosuppressive Myeloid Cell Populations in Human Interleukin-6 Transgenic NOG Mice

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Asami Hanazawa

2018-02-01

Full Text Available The tumor microenvironment contains unique immune cells, termed myeloid-derived suppressor cells (MDSCs, and tumor-associated macrophages (TAMs that suppress host anti-tumor immunity and promote tumor angiogenesis and metastasis. Although these cells are considered a key target of cancer immune therapy, in vivo animal models allowing differentiation of human immunosuppressive myeloid cells have yet to be established, hampering the development of novel cancer therapies. In this study, we established a novel humanized transgenic (Tg mouse strain, human interleukin (hIL-6-expressing NOG mice (NOG-hIL-6 transgenic mice. After transplantation of human hematopoietic stem cells (HSCs, the HSC-transplanted NOG-hIL-6 Tg mice (HSC-NOG-hIL-6 Tg mice showed enhanced human monocyte/macrophage differentiation. A significant number of human monocytes were negative for HLA-DR expression and resembled immature myeloid cells in the spleen and peripheral blood from HSC-NOG-hIL-6 Tg mice, but not from HSC-NOG non-Tg mice. Engraftment of HSC4 cells, a human head and neck squamous cell carcinoma-derived cell line producing various factors including IL-6, IL-1β, macrophage colony-stimulating factor (M-CSF, and vascular endothelial growth factor (VEGF, into HSC-NOG-hIL-6 Tg mice induced a significant number of TAM-like cells, but few were induced in HSC-NOG non-Tg mice. The tumor-infiltrating macrophages in HSC-NOG-hIL-6 Tg mice expressed a high level of CD163, a marker of immunoregulatory myeloid cells, and produced immunosuppressive molecules such as arginase-1 (Arg-1, IL-10, and VEGF. Such cells from HSC-NOG-hIL-6 Tg mice, but not HSC-NOG non-Tg mice, suppressed human T cell proliferation in response to antigen stimulation in in vitro cultures. These results suggest that functional human TAMs can be developed in NOG-hIL-6 Tg mice. This mouse model will contribute to the development of novel cancer immune therapies targeting immunoregulatory/immunosuppressive

Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.

Science.gov (United States)

Narita, Atsushi; Muramatsu, Hideki; Sekiya, Yuko; Okuno, Yusuke; Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Yoshida, Nao; Wang, Xinan; Xu, Yinyan; Kawashima, Nozomu; Doisaki, Sayoko; Hama, Asahito; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Kobayashi, Masao; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

2015-12-01

Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972. Copyright© Ferrata Storti Foundation.

Immunosuppressive compounds from a deep water marine sponge, Agelas flabelliformis.

Science.gov (United States)

Gunasekera, S P; Cranick, S; Longley, R E

1989-01-01

Two immunosuppressive compounds, 4 alpha-methyl-5 alpha-cholest-8-en-3 beta-ol and 4,5-dibromo-2-pyrrolic acid were isolated from a deep water marine sponge, Agelas flabelliformis. Their structures were determined by comparison of their spectral data with those of samples isolated from other organisms. Both compounds were highly active in suppression of the response of murine splenocytes in the two-way mixed lymphocyte reaction (MLR) with little to no demonstrable cytotoxicity at lower doses. In addition, 4,5-dibromo-2-pyrrolic acid suppressed the proliferative response of splenocytes to suboptimal concentrations of the mitogen, concanavalin A (Con A). These results describe for the first time compounds isolated from the marine sponge A. flabelliformis that possess potent in vitro immunosuppressive activity.

Assessment of non-standard HIV antiretroviral therapy regimens at ...

African Journals Online (AJOL)

2016-03-06

Mar 6, 2016 ... Most patients were transitioned to standard regimens, ... In cases of first-line regimen treatment failure, ..... tute; National Heart, Lung, and Blood Institute; National. Institute of Dental & Craniofacial Research; National Insti-.

Intestinal strongyloidiasis in a psoriatic patient following immunosuppressive therapy: Seeing the unforeseen

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Poongodi Lakshmi Santhana Kumaraswamy

2016-01-01

Full Text Available Strongyloides stercoralis , an intestinal nematode, has a complicated life cycle. Mostly asymptomatic, if symptomatic it has nonspecific, transient clinical manifestations. The two aggressive forms of the disease are: Hyperinfection syndrome (HS or disseminated syndrome (DS. Several risk factors have been associated with strongyloidiasis including immunosuppressive therapy, human immunodeficiency virus (HIV infection, diabetes, alcoholism, tuberculosis, impaired bowel motility, surgically created intestinal blind loops, chronic obstructive pulmonary disease, and chronic renal failure. We describe a case of intestinal strongyloidiasis in a psoriatic patient treated with immunosuppressive therapy.

Analysis of drug-drug interactions among patients receiving antiretroviral regimens using data from a large open-source prescription database.

Science.gov (United States)

Patel, Nimish; Borg, Peter; Haubrich, Richard; McNicholl, Ian

2018-06-14

Results of a study of contraindicated concomitant medication use among recipients of preferred antiretroviral therapy (ART) regimens are reported. A retrospective study was conducted to evaluate concomitant medication use in a cohort of previously treatment-naive, human immunodeficiency virus (HIV)-infected U.S. patients prescribed preferred ART regimens during the period April 2014-March 2015. Data were obtained from a proprietary longitudinal prescription database; elements retrieved included age, sex, and prescription data. The outcome of interest was the frequency of drug-drug interactions (DDIs) associated with concomitant use of contraindicated medications. Data on 25,919 unique treatment-naive patients who used a preferred ART regimen were collected. Overall, there were 384 instances in which a contraindicated medication was dispensed for concurrent use with a recommended ART regimen. Rates of contraindicated concomitant medication use differed significantly by ART regimen; the highest rate (3.2%) was for darunavir plus ritonavir plus emtricitabine-tenofovir disoproxil fumarate (DRV plus RTV plus FTC/TDF), followed by elvitegravir-cobicistat-emtricitabine-tenofovir disoproxil fumarate (EVG/c/FTC/TDF)(2.8%). The highest frequencies of DDIs were associated with ART regimens that included a pharmacoenhancing agent: DRV plus RTV plus FTC/TDF (3.2%) and EVG/c/FTC/TDF (2.8%). In a large population of treatment-naive HIV-infected patients, ART regimens that contained a pharmacoenhancing agent were involved most frequently in contraindicated medication-related DDIs. All of the DDIs could have been avoided by using therapeutic alternatives within the same class not associated with a DDI. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Late lumen loss and intima hyperplasia after sirolimus-eluting and zotarolimus-eluting stent implantation in diabetic patients: the diabetes and drug-eluting stent (DiabeDES III) angiography and intravascular ultrasound trial

DEFF Research Database (Denmark)

Jensen, Lisette Okkels; Mæng, Michael; Thayssen, Per

2011-01-01

Patients with diabetes mellitus have increased risk of in-stent restenosis after coronary stent implantation due to neointimal hyperplasia (NIH). The aim of this study was to use quantitative coronary angiography (QCA) and volumetric intravascular ultrasound (IVUS) to evaluate the effects...... of the sirolimus-eluting Cypher® stent (SES) and the zotarolimus-eluting Endeavor® stent (ZES) on angiographic late lumen loss and intima hyperplasia in diabetic patients....

Pneumonia in immunosuppressed patients; Pneumonien bei immunsupprimierten Patienten

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Solyanik, O.; Gaass, T.; Hellbach, K. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Campus Grosshadern, Institut fuer klinische Radiologie, Muenchen (Germany); Dinkel, J. [Klinikum der Ludwig-Maximilians-Universitaet Muenchen, Campus Grosshadern, Institut fuer klinische Radiologie, Muenchen (Germany); Comprehensive Pneumology Center Munich (CPC-M), Muenchen (Germany)

2017-01-15

Pulmonary infections are a common complication in immunosuppressed patients with a frequently fatal prognosis despite modern prophylactic therapy. An early and correct diagnosis is important for initiation of the appropriate therapy. Chest radiography is the preferred initial imaging examination but is not accurate enough for the detection of pulmonary infections in immunosuppressed patients. Pneumonia is caused by a broad spectrum of pathogens in immunocompromised patients. In addition to imaging, the clinical history and epidemiology also play an important role in the diagnostics. Using epidemiological and anamnestic information, computed tomography (CT) shows a significantly better sensitivity and specificity particularly for the diagnosis of atypical forms of pneumonia. Due to the exact imaging of the different infiltration patterns CT provides an increased sensitivity with respect to the etiological classification of pulmonary infections. This article reviews in particular the radiological findings of commonly occurring pulmonary infections in immunosuppressed patients. (orig.) [German] Pneumonien bei immunsupprimierten Patienten sind haeufige Komplikationen, die trotzt moderner Prophylaxe toedlich verlaufen koennen. Eine korrekte Diagnose ist daher von entscheidender Bedeutung, um die richtige Therapie einleiten zu koennen. Die Roentgenthoraxaufnahme ist selten spezifisch genug fuer die genaue Einordnung atypischer Pneumonien in Folge einer Immunsuppression. Pneumonien unter Immunsuppression werden durch ein sehr breites Erregerspektrum verursacht. Eine wichtige Rolle bei der Diagnosefindung spielen neben der Bildgebung auch die klinische Anamnese und Epidemiologie. Mithilfe der klinischen Anamnese und Epidemiologie bietet die Computertomographie (CT) bei immunsupprimierten Patienten zum einen eine erhoehte Sensitivitaet bei der Detektion insbesondere atypischer Pneumonien. Zum anderen weist die CT durch die exakte Abbildung unterschiedlicher Infiltratmuster

Immunosuppression and risk of cervical cancer

DEFF Research Database (Denmark)

Dugué, Pierre-Antoine; Rebolj, Matejka; Garred, Peter

2013-01-01

-stage renal disease seem to be at an increased risk of cervical cancer. A higher risk of cervical precancerous lesions was found in patients with some autoimmune diseases; particularly if treated with immunosuppressants. Among behavioral factors weakening the immune system, smoking appeared to strongly...... increase the risk of cervical cancer, while poor diet only moderately increased the risk. It is difficult to determine whether sexually transmitted infections other than human papillomavirus infection are independent risk factors. Identifying those groups of women likely to fail in clearing persistent...

Merkel cell carcinoma in an immunosuppressed patient.

Science.gov (United States)

Góes, Heliana Freitas de Oliveira; Lima, Caren Dos Santos; Issa, Maria Cláudia de Almeida; Luz, Flávio Barbosa; Pantaleão, Luciana; Paixão, José Gabriel Miranda da

2017-01-01

Merkel cell carcinoma is an uncommon neuroendocrine carcinoma with a rising incidence and an aggressive behavior. It predominantly occurs in older patients, with onset occurring at a mean age of 75-80 years. Recognized risk factors are ultraviolet sunlight exposure, immunosuppression, and, more recently, Merkel cell polyomavirus. We report a case of Merkel cell carcinoma in a young HIV positive patient with Merkel Cell polyomavirus detected in the tumor.

Immunosuppressive therapy for transplant-ineligible aplastic anemia patients.

Science.gov (United States)

Schrezenmeier, Hubert; Körper, Sixten; Höchsmann, Britta

2015-02-01

Aplastic anemia is a rare life-threatening bone marrow failure that is characterized by bicytopenia or pancytopenia in the peripheral blood and a hypoplastic or aplastic bone marrow. The patients are at risk of infection and hemorrhage due to neutropenia and thrombocytopenia and suffer from symptoms of anemia. The main treatment approaches are allogeneic stem cell transplantation and immunosuppression. Here, we review current standard immunosuppression and the attempts that have been made in the past two decades to improve results: review of recent developments also reveals that sometimes not only the advent of new drugs, good ideas and well-designed clinical trials decide the progress in the field but also marketing considerations of pharmaceutical companies. Aplastic anemia experts unfortunately had to face the situation that efficient drugs were withdrawn simply for marketing considerations. We will discuss the current options and challenges in first-line treatment and management of relapsing and refractory patients with an emphasis on adult patients. Some promising new approaches are currently under investigation in prospective, randomized trials.

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

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E. A. Drozdova

2014-07-01

Full Text Available Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years who received low dose methotrexate — 7.5-20 mg once a week (n=79 cyclosporine A 3.5-5.0 mg/kg/d (n=21 with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% of patients with chronic uveitis. Control of acute inflammation was achived in 71.1% patients, who received methotrexate in combination with prednisolone. Cyclosporine A was more effective in controlling inflammatory of the eye: remission of uveitis was achived in 85.7% in combination with glucocorticoids. No significant side effects have been noted.Conclusion: Methotrexate and cyclosporine A with low dose of prednisolone are well tolerated immunosuppressive agents andrather effective in the treatment of non-infectious uveitis and retinovasculitis that fails to respond to conventional steroid treatment.

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

Directory of Open Access Journals (Sweden)

E. A. Drozdova

2012-01-01

Full Text Available Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years who received low dose methotrexate — 7.5-20 mg once a week (n=79 cyclosporine A 3.5-5.0 mg/kg/d (n=21 with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% of patients with chronic uveitis. Control of acute inflammation was achived in 71.1% patients, who received methotrexate in combination with prednisolone. Cyclosporine A was more effective in controlling inflammatory of the eye: remission of uveitis was achived in 85.7% in combination with glucocorticoids. No significant side effects have been noted.Conclusion: Methotrexate and cyclosporine A with low dose of prednisolone are well tolerated immunosuppressive agents andrather effective in the treatment of non-infectious uveitis and retinovasculitis that fails to respond to conventional steroid treatment.

Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression

OpenAIRE

MCCANN, SHAUN

2002-01-01

PUBLISHED Background: Aplastic anemia may develop during pregnancy and sometimes improves spontaneously after delivery. The effects of pregnancy on aplastic anemia after immunosuppressive treatment and of aplastic anemia on the outcome of pregnancy have not been described. Objective: To determine the outcome of pregnancy and the disease course among women with aplastic anemia who received immunosuppressive therapy. Design: Retrospective multicenter study. Setting: Twelve cen...

Future immunosuppressive agents in solid-organ transplantation.

Science.gov (United States)

Gabardi, Steven; Cerio, Jeffrey

2004-06-01

To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium, everolimus, and FTY720. Clinical trials and abstracts evaluating mycophenolate sodium, everolimus, and FTY720 in solid-organ transplantation were considered for evaluation. English-language studies and published abstracts were selected for inclusion. Mycophenolate sodium has recently been approved by the Food and Drug Adminstration for marketing in the United States; everolimus and FTY720 are immunosuppressive agents that may soon be available in the United States. These agents have proven efficacy in reducing the incidence of acute rejection in solid-organ transplantation. Clinical trials have shown that these newer agents are relatively well tolerated. The most common adverse events associated with these agents were gastrointestinal and hematologic effects (mycophenolate sodium); hyperlipidemia, increased serum creatinine, and hematologic effects (everolimus): and gastrointestinal effects, headache, and bradycardia (FTY720). Mycophenolate sodium has been approved in some European countries and the United States. Everolimus has been approved in some European countries and a new drug application has been submitted to the Food and Drug Administration. FTY720 is currently in phase III clinical trials and submission to the Food and Drug Administration for approval is a few years away. The approval of these agents will furnish the transplant practitioner with even more options for immunosuppression.

Ganoderma atrum polysaccharide ameliorates ROS generation and apoptosis in spleen and thymus of immunosuppressed mice.

Science.gov (United States)

Li, Wen-Juan; Li, Lu; Zhen, Weng-Ya; Wang, Le-Feng; Pan, Meng; Lv, Jia-Qian; Wang, Fan; Yao, Yu-Fei; Nie, Shao-Ping; Xie, Ming-Yong

2017-01-01

Ganoderma atrum polysaccharide (PSG-1) is a bioactive compound with antioxidant and immunomodulatory activities. The aim of this study was to determine the effect of PSG-1 on reactive oxygen species (ROS) generation and apoptosis in spleen and thymus of cyclophosphamide (CTX)-induced immunosuppressed mice. The results showed that PSG-1 protected mice against CTX-mediated immunosuppression, as evidenced by enhancing the ratios of thymus and spleen weights to body weight, promoting T cell and B cell survival, and increasing levels of TNF-α and IL-2. Apoptosis, ROS generation and lipid peroxidation in the immune organs of the immunosuppressed animals were ameliorated by PSG-1. The immune benefits of PSG-1 were associated with the enhancement of the activities of glutathione peroxidase, superoxide dismutase and catalase in the immune organs, implying that antioxidant activities of PSG-1 may play an important role in PSG-1-evoked immune protection. Taken together, these findings have demonstrated that PSG-1 may ameliorate CTX-induced immunosuppression through reducing apoptosis and oxidative damage in immunological system. Copyright © 2016. Published by Elsevier Ltd.

Endolymphatic irradiation. A useful method for immunosuppression in renal transplantation

Energy Technology Data Exchange (ETDEWEB)

Galvao, M.M.; Ianhez, L.E.; Sabbaga, E. (Sao Paulo Univ. (Brazil). Faculdade de Medicina)

1982-02-01

The authors analysed the clinical evolution and the result of renal transplantation some years after irradiation in 24 patients (group I) who received endolymphatic /sup 131/I as a pre-transplantation immunosuppresive measure. The control group (group II) consisted of 24 non-irradiated patients comparable to group I in age, sex, primary disease, type of donor and immunosuppressive therapy. Significant differences were observed between the two groups regarding such factors as incidence and reversibility of rejection crises in the first 60 post-transplantation days, loss of kidney due to rejection, and dosage of azathioprine. The authors conclude that this method, besides being harmless, has prolonged immunosuppressive action, its administration being advised for receptors of cadaver kidneys, mainly those who show positive cross-match against HLA antigens for painel.

Management of HBV Infection During Immunosuppressive Treatment

OpenAIRE

Marzano, Alfredo

2009-01-01

The literature on hepatitis B virus (HBV) in immunocompromised patients is heterogeneous and refers mainly to the pre-antivirals era. Currently, a rational approach to the problem of hepatitis B in these patients provides for: a) the evaluation of HBV markers and of liver condition in all subjects starting immunosuppressive therapies (baseline), b) the treatment with antivirals (therapy) of active carriers, c) the pre-emptive use of antivirals (prophylaxis) in inactive carriers, especially if...

The role of immunosuppression of mesenchymal stem cells in tissue repair and tumor growth

OpenAIRE

Han Zhipeng; Jing Yingying; Zhang Shanshan; Liu Yan; Shi Yufang; Wei Lixin

2012-01-01

Abstract Mesenchymal stem cells (MSCs) have acquired great interests for their potential use in the clinical therapy of many diseases because of their functions including multiple lineage differentiation, low immunogenicity and immunosuppression. Many studies suggest that MSCs are strongly immunosuppressive in vitro and in vivo. MSCs exert a profound inhibitory effect on the proliferation of T cells, B cells, dendritic cells and natural killer cells. In addition, several soluble factors have ...

Rat allotransplantation of epigastric microsurgical flaps: a study of rejection and the immunosuppressive effect of cyclosporin A

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Carramaschi Fábio R.

2000-01-01

Full Text Available The rejection of allotransplantation of epigastric microsurgical flaps and the effect of immunosuppression have been studied in 58 rats. Three sets of experiments were planned: (1 Wistar Furth isogenic donors and receptors (control set; (2 Brown Norway donors and Wistar Furth receptors (rejection set; and (3 Brown Norway donors and Wistar Furth immunosuppressed receptors (cyclosporin A set. Cyclosporin A (10 mg/kg/d treated rats had a transplantation survival rate of up to 30 days: 83.3% among isogenic animals and 60% among allogeneic. There was 100% rejection by the 9th day after the transplantation in allogeneic non-immunosuppressed rats. Biopsies embedded with historesin were taken from the flap and normal contralateral skin (used as control on the 3rd, 7th, 15th, and 30th days after the surgery. A quantitative study of infiltrating lymphocytes in the flaps, with and without cyclosporin A, was done by evaluating the local inflammatory infiltrate. A significant increase in the number of lymphocytes among the rejection and immunosuppressed groups was seen, as compared to the isogenic set. Local lymphocytosis in allogeneic non-immunosuppressed transplantations reached its highest level on the 3rd day after surgery, before gross findings of rejection, which could only be seen by naked eye on the 5th or 6th day. Therefore, we conclude that cyclosporin A is effective in preserving allogenic transplantation in rats. Biopsies of transplanted areas may contribute to earlier diagnosis of the need for immunosuppressive therapy.

The use of immunosuppressive agents in the management of recalcitrant lower limb ulcers.

Science.gov (United States)

Millen, A; Coulston, J; Brennan, J; Kennedy, T

2014-08-01

Lower limb ulcers that are resistant to standard forms of treatment place a significant burden on both patients and health services. There is no widely agreed definition of a recalcitrant ulcer but failure to heal following 6-12 months of focused treatment would identify a small group of patients with highly resistant ulceration. We describe a series of patients with recalcitrant ulceration for which immunosuppressive agents have been used. This is a case series of 13 patients who underwent immunomodulation therapy for lower limb ulcers at a tertiary referral university hospital. Regimens of immunomodulation used mainly ciclosporin and/or cyclophosphamide, with concurrent antibiotic therapy. Case notes and computer systems were analysed by two reviewers. A patient was deemed to have a success if their ulcer fully healed while on immunomodulation therapy. Over a period of eight years, from 2004-2012, 13 patients underwent immunomodulation therapy. Among these patients there were 18 ulcerated limbs. Ulcer healing occurred in 10 limbs out of 18 (55.6%) and full healing occurred in six patients (46.2%). Ulcers were present for a median of five years (range 2-40 years), with a median diameter of 7.5 cm (range 4-18 cm) before treatment. Treatment of truly recalcitrant ulceration can be very frustrating for both the patient and physician, with poor success from more standard forms of treatment. We report experience with immunomodulation therapy that suggests there may be benefit from using this treatment in a subset of patients with this debilitating disease.

Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

Science.gov (United States)

Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

2017-06-03

To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

Cancer immunotherapy by immunosuppression

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Prehn Liisa M

2010-12-01

Full Text Available Abstract We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis.

Development of antibiotic regimens using graph based evolutionary algorithms.

Science.gov (United States)

Corns, Steven M; Ashlock, Daniel A; Bryden, Kenneth M

2013-12-01

This paper examines the use of evolutionary algorithms in the development of antibiotic regimens given to production animals. A model is constructed that combines the lifespan of the animal and the bacteria living in the animal's gastro-intestinal tract from the early finishing stage until the animal reaches market weight. This model is used as the fitness evaluation for a set of graph based evolutionary algorithms to assess the impact of diversity control on the evolving antibiotic regimens. The graph based evolutionary algorithms have two objectives: to find an antibiotic treatment regimen that maintains the weight gain and health benefits of antibiotic use and to reduce the risk of spreading antibiotic resistant bacteria. This study examines different regimens of tylosin phosphate use on bacteria populations divided into Gram positive and Gram negative types, with a focus on Campylobacter spp. Treatment regimens were found that provided decreased antibiotic resistance relative to conventional methods while providing nearly the same benefits as conventional antibiotic regimes. By using a graph to control the information flow in the evolutionary algorithm, a variety of solutions along the Pareto front can be found automatically for this and other multi-objective problems. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

2-year clinical outcomes after implantation of sirolimus-eluting, paclitaxel-eluting, and bare-metal coronary stents: results from the WDHR (Western Denmark Heart Registry)

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Kaltoft, Anne; Jensen, Lisette Okkels; Maeng, Michael

2009-01-01

OBJECTIVES: This registry study assessed the safety and efficacy of the 2 types of drug-eluting stents (DES), sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES), compared with bare-metal stents (BMS). BACKGROUND: Drug-eluting stents may increase the risk of stent thrombosis (ST...... databases. We used Cox regression analysis to control for confounding. RESULTS: The 2-year incidence of definite ST was 0.64% in BMS patients, 0.79% in DES patients (adjusted relative risk [RR]: 1.09; 95% confidence interval [CI]: 0.72 to 1.65), 0.50% in SES patients (adjusted RR: 0.63, 95% CI: 0.35 to 1...

Immunosuppressive therapy in glomerular diseases: major accomplishment of Tadeusz Orłowski and his school.

