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At least 19 recordsLinked to original sources
PubMed1999

Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. United States Simulect Renal Study Group.

BACKGROUND: A double-blind, placebo-controlled phase III study was performed to assess whether basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, reduced the incidence of acute rejection episodes in renal allograft recipients. METHODS: A total of 348 patients were randomized into two demographically matched, equally sized groups treated with either basiliximab or placebo. The dose of basiliximab-20-mg infusions on day 0 and day 4-was selected to block detection of interleukin-2 receptor on 97% of peripheral blood lymphocytes for 30-45 days. All patients received immunosuppressive therapy with cyclosporine microemulsion (Neoral) and steroids. An intent-to-treat analysis of 1-year data assessed the incidence of posttransplant acute rejection episodes, patient and graft survival rates, and the safety and tolerability of basiliximab. RESULTS: Among the eligible 346 patients equally divided into the two treatment groups, basiliximab reduced the proportion of patients who experienced biopsy-confirmed acute rejection episodes by 28%: 61 (35.3%) basiliximab vs. 85 (49.1%) placebo (P=0.009). Graft losses occurred in 9 (5.2%) basiliximab-treated and 12 (6.9%) placebo-treated patients. Five (2.9%) deaths in the basiliximab group and seven (4.0%) in the placebo group occurred. Compared with placebo, a higher fraction of basiliximab patients produced urine in the operating room, and a significantly lower fraction had renal dysfunction in the first month (serum creatinine > or =5 mg(dl) and between 1 and 12 months (serum creatinine > or =3 mg/dl). During the first 12 months, 94 (54%) basiliximab-treated patients experienced serious adverse events, compared with 106 (61%) who received placebo. CONCLUSIONS: Prophylactic basiliximab therapy is well tolerated, has an adverse event profile comparable to placebo, and significantly reduces the number of acute rejection episodes in renal allograft patients within the first year after transplantation.

Acute Disease↗
PubMed1999

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. The U.S. Simulect Renal Transplant Study Group.

BACKGROUND: Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. METHODS: Serial blood samples (8.2+/-1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 microg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. RESULTS: Basiliximab clearance was 36.7+/-15.2 ml/hr, distribution volume 8.0+/-2.4 L, and half life 7.4+/-3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed < or =6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36+/-14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 microg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33+/-13 days vs. 37+/-14 days for rejection-free patients, P=0.162). CONCLUSIONS: There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Adult↗
PubMed1997

Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group.

BACKGROUND: Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients. METHODS: 380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study. FINDINGS: 376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group. INTERPRETATION: Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.

Acute Disease↗
PubMed1999

Screening for basiliximab exposure-response relationships in renal allotransplantation.

The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

Adult↗
PubMed1999

Basiliximab.

The chimaeric monoclonal antibody basiliximab specifically binds the alpha subunit of the interleukin-2 (IL-2) receptor on activated T lymphocytes. Through competitive antagonism of IL-2, basiliximab supplements standard immunosuppressive therapy after renal transplantation. < or =24 Hours after a single intravenous dose of basiliximab 2.5 to 25 mg, approximately 90% of available IL-2 receptors on T lymphocytes were complexed with the drug. This level of basiliximab binding was maintained for 4 to 6 weeks when renal transplant patients received basiliximab 20 mg 2 hours before and then 4 days after transplantation surgery. In 2 large, well-designed trials, the percentage of patients with biopsy-confirmed acute rejection episodes after renal transplantation was significantly lower with basiliximab 20 mg (administered 2 hours before and then 4 days after transplantation surgery; 30 or 33%, respectively) than placebo (44 or 46%) at 6 months after surgery. Basiliximab was well tolerated during clinical trials. The incidence of infections (including active cytomegalovirus infection) and post-transplant lymphoproliferative disorders was similar with basiliximab and placebo. Cytokine release syndrome was not observed in patients who received basiliximab.

Animals↗
PubMed1997

Disposition of basiliximab, an interleukin-2 receptor monoclonal antibody, in recipients of mismatched cadaver renal allografts.

BACKGROUND: Basiliximab is an interleukin-2 receptor (IL-2R; CD25) chimeric monoclonal antibody for immunoprophylaxis against acute rejection in renal transplantation. Its pharmacokinetics were characterized in a multicenter open-label, prospective dose-escalation study to identify a single-dose regimen providing IL-2R-saturating serum concentrations in the critical first posttransplant month. METHODS: Thirty-two recipients of primary, mismatched cadaver kidneys were enrolled: 20 men and 12 women, who were 47+/-11 years old and weighed 65+/-12 kg. The immunosuppression regimen consisted of steroids and azathioprine from day 0 and cyclosporine from day 10. Basiliximab was infused over 30 min as a single dose preoperatively. RESULTS: Thirty patients were evaluable for basiliximab pharmacokinetics: 24 received 40 mg and 6 received 60 mg. Basiliximab was well tolerated without evidence of cytokine-release syndrome, hypersensitivity reactions, or anti-idiotype antibody response. Peak concentration and area under the concentration curve increased proportionally with dose. Postinfusion concentrations declined in a biphasic manner with a terminal half-life of 6.5+/-2.1 days. Weak, widely dispersed correlations were noted between body weight versus distribution volume (r=0.29) and versus clearance (r=0.45), suggesting no clinical relevance for weight-adjusted dosing. There were no apparent gender-related differences in basiliximab disposition. Previous phase II data indicated that serum concentrations in excess of 0.2 microg/ml are sufficient to saturate IL-2R epitopes on circulating T lymphocytes. Concentrations were above this threshold for 26+/-8 days (range 16 to 46) at the 40-mg dose level and for 32+/-11 days (range 22 to 51) at the 60-mg dose level. CONCLUSIONS: Total basiliximab doses of 40-60 mg were well tolerated, nonimmunogenic, and estimated to provide immunoprophylaxis to cover the first posttransplant month.