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Smogorzewski, Mirosław J; Lao, Mieczysław; Gradowska, Liliana; Rowińska, Danuta; Rancewicz, Zofia

2009-05-01

Glomerulopathies are the third most common cause of end-stage renal failure. Immunosuppressive treatment of glomerulonephritis in a systematic way was introduced in Poland by Professor Tadeusz Orłowski in the early 1960s. The studies were conducted at the First Department of Medicine and at the Transplantation Institute of the Medical Academy in Warsaw in the years 1962-1988. This paper critically reviews the results of studies on the use of combined, triple-drug (prednisone/chlorambucil/azathioprine), immunosuppressive protocol in various pathological forms of glomerulopathies. We conclude that immunosuppressive protocols pioneered by Tadeusz Orłowski continue to be the backbone of the treatment of glomerulonephritis, especially the one with nephrotic syndrome, progressive impairment of kidney function and poor prognosis.

Immunosuppressive activity enhances central carbon metabolism and bioenergetics in myeloid-derived suppressor cells in vitro models

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Hammami Ines

2012-07-01

Full Text Available Abstract Background The tumor microenvironment contains a vast array of pro- and anti-inflammatory cytokines that alter myelopoiesis and lead to the maturation of immunosuppressive cells known as myeloid-derived suppressor cells (MDSCs. Incubating bone marrow (BM precursors with a combination of granulocyte-macrophage colony-stimulating factor (GM-CSF and interleukin-6 (IL-6 generated a tumor-infiltrating MDSC-like population that impaired anti-tumor specific T-cell functions. This in vitro experimental approach was used to simulate MDSC maturation, and the cellular metabolic response was then monitored. A complementary experimental model that inhibited L-arginine (L-Arg metabolizing enzymes in MSC-1 cells, an immortalized cell line derived from primary MDSCs, was used to study the metabolic events related to immunosuppression. Results Exposure of BM cells to GM-CSF and IL-6 activated, within 24 h, L-Arg metabolizing enzymes which are responsible for the MDSCs immunosuppressive potential. This was accompanied by an increased uptake of L-glutamine (L-Gln and glucose, the latter being metabolized by anaerobic glycolysis. The up-regulation of nutrient uptake lead to the accumulation of TCA cycle intermediates and lactate as well as the endogenous synthesis of L-Arg and the production of energy-rich nucleotides. Moreover, inhibition of L-Arg metabolism in MSC-1 cells down-regulated central carbon metabolism activity, including glycolysis, glutaminolysis and TCA cycle activity, and led to a deterioration of cell bioenergetic status. The simultaneous increase of cell specific concentrations of ATP and a decrease in ATP-to-ADP ratio in BM-derived MDSCs suggested cells were metabolically active during maturation. Moreover, AMP-activated protein kinase (AMPK was activated during MDSC maturation in GM-CSF and IL-6–treated cultures, as revealed by the continuous increase of AMP-to-ATP ratios and the phosphorylation of AMPK. Likewise, AMPK activity was

Survival predictors in paraquat intoxification and role of immunosuppression

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Keng-Hee Koh

2014-01-01

In contrast, there was no difference in survival with immunosuppression regime (38 out of 64 patients (59.4% compared to historical control (30 out of 52 patients (57.7% (p = 0.885 in those with eGFR > 50 ml/min/1.73 m2 or WBC 11,000/μL.

Characteristics of HIV antiretroviral regimen and treatment adherence

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Vera Lúcia da Silveira

Full Text Available The relationship between characteristics of HIV antiretroviral regimens and treatment adherence was studied in adolescent and adult patients who underwent antiretroviral therapy from January 1998 to September 2000, at the Service for Specialized Assistance in Pelotas. The patients were interviewed on two occasions, and the use of antiretrovirals during the previous 48 hours was investigated by a self-report. Adherence was defined as use of 95% or more of the prescribed medication. Social-demographic variables were collected through direct questionnaires. The antiretroviral regimen and clinical data were copied from the patients' records. Associations between the independent variables and adherence were analyzed by means of logistic regression. The multivariate analysis included characteristics of the antiretroviral regimens, social-demographic variables, as well as perception of negative effects, negative physiological states, and adverse effects of the treatment. Among the 224 selected patients, 194 participated in our study. Their ages varied from 17 to 67 years; most patients were men, with few years of schooling and a low family income. Only 49% adhered to the treatment. Adherence to treatment regimens was reduced when more daily doses were indicated: three to four doses (odds ratio of adherence to treatment (OR=0.47, 95% confidence interval (CI 0.22-1.01 and five to six (OR=0.24, 95% CI 0.09-0.62; two or more doses taken in a fasting state (OR=0.59, 95% CI 0.11-0.68, and for patients who reported adverse effects to the treatment (OR=0.39, 95% CI 0.19-0.77. Most of the regimens with more than two daily doses of medication included at least one dose apart from mealtimes. The results suggest that, if possible, regimens with a reduced number of doses should be chosen, with no compulsory fasting, and with few adverse effects. Strategies to minimize these effects should be discussed with the patients.

Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model.

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Emily A Kendall

2017-01-01

Full Text Available Novel drug regimens are needed for tuberculosis (TB treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen's ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective.We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis, South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS or rifampicin-resistant (RR TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1 efficacy, (2 duration, (3 ease of adherence, (4 medical contraindications, (5 barrier to resistance, and (6 baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113-187 and 16 (95% UR: 9-23 per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4-10 and 0.6 (95% UR: 0.3-1.1 per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%-20% and 11% (95% UR: 6%-20%, respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%-46% and RR TB mortality by 30% (95% UR: 18%-44%. Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%-13%, half the

Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

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Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

2015-09-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Comparison of the efficacy and safety of S-1-based and capecitabine-based regimens in gastrointestinal cancer: a meta-analysis.

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Xunlei Zhang

Full Text Available Oral fluoropyrimidine (S-1, capecitabine has been considered as an important part of various regimens. We aimed to evaluate the efficacy and safety of S-1-based therapy versus capecitabine -based therapy in gastrointestinal cancers.Eligible studies were identified from Pubmed, EMBASE. Additionally, abstracts presented at American Society of Clinical Oncology (ASCO conferences held between 2000 and 2013 were searched to identify relevant clinical trials. The outcome included overall survival (OS, progression-free survival (PFS, overall response rate (ORR, disease control rate (DCR and advent events.A total of 6 studies (4 RCTs and 2 retrospective analysis studies containing 790 participants were included in this meta-analysis, including 401 patients in the S-1-based group and 389 patients in the capecitabine-based group. Results of our meta-analysis indicated that S-1-based and capecitabine-based regimens showed very similar efficacy in terms of PFS (HR 0.92, 95% CI 0.78-1.09, P = 0.360, OS (HR 1.01, 95% CI 0.84-1.21, P = 0.949, ORR (HR 1.04, 95% CI 0.87-1.25, P = 0.683 and DCR (HR 1.02, 95% CI 0.94-1.10, P = 0.639. There was also no significant difference in toxicity between regimens other than mild more hand-foot syndrome in capecitabine-based regimens.Both the S-1-based and capecitabine-based regimens are equally active and well tolerated, and have the potential of backbone chemotherapy regimen in further studies of gastrointestinal cancers.

Effectiveness of a sanguinarine regimen after scaling and root planing.

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Tenenbaum, H; Dahan, M; Soell, M

1999-03-01

A variety of chemical agents have been evaluated relative to their abilities to inhibit dental plaque and to improve gingival health. Chlorhexidine gluconate is the best known and most widely used member of these agents, but its long-term use is compromised by different side effects, especially extrinsic tooth and tongue staining. Another agent, sanguinarine, which is currently used in both a mouthrinse and toothpaste, leads in some cases only to a transient burning sensation and could be used on a long-term basis. The purpose of this 14-week controlled clinical trial was to assess the effectiveness of a toothpaste and oral rinse containing sanguinaria extract after scaling, root planing and a chlorhexidine regimen. Sixty patients diagnosed as having adult periodontitis received initial periodontal therapy including scaling and root planing, followed by a 2-week oral care regimen which included rinsing with 0.2% chlorhexidine gluconate oral rinse. Upon completion of this 2-week initial therapy phase, patients were randomly assigned to either sanguinarine toothpaste and oral rinse or to control toothpaste and oral rinse without sanguinarine. Plaque (modified Quigley-Hein index) and gingivitis (gingival index) were measured prior to periodontal therapy, at the end of the chlorhexidine phase (2 weeks), and after 8 and 14 weeks. Sanguinarine-containing toothpaste and oral rinse significantly inhibited the redevelopment of gingivitis through the 12 weeks following the chlorhexidine phase compared to the control toothpaste and rinse. Patients in the test group had 26% fewer bleeding sites at 8 weeks, and 32% fewer at 14 weeks, than the control group. Our results support the combined use of chlorhexidine mouthrinse for a short term (2 weeks) followed by sanguinaria mouthrinse and toothpaste up to 3 months in order to optimize the effectiveness of chlorhexidine without side effects. Further studies on the long-term effect of this combination should be established.

Genital lesions: An indication for changing ART regimen.

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Kumar, S Arun; Kumar, N; Kumarasamy, N

2011-01-01

Genital lesions are common in HIV positive patients and aetiology for these are mainly due to HSV, HPV or bacterial. They usually respond to HAART, antiviral or antimicrobials. We are presenting a young patient on HAART with non-healing genital ulcer lesions for sixteen months. He responded well to a change in ART regimen within a period of 15 days. This happened after a change to a more potent ART regimen.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

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Zhou, Xinna; Wang, Xiaoli; Song, Qingkun; Yang, Huabing; Zhu, Xishan; Yu, Jing; Song, Guohong; Di, Lijun; Ren, Jun; Shao, Hong; Lyerly, Herbert Kim

2015-11-01

The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island.

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Arriola Apelo, Sebastian I; Lamming, Dudley W

2016-07-01

Rapamycin (sirolimus) is a macrolide immunosuppressant that inhibits the mechanistic target of rapamycin (mTOR) protein kinase and extends lifespan in model organisms including mice. Although rapamycin is an FDA-approved drug for select indications, a diverse set of negative side effects may preclude its wide-scale deployment as an antiaging therapy. mTOR forms two different protein complexes, mTORC1 and mTORC2; the former is acutely sensitive to rapamycin whereas the latter is only chronically sensitive to rapamycin in vivo. Over the past decade, it has become clear that although genetic and pharmacological inhibition of mTORC1 extends lifespan and delays aging, inhibition of mTORC2 has negative effects on mammalian health and longevity and is responsible for many of the negative side effects of rapamycin. In this review, we discuss recent advances in understanding the molecular and physiological effects of rapamycin treatment, and we discuss how the use of alternative rapamycin treatment regimens or rapamycin analogs has the potential to mitigate the deleterious side effects of rapamycin treatment by more specifically targeting mTORC1. Although the side effects of rapamycin are still of significant concern, rapid progress is being made in realizing the revolutionary potential of rapamycin-based therapies for the treatment of diseases of aging. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Mecanismos moleculares de acción de algunas drogas inmunosupresoras Molecular mechanisms of action of some immunosuppresive drugs

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Ana C. Liberman

2008-12-01

Full Text Available Los tratamientos utilizados para desordenes inmunológicos son de origen empírico, utilizando drogas inmunosupresoras identificadas a través de la selección de un gran número de compuestos naturales y sintéticos. Las drogas inmunosupresoras son ampliamente utilizadas en tratamientos clínicos de desordenes autoinmunes, en la prevención de rechazo a transplantes así como también en desordenes de carácter no autoinmune tales como las alergias. El diseño de las terapias inmunosupresoras está basado en controlar una respuesta inmune exacerbada. La base fisiopatológica de este concepto es en modular la acción de células mononucleares, siendo el principal punto de control las células T. Estas drogas inhiben la función normal de protección del sistema inmune llevando a la aparición de complicaciones en las terapias de inmunosupresión. Las drogas inmunosupresoras tienen diferentes blancos en el proceso de inmunidad celular. Según su modo de acción pueden clasificarse en cuatro categorías: drogas antinflamatorias de la familia de los corticosteroides, inmunosupresoras específicas inhibidoras de la calcineurina, citotóxicas o antiproliferativas y anticuerpos específicos. En este trabajo describimos el mecanismo de acción molecular de agentes inmunosupresores tales como, esteroides, ciclosporina, tacrolimo, azatioprina, ciclofosfamida, sirolimus, mofetil mecofenolato, leflunomida y anticuerpos específicos, para contribuir a la comprensión de cómo utilizar y mejorar estos agentes.A number of natural and synthetic substances are used in the treatment of immunological disorders. The immunosuppressive drugs are widely utilized in clinical treatments of autoimmune disorders, in the prevention of transplant rejection as well as in non-autoimmune diseases such as allergy. The design of immunosuppressive therapies is based on the control of the exacerbated immune response. The pathophysiologic mean of this concept is to modulate the

A better cure rate with 800 mg than with 400 mg clarithromycin regimens in one-week triple therapy for Helicobacter pylori infection in cigarette-smoking peptic ulcer patients.

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Ishioka, Hidehiko; Mizuno, Motowo; Take, Susumu; Ishiki, Kuniharu; Nagahara, Yasuhiro; Yoshida, Tomowo; Okada, Hiroyuki; Yokota, Kenji; Oguma, Keiji

2007-01-01

In Helicobacter pylori eradication therapy, using a proton pump inhibitor plus amoxicillin and clarithromycin (PPI/AC regimen), the impact of the clarithromycin dose and smoking on efficacy is conflicting. Here, we compared the efficacy of 400 and 800 mg of clarithromycin in the regimen in relation to smoking in patients with peptic ulcer disease. We studied 601 H. pylori-positive patients with peptic ulcer disease who had received amoxicillin 750 mg and clarithromycin 200 or 400 mg together with lansoprazole 30 mg b.i.d. 305 patients were treated with a regimen containing 400 mg of clarithromycin (C400 group), and 296 patients with a regimen containing 800 mg (C800 group). Overall cure rates between the two groups were not significantly different, but the cure rate in the C800 group was significantly better than that in the C400 group among patients infected with clarithromycin-sensitive strains (p = 0.03). This difference could be attributed to differences among smokers versus non-smokers: the cure rate among smokers in the C800 group (91.0%) was better than that in the C400 group (80.0%, p = 0.003). 800 mg of clarithromycin is recommended in the PPI/AC regimen for patients who smoke and are infected with clarithromycin-sensitive H. pylori. 2007 S. Karger AG, Basel

The role of basiliximab in the evolving renal transplantation immunosuppression protocol

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Paola Salis

2008-06-01

Full Text Available Paola Salis, Chiara Caccamo, Roberto Verzaro, Salvatore Gruttadauria, Mary ArteroDivision of Nephrology and Division of Abdominal Transplantation, Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, ItalyAbstract: Basiliximab is a chimeric mouse-human monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2 receptor on activated T lymphocytes. It was shown in phase III trials to reduce the number and severity of acute rejection episodes in the first year following renal transplantation in adults and children, with a reasonable cost-benefit ratio. The drug does not increase the incidence of opportunistic infections or malignancies above baseline in patients treated with conventional calcineurin inhibitor-based immunosuppression. In the field of renal transplantation, basiliximab does not increase kidney or patient survival, despite the reduction in the number of rejection episodes. Basiliximab may reduce the incidence of delayed graft function. In comparison with lymphocyte-depleting antibodies basiliximab appears to have equal efficacy in standard immunological risk patients. Recently, IL-2 receptor monoclonal antibodies have been used with the objective of reducing or eliminating the more toxic elements of the standard immunosuppression protocol. Several trials have incorporated basiliximab in protocols designed to avoid or withdraw rapidly corticosteroids, as well as protocols which substitute target-of-rapamycin (TOR inhibitors for calcineurin inhibitors.Keywords: basiliximab, renal transplantation, IL-2 receptor antagonists, induction, immunosuppression, corticosteroids, calcineurin inhibitors

Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

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Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.

2013-01-01

Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2–53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17–0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17–50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease. PMID:23223591

Fluid regimens for colostomy irrigation: a systematic review.

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Lizarondo, Lucylynn; Aye Gyi, Aye; Schultz, Tim

2008-09-01

Background  Various techniques for managing faecal evacuation have been proposed; however, colostomy irrigation is favoured as it leads to better patient outcomes. Alternative fluid regimens for colostomy irrigation have been suggested to achieve effective evacuation. Aim  The objective of this review was to summarise the best available evidence on the most effective fluid regimen for colostomy irrigation. Search strategy  Trials were identified by electronic searches of CINAHL, PubMed, MEDLINE, Current Contents, the Cochrane Library and EMBASE. Unpublished articles and references lists from included studies were also searched. Selection criteria  Randomised controlled trials and before-and-after studies investigating any fluid regimen for colostomy irrigation were eligible for inclusion. Outcomes measured included fluid inflow time, total wash-out time, haemodynamic changes during irrigation, cramps, leakage episodes, quality of life and level of satisfaction. Data collection and analysis  Trial selection, quality appraisal and data extraction were carried out independently by two reviewers. Differences in opinion were resolved by discussion. Main results  The systematic literature search strategy identified two cross-over trials that compared water with another fluid regimen. Owing to the differences in irrigating solutions used, the results were not pooled for analysis. Both the polyethylene glycol electrolyte solution and glyceryl trinitrate performed significantly better than water. Conclusion  There is some evidence to support the effectiveness of fluid regimens other than water, such as polyethylene glycol electrolyte and glyceryl trinitrate, for colostomy irrigation. Further well-designed clinical trials are required to establish solid evidence on the effectiveness of other irrigating solutions that might enhance colonic irrigation. © 2008 The Authors. Journal Compilation © Blackwell Publishing Asia Pty Ltd.

In vivo biofilm formation on stainless steel bonded retainers during different oral health-care regimens.

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Jongsma, Marije A; van der Mei, Henny C; Atema-Smit, Jelly; Busscher, Henk J; Ren, Yijin

2015-03-23

Retention wires permanently bonded to the anterior teeth are used after orthodontic treatment to prevent the teeth from relapsing to pre-treatment positions. A disadvantage of bonded retainers is biofilm accumulation on the wires, which produces a higher incidence of gingival recession, increased pocket depth and bleeding on probing. This study compares in vivo biofilm formation on single-strand and multi-strand retention wires with different oral health-care regimens. Two-centimetre wires were placed in brackets that were bonded to the buccal side of the first molars and second premolars in the upper arches of 22 volunteers. Volunteers used a selected toothpaste with or without the additional use of a mouthrinse containing essential oils. Brushing was performed manually. Regimens were maintained for 1 week, after which the wires were removed and the oral biofilm was collected to quantify the number of organisms and their viability, determine the microbial composition and visualize the bacteria by electron microscopy. A 6-week washout period was employed between regimens. Biofilm formation was reduced on single-strand wires compared with multi-strand wires; bacteria were observed to adhere between the strands. The use of antibacterial toothpastes marginally reduced the amount of biofilm on both wire types, but significantly reduced the viability of the biofilm organisms. Additional use of the mouthrinse did not result in significant changes in biofilm amount or viability. However, major shifts in biofilm composition were induced by combining a stannous fluoride- or triclosan-containing toothpaste with the mouthrinse. These shifts can be tentatively attributed to small changes in bacterial cell surface hydrophobicity after the adsorption of the toothpaste components, which stimulate bacterial adhesion to the hydrophobic oil, as illustrated for a Streptococcus mutans strain.

Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly.

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Gabardi, Steven; Tullius, Stefan G; Krenzien, Felix

2015-08-01

This review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. Over the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. Despite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully.

The use of irradiated food for immuno-suppressed hospital patients

International Nuclear Information System (INIS)

Pryke, D.C.

1994-01-01

The treatment of leukaemia and other forms of haematological malignancies involves destruction of the bone marrow followed by bone-marrow transplant. This results in patients becoming severely immuno-suppressed. Other diseases result in a similar condition, most notably Acquired Immuno-Deficiency Syndrome (AIDS). Irradiation using radioactive sources or machines has been proposed as a method for preparing foods for immuno-suppressed patients and other high risk groups. Doses of around 30 kGy ensure a total sterility whilst a dose of 10 kGy (the recommended maximum for food available to the general public) results in a significant reduction in the number of pathogenic microorganisms. Irradiation has a number of advantages over other processing methods, in particular that flavour, texture and nutritional changes are limited. This is important as patients are often in a compromised state and need clinical assistance in returning to normal eating habits. In recognition of the potential of irradiated foods for hospital patients this use has been specifically exempted from regulatory control in the UK. This paper reviews the experience in the UK of irradiation-sterilized foods in hospitals. It was found that for practical reasons use is currently restricted. The future prospects for food irradiated at non-sterilized doses are also considered. It is concluded that as well as providing greater choice for consumers (high risk and the general public as a whole) irradiated foods could extend and improved the diets of immuno-suppressed hospital patients; this could be an important factor in recovery. (author)

Cost/efficacy analysis of preferred Spanish AIDS study group regimens and the dual therapy with lopinavir/ritonavir plus lamivudine for initial ART in HIV infected adults.

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Gatell Artigas, Josep María; Arribas López, José Ramón; Lázaro Y de Mercado, Pablo; Blasco Bravo, Antonio Javier

2016-01-01

The National AIDS Plan and the Spanish AIDS study group (GESIDA) proposes "preferred regimens" (PR) of antiretroviral treatment (ART) as initial therapy in HIV-infected patients. In 2013, the recommended regimens were all triple therapy regimens. The Gardel Study assessed the efficacy of a dual therapy (DT) combination of lopinavir/ritonavir (LPV/r) plus lamivudine (3TC). Our objective is to evaluate the GESIDA PR and the DT regimen LPV/r+3TC cost/efficacy ratios. Decision tree models were built. probability of having viral load cost: costs of ART, adverse effects, and drug resistance tests during the first 48 weeks. Cost/efficacy ratios varied between 5,817 and 13,930 euros per responder at 48 weeks, for the DT of LPV/r+3TC and tenofovir DF/emtricitabine+raltegravir, respectively. Taking into account the official Spanish prices of ART, the most efficient regimen was DT of LPV/r+3TC, followed by the triple therapy with non-nucleoside containing regimens. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Immunosuppressive Effect of Litsea cubeba L. Essential Oil on Dendritic Cell and Contact Hypersensitivity Responses

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Hsin-Chun Chen

2016-08-01

Full Text Available Litsea cubeba L., also named as Makauy, is a traditional herb and has been used as cooking condiment or tea brewing to treat diseases for aborigines. The present study was undertaken to explore the chemical compositions of the fruit essential oil of L. cubeba (LCEO and the immunomodulatory effect of LCEO on dendritic cells and mice. The LCEO was analyzed using gas chromatography (GC and gas chromatography/mass spectrometry (GC/MS with direct injection (DI/GC or headspace-solid phase microextraction (HS-SPME/GC. In total, 56 components were identified, of which 48 were detected by DI/GC and 49 were detected by HS-SPME/GC. The principal compounds were citral (neral and geranial. An immunosuppressive activity of LCEO was investigated with bone marrow-derived dendritic cells (DCs which have a critical role to trigger the adaptive immunity. Additionally, the inhibitory effect of LCEO on immune response was elucidated by performing the contact hypersensitivity (CHS responses in mice. Our results clearly showed that LCEO decreases the production of TNF-α and cytokine IL-12 in a dose-dependent manner in lipopolysaccharide (LPS-stimulated DCs. CHS response and the infiltrative T cells were inhibited in the tested ears of the mice co-treated with LCEO. We demonstrate, for the first time, that the LCEO mainly containing citral exhibits an immunosuppressive effect on DCs and mice, indicating that LCEO can potentially be applied in the treatment of CHS, inflammatory diseases, and autoimmune diseases.

Cell-mediated immune response to Leishmania chagasi experimental infection of BALB/c immunosuppressed mice

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JG Machado

2010-01-01

Full Text Available Leishmaniasis, a zoonosis of worldwide distribution, presents a significant impact on immunosupressed patients. This study aimed to evaluate Leishmania chagasi infection in BALB/c mice immunosuppressed with dexamethasone. Spleen cells stimulated or not with L. chagasi were cultured for cytokine quantification (IFN-γ, IL-2, IL-4 and IL-10 by sandwich ELISA. Parasite loads in the spleen and liver were determined by means of culture microtitration. Immunosuppressed groups showed statistically lower spleen weight and CD4-cell percentage in blood on the day of infection and produced Th1 and Th2 cytokines on other days of the study. The other infected groups, weather immunosupressed or not, also produced Th1 and Th2 cytokines. Parasite loads in the spleen and liver were not statistically different among the groups. It was concluded that L. chagasi infection was not affected by dexamethasone-induced immunosuppression, probably due the reversible effect of the treatment.

Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients

DEFF Research Database (Denmark)

Penninga, Luit; Penninga, Ida Elisabeth Irene; Møller, Christian H

2013-01-01

Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without...

Pathway-based analysis of a melanoma genome-wide association study: analysis of genes related to tumour-immunosuppression.

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Nils Schoof

Full Text Available Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs in 43 genes (39 genomic regions related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (p(emp=0.002, as well as the subgroups related to the generation of tolerogenic dendritic cells (p(emp=0.006 and secretion of suppressive factors (p(emp=0.0004, thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges.

Serial assessment by optical coherence tomography of early and late vascular responses after implantation of an absorbable-coating Sirolimus-Eluting stent (from the first-in-human DESSOLVE I trial).

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Attizzani, Guilherme F; Bezerra, Hiram G; Ormiston, John; Wang, Wei; Donohoe, Dennis; Wijns, William; Costa, Marco A

2013-11-15

The initial enthusiasm caused by the potent antirestenotic effect of early generation drug-eluting stents was recently plagued by concerns regarding their safety profile. Investigators worldwide were stimulated, therefore, to seek for improvement in drug-eluting stent technology, such as eliminating their permanent polymer blamed for vascular inflammation and delayed healing. Optical coherence tomography (OCT) assessments of stent-vessel interactions are used as a surrogate for vessel healing after DES implantation. Herewith, we report serial OCT assessments of vascular reactions to the implantation of a novel absorbable polymer sirolimus-eluting stent (MiStent). In total, 30 patients were included. At 4-, 6-, and 8-month follow-up, different groups of 10 patients underwent OCT imaging, whereas all the patients had OCT assessments scheduled at 18-month follow-up. A total of 13,569 stent struts were analyzed. Low rates of uncovered (14.34 ± 15.35%, 6.62 ± 10.93%, 3.51 ± 2.87%, and 0.84 ± 1.15%, respectively, p stent struts coupled with thin and increasingly homogenous neointimal proliferation were demonstrated. Neointimal area increased from 4- to 8-month follow-up (0.46 ± 0.29 and 1.12 ± 0.73 mm(2), respectively, p stent struts (8.8%, 3.1%, 0.3%, and 0%, respectively, p absorbable polymer sirolimus-eluting stent-vessel interactions up to 18-month follow-up. Copyright © 2013 Elsevier Inc. All rights reserved.

Open-label observational study to assess the efficacy and safety of aprepitant for chemotherapy-induced nausea and vomiting prophylaxis in Indian patients receiving chemotherapy with highly emetogenic chemotherapy/moderately emetogenic chemotherapy regimens

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Hingmire Sachin

2015-01-01

Full Text Available Context: Currently, there is limited data on the prevention of chemotherapy-induced nausea and vomiting (CINV in Indian population with aprepitant containing regimens. Aims: The aim was to assess the Efficacy and Safety of Aprepitant for the prevention of nausea and vomiting associated with highly emetogenic chemotherapy/moderately emetogenic chemotherapy (HEC/MEC regimens. Settings and Design: Investigator initiated, multicentric, open-label, prospective, noncomparative, observational trial. Subjects and Methods: Triple drug regimen with aprepitant, palonosetron, and dexamethasaone administration was assessed for the prevention of CINV during acute, delayed, and the overall phase (OP for HEC/MEC Regimens. The primary endpoint was complete response (CR; no emesis and no use of rescue medication and the key secondary endpoint was the complete control (CC; no emesis, no rescue medication and no more than mild nausea during the OP. Statistical Analysis Used: Perprotocol efficacy was analyzed for the first cycle with results represented in terms of CR/CC rates using descriptive statistics. Results: Seventy-five patients were included in the study with median age of 49.7 years and 89.7% being females. The CR rate (OP for patients administered HEC or MEC regimens during the first cycle were 92% and 90.9%, respectively. Similarly, the CC rates (OP were 75% and 90% for these regimens, respectively. 7 (9.2% patients reported adverse drug reactions that were mild and transient with no reports of any serious adverse events. Conclusions: Use of aprepitant containing regimen for patients receiving HEC/MEC regimen resulted in significantly high CR and CC response rates, which further consolidate its potential role to improve patient quality of life and compliance to disease management.

Population-based evaluation of the effectiveness of two regimens for emergency contraception.

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Leung, Vivian W Y; Soon, Judith A; Lynd, Larry D; Marra, Carlo A; Levine, Marc

2016-06-01

To estimate and compare the effectiveness of the levonorgestrel and Yuzpe regimens for hormonal emergency contraception in routine clinical practice. A retrospective population-based study included women who accessed emergency contraceptives for immediate use prescribed by community pharmacists in British Columbia, Canada, between December 2000 and December 2002. Linked administrative healthcare data were used to discern the timings of menses, unprotected intercourse, and any pregnancy-related health services. A panel of experts evaluated the compatibility of observed pregnancies with the timing of events. The two regimens were compared with statistical adjustments for potential confounding. Among 7493 women in the cohort, 4470 (59.7%) received levonorgestrel and 3023 (40.3%) the Yuzpe regimen. There were 99 (2.2%) compatible pregnancies in the levonorgestrel group and 94 (3.1%) in the Yuzpe group (P=0.017). The estimated odds ratio for levonorgestrel compared with the Yuzpe regimen after adjusting for potential confounders was 0.64 (95% confidence interval 0.47-0.87). Against an expected pregnancy rate of approximately 5%, the relative and absolute risk reductions were 56.0% and 2.8%, respectively, for levonorgestrel and 36.7% and 1.8% for the Yuzpe regimen. The levonorgestrel regimen is more effective than the Yuzpe regimen in routine use. The data suggest that both regimens are less effective than has been observed in randomized trials. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Improvement of Radiation-Mediated Immunosuppression of Human NSCLC Tumour Xenografts in a Nude Rat Model

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Sergey V. Tokalov

2010-01-01

Full Text Available Human tumour xenografts in a nude rat model have consistently been used as an essential part of preclinical studies for anticancer drugs activity in human. Commonly, these animals receive whole body irradiation to assure immunosuppression. But whole body dose delivery might be inhomogeneous and the resulting incomplete bone marrow depletion may modify tumour behaviour. To improve irradiation-mediated immunosuppression of human non-small cell lung cancer (NSCLC xenografts in a nude rat model irradiation (2 + 2 Gy from opposite sides of animals has been performed using a conventional X-ray tube. The described modification of whole body irradiation improves growth properties of human NSCLC xenografts in a nude rat model. The design of the whole body irradiation mediated immunosuppression described here for NSCLC xenografts may be useful for research applications involving other types of human tumours.

Fractionated total lymphoid irradiation as preparative immunosuppression in high risk renal transplantation

International Nuclear Information System (INIS)

Najarian, J.S.; Ferguson, R.M.; Sutherland, D.E.; Slavin, S.; Kim, T.; Kersey, J.; Simmons, R.L.

1982-01-01

Twenty-two patients at high risk to reject renal allografts have been treated with fractionated total lymphoid irradiation (FTLI) prior to transplantation of primary (2), secondary (16) or tertiary (4) renal allografts. All patients undergoing retransplantation had rapidly rejected previous grafts. At 24 months following transplantation, 72% of grafts were functioning in the TLI group compared with a 38% graft function in an historical control group of recipients receiving secondary or tertiary grafts and treated with conventional immunosuppression. Important variables in determining success of transplantation following fractionated TLI include the dose of TLI, the interval from radiation to transplantation, and maintenance post-transplant immunosuppressive therapy. Optimal results were achieved with 2500 rads delivered in 100 rad fractions followed by transplantation within two weeks, and a tapering prednisone schedule and maintenance azathioprine post-transplantation. Seventeen patients had significant complications of the radiation treatment and there was one death, prior to transplantation, associated with pneumonitis. In vitro assessment of immune function demonstrated marked peripheral T cell depletion and loss of in vitro responsiveness to mitogen and allogeneic stimulation following FTLI. The administration of donor bone marrow at the time of transplantation did not produce chimerism. The results suggest that when properly utilized FTLI can produce effective adjunctive immunosuppression for clinical transplantation

Long-term Outcomes of Paclitaxel-Eluting Versus Sirolimus-Eluting Stent for Percutaneous Coronary Intervention: A Meta-Analysis

International Nuclear Information System (INIS)

Kong, J.; Liu, P.; Fan, X.; Wen, J.; Zhang, J.; Zhen, Y.; Li, J.; Cui, Y.; Zheng, X.; Ye, Z.

2017-01-01

The relative long-term efficacy and safety of sirolimus-eluting stents (SES) compared with paclitaxel-eluting stents (PES) in multiple comparative studies remains controversial. This report evaluates 29 randomized trials with 18,379 patients in whom long-term (more than 1 year) outcomes were evaluated. The primary outcomes were target lesion revascularization (TLR) and the secondary end points were death, cardiac death, myocardial infarction (MI), major adverse cardiac events (MACEs), target vessel revascularization (TVR)and stent thrombosis (ST). In comparison with PES, SES significantly reduced the long-term risk of TLR (RR=0.68; 95% CI=0.57 to 0.80, p<0.001), TVR (RR=0.69; 95% CI= 0.60 to 0.79, p<0.001) and MACE (RR=0.82; 95% CI= 0.77 to 0.88, p<0.001), while there were no significant difference with respect to death, cardiac death, MI and ST between the two groups. SES performance was significantly better for reducing the former three outcomes and comparable for the majority of the secondary end points when compared against PES. (author)

Cervical HPV prevalence and genotype distribution in immunosuppressed Danish women

DEFF Research Database (Denmark)

Roensbo, Mette T; Blaakær, Jan; Skov, Karin

2018-01-01

INTRODUCTION: Women receiving immunosuppressive treatment due to organ transplantation are at increased risk of Human papilloma virus (HPV)-related diseases, including cervical neoplasia. This pilot study aimed to describe the cervical HPV prevalence and genotype distribution in immunosuppressed...... in 2014 had three cervical cytologies performed; one before and two after transplantation. The samples were examined for cytological abnormalities and tested for HPV using Cobas(®) HPV Test and CLART(®) HPV2 Test. RESULTS: Of 94 eligible cases we included 60 RTR and BMTR. The overall prevalence of high......-risk HPV was 15.0 (95% CI; 7.1-26.6) and the prevalence was higher among BMTR (29.4, CI; 10.3-56.0) than in RTR (9.3%, CI; 2.6-22.1) although this was not statistically significant (p=0.10). The distribution of high-risk HPV was broad with HPV 45 as the most common genotype (3.3%). The prevalences of high...

Incidence of herpes zoster amongst adults varies by severity of immunosuppression.

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Schröder, Carsten; Enders, Dirk; Schink, Tania; Riedel, Oliver

2017-09-01

We examined the incidence of herpes zoster in immunocompromised adults (≥18 years) with different severities of immunosuppression and assessed the prevalence of complications and of various kinds of healthcare resource utilisation. German claims data from more than ten million adults were used to calculate annual incidence rates of herpes zoster for the years 2006-2012 and to analyse the prevalence of complications, physician visits, hospitalisations, and antiviral and analgesic treatments using a cohort design. The analyses were stratified by age, sex, and severity of immunosuppression, defined by immunocompromising conditions and drug therapies. The incidence rate per 1000 person-years of herpes zoster was almost twice as high in immunocompromised patients (11.5 (95% confidence interval (CI): 11.4-11.6)) compared to immunocompetent subjects (5.9 (95% CI: 5.8-5.9)). The incidence rate was higher in highly immunocompromised patients (13.4 (95% CI: 13.2-13.6)) than in patients with a low severity of immunosuppression (10.0 (95% CI: 9.8-10.1)). These differences were observed for both sexes and in all age groups. Complications, outpatient physician visits, hospitalisations, and analgesic treatments occurred more frequently in immunocompromised patients as well. Our results show that immunocompromised individuals are affected by the disease in particular and that the burden of herpes zoster is highest in severely immunocompromised patients. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?

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Passweg, Jakob R.; Tichelli, André

2009-01-01

The combination of antithymocyte globulin of horse origin and cyclosporine A is the standard treatment for aplastic anemia in patients not eligible for bone marrow transplantation. In this perspective article, Drs. Passweg and Tichelli discuss the current immunosuppressive therapy of aplastic anemia. See related article on page 348.

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study

OpenAIRE

Marsicano, Elisa Oliveira; Fernandes, Neimar Silva; Colugnati, Fernando Ant?nio Basile; Fernandes, Natalia Maria Silva; De Geest, Sabina; Sanders-Pinheiro, Helady

2015-01-01

Background Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system. Methods Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adher...

Comparison of the Absorbable Polymer Sirolimus-Eluting Stent (MiStent) to the Durable Polymer Everolimus-Eluting Stent (Xience) (from the DESSOLVE I/II and ISAR-TEST-4 Studies).

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Lansky, Alexandra J; Kastrati, Adnan; Edelman, Elazer R; Parise, Helen; Ng, Vivian G; Ormiston, John; Wijns, William; Byrne, Robert A

2016-02-15

We compared the outcomes of a novel, thin-strut, cobalt-chromium, absorbable, polymer sirolimus-eluting stent (APSES; MiStent) to the durable polymer cobalt-chromium everolimus-eluting stent (EES; Xience). A propensity-matched analysis was performed comparing data from the DES With Sirolimus and a Bioabsorbable Polymer for the Treatment of Patients With De Novo Lesions in the Native Coronary Arteries (DESSOLVE) I and II studies, evaluating the APSES to the EES arm of the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4 study. Target lesion failure (TLF) and its components were evaluated at 12 months and annually to 3 years; 805 patients (APSES = 153; EES = 652) were included with propensity matching in 204 patients (APSES = 102; EES = 102). APSES compared with EES had lower TLF at 1 year (3.0% vs 8.0%, p = 0.12) driven by a difference in target lesion revascularization (TLR; 1% vs 6%, p = 0.05), with no difference in target vessel myocardial infarction (p = 0.56) or stent thrombosis (p = 0.31). At 3 years, TLF (5.0% vs 12.5%, p = 0.07) and TLR (2.0% vs 8.4%, p = 0.04) remained lower with APSES. By landmark analysis, there was no significant difference in TLF between 1 and 3 years (p = 0.36). In conclusion, in a propensity-matched analysis, the APSES demonstrated reduced clinically indicated TLR rates at 1 and 3 years compared with the durable polymer EES, with minimal accrual of events between 1 and 3 years. Copyright © 2016 Elsevier Inc. All rights reserved.

Dietary regimens of athletes competing at the Delhi 2010 Commonwealth Games.

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Pelly, Fiona E; Burkhart, Sarah J

2014-02-01

The aim of this study was to investigate the dietary regimens reported by athletes competing at a major international competition and report whether these were based on nutrient composition, religious beliefs, cultural eating style, food intolerance or avoidance of certain ingredients. A questionnaire was randomly distributed to 351 athletes in the main dining hall of the athletes' village over the three main meal periods during the Delhi 2010 Commonwealth Games (23rd Sept-14th Oct, 2010). The majority (n = 218, 62%) of athletes reported following one or more dietary regimens, with 50% (n = 174) following a diet based on the nutrient composition of the food. Significantly more athletes from weight category and aesthetic sports (28%, p = .005) and from power/sprint sports (41%, p = .004) followed low fat and high protein regimens respectively. Other specialized dietary regimens were followed by 33% of participants, with avoidance of red meat (13%), vegetarian (7%), Halal (6%), and low lactose regimens (5%) reported most frequently. Significantly more athletes from non-Western regions followed a vegetarian diet (p food items are available at similar events.

The peripheral NK cell repertoire after kidney transplantation is modulated by different immunosuppressive drugs

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Christine eNeudoerfl

2013-02-01

Full Text Available In the context of kidney transplantation, little is known about the involvement of NK cells in the immune reaction leading to either rejection or immunological tolerance under immunosuppression. Therefore, the peripheral NK cell repertoire of patients after kidney transplantation was investigated in order to identify NK cell subsets that may be associated with the individual immune status at the time of their protocol biopsies for histopathological evaluation of the graft. Alterations in the peripheral NK cell repertoire could be correlated to the type of immunosuppression, i.e. calcineurin-inhibitors like CyclosporinA vs. Tacrolimus with or without addition of mTOR inhibitors. Here, we could demonstrate that the NK cell repertoire in peripheral blood of kidney transplant patients differs significantly from healthy individuals. The presence of donor-specific antibodies was associated with reduced numbers of CD56dim NK cells. Moreover, in patients, down-modulation of CD16 and CD6 on CD56dim NK cells was observed with significant differences between CyclosporinA- and Tac-treated patients. Tac-treatment was associated with decreased CD69, HLA-DR and increased CD94/NKG2A expression in CD56dim NK cells indicating that the quality of the immunosuppressive treatment impinges on the peripheral NK cell repertoire. In vitro studies with PBMC of healthy donors showed that this modulation of CD16, CD6, CD69, and HLA-DR could also be induced experimentally. The presence of calcineurin or mTOR inhibitors had also functional consequences regarding degranulation and IFN--production against K562 target cells, respectively. In summary, we postulate that the NK cell composition in peripheral blood of kidney transplanted patients represents an important hallmark of the efficacy of immunosuppression and may be even informative for the immune status after transplantation in terms of rejection vs. drug-induced allograft tolerance. Thus,NK cells can serve as sensors

Efficacy and safety of weight-based insulin glargine dose titration regimen compared with glucose level- and current dose-based regimens in hospitalized patients with type 2 diabetes: a randomized, controlled study.

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Li, Xiaowei; Du, Tao; Li, Wangen; Zhang, Tong; Liu, Haiyan; Xiong, Yifeng

2014-09-01

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens. A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ(2) test were used to compare data between the 3 groups. All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence

The Sex Res Non Naturales and the Regimen of Health

DEFF Research Database (Denmark)

Agerholm, Frank Juul

The paper discusses the ethical and social soundness of the classical idea of diaita/regimen vis-à-vis the contemporary focus on healthy lifestyle......The paper discusses the ethical and social soundness of the classical idea of diaita/regimen vis-à-vis the contemporary focus on healthy lifestyle...

Relationship between person's health beliefs and diabetes self-care management regimen.

Science.gov (United States)

Albargawi, Moudi; Snethen, Julia; Al Gannass, Abdulaziz; Kelber, Sheryl

2017-12-01

To examine the relationship between the health beliefs of Saudi adults with type 2 diabetes mellitus (T2DM) and their adherence to daily diabetes self-care management regimen. A secondary aim was to examine the health beliefs of adults with a diabetic foot ulcer (DFU) and participants without a DFU. Descriptive correlational design with a convenience sample of 30 participants. Participants were recruited for this pilot study from an outpatient clinic at King Abdulaziz Medical City in Riyadh. The participants completed self-reported questionnaires about their health beliefs, daily diabetes self-care management regimen, and demographic characteristics. Hierarchical multiple regression analysis was used to test the interaction effects. Participants who reported having a high internal health locus of control (IHLoC) and a high level of self-efficacy (SE) adhered well to their foot care regimen (P = .038). The more the participants believed that God controls their health, and the higher their SE, the greater the participant's adherence to their medication regimen (P = .035). The stronger the participant's belief that following their diabetes treatment regimen will lead to good outcomes, the greater the participant's adherence to their dietary regimen for those with a low IHLoC (P = .015). Participants with a high SE and reported that their doctor is able to help them control their diabetes were more likely to follow their dietary regimen (P = .048). Participants with a DFU reported having additional health conditions besides T2DM (P = .018) and had less than a college education (P = .015). Although participants with a DFU reported that they were responsible for their diabetes (P = .21), they stated that God manages their diabetes (P = .29), and the disease can be controlled based on luck (P = .10). Participants' beliefs were found to influence their daily self-care management regimen. Further studies are needed using a larger sample. Copyright © 2017

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

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Gianluigi Zaza

2013-01-01

Full Text Available The mammalian target of rapamycin inhibitors (mTOR-I, sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR, a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

Effect of β-3-Thienylalanine on Antibody Synthesis V. Immunosuppression in Mice by Short Diet and Drug Treatments

Science.gov (United States)

Misefari, Aldo; La Via, Mariano F.

1971-01-01

The analogue of phenylalanine, β-3-thienylalanine, depresses severely the primary and secondary immune response to sheep erythrocytes in mice when administered for a few days immediately before and after each injection of antigen. For this immunosuppression to occur, animals must be maintained on a phenylalanine-free diet during the times of drug injection since dietary phenylalanine will restore anamnestic response. With these experimental conditions, the number of direct and indirect plaque-forming cells is greatly reduced during immune responses. The finding that marked immunosuppression can be obtained with a very short drug and diet treatment points to a potential usefullness of the analogue as a powerful immunosuppressant. PMID:5154884

[Treatment with immunosuppressive and biologic drugs of pregnant women with systemic rheumatic or autoimmune disease].

Science.gov (United States)

Alijotas-Reig, Jaume; Esteve-Valverde, Enrique; Ferrer-Oliveras, Raquel

2016-10-21

Rheumatic and systemic autoimmune diseases occur in women and, to a lesser degree, men of reproductive age. These disorders have to be clinically nonactive before conception, which is usually only possible after anti-inflammatory and immunosuppressive treatment. We must be alert since 50% of pregnancies are unplanned. Physicians should know the embryo-foetal toxicity of these drugs during pregnancy and lactation. This January 2016-updated review allows us to conclude that the majority of immunosuppressives available -anti-TNF inhibitors included- can be used before and during pregnancy, with the exception of cyclophosphamide, methotrexate, mycophenolate and leflunomide. Lactation is permitted with all drugs except methotrexate, leflunomide, mycophenolate and cyclophosphamide. Although data on abatacept, belimumab, rituximab, tocilizumab and anakinra are scant, preliminary reports agree on their safety during pregnancy and, probably, lactation. Cyclophosphamide and sulfasalazine apart, no negative effects on sperm quality, or embryo-foetal anomalies in men treated with immunosuppressives have been described. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Immunosuppression following radiation therapy for carcinoma of the nasopharynx

International Nuclear Information System (INIS)

Wara, W.M.; Phillips, T.L.; Wara, D.W.; Ammann, A.J.; Smith, V.

1975-01-01

Eleven patients treated for nasopharyngeal carcinoma with standard radiation therapy were found to have depressed cell mediated immunity. Post-treatment their total lymphocyte count was decreased by 60 percent. Eight of 11 patients had depressed T-cell rosettes, and 9 of 10 had abnormal lymphocyte response to PHA. Immunosuppression was probably related to irradiation of large blood volumes, irradiation of the thymus, and malnutrition. (U.S.)

Fungemia Due to Fusarium sacchari in an Immunosuppressed Patient

Science.gov (United States)

Guarro, Josep; Nucci, Marcio; Akiti, Tiyomi; Gené, Josepa; Barreiro, M. Da Gloria C.; Gonçalves, Renato T.

2000-01-01

The fungus Fusarium sacchari was isolated repeatedly from the blood of an immunosuppressed host. The infection was treated successfully with a small dose of amphotericin B. The strain was resistant to this antifungal in vitro. MICs and minimum fungicidal concentrations of six antifungals for the clinical isolate are provided. To our knowledge, this is the first report involving this fungus in a case of fungemia. PMID:10618130

IL-10 is an effector molecule mediating urocanic acid-induced immunosuppression

Czech Academy of Sciences Publication Activity Database

Krulová, Magdalena; Kuffová, Lucia; Zajícová, Alena; Filipec, M.; Holáň, Vladimír

1999-01-01

Roč. 31, - (1999), s. 1218-1219 ISSN 0041-1345 R&D Projects: GA MZd IZ3964; GA ČR GA310/97/1261; GA MŠk VS97099 Keywords : immunosuppression, urocanic acid Subject RIV: EC - Immunology Impact factor: 0.590, year: 1999

Nine-month Angiographic and Two-year Clinical Follow-up of Novel Biodegradable-polymer Arsenic Trioxide-eluting Stent Versus Durable-polymer Sirolimus-eluting Stent For Coronary Artery Disease

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Li Shen

2015-01-01

Full Text Available Background: Despite great reduction of in-stent restenosis, first-generation drug-eluting stents (DESs have increased the risk of late stent thrombosis due to delayed endothelialization. Arsenic trioxide, a natural substance that could inhibit cell proliferation and induce cell apoptosis, seems to be a promising surrogate of sirolimus to improve DES performance. This randomized controlled trial was to evaluate the efficacy and safety of a novel arsenic trioxide-eluting stent (AES, compared with traditional sirolimus-eluting stent (SES. Methods: Patients with symptoms of angina pectoris were enrolled and randomized to AES or SES group. The primary endpoint was target vessel failure (TVF, and the second endpoint includes rates of all-cause death, cardiac death or myocardial infarction, target lesion revascularization (TLR by telephone visit and late luminal loss (LLL at 9-month by angiographic follow-up. Results: From July 2007 to 2009, 212 patients were enrolled and randomized 1:1 to receive either AES or SES. At 2 years of follow-up, TVF rate was similar between AES and SES group (6.67% vs. 5.83%, P = 0.980. Frequency of all-cause death was significantly lower in AES group (0 vs. 4.85%, P = 0.028. There was no significant difference between AES and SES in frequency of TLR and in-stent restenosis, but greater in-stent LLL was observed for AES group (0.29 ± 0.52 mm vs. 0.10 ± 0.25 mm, P = 0.008. Conclusions: After 2 years of follow-up, AES demonstrated comparable efficacy and safety to SES for the treatment of de novo coronary artery lesions.

Immunosuppressive sesquiterpenes from Buddleja daviddi.

Science.gov (United States)

Zhang, Wen; Yao, Zhi; Zhang, Yan Wen; Zhang, Xing Xiang; Takaishi, Yoshihisa; Duan, Hong Quan

2010-11-01

Six new sesquiterpenes, 2,6(12),10-humulatrien-7β-ol-1-one (1), 2 α-acetoxy-5α-methoxy-enantio-caryophylla-8(15)-en-3-one (2), 2α-acetoxy-5α-hydroxy-enantio-caryophylla-8(15)-en-3-one (3), 2α-acetoxy-4β,5α-hydroxy-enantio-caryophylla-8(15)-en-3-one ( 4), 2α-acetoxy-4β,5β-hydroxy-enantio-caryophylla-8(15)-en-3-one (5), 2β-acetoxy-4-caryophyllen-8β-ol-3-one (6), and nineteen known compounds were isolated from the ethanol extract of Buddleja daviddi. The structures were elucidated by spectroscopic methods. Compounds 8-11, 14, 16, 17, and 20 showed significant immunosuppressive activities, and 8-11 and 14 were cytotoxic on HeLa and L929 cell lines. © Georg Thieme Verlag KG Stuttgart · New York.

Eruptive furunculosis following the soak and smear regimen.

Science.gov (United States)

Martires, Kathryn; Sukhdeo, Kumar; Meinhardt, Eric

2015-02-18

The 'soak and smear' regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA)-positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community. 2015 BMJ Publishing Group Ltd.

Low-dose-rate total lymphoid irradiation: a new method of rapid immunosuppression

International Nuclear Information System (INIS)

Blum, J.E.; de Silva, S.M.; Rachman, D.B.; Order, S.E.

1988-01-01

Total Lymphoid Irradiation (TLI) has been successful in inducing immunosuppression in experimental and clinical applications. However, both the experimental and clinical utility of TLI are hampered by the prolonged treatment courses required (23 days in rats and 30-60 days in humans). Low-dose-rate TLI has the potential of reducing overall treatment time while achieving comparable immunosuppression. This study examines the immunosuppressive activity and treatment toxicity of conventional-dose-rate (23 days) vs low-dose-rate (2-7 days) TLI. Seven groups of Lewis rats were given TLI with 60Co. One group was treated at conventional-dose-rates (80-110 cGy/min) and received 3400 cGy in 17 fractions over 23 days. Six groups were treated at low-dose-rate (7 cGy/min) and received total doses of 800, 1200, 1800, 2400, 3000, and 3400 cGy over 2-7 days. Rats treated at conventional-dose-rates over 23 days and at low-dose-rate over 2-7 days tolerated radiation with minimal toxicity. The level of immunosuppression was tested using allogeneic (Brown-Norway) skin graft survival. Control animals retained allogeneic skin grafts for a mean of 14 days (range 8-21 days). Conventional-dose-rate treated animals (3400 cGy in 23 days) kept their grafts 60 days (range 50-66 days) (p less than .001). Low-dose-rate treated rats (800 to 3400 cGy total dose over 2-7 days) also had prolongation of allogeneic graft survival times following TLI with a dose-response curve established. The graft survival time for the 3400 cGy low-dose-rate group (66 days, range 52-78 days) was not significantly different from the 3400 cGy conventional-dose-rate group (p less than 0.10). When the total dose given was equivalent, low-dose-rate TLI demonstrated an advantage of reduced overall treatment time compared to conventional-dose-rate TLI (7 days vs. 23 days) with no increase in toxicity

Immunosuppressive therapy in patients with aplastic anemia: a single-center retrospective study.

Directory of Open Access Journals (Sweden)

Hasan Jalaeikhoo

Full Text Available Aplastic anemia (AA is a rare disease in which hematopoietic stem cells are severely diminished resulting in hypocellular bone marrow and pancytopenia. Etiology of AA includes auto immunity, toxins, infection, ionizing radiation, drugs and rare genetic disorders, but in the majority of cases no cause can be identified. In the present study we assessed response rate, survival, relapse and clonal evolution in patients with AA treated with immunosuppressive therapy.Patients with AA who received immunosuppressive therapy between May 1998 and September 2013 were included in this study. Patients with non-severe AA (NSAA were treated with cyclosporine (CsA and danazol while patients with severe AA (SAA as well as patients with NSAA who progressed to SAA after beginning of the treatment, were candidates for receiving antithymocyte globulin in addition to CsA and danazol.Among the 63 studied patients, 29 (46% had NSAA and 34 (54% had SAA. Three months after treatment, overall response was 58.6% in NSAA and 12.9% in patients with SAA. Survival of all patients at 5, 10 and 15 years were 73%, 55% and 49%, respectively. Survival rates were significantly higher in patients with NSAA compared to patients with SAA as well as in patients who responded at 6 months compared to non-responders. The relapse risk was 39.7% at 10 years. Relapse occurred in patients who discontinued the therapy more than those who continued taking CsA (p value<0.01. The risk of clonal evolution was 9.9% at 10 years and 22.8% at 15 years after treatment.This long-term retrospective study indicated that immunosuppressive therapy should be recommended to patients with AA. Also, our experience indicated that immunosuppressive therapy should not be discontinued after response to therapy in patients with both NSAA and SAA due to high risk of relapse. Low dose of CsA should be continued indefinitely.

Geranylated flavonoids from the roots of Campylotropis hirtella and their immunosuppressive activities.

Science.gov (United States)

Shou, Qing-Yao; Fu, Run-Zhong; Tan, Qing; Shen, Zheng-Wu

2009-08-12

In an effort to identify new immunosuppressive agents from natural sources, 12 new geranylated flavonoids, 5,7,4'-trihydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavone (1), a racemate of 5,7,2',4'-tetrahydroxy-3'-[7-hydroxy-3,7-dimethyl-2(E)-octenyl]isoflavanone (2), 2''(S)-5,7-dihydroxy-[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (3), (2''S,3''R,4''S)-5,7,3'',4''-tetrahydroxy[2''-methyl-2''-(4-methyl-3-pentenyl)pyrano]-5'',6'':3',4'-isoflavone (4), a racemate of 3'-geranyl-5,7,2',4'-tetrahydroxyisoflavanone (5), a racemate of 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavanone (6), 3'-geranyl-5,7,4',5'-tetrahydroxyisoflavone (8), 3'-geranyl-5,7,2',5'-tetrahydroxyisoflavone (9), 3'-geranyl-4'-methoxy-5,7,2'-trihydroxyisoflavone (10), 2(R),3(R)-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (12), (2R,3R)-6-methyl-3'-geranyl-2,3-trans-5,7,4'-trihydroxyflavonol (13), and 5,7-dihydroxy-4'-O-geranylisoflavone (14), were isolated from the roots of Campylotropis hirtella (Franch.) Schindl. together with three previously described flavonoids. Their structures were elucidated by spectroscopic measurements, including two-dimensional nuclear magnetic resonance (NMR) techniques. The immunosuppressive effects of these compounds were assessed using mitogen-induced splenocyte proliferation, and the cytotoxicity of the compounds was also examined. The IC50 values of the compounds were found to be in the range of 1.49-61.23 microM for T lymphocyte suppression and 1.16-73.07 microM for B lymphocyte suppression. An analysis of their structure-activity relationships revealed that an isoflavonoid carbon skeleton with a C10 substituent at the C3' position was necessary for the activity. As many of the compounds exhibited good immunosuppressive activities, they may be promising as novel immunosuppressive agents.

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET.

Science.gov (United States)

Fouda, Usama M; Sayed, Ahmed M

2011-12-01

To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

Non-adherence to immunosuppressive medications in kidney transplantation: intent vs. forgetfulness and clinical markers of medication intake.

Science.gov (United States)

Griva, Konstadina; Davenport, Andrew; Harrison, Michael; Newman, Stanton P

2012-08-01

Although adherence to immunosupressive medication after transplantation is important to maximize good clinical outcomes it remains suboptimal and not well-understood. The purpose of this study was to examine intentional and unintentional non-adherence to immunosuppression medication in kidney transplant patients. A cross-sectional sample of N=218 patients [49.6 ± 12.3 years] recruited in London, UK (1999-2002) completed measures of medication beliefs, quality-of-life, depression, and transplantation-specific emotions. Adherence was measured with self-report and serial immunosuppressive assays. Intentional non-adherence was low (13.8 %) yet 62.4 % admitted unintentional non-adherence and 25.4 % had sub-target immunosuppressive levels. The risk of sub-target serum immunosuppressive levels was greater for patients admitting unintentional non-adherence (OR=8.4; p=0.004). Dialysis vintage, doubts about necessity, and lower worry about viability of graft explained R(2)=16.1 to 36 % of self-report non-adherence. Depression was related only to intentional non-adherence. Non-adherence is common in kidney transplantation. Efforts to increase adherence should be implemented by targeting necessity beliefs, monitoring depression, and promoting strategies to decrease forgetfulness.

Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression.

Science.gov (United States)

Aron Badin, R; Vadori, M; Vanhove, B; Nerriere-Daguin, V; Naveilhan, P; Neveu, I; Jan, C; Lévèque, X; Venturi, E; Mermillod, P; Van Camp, N; Dollé, F; Guillermier, M; Denaro, L; Manara, R; Citton, V; Simioni, P; Zampieri, P; D'avella, D; Rubello, D; Fante, F; Boldrin, M; De Benedictis, G M; Cavicchioli, L; Sgarabotto, D; Plebani, M; Stefani, A L; Brachet, P; Blancho, G; Soulillou, J P; Hantraye, P; Cozzi, E

2016-07-01

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

A targeted mutation within the feline leukemia virus (FeLV) envelope protein immunosuppressive domain to improve a canarypox virus-vectored FeLV vaccine.

Science.gov (United States)

Schlecht-Louf, Géraldine; Mangeney, Marianne; El-Garch, Hanane; Lacombe, Valérie; Poulet, Hervé; Heidmann, Thierry

2014-01-01

We previously delineated a highly conserved immunosuppressive (IS) domain within murine and primate retroviral envelope proteins that is critical for virus propagation in vivo. The envelope-mediated immunosuppression was assessed by the ability of the proteins, when expressed by allogeneic tumor cells normally rejected by engrafted mice, to allow these cells to escape, at least transiently, immune rejection. Using this approach, we identified key residues whose mutation (i) specifically abolishes immunosuppressive activity without affecting the "mechanical" function of the envelope protein and (ii) significantly enhances humoral and cellular immune responses elicited against the virus. The objective of this work was to study the immunosuppressive activity of the envelope protein (p15E) of feline leukemia virus (FeLV) and evaluate the effect of its abolition on the efficacy of a vaccine against FeLV. Here we demonstrate that the FeLV envelope protein is immunosuppressive in vivo and that this immunosuppressive activity can be "switched off" by targeted mutation of a specific amino acid. As a result of the introduction of the mutated envelope sequence into a previously well characterized canarypox virus-vectored vaccine (ALVAC-FeLV), the frequency of vaccine-induced FeLV-specific gamma interferon (IFN-γ)-producing cells was increased, whereas conversely, the frequency of vaccine-induced FeLV-specific interleukin-10 (IL-10)-producing cells was reduced. This shift in the IFN-γ/IL-10 response was associated with a higher efficacy of ALVAC-FeLV against FeLV infection. This study demonstrates that FeLV p15E is immunosuppressive in vivo, that the immunosuppressive domain of p15E can modulate the FeLV-specific immune response, and that the efficacy of FeLV vaccines can be enhanced by inhibiting the immunosuppressive activity of the IS domain through an appropriate mutation.

Simultaneous Hodgkin′s disease and kaposi sarcoma in a renal transplant recipient

Directory of Open Access Journals (Sweden)

Yaich S

2010-01-01

Full Text Available A 38-year-old women underwent first cadaver kidney transplantation. Her panel re-active antibody was 0%, and she had never previously been transfused nor pregnant. She received induction therapy with antithymoglobulin (ATG as standard protocol and maintained on immuno-suppressive treatment of cyclosporine A, mycophenolate mofetil (MMF, and prednisone. Nine months after transplantation, she presented with anorexia, asthenia and weight loss. Cutaneous Ka-posi′s sarcoma and a Hodgkin disease were diagnosed. MMF was discontinued and cyclosporin A was switched to sirolimus. She also received a poly-chemotherapy associated with 4 courses of rituximab. Twelve months later, the patient had normal graft function and both malignancies were in complete remission.

aPKC-ι/P-Sp1/Snail signaling induces epithelial-mesenchymal transition and immunosuppression in cholangiocarcinoma.

Science.gov (United States)

Qian, Yawei; Yao, Wei; Yang, Tao; Yang, Yan; Liu, Yan; Shen, Qi; Zhang, Jian; Qi, Weipeng; Wang, Jianming

2017-10-01

Cholangiocarcinoma (CCA) is a highly malignant bile duct cancer that tends to invade and metastasize early. The epithelial-mesenchymal transition (EMT) has been implicated in cancer cell invasion and metastasis, as well as in cancer cell evasion of host immunity. In this study, we investigated the interaction between atypical protein kinase C-iota (aPKC-ι) and Snail in the regulation of EMT and its relationship to CCA immunosuppression. Our results demonstrated that aPKC-ι, Snail, and infiltrated immunosuppressive cells were significantly up-regulated in CCA tumor tissues and linked to poor prognosis. aPKC-ι induced EMT and immunosuppression by regulating Snail in vitro and in vivo, although aPKC-ι did not directly interact with Snail in coimmunoprecipitation experiments. To further clarify the molecular interaction between aPKC-ι and Snail in relation to EMT, quantitative iTRAQ-based phosphoproteomic analysis and liquid chromatography-tandem mass spectrometry were conducted to identify the substrates of aPKC-ι-dependent phosphorylation. Combined with coimmunoprecipitation, we showed that specificity protein 1 (Sp1) was directly phosphorylated by aPKC-ι on Ser59 (P-Sp1). Both Sp1 and P-Sp1 were up-regulated in CCA tumor tissues and associated with clinicopathological features and poor prognosis in CCA patients. Moreover, using chromatin immunoprecipitation assays, we found that P-Sp1 regulated Snail expression by increasing Sp1 binding to the Snail promoter. P-Sp1 also regulated aPKC-ι/Snail-induced EMT-like changes and immunosuppression in CCA cells. Our findings further indicated that CCA cells with EMT-like features appear to generate immunosuppressive natural T regulatory-like cluster of differentiation 4-positive (CD4 + )CD25 - cells rather than to increase CD4 + CD25 + natural T regulatory cells, in part by mediating T regulatory-inducible cytokines such as transforming growth factor β1 and interleukin 2. These results demonstrate that a

Assessment of readiness for clinical decision support to aid laboratory monitoring of immunosuppressive care at U.S. liver transplant centers.

Science.gov (United States)

Jacobs, J; Weir, C; Evans, R S; Staes, C

2014-01-01

Following liver transplantation, patients require lifelong immunosuppressive care and monitoring. Computerized clinical decision support (CDS) has been shown to improve post-transplant immunosuppressive care processes and outcomes. The readiness of transplant information systems to implement computerized CDS to support post-transplant care is unknown. a) Describe the current clinical information system functionality and manual and automated processes for laboratory monitoring of immunosuppressive care, b) describe the use of guidelines that may be used to produce computable logic and the use of computerized alerts to support guideline adherence, and c) explore barriers to implementation of CDS in U.S. liver transplant centers. We developed a web-based survey using cognitive interviewing techniques. We surveyed 119 U.S. transplant programs that performed at least five liver transplantations per year during 2010-2012. Responses were summarized using descriptive analyses; barriers were identified using qualitative methods. Respondents from 80 programs (67% response rate) completed the survey. While 98% of programs reported having an electronic health record (EHR), all programs used paper-based manual processes to receive or track immunosuppressive laboratory results. Most programs (85%) reported that 30% or more of their patients used external laboratories for routine testing. Few programs (19%) received most external laboratory results as discrete data via electronic interfaces while most (80%) manually entered laboratory results into the EHR; less than half (42%) could integrate internal and external laboratory results. Nearly all programs had guidelines regarding pre-specified target ranges (92%) or testing schedules (97%) for managing immunosuppressive care. Few programs used computerized alerting to notify transplant coordinators of out-of-range (27%) or overdue laboratory results (20%). Use of EHRs is common, yet all liver transplant programs were largely

Dealing with large-scale supply lines when introducing new regimens.

Science.gov (United States)

Malati, Christine; Rosenfeld, Joshua; Mowafy, Sherif; Rittmiller, Trevor; Kuritsky, Joel; Crowley, John

2017-07-01

As programs plan the introduction of a new antiretroviral as part of a regimen for HIV treatment, supply chain considerations need to be taken into account. The key to success is balancing the introduction of a new regimen with the phasing out of an old regimen in a manner that does not result in either a shortage or an excess supply of either product while ensuring that patients continue receiving their medications. This necessitates that country programs, donors, and procurement entities possess an appreciation of the global antiretroviral market and understand the dynamics that the manufacturing of new antiretrovirals will have on the transition. Supply, demand, and financial considerations affect the capacity of the supply chain to facilitate a successful antiretroviral transition. Although this commentary draws on United States Agency for International Development experiences under the President's Emergency Plan for AIDS Relief from earlier antiretroviral treatment shifts, the approaches are applicable to other institutions and to future transitions. Three approaches were employed: ensuring the engagement of all key stakeholders in transition planning and execution, including clinicians, advocacy groups, supply chain professionals, ministry, and donors; conducting and updating regularly the national quantification and supply plans for all regimens; and introducing antiretroviral products into programs from regional warehouses based on firm orders. Extensive planning and accounting for supply chain factors is essential to ensuring a smooth transition to a new regimen and to enable the global antiretroviral market to respond adequately.

Fatal tick-borne encephalitis in an immunosuppressed 12-year-old patient

Czech Academy of Sciences Publication Activity Database

Chmelík, V.; Chrdle, A.; Růžek, Daniel

2016-01-01

Roč. 74, 1 January (2016), s. 73-74 ISSN 1386-6532 R&D Projects: GA ČR GAP502/11/2116 Institutional support: RVO:60077344 Keywords : Tick-borne encephalitis * immunosuppressed patient * fatal case * haemophagocytic lymphohistiocytosis Subject RIV: EE - Microbiology, Virology Impact factor: 3.051, year: 2016

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression.

Science.gov (United States)

Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-06-02

To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Retrospective multicenter study using the Swiss Pediatric Rheumatology registry. Children with rheumatic diseases followed in a Swiss center for pediatric rheumatology and treated with cDMARD and/or bDMARD with a clinical diagnosis of varicella or herpes zoster between January 2004 and December 2013 were included. Twenty-two patients were identified, of whom 20 were treated for juvenile idiopathic arthritis, 1 for a polyglandular autoimmune syndrome type III, and 1 for uveitis. Of these 22 patients, 16 had varicella and 6 had herpes zoster. Median age at VZV disease was 7.6 years (range 2 to 17 years), with 6.3 years (range 2 to 17 years) for those with varicella and 11.6 years (range 5 to 16 years) for those with herpes zoster. The median interval between start of immunosuppression and VZV disease was 14.1 months (range 1 to 63 months). Two patients had received varicella vaccine (1 dose each) prior to start of immunosuppression. Concomitant immunosuppressive therapy was methotrexate (MTX) monotherapy (n = 9) or bDMARD monotherapy (n = 2), or a combination of bDMARD with prednisone, MTX or Leflunomide (n = 11). Four patients experienced VZV related complications: cellulitis in 1 patient treated with MTX, and cellulitis, sepsis and cerebellitis in 3 patients treated with biological agents and MTX combination therapy. Six children were admitted to hospital (range of duration: 4 to 9 days) and 12 were treated with valaciclovir or aciclovir. The clinical course of varicella and herpes zoster in children under

Randomized comparison of a sirolimus-eluting Orsiro stent with a biolimus-eluting Nobori stent in patients treated with percutaneous coronary intervention

DEFF Research Database (Denmark)

Jensen, Lisette Okkels; Thayssen, Per; Maeng, Michael

2015-01-01

BACKGROUND: Third-generation coronary drug-eluting stents (DES) with biodegradable polymers have been designed to improve safety and efficacy. We designed a large scale registry-based randomized clinical trial to compare 2 third-generation DES: a thin strut, cobalt-chromium DES with silicon carbide......-coating releasing sirolimus from a biodegradable polymer (O-SES, Orsiro; Biotronik, Bülach, Switzerland) with the stainless steel biodegradable polymer biolimus-eluting Nobori stents (N-BES, Nobori; Terumo, Tokyo, Japan) in an all-comer patient population. DESIGN: The multicenter SORT OUT VII trial (NCT01879358...... will be used. An event rate of 6.5% is assumed in each stent group. With a sample size of 1,157 patients in each treatment arm, a 2-group large-sample normal approximation test of proportions with a 1-sided 5% significance level will have 90% power to detect noninferiority of the O-SES compared with the N...

Long-term outcome of intensive initial immunosuppression protocol in pediatric deceased donor renal transplantation.

LENUS (Irish Health Repository)

Olaitan, Oyedolamu K

2010-02-01

To report the long-term outcome of deceased donor kidney transplantation in children with emphasis on the use of an intensive initial immunosuppression protocol using R-ATG as antibody induction. Between January 1991 and December 1997, 82 deceased donor kidney transplantations were performed in 75 pediatric recipients. Mean recipient age at transplantation was 12.9 yr and the mean follow-up period was 12.6 yr. All patients received quadruple immunosuppression with steroid, cyclosporine, azathioprine, and antibody induction using R-ATG-Fresenius. Actual one, five, and 10 yr patient survival rates were 99%, 97%, and 94%, respectively; only one patient (1.2%) developed PTLD. Actual one, five, and 10 yr overall graft survival rates were 84%, 71%, and 50%, respectively; there were five cases (6%) of graft thrombosis and the actual immunological graft survival rates were 91%, 78%, and 63% at one, five, and 10 yr, respectively. The use of an intensive initial immunosuppression protocol with R-ATG as antibody induction is safe and effective in pediatric recipients of deceased donor kidneys with excellent immunological graft survival without an increase in PTLD or other neoplasms over a minimum 10-yr follow up.

Role of total body irradiation as based on the comparison of preparation regimens for allogeneic bone marrow transplantation for acute leukemia in first complete remission

International Nuclear Information System (INIS)

Inoue, T.; Ikeda, H.; Yamazaki, H.; Tang, J.T.; Song, C.; Teshima, T.; Murayama, S.; Ohtani, M.; Shibata, H.; Masaoka, T.

1993-01-01

The role of total body irradiation (TBI) for allogeneic bone marrow transplantation (BMT) for acute leukemia in first complete remission was reevaluated in this study. From Japanese BMT Registry, data of 123 acute leukemia patients in first complete remission who underwent allogeneic bone marrow transplantation in 22 hospitals between 1988 and 1990 were available for the present comparative study of preparation regimens with or without total body irradiation. Two-year survivals were 77% and 51% in the TBI containing regimen group and in the non-TBI regimen group, respectively (p=0.0010). Corresponding two-year relapse rates were 16% and 37%, respectively (p=0.0197). Corresponding probabilities of developing interstitial pneumonitis were 21% and 24%, respectively (p=0.8127). The analysis of causes of death indicated that non-TBI regimen increased the incidence of septicemia and lethal organ failures, such as liver, heart, lung and other multiple sites. It was emphasized that an additional role of total body irradiation was to disperse the treatment-related toxicity in allogeneic bone marrow transplantation for acute leukemia. (orig.) [de

Immunosuppressive therapy in non-infections uveitis and retinovasculitis

OpenAIRE

E. A. Drozdova

2012-01-01

Purpose: to evaluate the efficacy and safety of the immunosuppressive therapy for severe forms of non-infections uveitis and retinovasculitis.Methods: 107 patients (62 males and 45 females aged 9 to 54 years) who received low dose methotrexate — 7.5-20 mg once a week (n=79) cyclosporine A 3.5-5.0 mg/kg/d (n=21) with prednisone or other antimetabolites and local corticosteroid therapy for severe forms of inflammatory eye diseases.Results: the efficacy of methotrexate as monotherapy was 51.8% o...

Effect of iron containing supplements on rats' dental caries progression.

Science.gov (United States)

Eshghi, Ar; Kowsari-Isfahan, R; Rezaiefar, M; Razavi, M; Zeighami, S

2012-01-01

Iron deficiency is the most common form of malnutrition in developing countries. Iron containing supplements have been used effectively to solve this problem. In children, because of teeth staining after taking iron drops, parents have the idea that iron drops are the cause of tooth decay; therefore, they limit this vital supplement in their children's diet. Hereby, we evaluate the histologic effect of iron containing supplements on tooth caries in rice rats with cariogenic or non-cariogenic diet. Twelve rats were selected and divided into four groups for this interventional experimental study. Four different types of dietary regimens were used for four months; group A, cariogenic diet with iron containing supplements; group B, cariogenic diet without iron containing supplements; group C, non-cariogenic diet with iron containing supplements; group D, non-cariogenic diet without iron containing supplements. After sacrificing the rats, 20-micron histological sections of their posterior teeth were prepared using the Ground Section method, then they were studied under polarized light microscopy. In order to compare the progression of caries in different samples, the depth of the lesions in the enamel was measured as three grades I, II and III. The mean grade value of A, B, C and D groups were 1.61, 2.61, 1.37 and 1.80, respectively. Statistical analysis revealed that significantly fewer caries were seen in the group which had received iron containing supplements and cariogenic diet compared with cariogenic diet without iron supplements (pcariogenic dietary regimen.

Renal cancer in kidney transplanted patients.

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Frascà, Giovanni M; Sandrini, Silvio; Cosmai, Laura; Porta, Camillo; Asch, William; Santoni, Matteo; Salviani, Chiara; D'Errico, Antonia; Malvi, Deborah; Balestra, Emilio; Gallieni, Maurizio

2015-12-01

Renal cancer occurs more frequently in renal transplanted patients than in the general population, affecting native kidneys in 90% of cases and the graft in 10 %. In addition to general risk factors, malignancy susceptibility may be influenced by immunosuppressive therapy, the use of calcineurin inhibitors (CNI) as compared with mammalian target of rapamycin inhibitors, and the length of dialysis treatment. Acquired cystic kidney disease may increase the risk for renal cancer after transplantation, while autosomal dominant polycystic kidney disease does not seem to predispose to cancer development. Annual ultrasound evaluation seems appropriate in patients with congenital or acquired cystic disease or even a single cyst in native kidneys, and every 2 years in patients older than 60 years if they were on dialysis for more than 5 years before transplantation. Immunosuppression should be lowered in patients who develop renal cancer, by reduction or withdrawal of CNI. Although more evidence is still needed, it seems reasonable to shift patients from CNI to everolimus or sirolimus if not already treated with one of these drugs, with due caution in subjects with chronic allograft nephropathy.

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens

International Nuclear Information System (INIS)

Novetsky, G.J.; Turner, D.A.; Ali, A.; Raynor, W.J.; Fordham, E.W.

1981-01-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) no preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after adminstration of castor oil than after no prepartion (p = 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p = 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients

Extended regimen combined oral contraception: A review of evolving concepts and acceptance by women and clinicians.

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Nappi, Rossella E; Kaunitz, Andrew M; Bitzer, Johannes

2016-01-01

The clinical utility of extended regimen combined oral contraceptives (COCs) is increasingly being recognised. Our objective was to understand the attitudes of women and clinicians about the use of these regimens. We present the rationale for extended regimen COCs from a historical perspective, and trace their evolution and growing popularity in light of their clinical benefits. We conclude by offering potential strategies for counselling women about extended regimen COC options. We conducted a MEDLINE search to identify and summarise studies of extended regimen COCs, focusing on attitudes of women and clinicians regarding efficacy, safety/tolerability and fewer scheduled bleeding episodes and other potential benefits. The body of contemporary literature on extended regimen COCs suggests that their contraceptive efficacy is comparable to that of conventional 28-day (i.e., 21/7) regimens. For women seeking contraception that allows infrequent scheduled bleeding episodes, particularly those who suffer from hormone withdrawal symptoms and cyclical symptoms (e.g., headache, mood changes, dysmenorrhoea, heavy menstrual bleeding), extended regimen COCs are an effective and safe option. Although satisfaction with extended regimen COCs in clinical trials is high, misperceptions about continuous hormone use may still limit the widespread acceptance of this approach. Despite the widespread acceptance among clinicians of extended regimen COCs as an effective and safe contraceptive option, these regimens are underused, likely due to a lack of awareness about their availability and utility among women. Improved patient education and counselling regarding the safety and benefits of extended regimen COCs may help women make more informed contraceptive choices.

Self-efficacy beliefs, locus of control, religiosity and non-adherence to immunosuppressive medications in kidney transplant patients.

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Silva, Andresa Nascimento; Moratelli, Lucas; Tavares, Paula Liziero; Marsicano, Elisa De Oliveira; Pinhati, Renata Romanholi; Colugnati, Fernando Antonio Basile; Lucchetti, Giancarlo; Sanders-Pinheiro, Helady

2016-11-01

Adherence to immunosuppressive medication is essential for favourable kidney transplant outcomes. The present study aims to investigate how self-efficacy beliefs, health locus of control and religiosity are associated with adherence to immunosuppressives in post kidney transplant recipients. This is a cross-sectional study with 88 recipients with more than 1 year after transplantation. Three methods were used to classify patients as adherent or non-adherent: Basel Assessment of Adherence Scale for Immunosuppressives - BAASIS, the collateral report and blood levels of immunosuppressive medications. Self-efficacy, health locus of control, and religiosity were evaluated applying General Perceived Self-Efficacy Scale, Multidimensional Health Locus of Control Scale and Duke University Religion Index, respectively. Non-adherence was modelled by uni- and multivariated analysis. Sixty-three percent of the patients were male, age 47.2 ± 12.9 years, and median post-transplant time 108.71 (49.0-266.0) months. We found 70.5% of patients were non-adherent through at least one method. Adherent patients presented higher self-efficacy scores (45.1 ± 4.9 vs 38.3 ± 8.6; P locus of control (OR 1.23, IC 1.04-1.45, P = 0.016) and lower intrinsic religiosity (OR 0.56, IC 0.38-0.84, P = 0.006). Our study showed that self-efficacy, chance locus of control, and intrinsic religiosity were associated with non-adherence to immunosuppressives. A broader perception of the kidney transplant patient´s integrality can help health professionals to design strategies to promote adherence in this population. © 2015 Asian Pacific Society of Nephrology.

Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.

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Sippel, Trisha R; White, Jason; Nag, Kamalika; Tsvankin, Vadim; Klaassen, Marci; Kleinschmidt-DeMasters, B K; Waziri, Allen

2011-11-15

The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM. Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation. We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3ζ expression within peripheral blood from patients with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients.

Abnormal chest shadow on CT in immunosuppressed patients

International Nuclear Information System (INIS)

Tanaka, Nobuyuki; Matsumoto, Tsuneo; Nakamura, Hiroshi

1992-01-01

An abnormal chest shadow was observed on CT scans in 25 cases of 23 immunosuppressed patients. Pulmonary disease was pathologically confirmed to be pneumocystis carinii pneumonia (PC pneumonia) in four patients, cytomegalovirus pneumonia (CMV pneumonia) in one, bacterial pneumonia in seven, fungal infection in three, miliary tuberculosis in one, leukemic infiltration in two, lymphangitis carcinomatosa in three, drug-induced pneumonitis in three, and ARDS in one. In almost all patients, especially those with infectious diseases such as PC pneumonia, CMV pneumonia, and bacterial pneumonia, the abnormal shadow was wide and visible in the bilateral lung fields. We presumed that such findings as lobular shadow, centrilobular shadow, and mosaic pattern reflected the extension of disease via the respiratory tract, and that those findings are typical of infectious diseases. Because such findings as abnormal linear shadow and swelling of a broncho-vascular bundle were very frequently recognized in patients with lymphangitis carcinomatosa and frequently recognized in those with drug-induced pneumonitis, these diseases may be distinguished from other diseases. An area of slightly increased density was frequently recognized in patients with PC pneumonia, bacterial pneumonia, and drug-induced pneumonitis. Such lesions were pathologically confirmed to be located in the interstitium and/or alveolus. CT was extremely useful in comprehending the character and extension of particular diseases among various diseases. As the number of patients studied was small, the utility of CT in immunosuppressed patients requires further investigation in a larger number of patients. (author)

Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.

Science.gov (United States)

Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G

2017-05-01

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4 + T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4 + T cells more effectively while inhibiting the proliferation of CD4 + T cells in old mice. Both TAC-treated murine and human CD4 + T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8 + T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4 + T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC. © 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

[Mechanisms of retroviral immunosuppressive domain-induced immune modulation].

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Blinov, V M; Krasnov, G S; Shargunov, A V; Shurdov, M A; Zverev, V V

2013-01-01

Immunosuppressive domains (ISD) of viral envelope glycoproteins provide highly pathogenic phenotypes of various retroviruses. ISD interaction with immune cells leads to an inhibition of a response. In the 1980s it was shown that the fragment of ISD comprising of 17 amino acids (named CKS-17) is carrying out such immune modulation. However the underlying mechanisms were not known. The years of thorough research allowed to identify the regulation of Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR cellular pathways as a result of ISD interaction with immune cells. By the way, this leads to decrease of secretion of stimulatory cytokines (e.g., IL-12) and increase of inhibitory, anti-inflammatory ones (e.g., IL-10). One of the receptor tyrosine kinases inducing signal in these pathways acts as the primary target of ISD while other key regulators--cAMP and diacylglycerol (DAG), act as secondary messengers of signal transduction. Immunosuppressive-like domains can be found not only in retroviruses; the presence of ISD within Ebola viral envelope glycoproteins caused extremely hard clinical course of virus-induced hemorrhagic fever. A number of retroviral-origin fragments encoding ISD can be found in the human genome. These regions are expressed in the placenta within genes of syncytins providing a tolerance of mother's immune system to an embryo. The present review is devoted to molecular aspects of retroviral ISD-induced modulation of host immune system.

Tuberculin Skin Test and Quantiferon in BCG Vaccinated, Immunosuppressed Patients with Moderate-to-Severe Inflammatory Bowel Disease.

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Kurti, Zsuzsanna; Lovasz, Barbara Dorottya; Gecse, Krisztina Barbara; Balint, Anita; Farkas, Klaudia; Morocza-Szabo, Agnes; Gyurcsanyi, Andras; Kristof, Katalin; Vegh, Zsuzsanna; Gonczi, Lorant; Kiss, Lajos Sandor; Golovics, Petra Anna; Lakatos, Laszlo; Molnar, Tamas; Lakatos, Peter Laszlo

2015-12-01

There are few data available on the effect of immunomodulator/biological therapy on the accuracy of the tuberculin skin test (TST) and interferon-gamma release assay (IGRA) in BCG-vaccinated immunosuppressed patients with inflammatory bowel disease (IBD). Our aim was to define the accuracy, predictors and agreement of TST and IGRA in a BCG-vaccinated immunosuppressed referral IBD cohort. 166 consecutive moderate-to-severe IBD patients (122 Crohn's disease, CD and 44 ulcerative colitis, UC) were enrolled in a prospective study from three centers. Patients were treated with immunosuppressives and/or biologicals. IGRA and TST were performed on the same day. Both in- and outpatient records were collected and comprehensively reviewed. TST positivity rate was 23.5%, 21.1%,14.5% and 13.9% when cut-off values of 5, 10, 15 and 20mm were used. IGRA positivity rate was 8.4% with indeterminate result in 0.6%. Chest X-ray was suggestive of latent tuberculosis in 2 patients. Correlation between TST and IGRA was moderate (kappa: 0.39-0.41, p15mm) should be considered to identify patients at risk for latent TB. Accuracy is satisfactory in BCG-vaccinated, immunosuppressed IBD patients. Smoking is a risk factor for TST positivity.

Serum levels of the pro-inflammatory cytokine interleukin-12 and the anti-inflammatory cytokine interleukin-10 in patients with psoriasis treated by the Goeckerman regimen

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Borska, L.; Andrys, C.; Krejsek, J.; Hamakova, K.; Kremlacek, J.; Ettler, K.; Fiala, Z. [Charles University Prague, Hradec Kralove (Czech Republic)

2008-08-15

The Goeckerman regimen (GR) involves the dermal application of a crude coal tar (polycyclic aromatic hydrocarbon, PAH) and exposure to ultraviolet (UV) radiation. Both PAH and UV radiation exhibit immunosuppressive activity. This study describes the changes in the serum levels of the pro-inflammatory cytokine interleukin-12 (IL-12) and the anti-inflammatory cytokine IL-10 in patients with psoriasis (n = 55) treated with GR. The serum levels of IL-12 and IL-10 were compared before and after GR. In addition, the IL-12 and IL-10 levels in psoriatic patients were compared with those in a control group of healthy blood donors (n = 47). The Psoriasis Area and Severity Index (PASI) was used to evaluate the efficacy of GR. When compared with the control group, both IL-12 and IL-10 were significantly higher in psoriatic patients in all cases (P < 0.001). When compared before and after GR, the IL-12 and IL-10 levels (P < 0.01) and PASI value (P < 0.001) were significantly lower after GR. The decrease in the serum level of IL-12 and IL-10 after GR was related to the entry value before GR (IL-12, r = 0.60, P < 0.001; IL-10, r = 0.36, P < 0.01). There was a significant correlation between the IL-10 level before GR and the PASI value after GR = -0.39; P < 0.01). The results indicate a strong pro-inflammatory effect of IL-12 in the immunopathogenesis of psoriasis, and confirm the immunosuppressive and anti-inflammatory effect of GR. IL-10 seems to be a promising individual marker for a positive effect of GR therapy.

Belatacept-based, ATG-Fresenius-induction regimen for kidney transplant recipients: a proof-of-concept study.

Science.gov (United States)

Cicora, Federico; Mos, Fernando; Petroni, Jorgelina; Casanova, Matías; Reniero, Liliana; Roberti, Javier

2015-01-01

Belatacept provides effective immunosuppression while avoiding the nephrotoxicities associated with calcineurin inhibitors (CNIs). However, existing belatacept-based regimens still have high rates of acute rejection. We hypothesized that therapy with belatacept, mycophenolic acid (MMA), steroids and induction therapy with rabbit anti-thymocyte globulin Fresenius (ATGF), rejection rate could be reduced. Prospective, single center, proof-of-concept study including males and females aged ≥18years, Epstein-Barr virus (EBV)-seropositive recipients of a first, HLA non-identical, live or deceased donor kidney allograft. Only patients with a calculated panel reactive antibody score of 0% were included. Three donors were positive for Chagas disease. Six of twelve patients had at least one infection and five were readmitted to the hospital for treatment. One patient had a Trypanosoma cruzi infection via the graft treated successfully. Median cold ischemia time for the transplant patients with a deceased donor was 21.5h. Mean serum creatinine levels at 1, 3 and 6months were 1.76±0.59, 1.55±0.60 and 1.49±0.60mg/dl, respectively. Two of twelve patients experienced clinical, biopsy-proven rejection, successfully treated with methylprednisolone. No patient developed post-transplant lymphoproliferative disorder (PTLD) or any other malignancy and no patient lost their graft or died during follow-up. The potential of this approach makes it worthy of further investigation. Copyright © 2014 Elsevier B.V. All rights reserved.

In Silico Characterization and Structural Modeling of Dermacentor andersoni p36 Immunosuppressive Protein

Directory of Open Access Journals (Sweden)

Martin Omulindi Oyugi

2018-01-01

Full Text Available Ticks cause approximately $17–19 billion economic losses to the livestock industry globally. Development of recombinant antitick vaccine is greatly hindered by insufficient knowledge and understanding of proteins expressed by ticks. Ticks secrete immunosuppressant proteins that modulate the host’s immune system during blood feeding; these molecules could be a target for antivector vaccine development. Recombinant p36, a 36 kDa immunosuppressor from the saliva of female Dermacentor andersoni, suppresses T-lymphocytes proliferation in vitro. To identify potential unique structural and dynamic properties responsible for the immunosuppressive function of p36 proteins, this study utilized bioinformatic tool to characterize and model structure of D. andersoni p36 protein. Evaluation of p36 protein family as suitable vaccine antigens predicted a p36 homolog in Rhipicephalus appendiculatus, the tick vector of East Coast fever, with an antigenicity score of 0.7701 that compares well with that of Bm86 (0.7681, the protein antigen that constitute commercial tick vaccine Tickgard™. Ab initio modeling of the D. andersoni p36 protein yielded a 3D structure that predicted conserved antigenic region, which has potential of binding immunomodulating ligands including glycerol and lactose, found located within exposed loop, suggesting a likely role in immunosuppressive function of tick p36 proteins. Laboratory confirmation of these preliminary results is necessary in future studies.

Outcomes of changing immunosuppressive therapy after treatment failure in patients with noninfectious uveitis.

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Joshi, Lavnish; Talat, Lazha; Yaganti, Satish; Sandhu, Sartaj; Taylor, Simon R J; Wakefield, Denis; McCluskey, Peter; Lightman, Susan

2014-05-01

To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure. Retrospective cohort study. Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom and Australia. Participants with a history of using immunosuppressive therapy were identified in clinics, and notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a therapy) was identified, and demographic details, clinical characteristics, drug used (second-line immunosuppressive agent [ISA] or biologicals), and drug doses were obtained. For each treatment episode, the reasons for changing therapy, corticosteroid-sparing effects, and control of inflammation were determined. A total of 147 patients were identified who underwent 309 different treatment episodes. Fifty-five percent of patients eventually required a change in treatment after their first treatment episode/course. Forty-five episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving "success" (prednisolone ≤10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53 episodes, with "success" being achieved in 50% to 71% of these patients. Biological agents were used in 45 episodes, the most common one being infliximab, which achieved success in 80% of patients. Our data suggest that control of inflammation can be achieved after switching or combining ISAs. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

The influence of immunosuppressive drugs on neural stem/progenitor cell fate in vitro

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Skardelly, Marco, E-mail: Marco.Skardelly@med.uni-tuebingen.de [Department of Neurosurgery, University Hospital, Leipzig (Germany); Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany); Glien, Anja; Groba, Claudia; Schlichting, Nadine [Department of Neurosurgery, University Hospital, Leipzig (Germany); Kamprad, Manja [Institute of Clinical Immunology, Medical Faculty, University of Leipzig, Leipzig (Germany); Meixensberger, Juergen [Department of Neurosurgery, University Hospital, Leipzig (Germany); Milosevic, Javorina [Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig (Germany)

2013-12-10

In allogenic and xenogenic transplantation, adequate immunosuppression plays a major role in graft survival, especially over the long term. The effect of immunosuppressive drugs on neural stem/progenitor cell fate has not been sufficiently explored. The focus of this study is to systematically investigate the effects of the following four different immunotherapeutic strategies on human neural progenitor cell survival/death, proliferation, metabolic activity, differentiation and migration in vitro: (1) cyclosporine A (CsA), a calcineurin inhibitor; (2) everolimus (RAD001), an mTOR-inhibitor; (3) mycophenolic acid (MPA, mycophenolate), an inhibitor of inosine monophosphate dehydrogenase and (4) prednisolone, a steroid. At the minimum effective concentration (MEC), we found a prominent decrease in hNPCs' proliferative capacity (BrdU incorporation), especially for CsA and MPA, and an alteration of the NAD(P)H-dependent metabolic activity. Cell death rate, neurogenesis, gliogenesis and cell migration remained mostly unaffected under these conditions for all four immunosuppressants, except for apoptotic cell death, which was significantly increased by MPA treatment. - Highlights: • Four immunosuppresants (ISs) were tested in human neural progenitor cells in vitro. • Cyclosporine A and mycophenolic acid showed a prominent anti-proliferative activity • Mycophenolic acid exhibited a significant pro-apoptotic effect. • NAD(P)H-dependent metabolic activity was occasionally induced by ISs. • Neuronal differentiation and migration potential remained unaffected by ISs treatment.

Nicorandil prevents sirolimus-induced production of reactive oxygen species, endothelial dysfunction, and thrombus formation

Directory of Open Access Journals (Sweden)

Ken Aizawa

2015-03-01

Full Text Available Sirolimus (SRL is widely used to prevent restenosis after percutaneous coronary intervention. However, its beneficial effect is hampered by complications of thrombosis. Several studies imply that reactive oxygen species (ROS play a critical role in endothelial dysfunction and thrombus formation. The present study investigated the protective effect of nicorandil (NIC, an anti-angina agent, on SRL-associated thrombosis. In human coronary artery endothelial cells (HCAECs, SRL stimulated ROS production, which was prevented by co-treatment with NIC. The preventive effect of NIC on ROS was abolished by 5-hydroxydecanoate but not by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. NIC also inhibited SRL-induced up-regulation of NADPH oxidase subunit p22phox mRNA. Co-treatment with NIC and SRL significantly up-regulated superoxide dismutase 2. NIC treatment significantly improved SRL-induced decrease in viability of HCAECs. The functional relevance of the preventive effects of NIC on SRL-induced ROS production and impairment of endothelial viability was investigated in a mouse model of thrombosis. Pretreatment with NIC inhibited the SRL-induced acceleration of FeCl3-initiated thrombus formation and ROS production in the testicular arteries of mice. In conclusion, NIC prevented SRL-induced thrombus formation, presumably due to the reduction of ROS and to endothelial protection. The therapeutic efficacy of NIC could represent an additional option in the prevention of SRL-related thrombosis.

Efficacy of combination of glycolic acid peeling with topical regimen in treatment of melasma.

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Chaudhary, Savita; Dayal, Surabhi

2013-10-01

Various treatment modalities are available for management of melasma, ranging from topical and oral to chemical peeling, but none is promising alone. Very few studies are available regarding efficacy of combination of topical treatment with chemical peeling. Combination of chemical peeling and topical regimen can be a good treatment modality in the management of this recalcitrant disorder. To assess the efficacy of combination of topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling in the treatment of melasma in Indian patients. Forty Indian patients of moderate to severe epidermal variety melasma were divided into two groups of 20 each. One Group i.e. peel group received topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling and other group i.e. control group received topical regimen (2% hydroquinone, 1% hydrocortisone, 0.05% tretinoin). There was an overall decrease in MASI from baseline in 24 weeks of therapy in both the groups (P value peel with topical regimen showed early and greater improvement than the group which was receiving topical regimen only. This study concluded that combining topical regimen (2% hydroquinone, 1% hydrocortisone and 0.05% tretinoin) with serial glycolic acid peeling significantly enhances the therapeutic efficacy of glycolic acid peeling. The combination of glycolic acid peeling with the topical regimen is a highly effective, safe and promising therapeutic option in treatment of melasma.

Pharmacodynamic Monitoring of Tacrolimus-based Immunosuppression in CD14+ Monocytes after Kidney Transplantation

NARCIS (Netherlands)

N.M. Kannegieter (Nynke); D.A. Hesselink (Dennis); M. Dieterich (Marjolein); G.N. de Graav (Gretchen); R. Kraaijeveld (Rens); A.T. Rowshani (Ajda); P.J. Leenen (Pieter); C.C. Baan (Carla)

2017-01-01

markdownabstractBackground: Monocytes significantly contribute to ischemia-reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Conventional pharmacokinetic methods for

Case Report: Stevens-Johnson syndrome following a single double dosing of nevirapine-containing regimen once in an HIV-infected woman on long-term antiretroviral therapy.

Science.gov (United States)

Kakande, Betty; Isaacs, Thuraya; Muloiwa, Rudzani; Dlamini, Sipho; Lehloenya, Rannakoe

2015-01-01

A 31-year old HIV-infected African woman on nevirapine, tenofovir and lamivudine for more than 4 years presented with an 8-day history of symptoms and signs of Stevens-Johnson syndrome. She was on no other medication. Her viral load was undetectable and she had maintained a CD4 count of between 356 and 387cells/mm (3) in the preceding 2½ years. She missed her antiretrovirals 10 days before the onset of her symptoms and subsequently doubled her daily dose the following day. She had been on no other medication in the preceding 8 weeks. Her ARVs were stopped and she fully re-epithelialized with the exception of the lips, over the following 10 days. She was started on a daily single tablet of Odimune® (a fixed drug combination antiretroviral containing tenofovir, emtricitabine and efavirenz). Nevirapine is the most common offender in cases of antiretroviral-associated SJS in published literature. Lamivudine is very rarely implicated while there are no similar reports with tenofovir.  We concluded that nevirapine was by far the most likely offender in this case. Nevirapine toxicity is associated with high CD4 counts, undetectable viral load and high drug plasma level. We postulate that the sudden increase of the plasma levels of nevirapine in a patient with a high CD4 count and undetectable viral load created a perfect storm for the development of SJS in our patient, who had been on the NVP-containing regimen for many years. Clinicians should be aware that severe adverse drug reactions are dynamic and can occur even when the drug has been in use for a long time.

Differential role of basal keratinocytes in UV-induced immunosuppression and skin cancer

NARCIS (Netherlands)

J. Jans (Judith); G.A. Garinis (George); W. Schul; A. van Oudenaren (Adri); M.J. Moorhouse (Michael); M. Smid (Marcel); Y.-G. Sert (Yurda-Gul); A. van der Velde (Albertina); Y.M. Rijksen (Yvonne); F.R. de Gruijl (Frank); P.J. van der Spek (Peter); A. Yasui (Akira); J.H.J. Hoeijmakers (Jan); P.J. Leenen (Pieter); G.T.J. van der Horst (Gijsbertus)

2006-01-01

textabstractCyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type

Clinical course and therapeutic approach to varicella zoster virus infection in children with rheumatic autoimmune diseases under immunosuppression

OpenAIRE

Leuvenink, Raphael; Aeschlimann, Florence; Baer, Walter; Berthet, Gerald; Cannizzaro, Elvira; Hofer, Michael; Kaiser, Daniela; Schroeder, Silke; Heininger, Ulrich; Woerner, Andreas

2016-01-01

Background To analyze the clinical presentation and complications of varicella zoster virus (VZV) infection in children with rheumatic diseases treated with immunosuppressive medication such as biological disease-modifying antirheumatic drugs (bDMARDs) and/or conventional disease-modifying antirheumatic drugs (cDMARDs), and to analyze the therapeutic approach to VZV infections with respect to the concomitant immunosuppressive treatment. Methods Retrospective multicenter study using the Swiss ...

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens.

Science.gov (United States)

Novetsky, G J; Turner, D A; Ali, A; Raynor, W J; Fordham, E W

1981-11-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) not preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after administration of castor oil than after no preparation (p = 0.047). A high fiber diet also resulted in a substantial reduction of colonic activity when compared with no preparation; the difference, however, was not statistically significant (p = 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p = 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients.

Cleansing the colon in gallium-67 scintigraphy: a prospective comparison of regimens

International Nuclear Information System (INIS)

Novetsky, G.J.; Turner, D.A.; Ali, A.; Raynor, W.J. Jr.; Fordham, E.W.

1981-01-01

Colonic accumulation of gallium-67 frequently complicates the interpretation of gallium-67 scintigrams. Although various modes of cleansing the colon prior to scintigraphy have been suggested, there is controversy over their efficacy and none have been tested prospectively. Three hundred nine patients undergoing gallium-67 scintigraphy were randomly assigned to one of four cleansing regimens: (1) a high fiber diet (78 patients); (2) castor oil (76); (3) milk of magnesia and cascara (76); and (4) not preparation (79). Patient compliance rates for the four regimens were 17%, 32%, 36%, and 46%, respectively. After noncompliant patients were excluded, gallium-67 scintigrams were graded for colonic activity on a scale of 0-3 by three independent, experienced observers. Gallium-67 activity in the colon was significantly less after administration of castor oil than after no preparation (p . 0.047). A high fiber diet also resulted in a substantial reduction of colonic activity when compared with no preparation; the difference, however, was not statistically significant (p . 0.083). Regimen 3 did not produce significantly better results than regimen 4 (p . 0.42). A major impediment to the success of any cleansing regimen seems to be poor compliance of patients

Clarithromycin vs. Gemifloxacin in Quadruple Therapy Regimens for Empiric Primary Treatment of Helicobacter pylori Infection: A Randomized Clinical Trial

Science.gov (United States)

Masoodi, Mohsen; Talebi-Taher, Mahshid; Tabatabaie, Khadijeh; Khaleghi, Siamak; Faghihi, Amir-Hossein; Agah, Shahram; Asadi, Reyhaneh

2015-01-01

BACKGROUND Eradication of Helicobacter pylori infection plays a crucial role in the treatment of peptic ulcer. Clarithromycin resistance is a major cause of treatment failure. This randomized clinical trial aimed at evaluating the efficacy of a clarithromycin versus gemifloxacin containing quadruple therapy regimen in eradication of H.pylori infection. METHODS In this randomized double blind clinical trial (RCT 2012102011054N2), a total of 120 patients were randomized to two groups of 60 patients each. Patients with proven H.pylori infection were consecutively assigned into two groups to receive OBAG or OBAC in gastroenterology clinic in Rasoul-e- Akram General Hospital in Tehran, Iran. The patients in the OBAG group received omeprazole (20 mg) twice daily, bismuth subcitrate (240 mg) twice daily, amoxicillin (1 gr) twice daily, and gemifloxacin (320 mg) once daily, and those in the OBAC group received omeprazole (20 mg) twice daily, 240 mg of bismuth subcitrate twice daily, amoxicillin (1 gr) twice daily, and clarithromycin (500 mg) twice daily for 10 days. RESULTS Five patients from each group were excluded from the study because of poor compliance, so 110 patients completed the study. The intention-to-treat eradication rate was 61.6% and 66.6% for the OBAC and OBAG groups, respectively. According to the per protocol analysis, the success rates of eradication of H.pylori infection were 67.2% and 72.7% for OBAC and OBAG groups, respectively (p=0.568). CONCLUSION The results of this study suggest that gemifloxacin containing regimen is at least as effective as clarithromycin regimen; hence, this new treatment could be considered as an alternative for the patients who cannot tolerate clarithromycin. PMID:26106468

Efficacy and safety of zotarolimus-eluting and sirolimus-eluting coronary stents in routine clinical care (SORT OUT III): a randomised controlled superiority trial

DEFF Research Database (Denmark)

Rasmussen, Klaus; Maeng, Michael; Kaltoft, Anne

2010-01-01

BACKGROUND: In low-risk patients, the zotarolimus-eluting stent has been shown to reduce rates of restenosis without increasing the risk of stent thrombosis. We compared the efficacy and safety of the zotarolimus-eluting stent versus the sirolimus-eluting stent in patients with coronary artery...... disease who were receiving routine clinical care with no direct follow-up. METHODS: We did a single-blind, all-comer superiority trial in adult patients with chronic stable coronary artery disease or acute coronary syndromes, and at least one target lesion. Patients were treated at one of five...... Danish administrative and health-care registries. The primary endpoint was a composite of major adverse cardiac events within 9 months: cardiac death, myocardial infarction, and target vessel revascularisation. Intention-to-treat analyses were done at 9-month and 18-month follow-up. This trial...

Immunosuppression by fractionated total lymphoid irradiation in collagen arthritis

International Nuclear Information System (INIS)

McCune, W.J.; Buckley, J.A.; Belli, J.A.; Trentham, D.E.

1982-01-01

Treatments with fractionated total lymphoid irradiation (TLI) and cyclophosphamide were evaluated for rats injected with type II collagen. Preadministration of TLI and repeated injections of cyclophosphamide suppressed the severity of arthritis and lowered antibody titers to collagen significantly. TLI initiated at the onset of collagen arthritis decreased humoral and cellular responses to collagen but did not affect the severity of arthritis. These data demonstrate that both TLi and cyclophosphamide are immunosuppressive in an experimentally inducible autoimmune disease

Albendazole inhibits Pneumocystis carinii proliferation in inoculated immunosuppressed mice.

OpenAIRE

Bartlett, M S; Edlind, T D; Lee, C H; Dean, R; Queener, S F; Shaw, M M; Smith, J W

1994-01-01

Albendazole, a benzimidazole derivative widely used for treating helminth infections, was successfully used to treat and prevent development of Pneumocystis carinii pneumonia in transtracheally inoculated immunosuppressed mice. For treatment, 3 weeks postinoculation, albendazole at 300 and 600 mg/kg of body weight per day was administered in food for 3 weeks. For prophylaxis, albendazole was begun on the same day as inoculation at 300 mg/kg/day for 7 days, and then the dose was reduced to 150...

Incident AIDS or Death After Initiation of Human Immunodeficiency Virus Treatment Regimens Including Raltegravir or Efavirenz Among Adults in the United States.

Science.gov (United States)

Cole, Stephen R; Edwards, Jessie K; Hall, H Irene; Brookhart, M Alan; Mathews, W Christopher; Moore, Richard D; Crane, Heidi M; Kitahata, Mari M; Mugavero, Michael J; Saag, Michael S; Eron, Joseph J

2017-06-01

The long-term effectiveness of human immunodeficiency virus (HIV) treatments containing integrase inhibitors is unknown. We use observational data from the Centers for AIDS Research Network of Integrated Clinical Systems and the Centers for Disease Control and Prevention to estimate 4-year risk of AIDS and all-cause mortality among 415 patients starting a raltegravir regimen compared to 2646 starting an efavirenz regimen (both regimens include emtricitabine and tenofovir disoproxil fumarate). We account for confounding and selection bias as well as generalizability by standardization for measured variables, and present both observational intent-to-treat and per-protocol estimates. At treatment initiation, 12% of patients were female, 36% black, 13% Hispanic; median age was 37 years, CD4 count 321 cells/µL, and viral load 4.5 log10 copies/mL. Two hundred thirty-five patients incurred an AIDS-defining illness or died, and 741 patients left follow-up. After accounting for measured differences, the 4-year risk was similar among those starting both regimens (ie, intent-to treat hazard ratio [HR], 0.96 [95% confidence interval {CI}, .63-1.45]; risk difference, -0.9 [95% CI, -4.5 to 2.7]), as well as among those remaining on regimens (ie, per-protocol HR, 0.95 [95% CI, .59-1.54]; risk difference, -0.5 [95% CI, -3.8 to 2.9]). Raltegravir and efavirenz-based initial antiretroviral therapy have similar 4-year clinical effects. Vigilance regarding longer-term comparative effectiveness of HIV regimens using observational data is needed because large-scale experimental data are not forthcoming. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

New Treatment Regimen for Latent Tuberculosis Infection

Centers for Disease Control (CDC) Podcasts

In this podcast, Dr. Kenneth Castro, Director of the Division of Tuberculosis Elimination, discusses the December 9, 2011 CDC guidelines for the use of a new regimen for the treatment of persons with latent tuberculosis infection.

Surveillance of polyomavirus BK in relation to immunosuppressive therapy in kidney transplantation

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Cristina Costa

2012-03-01

Full Text Available Introduction. Reactivation of polyomavirus BK in kidney transplant recipients has been associated to the development of nephropathy (polyomavirus-associated nephropathy, PVAN, possibly leading to the loss of the transplanted organ. Immunosuppression is the condicio sine qua non for the onset of PVAN; however, a lower incidence of BK viremia has been reported with low-level tacrolimus based immunosuppressive protocols in comparison to cyclosporine A.Aim of this study was to compare the two immunosuppressive protocols. Methods. Virological monitoring of BK was performed in 468 consecutive renal transplant patients over a period of 3 years (2370 urine e 2370 serum specimens: in particular, 1780 specimens from 362 patients treated with tacrolimus and 590 from 106 treated with cyclosporine A. Results. BK viremia was evidenced in 124 (7.0% and 12 (2.0% specimens from 40 (11.0% and 11 (10.4% patients treated with tacrolimus and cyclosporine A, respectively; similarly, BK viruria in 289 (16.2% and 58 (9.8% specimens from 67 (18.5% and 27 (25.5% patients, being the difference of incidence highly significant (p <0.0001 for both viremia and viruria at comparison between specimens and not significant for patients. No case of PVAN was diagnosed at histophatology evaluation. Conclusions. The incidence of viremia and viruria was similar to that previously reported. Our results evidenced that with low-level tacrolimus-based protocols the overall incidence of reactivation in renal transplant patients is not significantly different and there is no increased risk of PVAN, nevertheless the higher incidence of episodes of reactivation.

Forging a link between oncogenic signaling and immunosuppression in melanoma.

Science.gov (United States)

Khalili, Jahan S; Hwu, Patrick; Lizée, Gregory

2013-02-01

Immunosuppressive tumor microenvironments limit the efficacy of T cell-based immunotherapy. We have recently demonstrated that the inhibition of BRAF V600E with vemurafenib relieves interleukin-1 (IL-1)-induced T-cell suppression as mediated by melanoma tumor associated fibroblasts (TAFs). These results suggest that inhibitors of the MAPK pathway in combination with T cell-based immunotherapies may induce long-lasting and durable responses.

The Interplay between Inflammation and Fibrosis in Kidney Transplantation

Directory of Open Access Journals (Sweden)

Irina B. Torres

2014-01-01

Full Text Available Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

Randomized Comparison of Everolimus-Eluting and Sirolimus-Eluting Stents in Patients Treated With Percutaneous Coronary Intervention: The Scandinavian Organization for Randomized Trials With Clinical Outcome IV (SORT OUT IV)

DEFF Research Database (Denmark)

Okkels Jensen, Lisette; Thayssen, Per; Hansen, Henrik Steen

2012-01-01

was a composite of safety (cardiac death, myocardial infarction, definite stent thrombosis) and efficacy (target vessel revascularization) parameters. The noninferiority criterion was a risk difference of 0.015. Intention-to-treat analyses were done at 9- and 18-month follow-ups. A total of 1390 patients were.......71-1.23). At the 9-month follow-up, the rate of definite stent thrombosis was higher in the sirolimus-eluting group (2 patients [0.1%] versus 9 patients [0.7%]; hazard ratio, 0.22; 95% confidence interval, 0.05-1.02). At the 18-month follow-up, this difference was sustained (3 patients [0.2%] versus 12 patients [0...

Hepatitis B Virus (HBV) Load Response to 2 Antiviral Regimens, Tenofovir/Lamivudine and Lamivudine, in HIV/ HBV-Coinfected Pregnant Women in Guangxi, China: The Tenofovir in Pregnancy (TiP) Study.

Science.gov (United States)

Wang, Liming; Wiener, Jeffrey; Bulterys, Marc; Wei, Xiaoyu; Chen, Lili; Liu, Wei; Liang, Shujia; Shepard, Colin; Wang, Linhong; Wang, Ailing; Zhang, Fujie; Kourtis, Athena P

2016-12-01

 There is limited information on antiviral therapy for hepatitis B virus (HBV) infection among pregnant women coinfected with human immunodeficiency virus (HIV) and HBV.  A phase 2 randomized, controlled trial of a regimen containing tenofovir (TDF)/lamivudine (3TC) and a regimen containing 3TC in HIV/HBV-coinfected pregnant women in China. The HBV virological response was compared in study arms.  The median decline in the HBV DNA level was 2.60 log 10 copies/mL in the TDF/3TC arm and 2.24 log 10 copies/mL in the 3TC arm (P = .41). All women achieved HBV DNA levels of <6 log 10 copies/mL at delivery.  Initiation of either regimen led to achievement of HBV DNA levels below the threshold associated with perinatal HBV transmission.  NCT01125696. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

The release of immunosuppressive factor(s) in young males following exercise.

Science.gov (United States)

Tian, Ye; Nie, Jinlei; Tong, Tom K; Baker, Julien S

2012-01-01

It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years) were taken before and immediately after ten sets of exercise consisting of 15 free and 30 10-kg loaded squat jumps in each set. The suppression of lymphocyte proliferation was analysed with high pressure liquid chromatography. It was noted from the result of gel chromatography columns that the post-exercise values of the suppression of lymphocyte proliferation, in comparison to corresponding pre-exercise values, were generally greater with significant differences observed in 7.5th-9th min post-exercise eluates (P exercise may lead to generation of immunosuppressive factor(s) in young males.

The Release of Immunosuppressive Factor(s in Young Males Following Exercise

Directory of Open Access Journals (Sweden)

Julien S. Baker

2012-05-01

Full Text Available It has been shown that a suppressive protein, acting as an immune suppressor, is generated in animals and humans under particular stresses. However, studies related to immunosuppressive factors in response to the stress resulting from acute exercise are limited. This study compares the effects of pre- and post-exercise human serum on concanavalin A stimulated lymphocyte proliferation of mice. In the present study, blood samples in eight male undergraduates (age 21 ± 0.7 years were taken before and immediately after ten sets of exercise consisting of 15 free and 30 10-kg loaded squat jumps in each set. The suppression of lymphocyte proliferation was analysed with high pressure liquid chromatography. It was noted from the result of gel chromatography columns that the post-exercise values of the suppression of lymphocyte proliferation, in comparison to corresponding pre-exercise values, were generally greater with significant differences observed in 7.5th–9th min post-exercise eluates (P < 0.05. Such findings suggest that intense eccentric type exercise may lead to generation of immunosuppressive factor(s in young males.

Sequential kidney/islet transplantation using prednisone-free immunosuppression.

Science.gov (United States)

Kaufman, Dixon B; Baker, Marshall S; Chen, Xiaojuan; Leventhal, Joseph R; Stuart, Frank P

2002-08-01

Islet transplantation is becoming established as a treatment option for type I diabetes in select patients. Individuals with type I diabetes who have previously received a successful kidney allograft may be good candidates for islet transplantation. They have already assumed the risks of chronic immunosuppression, so the added procedural risk of a subsequent islet transplant would be minimal. Furthermore, because of the preimmunosuppressed state it is possible that islet-after-kidney transplantation may result in a more efficient early islet engraftment. Consequently, insulin independence might be achieved with significantly fewer islets than the approximately 8-10,000 islet equivalents/kg/b.w. currently required. A mass that usually demands two or more cadaveric donors. A case of successful islet-after-kidney transplantation is described using the steroid-free Edmonton immunosuppression protocol. Characteristics of the final islet product are: a) islet equivalents: 265,888 (4100 islet equivalents/kg/b.w.); b) islet purity: 75-80%; c) viability: >95% (trypan blue exclusion); and d) mean islet potency (static low-high glucose challenge): 4.16 +/- 1.91-fold increase. Post-transplant the patient's hypoglycemic episodes abated. Exogenous insulin requirements were eliminated at week 12 post-transplant as basal and Ensure (Abbott Laboratories, Abbott Park, IL, USA) oral glucose stimulated C-peptide levels peaked and stabilized. Twenty-four-hour continuous glucose monitoring confirmed moment-to-moment glycemic control, and periodic nonfasting finger stick glucose determinations over the next month confirmed glycemia was controlled. Hemoglobin A1c levels declined from a pretransplant level of 6.9% to 5.3%. Renal allograft function remained changed.

Superiority of Interferon-Free Regimens for Chronic Hepatitis C

Science.gov (United States)

Younossi, Zobair M.; Stepanova, Maria; Esteban, Rafael; Jacobson, Ira; Zeuzem, Stefan; Sulkowski, Mark; Henry, Linda; Nader, Fatema; Cable, Rebecca; Afendy, Mariam; Hunt, Sharon

2017-01-01

Abstract Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients. Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy—Fatigue, Chronic Liver Disease Questionnaire— HCV, Work Productivity and Activity—Specific Health Problem) before, during, and after treatment. A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to −24.4% by treatment week 12, up to −8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to −7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs. IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores. PMID:28207507

Differences in Lipid Measurements by Antiretroviral Regimen Exposure in Cohorts from Asia and Australia

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Amit C. Achhra

2012-01-01

Full Text Available We explored the mean differences in routinely measured lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol according to exposure to different combination antiretroviral regimens in Asian (n=2051 and Australian (predominantly Caucasian, n=794 cohorts. The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs and either of at least one protease inhibitor (PI or non-nucleoside-reverse transcriptases (NNRTIs. We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both; and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol (P for interaction between regimen and cohort: 0.05. The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations.

Function of external respiration in patients after kidney transplantation under conditions of immunosuppressive therapy.

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O. V. Kuryata

2018-04-01

Full Text Available The aim of our study was to evaluate the changes in the parameters of the function of external respiration in patients after kidney transplantation due to chronic kidney disease and to assess the relationship between the level of cyclosporin A and tacrolimus in the blood with FVD indices. The study included 37 patients after kidney transplantation. The first group included 27 patients who received cyclosporine at an average dose of 225 [175-350] mg/day under the immunosuppressive therapy regimen, the second group included 10 patients who received tacrolimus at an average dose of 8.25 [5.0-9.0] mg/day. A significant difference (p˂0.05 between the indicators of the VCmax (78 [71-90]% and 76.5 [72-78]%, FVC (93 [85-99]% and 95 [91-98]%, PEF (82 [64-94]% and 80 [69-84]%, MEF25-75 (75 [66-112]% and 82.5 [67-90]% was found in patients of the first and second groups relative to the FVD of the comparison group: VCmax (102.5 [98-113]%, FVC (107.5 [105.5-124]%, PEF (99.5 [95-102.5]%, MEF25-75 (98.5 [97.5-101.5]%. In both groups, a statistically significant negative correlation between the indicators of the VCmax, FVC and the level of cyclosporin A (R=-0.69, p<0.0001 and R=-0.4, p<0.037 in the blood in the first group and FVC and tacrolimus (R=-0.72, p<0.018 in the second group was found. A moderate decrease in the VCmax values in patients after kidney transplantation requires monitoring of the function of external respiration and managing such patients by nephrologists together with specialists in the pulmonological profile.

New drugs and perspectives for new anti-tuberculosis regimens

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S. Tiberi

2018-03-01

Full Text Available Tuberculosis (TB is the ninth cause of global death, more than any other infectious disease. With growing drug resistance the epidemic remains and will require significant attention and investment for the elimination of this disease to occur. With susceptible TB treatment not changing over the last four decades and the advent of drug resistance, new drugs and regimens are required.Recently, through greater collaboration and research networks some progress with significant advances has taken place, not withstanding the comparatively low amount of resources invested. Of late the availability of the new drugs bedaquiline, delamanid and repurposed drugs linezolid, clofazimine and carbapenems are being used more frequently in drug-resistant TB regimens.The WHO shorter multidrug-resistant tuberculosis regimen promises to reach more patients and treat them more quickly and more cheaply.With this new enthusiasm and hope we this review gives an update on the new drugs and perspectives for the treatment of drug-susceptible and drug-resistant tuberculosis. Keywords: Bedaquiline, Delamanid, Linezolid, MDR, XDR-TB, TB

Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis.

Science.gov (United States)

Bartacek, A; Schütt, D; Panosch, B; Borek, M

2009-06-01

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB). This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

CEFTRIAXONE EFFICIENCY AMONG PATIENTS, SUFFERING FROM JUVENILE ARTHRITIS AND RECEIVING IMMUNOSUPPRESSIVE THERAPY

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A.M. Chomakhidze

2007-01-01

Full Text Available The article is dedicated to diagnostics and treatment of infectious complications among children with juvenile rheumatoid arthritis, receiving immunosuppressive therapy. The research involves 92 children with different variants of the illness run, who received immunosuppressive therapy. All the patients showed development of the systemic inflammatory response manifestations. The researchers used the definition of the procalcytonine levels as a marker for the bacterial infectiondevelopment. All the patients showed it higher than 0,5 ng/ml, while 7 patients — higher than 10 ng/ml. keeping in mind several courses of the antibacterial therapy in the anamnesis and presence of the combined bacterial infection, ceftriaxone was prescribed to all the children. As a result of the ceftriaxone based therapy, reduction of the clinical and laboratory manifestations of the bacterial infection was noted among more than 90% of patients. The development of the allergic reaction was noted in 1 case, and leukopenia was also found in 1 patient.Key words: children, juvenile rheumatoid arthritis, ceftriaxone.

Pulmonary aspergillosis in immunosuppressed patients with haematological malignancies.

Science.gov (United States)

Spearing, R L; Pamphilon, D H; Prentice, A G

1986-06-01

Invasive pulmonary aspergillosis as a cause of mortality and morbidity in patients with haematological malignancies is becoming more common. Predisposing factors are powerful immunosuppressive chemotherapy, neutropenia and synergistic combinations of antibiotics of great potency and wide spectrum of activity. Clinical and radiological signs are heterogeneous, sometimes misleading and often absent. Treatment is often empirical on suspicion alone. Amphotericin B is the only effective drug but it has marked toxicity, mainly renal. Infection is usually fatal without adequate treatment. This paper describes eight cases of invasive pulmonary aspergillosis seen in one centre in two years, reviews the literature and assesses associated problems.

Systemic increased immune response to Nocardia brasiliensis co-exists with local immunosuppressive microenvironment.

Science.gov (United States)

Salinas-Carmona, Mario Cesar; Rosas-Taraco, Adrian Geovanni; Welsh, Oliverio

2012-10-01

Human diseases produced by pathogenic actinomycetes are increasing because they may be present as opportunistic infections. Some of these microbes cause systemic infections associated with immunosuppressive conditions, such as chemotherapy for cancer, immunosuppressive therapy for transplant, autoimmune conditions, and AIDS; while others usually cause localized infection in immunocompetent individuals. Other factors related to this increase in incidence are: antibiotic resistance, not well defined taxonomy, and a delay in isolation and identification of the offending microbe. Examples of these infections are systemic disease and brain abscesses produced by Nocardia asteroides or the located disease by Nocardia brasiliensis, named actinomycetoma. During the Pathogenic Actinomycetes Symposium of the 16th International Symposium on Biology of Actinomycetes (ISBA), held in Puerto Vallarta, Mexico, several authors presented recent research on the mechanisms by which N. brasiliensis modulates the immune system to survive in the host and advances in medical treatment of human actinomycetoma. Antibiotics and antimicrobials that are effective against severe actinomycetoma infections with an excellent therapeutic outcome and experimental studies of drugs that show promising bacterial inhibition in vivo and in vitro were presented. Here we demonstrate a systemic strong acquired immune response in humans and experimental mice at the same time of a local dominance of anti inflammatory cytokines environment. The pathogenic mechanisms of some actinomycetes include generation of an immunosuppressive micro environment to evade the protective immune response. This information will be helpful in understanding pathogenesis and to design new drugs for treatment of actinomycetoma.

Immunosuppressive effects of sesquiterpene lactones from Laser trilobum (L.) Borkh

Czech Academy of Sciences Publication Activity Database

Zídek, Zdeněk; Harmatha, Juraj; Vokáč, Karel; Kmoníčková, Eva

2009-01-01

Roč. 75, č. 9 (2009), s. 905-905 ISSN 0032-0943. [International Congress and Annual Meeting of the Society for Medicinal Plant and Natural Product Research /57./. 16.08.2009-20.08.2009, Geneva] R&D Projects: GA ČR GA305/07/0061 Institutional research plan: CEZ:AV0Z40550506; CEZ:AV0Z50390512 Keywords : immunosuppressive effects * Laser trilobum Subject RIV: CC - Organic Chemistry

Nocardia brasiliensis induces an immunosuppressive microenvironment that favors chronic infection in BALB/c mice.

Science.gov (United States)

Rosas-Taraco, Adrian G; Perez-Liñan, Amira R; Bocanegra-Ibarias, Paola; Perez-Rivera, Luz I; Salinas-Carmona, Mario C

2012-07-01

Nocardia brasiliensis is an intracellular microorganism and the most common etiologic agent of actinomycetoma in the Americas. Several intracellular pathogens induce an immunosuppressive microenvironment through increases in CD4+ Foxp3+ regulatory T cells (Treg), thus downregulating other T-cell subpopulations and assuring survival in the host. In this study, we determined whether N. brasiliensis modulates T-lymphocyte responses and their related cytokine profiles in a murine experimental model. We also examined the relationship between N. brasiliensis immunomodulation and pathogenesis and bacterial survival. In early infection, Th17/Tc17 cells were increased at day 3 (P 1 log) was also observed (P brasiliensis modulates the immune system to induce an immunosuppressive microenvironment that benefits its survival during the chronic stage of infection.

Renal impairment in HIV-infected patients initiating tenofovir-containing antiretroviral therapy regimens in a Primary Healthcare Setting in South Africa.

Science.gov (United States)

Kamkuemah, Monika; Kaplan, Richard; Bekker, Linda-Gail; Little, Francesca; Myer, Landon

2015-04-01

Long-term use of tenofovir disoproxil fumarate is associated with declines in glomerular function and chronic kidney disease in HIV-infected patients. We aimed to assess the prevalence and incidence of renal impairment in a primary care setting in sub-Saharan Africa. We analysed data from 1092 HIV-infected patients initiating tenofovir at a primary care clinic in Cape Town, South Africa. Renal function was assessed for the first 12 months on ART by estimating glomerular filtration rate (eGFR) calculated using the Cockroft-Gault equation categorised into normal, mild, moderate and severe reduction in renal function based on values >90, 60-89, 30-59 and <30 ml/min/1.73 m(2) , respectively. Associations were assessed using logistic regression, and average GFR trajectory over time was modelled using linear mixed-effects models. The cohort consisted of 62% women; median age was 34 years (IQR 29; 41 years). The majority had normal renal function pre-ART (79%), 19% had mildly reduced GFR, and 2% had moderate renal impairment. Older age, more advanced WHO stage and anaemia were independently associated with prevalent renal impairment. On average, estimated glomerular function improved over the first year on tenofovir [1.10 ml/min/1.73 m(2) average increase over 12 months (95% CI: 0.80; 1.40)]. Male gender, anaemia and immunosuppression (WHO Stage III/IV and CD4 cell counts <100 cells/mm(3) ) were associated with lower average eGFR levels over time. Overall, 3% developed eGFR <50 ml/min/1.73 m(2) during this period. Serum creatinine tests conducted before 4 months on ART had low predictive value for predicting change in eGFR after a year on ART. Generally, renal function improved in HIV-infected adults initiating ART in this primary healthcare setting during the first year on ART. While monitoring of renal function is recommended in the first 4 months on ART, renal impairment appears uncommon during the first 12 months of tenofovir-containing ART in primary

Identification of poly(rC) binding protein 2 (PCBP2) as a target protein of immunosuppressive agent 15-deoxyspergualin

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Murahashi, Masataka; Simizu, Siro; Morioka, Masahiko [Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan); Umezawa, Kazuo, E-mail: umezawa@aichi-med-u.ac.jp [Department of Molecular Target Medicine, Aichi Medical University School of Medicine, 1-1 Yazako-Karimata, Nagakute 480-1195 (Japan)

2016-08-05

15-Deoxyspergualin (DSG) is an immunosuppressive agent being clinically used. Unlike tacrolimus and cyclosporine A, it does not inhibit the calcineurin pathway, and its mechanism of action and target molecule have not been elucidated. Therefore, we previously prepared biotinylated derivative of DSG (BDSG) to fish up the target protein. In the present research, we identified poly(rC) binding protein 2 (PCBP2) as a DSG-binding protein using this probe. DSG was confirmed to bind to PCBP2 by pull-down assay. Intracellular localization of PCBP2 was changed from the nucleus to the cytoplasm by DSG treatment. DSG inhibited the cell growth, and over-expression of PCBP2 reduced the anti-proliferative activity of DSG. PCBP2 is known to regulate various proteins including STAT1/2. Thus, we found PCBP2 as the first target protein of DSG that can explain the immunosuppressive activity. -- Highlights: •Fifteen-deoxyspergualin (DSG) is an immunosuppressive agent clinically used. •We have identified PCBP2, an RNA-binding protein, as a molecular target of DSG. •Alteration of PCBP2 activity may explain the immunosuppressive activity of DSG.

The safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious uveitis in childhood.

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Little, Jessica A; Sen, Ethan S; Strike, Helen; Hinchcliffe, Annie; Guly, Catherine M; Lee, Richard W J; Dick, Andrew D; Ramanan, Athimalaipet V

2014-01-01

To assess the safety and efficacy of noncorticosteroid triple immunosuppressive therapy in the treatment of refractory chronic noninfectious childhood uveitis. Subjects were retrospectively selected from a database. Patients were included if they were diagnosed with chronic, noninfectious uveitis at 16 years of age or under and treated with triple immunosuppressive therapy for at least 6 months (following failure of a combination of 2 immunosuppressants). Patient demographics, diagnoses, duration of uveitis, drug dosages, active joint inflammation, and ophthalmologic data were recorded. Efficacy outcomes for triple therapy were recorded at 6 months. Thirteen patients with bilateral uveitis were included. Using Standardized Uveitis Nomenclature (SUN) criteria, at 6 months only 11 eyes (42%) had a 2-step improvement in anterior chamber cell inflammation (n = 26). In addition, 2 patients required additional oral corticosteroid treatment. There were 4 significant infectious adverse events during a total of 21.9 patient-years (PY) on triple therapy (0.18 events per PY). In this group of children with refractory uveitis, addition of a third immunosuppressive agent did not confer substantial benefit in redressing ocular inflammation and was associated with significant infections in a minority of patients.

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study.

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Elisa Oliveira Marsicano

Full Text Available Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system.Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adherence score consisting of three methods (self-report [i.e., The Basel Adherence Scale for Assessment of Immunossupressives-BAASIS], collateral report, and immunosuppressive blood levels. Multilevel correlations of non-adherence were assessed (macro, meso, micro and patient level. Univariate and multivariate logistic regression was applied to assess the correlates of non-adherence.Our sample consisted primarily of male (65%, Caucasians (72% with a mean age of 45.0 ± 13.5 years old, who received grafts from a living donor (89%, with a mean time after transplantation of 72.3 ± 44.4 months. Prevalence of non-adherence was 51%. Family income higher than five reference wages (21.6 vs. 4%; OR 6.46 [1.35-30.89], p = 0.009; patient level, and having access to private health insurance (35.3% vs. 18.4%; OR 2.42 [0.96-6.10], p = 0.04; meso level were associated with non-adherence in univariate analysis. Only the higher family income variable was retained in the multiple logistic regression model (OR 5.0; IC: 1.01-25.14; p = 0.04.Higher family income was the only factor that was associated with immunosuppressive non-adherence. In Brazil, lower income recipients benefit from better access to care and coverage of health care costs after transplantation. This is supposed to result in a better immunosuppressive adherence compared to high-income patients who have experienced these benefits continuously.

Multilevel Correlates of Non-Adherence in Kidney Transplant Patients Benefitting from Full Cost Coverage for Immunosuppressives: A Cross-Sectional Study.

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Marsicano, Elisa Oliveira; Fernandes, Neimar Silva; Colugnati, Fernando Antônio Basile; Fernandes, Natalia Maria Silva; De Geest, Sabina; Sanders-Pinheiro, Helady

2015-01-01

Adherence is the result of the interaction of the macro, meso, micro, and patient level factors. The macro level includes full coverage of immunosuppressive medications as is the case in Brazil. We studied the correlates of immunosuppressive non-adherence in post kidney transplant patients in the Brazilian health care system. Using a cross-sectional design, adherence to immunosuppressives was assessed in a sample of 100 kidney transplant patients using a composite non-adherence score consisting of three methods (self-report [i.e., The Basel Adherence Scale for Assessment of Immunossupressives-BAASIS], collateral report, and immunosuppressive blood levels). Multilevel correlations of non-adherence were assessed (macro, meso, micro and patient level). Univariate and multivariate logistic regression was applied to assess the correlates of non-adherence. Our sample consisted primarily of male (65%), Caucasians (72%) with a mean age of 45.0 ± 13.5 years old, who received grafts from a living donor (89%), with a mean time after transplantation of 72.3 ± 44.4 months. Prevalence of non-adherence was 51%. Family income higher than five reference wages (21.6 vs. 4%; OR 6.46 [1.35-30.89], p = 0.009; patient level), and having access to private health insurance (35.3% vs. 18.4%; OR 2.42 [0.96-6.10], p = 0.04; meso level) were associated with non-adherence in univariate analysis. Only the higher family income variable was retained in the multiple logistic regression model (OR 5.0; IC: 1.01-25.14; p = 0.04). Higher family income was the only factor that was associated with immunosuppressive non-adherence. In Brazil, lower income recipients benefit from better access to care and coverage of health care costs after transplantation. This is supposed to result in a better immunosuppressive adherence compared to high-income patients who have experienced these benefits continuously.

First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy.

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Yoshida, Nao; Kobayashi, Ryoji; Yabe, Hiromasa; Kosaka, Yoshiyuki; Yagasaki, Hiroshi; Watanabe, Ken-Ichiro; Kudo, Kazuko; Morimoto, Akira; Ohga, Shouichi; Muramatsu, Hideki; Takahashi, Yoshiyuki; Kato, Koji; Suzuki, Ritsuro; Ohara, Akira; Kojima, Seiji

2014-12-01

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86-90) versus 92% (90-94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54-59) versus 87% (85-90); Paplastic anemia. Copyright© Ferrata Storti Foundation.

Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination.

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Ren, Jiangping; Yao, Linong; Sun, Jimin; Gong, Zhenyu

2015-01-01

The Zagreb regimen, an abbreviated intramuscular schedule for rabies vaccination, was developed by I. Vodopija and colleagues of the Zagreb Institute of Public Health in Croatia in the 1980s. It was recommended by WHO as one of the intramuscular (IM) schedules for rabies vaccination in 2010. We reviewed the literature on the immunogenicity, safety, economic burden, and compliance of the Zagreb 2-1-1 regimen. Compared to Essen, another IM schedule recommended by WHO, Zagreb has higher compliance, lower medical cost, and better immunogenicity at an early stage. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination.

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Cheetham, T Craig; Marcy, S Michael; Tseng, Hung-Fu; Sy, Lina S; Liu, In-Lu Amy; Bixler, Felicia; Baxter, Roger; Donahue, James G; Naleway, Allison L; Jacobsen, Steven J

2015-07-01

To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines. Copyright © 2015 Mayo Foundation for Medical Education and Research. All rights reserved.

Variability in Antibiotic Regimens for Surgical Necrotizing Enterocolitis Highlights the Need for New Guidelines.

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Blackwood, Brian P; Hunter, Catherine J; Grabowski, Julia

Necrotizing enterocolitis or NEC is the most common gastrointestinal emergency in the newborn. The etiology of NEC remains unknown, and treatment consists of antibiotic therapy and supportive care with the addition of surgical intervention as necessary. Unlike most surgical diseases, clear guidelines for the type and duration of peri-operative antibiotic therapy have not been established. Our aim was to review the antibiotic regimen(s) applied to surgical patients with NEC within a single neonatal intensive care unit (NICU) and to evaluate outcomes and help develop guidelines for antibiotic administration in this patient population. A single-center retrospective review was performed of all patients who underwent surgical intervention for NEC from August 1, 2005 through August 1, 2015. Relevant data were extracted including gestational age, age at diagnosis, gender, pre-operative antibiotic treatment, post-operative antibiotic treatment, development of stricture, and mortality. Patients were excluded if there was incomplete data documentation. A total of 90 patients were identified who met inclusion criteria. There were 56 male patients and 34 female patients. The average gestational age was 30 5/7 wks and average age of diagnosis 16.7 d. A total of 22 different pre-operative antibiotic regimens were identified with an average duration of 10.6 d. The most common pre-operative regimen was ampicillin, gentamicin, and metronidazole for 14 d. A total of 15 different post-operative antibiotic regimens were identified with an average duration of 6.6 d. The most common post-operative regimen was ampicillin, gentamicin, and metronidazole for two days. There were 26 strictures and 15 deaths. No regimen or duration proved superior. We found that there is a high degree of variability in the antibiotic regimen for the treatment of NEC, even within a single NICU, with no regimen appearing superior over another. As data emerge that demonstrate the adverse effects of

An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis.

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Wong, S H; Saunders, M D; Larner, A J; Das, K; Hart, I K

2010-10-01

Voltage-gated potassium channel antibody-positive limbic encephalitis (VGKC+LE) frequently improves with immunotherapy, although the optimum regimen is unknown. The effectiveness of a combination immunomodulatory regimen was tested in consecutive VGKC+LE patients. This was an open-label prospective study of nine VGKC+LE patients. All patients had plasma exchange (50 ml/kg), intravenous immunoglobulin (2 g/kg) and intravenous methylprednisolone (1 g×3), followed by maintenance oral prednisolone (1 mg/kg/day). Mycophenolate (2 g/day) was used in the first three patients. Assessments included serial clinical, cognitive, brain MRI and VGKC antibody testing. Within 1 week, seizures and hyponatraemia remitted in all affected patients. Cognitive function improved in all patients within 3 months. MRI appearances improved substantially within 9 months, with remission of inflammation in the majority of patients. All achieved immunological remission with normal VGKC antibody titres within 1-4 months. Major adverse events of therapy included one septicaemia and one thrombosis on plasma exchange and one death from sepsis after incidental bowel surgery. One patient remains in remission after 40 months of follow up, 26 months after being off all treatment. Our immunotherapy regimen was effective for the treatment of the clinical, cognitive and immunological features of VGKC+LE. Radiological improvement was seen in the majority. Pending randomised controlled trials, this regimen is proposed for the treatment of VGKC+LE.

Maintenance immunosuppression with intermittent intravenous IL-2 receptor antibody therapy in renal transplant recipients.

LENUS (Irish Health Repository)

Gabardi, Steven

2011-09-01

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation.

Modified uterine allotransplantation and immunosuppression procedure in the sheep model.

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Li Wei

Full Text Available OBJECTIVE: To develop an orthotopic, allogeneic, uterine transplantation technique and an effective immunosuppressive protocol in the sheep model. METHODS: In this pilot study, 10 sexually mature ewes were subjected to laparotomy and total abdominal hysterectomy with oophorectomy to procure uterus allografts. The cold ischemic time was 60 min. End-to-end vascular anastomosis was performed using continuous, non-interlocking sutures. Complete tissue reperfusion was achieved in all animals within 30 s after the vascular re-anastomosis, without any evidence of arterial or venous thrombosis. The immunosuppressive protocol consisted of tacrolimus, mycophenolate mofetil and methylprednisolone tablets. Graft viability was assessed by transrectal ultrasonography and second-look laparotomy at 2 and 4 weeks, respectively. RESULTS: Viable uterine tissue and vascular patency were observed on transrectal ultrasonography and second-look laparotomy. Histological analysis of the graft tissue (performed in one ewe revealed normal tissue architecture with a very subtle inflammatory reaction but no edema or stasis. CONCLUSION: We have developed a modified procedure that allowed us to successfully perform orthotopic, allogeneic, uterine transplantation in sheep, whose uterine and vascular anatomy (apart from the bicornuate uterus is similar to the human anatomy, making the ovine model excellent for human uterine transplant research.

Determining the optimal pelvic floor muscle training regimen for women with stress urinary incontinence.

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Dumoulin, Chantale; Glazener, Cathryn; Jenkinson, David

2011-06-01

Pelvic floor muscle (PFM) training has received Level-A evidence rating in the treatment of stress urinary incontinence (SUI) in women, based on meta-analysis of numerous randomized control trials (RCTs) and is recommended in many published guidelines. However, the actual regimen of PFM training used varies widely in these RCTs. Hence, to date, the optimal PFM training regimen for achieving continence remains unknown and the following questions persist: how often should women attend PFM training sessions and how many contractions should they perform for maximal effect? Is a regimen of strengthening exercises better than a motor control strategy or functional retraining? Is it better to administer a PFM training regimen to an individual or are group sessions equally effective, or better? Which is better, PFM training by itself or in combination with biofeedback, neuromuscular electrical stimulation, and/or vaginal cones? Should we use improvement or cure as the ultimate outcome to determine which regimen is the best? The questions are endless. As a starting point in our endeavour to identify optimal PFM training regimens, the aim of this study is (a) to review the present evidence in terms of the effectiveness of different PFM training regimens in women with SUI and (b) to discuss the current literature on PFM dysfunction in SUI women, including the up-to-date evidence on skeletal muscle training theory and other factors known to impact on women's participation in and adherence to PFM training. Copyright © 2011 Wiley-Liss, Inc.

Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin)

DEFF Research Database (Denmark)

Bramow, S; Ott, P; Thomsen Nielsen, F

2001-01-01

then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9...... secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most...... CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA....

Electronically-measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation*

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Israni, Ajay K.; Weng, Francis L.; Cen, Ye-Ying; Joffe, Marshall; Kamoun, Malek; Feldman, Harold I.

2013-01-01

Background Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss. Methods In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR. Results The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%) and 30 (12%) had >85–100%, 50–85% and adherence, respectively. 79 (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time. Conclusions Non-adherence with a single immunosuppressive medication, was not associated with kidney allograft outcomes. PMID:20977496

Electronically measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation.

Science.gov (United States)

Israni, Ajay K; Weng, Francis L; Cen, Ye-Ying; Joffe, Marshall; Kamoun, Malek; Feldman, Harold I

2011-01-01

Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss. In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR. The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%), and 30 (12%) had >85-100%, 50-85%, and adherence, respectively. Seventy-nine (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time. Non-adherence with a single immunosuppressive medication was not associated with kidney allograft outcomes. © 2010 John Wiley & Sons A/S.

Progressive outer retinal necrosis and immunosuppressive therapy in myasthenia gravis.

Science.gov (United States)

Coisy, Solène; Ebran, Jean-Marc; Milea, Dan

2014-01-01

Progressive outer retinal necrosis (PORN) is a rare but devastating infectious retinitis associated with varicella zoster virus (VZV) and responsible for severe visual loss. A 59-year-old man treated for generalized myasthenia with oral azathioprine and prednisone presented with severe unilateral necrotizing retinitis. Polymerase chain reaction of the aqueous and vitreous humors was diagnostic for VZV PORN. VZV PORN is a severe potential ocular complication of immunosuppression, prompting urgent diagnosis and appropriate treatment.

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

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Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Jambunathan, Kalyani; Baluya, Dodge L.; Brown, David L.; Kwara, Awewura; Mirsalis, Jon C.; Hafner, Richard; Louie, Arnold

2015-01-01

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. PMID:26530386

A 27-Year-Old Severely Immunosuppressed Female with Misleading Clinical Features of Disseminated Cutaneous Sporotrichosis

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Atiyah Patel

2016-01-01

Full Text Available Sporotrichosis is a subacute or chronic granulomatous mycosis caused by fungus of the Sporothrix schenckii complex. It is considered to be a rare condition in most parts of the world. It mostly causes cutaneous infection but can also cause multisystemic disease. Unlike most deep cutaneous mycoses which have a primary pulmonary focus, it is usually caused by direct inoculation of the fungus into the skin causing a classical linear, lymphocutaneous nodular eruption. However, atypical presentations of the condition can occur especially in immunosuppressed individuals. We report the case of a severely immunosuppressed female who presented with disseminated cutaneous sporotrichosis which was initially diagnosed and treated as disseminated cutaneous Kaposi’s sarcoma.

A 27-Year-Old Severely Immunosuppressed Female with Misleading Clinical Features of Disseminated Cutaneous Sporotrichosis

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Patel, Atiyah; Mudenda, Victor; Lakhi, Shabir; Ngalamika, Owen

2016-01-01

Sporotrichosis is a subacute or chronic granulomatous mycosis caused by fungus of the Sporothrix schenckii complex. It is considered to be a rare condition in most parts of the world. It mostly causes cutaneous infection but can also cause multisystemic disease. Unlike most deep cutaneous mycoses which have a primary pulmonary focus, it is usually caused by direct inoculation of the fungus into the skin causing a classical linear, lymphocutaneous nodular eruption. However, atypical presentations of the condition can occur especially in immunosuppressed individuals. We report the case of a severely immunosuppressed female who presented with disseminated cutaneous sporotrichosis which was initially diagnosed and treated as disseminated cutaneous Kaposi's sarcoma. PMID:26881148

Eficácia, tolerabilidade e segurança do uso do sirolimo após o transplante renal Sirolimus efficacy, tolerability, and safety for treatment after kidney transplantation

Directory of Open Access Journals (Sweden)

Nagilla Ione Oliveira

2009-12-01

Full Text Available INTRODUÇÃO: Sirolimo (SRL é um imunossupressor com conhecida eficácia e perfil de segurança na profilaxia da rejeição aguda após o transplante renal. OBJETIVOS: Avaliar eficácia, tolerabilidade e segurança do uso do SRL e de prednisona em associação a ciclosporina (CSA ou tacrolimo (TAC após o transplante renal. METODOLOGIA: Estudo retrospectivo de 332 receptores de transplantes renais realizados entre 1999 e 2006. O desfecho primário foi a falha de tratamento, definida como a incidência cumulativa de rejeição aguda confirmada por biópsia (RACB, perda do enxerto, óbito ou descontinuação do SRL. RESULTADOS: Dos 332 transplantes, 92% foram com doador vivo. A média de idade dos receptores foi de 37 anos, sendo 65% homens, 46% brancos e 6% diabéticos. SRL foi associado a CSA ou TAC em 70,8% e 29,2% dos pacientes. A incidência de falha de tratamento foi de 22,2% e de 47,8% no final do primeiro e do quinto ano de transplante, sem diferença entre pacientes recebendo CSA ou TAC. Ao final do quinto ano, as sobrevidas do paciente, do enxerto, do enxerto censorando o óbito e livre de RACB foram de 92,8%, 86,1%, 92,7% e 82,2%, respectivamente. O tratamento com SRL foi interrompido em 27,1% dos pacientes: 22,9% em razão de reações adversas e 3,3% devido à ineficácia. Os principais motivos de suspensão do SRL foram dislipidemia (6,0%, disfunção do enxerto (5,2%, proteinúria (4,5%, infecções (1,5%, dificuldade de cicatrização (1,2% e anemia (0,9%. CONCLUSÃO: Na população estudada, a eficácia e a segurança do SRL foram semelhantes quando combinado com CSA ou TAC. A tolerabilidade oral foi adequada considerando-se a relativa baixa taxa de interrupção do uso de SRL.INTRODUCTION: Sirolimus (SRL is an immunosuppressive drug with confirmed efficacy and safety profile in the prophylaxis of acute rejection after renal transplantation. OBJECTIVES: To assess the efficacy, safety, and tolerability of SRL and prednisone in

96 Week Follow-Up of HIV-Infected Patients in Rescue with Raltegravir Plus Optimized Backbone Regimens: A Multicentre Italian Experience

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Capetti, Amedeo; Landonio, Simona; Meraviglia, Paola; Di Biagio, Antonio; Lo Caputo, Sergio; Sterrantino, Gaetana; Ammassari, Adriana; Menzaghi, Barbara; Franzetti, Marco; De Socio, Giuseppe Vittorio; Pellicanò, Giovanni; Mazzotta, Elena; Soria, Alessandro; Meschiari, Marianna; Trezzi, Michele; Sasset, Lolita; Celesia, Benedetto Maurizio; Zucchi, Patrizia; Melzi, Sara; Ricci, Elena; Rizzardini, Giuliano

2012-01-01

Background Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. Methods Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. Results Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm3; 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA 4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm3, respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. Conclusions In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events. PMID:22808029

96 Week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience.

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Amedeo Capetti

Full Text Available BACKGROUND: Long term efficacy of raltegravir (RAL-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. METHODS: Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. RESULTS: Out of 320 patients enrolled, 292 (91.25% subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11, viral failure (8, adverse events (5, loss to follow-up (3, consent withdrawal (1. Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm(3; 273 out of 300 patients (91%, who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA 4 (n = 40, CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm(3, respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. CONCLUSIONS: In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Reactivation of tuberculosis during immunosuppressive treatment in a patient with a positive QuantiFERON-RD1 test

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Ravn, Pernille; Munk, Martin E; Andersen, Ase Bengaard

2004-01-01

A patient with polymyositis developed tuberculosis during immunosuppressive treatment. Tuberculin Skin Test and chest X-ray failed to demonstrate latent tuberculosis, whereas a blood sample that was tested with a modified QuantiFERON-TB-assay, using the recombinant ESAT-6 and CFP-10, was positive...... indicating that this patient was latently infected before immunosuppressive therapy. This case indicates the risk of progressing from latent to active tuberculosis given that the subject is RD1 responsive, and we believe that preventive anti-tuberculous treatment could have prevented this case...

Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma

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Kopecka, Joanna; Gazzano, Elena; Sara, Orecchia; Ghigo, Dario; Riganti, Chiara

2015-01-01

The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-regulated kinase1/2 (ERK1/2)/hypoxia inducible factor-1α (HIF-1α) pathway and up-regulation of the drug efflux transporter P-glycoprotein (Pgp). By decreasing the isoprenoid supply, zoledronic acid down-regulated the Ras/ERK1/2/HIF-1α/Pgp axis and chemosensitized the HMM cells to Pgp substrates. The HMM cells also produced higher amounts of kynurenine, decreased the proliferation of T-lymphocytes and expanded the number of T-regulatory (Treg) cells. Kynurenine synthesis was due to the transcription of the indoleamine 1,2 dioxygenase (IDO) enzyme, consequent to the activation of the signal transducer and activator of transcription-3 (STAT3). By reducing the activity of the Ras/ERK1/2/STAT3/IDO axis, zoledronic acid lowered the kyurenine synthesis and the expansion of Treg cells, and increased the proliferation of T-lymphocytes. Thanks to its ability to decrease Ras/ERK1/2 activity, which is responsible for both Pgp-mediated chemoresistance and IDO-mediated immunosuppression, zoledronic acid is an effective chemo-immunosensitizing agent in HMM cells. PMID:25544757

Effect of Iron Containing Supplements on Rats' Dental Caries Progression

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AR. Eshghi

2012-01-01

Full Text Available Objective: Iron deficiency is the most common form of malnutrition in developing countries. Iron containing supplements have been used effectively to solve this problem. In children, because of teeth staining after taking iron drops, parents have the idea that iron drops are the cause of tooth decay; therefore, they limit thisvital supplement in their children’s diet. Hereby, we evaluate the histologic effect of iron containing supplements on tooth caries in rice rats with cariogenic or noncariogenic diet.Materials and Methods: Twelve rats were selected and divided into four groups for this interventional experimental study. Four different types of dietary regimens were used for four months; group A, cariogenic diet with iron containing supplements; group B, cariogenic diet without iron containing supplements; groupC, non-cariogenic diet with iron containing supplements; group D, non-cariogenic diet without iron containing supplements. After sacrificing the rats, 20-micron histological sections of their posterior teeth were prepared using the Ground Sectionmethod, then they were studied under polarized light microscopy. In order to compare the progression of caries in different samples, the depth of the lesions in the enamel was measured as three grades I, II and III.Results: The mean grade value of A, B, C and D groups were 1.61, 2.61, 1.37 and 1.80, respectively. Statistical analysis revealed that significantly fewer caries were seen in the group which had received iron containing supplements and cariogenicdiet compared with cariogenic diet without iron supplements (p<0.05.Conclusion: Ferrous sulfate reduces the progression of dental caries in the cariogenic dietary regimen.

Correlation of immunosuppression scheme with renal graft complications detected by dynamic renal scintigraphy

International Nuclear Information System (INIS)

Martins, Flavia Paiva Proenca; Gutfilen, Bianca

2001-01-01

Dynamic renal scintigraphy allows the diagnosis of complications in patients submitted to organ transplantation, such as perfusion abnormalities, acute tubular necrosis and rejection. In this study we employed 99m Tc-DTPA scintigraphy to study patients submitted to kidney transplantation. The results obtained and the clinical findings were conjunctively analyzed in order to detect graft rejection or other complications. The type of immunosuppressive scheme used was also correlated with the observed complications. Fifty-five patients submitted to kidney transplantation from 1989 to 1999 were evaluated. All patients with nephrotoxicity received a 3-drug immunosuppressive scheme. In this study, acute rejection was the most frequent complication (40.4%) observed following transplantation. Thirteen of 15 recipients of cadaveric kidney grafts presented acute tubular necrosis. Only one false-positive case was observed when scintigraphy and clinical findings were not concordant. We suggest carrying out renal scintigraphy to follow-up post-transplantation patients. (author)

Leveraging protein binding and the EPR effect in legacy chemotherapy regimens

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Shireesh Apte

2016-12-01

Full Text Available Legacy chemotherapy regimens have the potential to be significantly more effective and less toxic if the dosage is titrated so that the mole ratio of drugs to circulating albumin is less than or equal to 1 and the order of administration of the drugs within each course of the regimen follows the sequence most hydrophobic (usually the least dose to least hydrophobic (usually the largest dose

Microwave – assisted reduction of racemic intermediates potential immunosuppressant

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Wender A. Silva

2012-06-01

Full Text Available Immunosuppressant are drugs that reduce the immune response, as important in the treatment of autoimmune diseases and rejection attenuators in organ transplants, the structural point of view generally have a high complexity. Within this context it is indispensable structural simplifications, new molecules are proposed with potential action on a stage is a necessary, reduction system α,β-unsaturated specifically, chalcone, to their respective alcohol saturated. Therefore, a new method was developed for microwave assisted subsequently coupling to other fragments to the total synthesis of the novel compounds.

Acute Hepatitis E Virus infection with coincident reactivation of Epstein-Barr virus infection in an immunosuppressed patient with rheumatoid arthritis: a case report.

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Schultze, Detlev; Mani, Bernhard; Dollenmaier, Günter; Sahli, Roland; Zbinden, Andrea; Krayenbühl, Pierre Alexandre

2015-10-29

Hepatitis E virus (HEV) is the most recently discovered of the hepatotropic viruses, and is considered an emerging pathogen in developed countries with the possibility of fulminant hepatitis in immunocompromised patients. Especially in the latter elevated transaminases should be taken as a clue to consider HEV infection, as it can be treated by discontinuation of immunosuppression and/or ribavirin therapy. To our best knowledge, this is a unique case of autochthonous HEV infection with coincident reactivation of Epstein-Barr virus (EBV) infection in an immunosuppressed patient with rheumatoid arthritis (RA). A 68-year-old Swiss woman with RA developed hepatitis initially diagnosed as methotrexate-induced liver injury, but later diagnosed as autochthonous HEV infection accompanied by reactivation of her latent EBV infection. She showed confounding serological results pointing to three hepatotropic viruses (HEV, Hepatitis B virus (HBV) and EBV) that could be resolved by detection of HEV and EBV viraemia. The patient recovered by temporary discontinuation of immunosuppressive therapy. In immunosuppressed patients with RA and signs of liver injury, HEV infection should be considered, as infection can be treated by discontinuation of immunosuppression. Although anti-HEV-IgM antibody assays can be used as first line virological tools, nucleic acid amplification tests (NAAT) for detection of HEV RNA are recommended--as in our case--if confounding serological results from other hepatotropic viruses are obtained. After discontinuation of immunosuppressive therapy, our patient recovered from both HEV infection and reactivation of latent EBV infection without sequelae.

Ultraviolet spectral energy differences affect the ability of sunscreen lotions to prevent ultraviolet-radiation-induced immunosuppression

International Nuclear Information System (INIS)

Roberts, L.K.; Beasley, D.G.; Learn, D.B.; Giddens, L.D.; Beard, J.; Stanfield, J.W.

1996-01-01

Acute exposure to UV radiation causes immunosuppression of contact hypersensitivity (CH) responses. Past studies conducted with unfiltered sunlamps emitting non-solar spectrum UV power (wavelengths below 295 nm) or using excessive UV doses have suggested sunscreens may not prevent UV-induced immunosuppression in mice. This study was thus designed to evaluate critically the effects of different UV energy spectra on the immune protection capacity of sunscreen lotions. Minimum immune suppression doses (MISD), i.e. the lowest UV dose to cause ∼ 50% suppression of the CH response to dinitrofluorobenzene in C3H mice, were established for three artificial UV sources. The MISD for each UV source was 0.25 kJ/m 2 for unfiltered FS20 sunlamps (FS), 0.90 kJ/m 2 for Kodacel-filtered FS20 sunlamps (KFS), which do not emit UV power at wavelengths 2 for a 1000 W filtered xenon arc lamp solar simulator. Using MISD as baseline, sunscreens with labeled sun protection factors (SPF) of 2, 8, 15 and 30 were tested with each UV source to establish their relative immune protection factors. The immune protection factor of each sunscreen exceeded its labeled SPF in tests conducted with the solar simulator, which has a UV power spectrum (295-400 nm) similar to that of sunlight. Conversely, sunscreen immune protection factors were significantly less than the labeled SPF in tests conducted with FS and KFS. Comparison of the immunosuppression effectiveness spectra showed that relatively small amounts of nonsolar spectrum UV energy, i.e. UVC (200-290 nm) and/or shorter wavelength UVB (between 290 and 295 nm), produced by FS and KFS contributes significantly to the induction of immunosuppression. (Author)

Immunosuppressive effect of the anti-IL-2-receptor monoclonal antibody, AMT-13, on organ-cultured fetal pancreas allograft survival

International Nuclear Information System (INIS)

Burkhardt, K.; Loughnan, M.S.; Diamantstein, T.; Mandel, T.E.

1988-01-01

Recently, prolongation of cardiac allograft survival in mice was reported using a rat anti-IL-2R mAb (AMT-13). However, its immunosuppressive action in vivo, alone and in combination with other immunosuppressants, and its effect on other organ transplants has not been extensively studied. We grafted cultured fetal pancreas from CBA (H-2k) donors to Balb/c (H-2d) mice. Recipients were treated with 10 consecutive daily injections each of 20 micrograms AMT-13 only, or with an additional mild immunosuppression of 350 rads irradiation. Control groups received rat immunoglobulin or 350 rads irradiation. Graft survival and the phenotype of infiltrating cells were assessed histologically and immunocytochemically on days 12, 17, and 21, and soluble IL-2R levels were measured in the serum with a quantitative ELISA in all recipients. Two of five grafts in the AMT-13-treated group had islets on day 12 posttransplantation despite lymphocytic infiltration in all grafts, while at this time all grafts of rat Ig treated control mice were completely rejected with only scar tissue and a few lymphocytes remaining. Additional immunosuppression with 350 rads irradiation had a marked additive effect with AMT-13. Soluble IL-2R levels in the serum of untreated recipients were not elevated compared with normal serum levels, but recipients injected with AMT-13 had multifold increased soluble IL-2R levels. The percentage of IL-2R+ cells in the grafts of AMT-13-treated animals was either normal (less than 5%) or increased (20%) in the additionally irradiated mice, providing strong evidence that the immunosuppressive effect of AMT-13 is not due to a depletion of activated IL-2R+ lymphocytes

A randomized open-labeled study to demonstrate the non-inferiority of purified chick-embryo cell rabies vaccine administered in the Zagreb regimen (2-1-1) compared with the Essen regimen in Chinese adults.

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Ma, Jingchen; Wang, Hongchang; Li, Jun; Chang, Likuan; Xie, Yun; Liu, Zhonglin; Zhao, Yuliang; Malerczyk, Claudius; Claudius, Malerczyk

2014-01-01

The Zagreb regimen has been used for 20 years in various countries. In China, until 2010, the Zagreb schedule was only approved for purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccines (PVRV). In this phase III clinical trial, we aimed to demonstrate the safety and immunogenic non-inferiority of the Zagreb regimen compared with the Essen regimen in healthy adult Chinese immunized with PCECV (Rabipur®). The study enrolled 825 subjects aged 18 to 50 years; serum samples were collected on Days 0, 7, 14, 42, and at 13 months to assess rabies virus neutralizing antibody (RVNA) concentrations. Solicited and unsolicited local and systemic reactions were recorded for 6 days following the day of vaccination, and collected throughout the entire study period (Day 1 until Month 13). The Zagreb regimen was non-inferior to the Essen regimen with regard to RVNA concentrations after 7, 14, and 42 days, and 13 months of immunization. The non-inferiority of seroconversion was established at Days 14 and 42. The incidence of local and systemic reactions was similar between groups, and mostly of mild or moderate severity. Vaccine-related adverse events occurred more frequently in the Essen group than in the Zagreb group. Vaccination with PCECV under a 2-1-1 regimen is as safe and immunogenic as under the traditional 5-dose Essen regimen for rabies post-exposure prophylaxis, and is a more cost-effective option, has a more practical vaccination schedule, and can potentially increase compliance.

Dynamic Quantification of Host Schwann Cell Migration into Peripheral Nerve Allografts

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Whitlock, Elizabeth L.; Myckatyn, Terence M.; Tong, Alice Y.; Yee, Andrew; Yan, Ying; Magill, Christina K.; Johnson, Philip J.; Mackinnon, Susan E.

2010-01-01

Host Schwann cell (SC) migration into nerve allografts is the limiting factor in the duration of immunosuppression following peripheral nerve allotransplantation, and may be affected by different immunosuppressive regimens. Our objective was to compare SC migration patterns between clinical and experimental immunosuppression regimens both over time and at the harvest endpoint. Eighty mice that express GFP under the control of the Schwann cell specific S100 promoter were engrafted with allogeneic, nonfluorescent sciatic nerve grafts. Mice received immunosuppression with either tacrolimus (FK506), or experimental T-cell triple costimulation blockade (CSB), consisting of CTLA4-immunoglobulin fusion protein, anti-CD40 monoclonal antibody, and anti-inducible costimulator monoclonal antibody. Migration of GFP-expressing host SCs into wild-type allografts was assessed in vivo every 3 weeks until 15 weeks postoperatively, and explanted allografts were evaluated for immunohistochemical staining patterns to differentiate graft from host SCs. Immunosuppression with tacrolimus exhibited a plateau of SC migration, characterized by significant early migration (< 3 weeks) followed by a constant level of host SCs in the graft (15 weeks). At the endpoint, graft fluorescence was decreased relative to surrounding host nerve, and donor SCs persisted within the graft. CSB-treated mice displayed gradually increasing migration of host SCs into the graft, without the plateau noted in tacrolimus-treated mice, and also maintained a population of donor SCs at the 15-week endpoint. SC migration patterns are affected by immunosuppressant choice, particularly in the immediate postoperative period, and the use of a single treatment of CSB may allow for gradual population of nerve allografts with host SCs. PMID:20633557

[Morpho-functional reaction of spleen natural killer cells and macrophages to melatonin administration to the animals kept on different illumination regimens].

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Shatskikh, O A; Luzikova, E M

2012-01-01

The aim this investigation was to study the changes in the numbers of spleen CD57+ and CD68+ cells (natural killer cells and macrophages respectively) after melatonin administration to the animals kept on different illumination regimens. The experimental animals were given melatonin in dose of 0.03 mg per day for 2 and 4 weeks under conditions of natural illumination or artificial darkening. Spleen paraffin sections were stained using immunohistochemical methods for detection of CD57+ and CD68+ cells. It was shown that long-term administration of melatonin under conditions of natural illumination had an immunosuppressive effect, that was manifested by the depopulation of the marginal zones, white pulp and all the zones of the red pulp, parenchyma loosening and denudation of the reticular stroma of the organ. However, long-term hormone administration under conditions of artificial darkening had an immunostimulatory effect as evidenced by the increased inflow of immunocompetent cells into the spleen, their migration from the white pulp into the marginal zones and emigration into peripheral blood flow, concomitant with the increase in the number of lymphoid nodules. The number of CD57+ and CD68+ cells was increased in splenic periarterial lymphoid sheaths and decreased in B-dependent zones of the organ.

Listeria monocytogenes Meningitis in an Immunosuppressed Patient with Autoimmune Hepatitis and IgG4 Subclass Deficiency

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Shahin Gaini

2015-01-01

Full Text Available A 51-year-old Caucasian woman with Listeria monocytogenes meningitis was treated and discharged after an uncomplicated course. Her medical history included immunosuppressive treatment with prednisolone and azathioprine for autoimmune hepatitis. A diagnostic work-up after the meningitis episode revealed that she had low levels of the IgG4 subclass. To our knowledge, this is the first case report describing a possible association between autoimmune hepatitis and the occurrence of Listeria monocytogenes meningitis, describing a possible association between Listeria monocytogenes meningitis and deficiency of the IgG4 subclass and finally describing a possible association between Listeria monocytogenes meningitis and immunosuppressive therapy with prednisolone and azathioprine.

Listeria monocytogenes Meningitis in an Immunosuppressed Patient with Autoimmune Hepatitis and IgG4 Subclass Deficiency

DEFF Research Database (Denmark)

Gaini, Shahin

2015-01-01

A 51-year-old Caucasian woman with Listeria monocytogenes meningitis was treated and discharged after an uncomplicated course. Her medical history included immunosuppressive treatment with prednisolone and azathioprine for autoimmune hepatitis. A diagnostic work-up after the meningitis episode...... revealed that she had low levels of the IgG4 subclass. To our knowledge, this is the first case report describing a possible association between autoimmune hepatitis and the occurrence of Listeria monocytogenes meningitis, describing a possible association between Listeria monocytogenes meningitis...... and deficiency of the IgG4 subclass and finally describing a possible association between Listeria monocytogenes meningitis and immunosuppressive therapy with prednisolone and azathioprine....

Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia

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Sakaguchi, Hirotoshi; Nishio, Nobuhiro; Hama, Asahito; Kawashima, Nozomu; Wang, Xinan; Narita, Atsushi; Doisaki, Sayoko; Xu, Yinyan; Muramatsu, Hideki; Yoshida, Nao; Takahashi, Yoshiyuki; Kudo, Kazuko; Moritake, Hiroshi; Nakamura, Kazuhiro; Kobayashi, Ryoji; Ito, Etsuro; Yabe, Hiromasa; Ohga, Shouichi; Ohara, Akira; Kojima, Seiji

2014-01-01

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5–16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41–69%) and 97% (95%CI: 87–99%), respectively. Median telomere length in responders was −0.4 standard deviation (SD) (−2.7 to +3.0 SD) and −1.5 SD (−4.0 to +1.6 (SD)) in non-responders (Paplastic anemia. PMID:24816243

Effects of Immunosuppressants on Immune Response to Vaccine in Inflammatory Bowel Disease

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Yuan Cao

2015-01-01

Full Text Available Objective: To evaluate the response rate to vaccination in different treatment groups (nonimmunosuppressants and immunosuppressants. Data Sources: We completed an online systematic search using PubMed to identify all articles published in English between January 1990 and December 2013 assessing the effect of the response rate to vaccination in different treatment groups (with and without immunomodulators. The following terms were used: "inflammatory bowel disease (IBD" OR "Crohn′s disease" OR "ulcerative colitis" AND ("vaccination" OR "vaccine" AND ("corticosteroids" OR "mercaptopurine" OR "azathioprine" OR "methotrexate [MTX]" AND "immunomodulators." Study Selection: The inclusion criteria of articles were that the studies: (1 Randomized controlled trials which included patients with a diagnosis of IBD (established by standard clinical, radiographic, endoscopic, and histologic criteria; (2 exposed patients received immunomodulators for maintenance (weight-appropriate doses of 6-mercaptopurine/azathioprine or within 3 months of stopping, 15 mg or more MTX per week or within 3 months of stopping; (3 exposed patients received nonimmunomodulators (no therapy, antibiotics only, mesalazine only, biological agent only such as infliximab, adalimumab, certolizumab or natalizumab or within 3 months of stopping one of these agents. The exclusion criteria of articles were that the studies: (1 History of hepatitis B virus (HBV, influenza or streptococcus pneumoniae infection; (2 patients who had previously been vaccinated against HBV, influenza or streptococcus pneumoniae; (3 any medical condition known to cause immunosuppression (e.g. chronic renal failure and human immunodeficiency virus infection; (4 individuals with positive hepatitis markers or liver cirrhosis; (5 patients with a known allergy to eggs or other components of the vaccines and (6 pregnancy. Results: Patients treated with immunomodulators were associated with lower response rates to

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

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Mary J Warrell

2008-04-01

Full Text Available The need for economical rabies post-exposure prophylaxis (PEP is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90; or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

Science.gov (United States)

Warrell, Mary J; Riddell, Anna; Yu, Ly-Mee; Phipps, Judith; Diggle, Linda; Bourhy, Hervé; Deeks, Jonathan J; Fooks, Anthony R; Audry, Laurent; Brookes, Sharon M; Meslin, François-Xavier; Moxon, Richard; Pollard, Andrew J; Warrell, David A

2008-04-23

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Controlled

Monitoring the patient off immunosuppression. Conceptual framework for a proposed tolerance assay study in liver transplant recipients.

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Thomson, A W; Mazariegos, G V; Reyes, J; Donnenberg, V S; Donnenberg, A D; Bentlejewski, C; Zahorchak, A F; O'Connell, P J; Fung, J J; Jankowska-Gan, E; Burlingham, W J; Heeger, P S; Zeevi, A

2001-10-27

The mission of the recently established Immune Tolerance Network includes the development of protocols for the induction of transplant tolerance in organ allograft recipients and the development of assays that correlate with and may be predictive of the tolerant state. The state of clinical organ transplant tolerance seems to already exist in a small minority of conventionally immunosuppressed liver and, more rarely, kidney transplant patients. Immunosuppressive drug therapy has been withdrawn from these patients for a variety of reasons, including protocolized weaning for a uniquely large group of liver patients at the University of Pittsburgh. In this study, we propose to evaluate the validity of a variety of in vitro immunologic and molecular biologic tests that may correlate with, and be predictive of, the state of organ transplant tolerance in stable liver patients off immunosuppression. Only peripheral blood will be available for the execution of these tests. Both adult and pediatric liver graft recipients will be studied, in comparison to appropriate controls. We shall examine circulating dendritic cell (DC) subsets [precursor (p) DC1 and p DC2] including cells of donor origin, and assess both the frequency and function of donor-reactive T cells by ELISPOT and by trans-vivo delayed-type hypersensitivity analysis in a surrogate murine model. Cytokine gene polymorphism and alloantibody titers will also be investigated. It is anticipated that the results obtained may provide physicians with a tolerance assay "profile" that may determine those patients from whom immunosuppressive therapy may be safely withdrawn.