Adult↗
PubMed1998

Disposition and immunodynamics of basiliximab in liver allograft recipients.

A randomized, open-label prospective study was conducted with recipients of primary cadaveric liver allografts to characterize the disposition and immunodynamics of basiliximab, an interleukin-2 receptor, alpha-chain chimeric monoclonal antibody for immunoprophylaxis of acute rejection. Patients received a total intravenous dose of 40 mg basiliximab in addition to baseline dual immunosuppression consisting of cyclosporine (INN, ciclosporin) and steroids. The central distribution volume was 5.6 +/- 1.7 L with a steady-state volume of 7.5 +/- 2.5 L. It was cleared slowly with a total body clearance of 75 +/- 24 ml/hr and an elimination half-life of 4.1 +/- 2.1 days. Basiliximab was measurable in drained ascites fluid, and clearance by this route was an average of 20% of total clearance. Total body clearance correlated positively with volume of postoperative blood loss (r = 0.5253, p = 0.0101), suggesting that bleeding may represent an additional route of drug removal. A threshold relation was observed between serum concentration of basiliximab and CD25 expression on T lymphocytes whereby complete saturation of interleukin-2 receptor alpha-chain was maintained as long as serum concentrations exceeded 0.1 microgram/ml. The duration of receptor saturation was 23 +/- 7 days after transplantation (range, 13 to 41 days).

Adolescent↗
PubMed1999

Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation.

Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor alpha-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 microgram/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20 mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7-52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7-58.3 days.

Algorithms↗
PubMed2000

Prevention of acute allograft rejection in nonhuman primate lung transplant recipients: induction with chimeric anti-interleukin-2 receptor monoclonal antibody improves the tolerability and potentiates the immunosuppressive activity of a regimen using low doses of both microemulsion cyclosporine and 40-O-(2-hydroxyethyl)-rapamycin.

BACKGROUND: In previous studies of cynomolgus monkey lung allograft recipients, we demonstrated significant immunosuppressive efficacy but reduced tolerability after combined treatment with high doses of microemulsion cyclosporine (CsA) and SDZ RAD (40-O-(2-hydroxyethyl)-rapamycin). The current study was designed to compare efficacy and tolerability of a combination of low-dose CsA and high-dose SDZ RAD (CTL group) to triple therapy using the chimeric anti-interleukin-2 (IL-2) receptor (CD25) monoclonal antibody (mAb) basiliximab (anti-IL-2 receptor mAb) for induction therapy (basiliximab: 5 mg intravenously on days 0 and 4) plus low-dose CsA and low-dose SDZ RAD for maintenance immunosuppression (CD25 group). CsA and anti-IL-2 receptor mAb are drugs that reduce cytokine synthesis and block IL-2-mediated lymphocyte stimulation, respectively. SDZ RAD blocks lymphocyte stimulation by other cytokines (e.g., IL-15) that are not inhibited by anti-IL-2 receptor mAb. METHODS: Twelve unilateral lung transplants were performed. Recipients were observed for 49 days by daily weight assessment, hemograms, blood chemistries, radiographs, and lung biopsies. Monkeys were euthanized before day 49 in the event of excessive weight loss (>25%) or organ failure. Target CsA trough levels were 100-200 ng/ml. Target SDZ RAD trough levels in the CTL group (no mAb) were 20-40 ng/ml, and 10-20 ng/ml in the CD25 group. RESULTS: None of the monkeys in the CD25 group needed to be euthanized early due to signs of drug toxicity. In contrast, four monkeys in the CTL group were sacrificed on days 28-35 as a result of excessive weight loss (n=3) and renal functional impairment (n=1). Three recipients in the CD25 group were euthanized on days 36, 38, and 46 as a result of persistent high fever associated with severe rejection. The median animal survival in the CTL group was 32 vs. 46 days in the CD25 group (P<0.04). The only two long-term survivors in the CTL group showed moderate rejection at day 49. The median rejection scores at day 14 (A0) and day 28 (A2) were identical in the two groups, despite the fact that the mean SDZ RAD trough level was significantly lower in the CD25 group (CTL: 38+/-3 ng/ml, CD25: 18+/-2 ng/ml, P<0.0001). After basiliximab levels fell below the minimum therapeutic level (1 mg/ml) on day 28, the median rejection score at day 49 increased to A4 in the CD25 group. CONCLUSION: This is the first study to combine an anti-IL-2 receptor mAb with a drug from the rapamycin class plus CsA. Our study shows that induction therapy with basiliximab enabled SDZ RAD blood levels to be significantly reduced, which led to improved tolerability without the penalty of increased rejection.

Animals↗
PubMed2000

A single center's clinical experience with quadruple immunosuppression including ATG or IL2 antibodies and mycophenolate mofetil in simultaneous pancreas-kidney transplants.

UNLABELLED: Acute rejection remains a major problem in simultaneous pancreas-kidney (SPK) transplant and occurs in 60-100% of the cases. With the introduction of mycophenolate mofetil (MMF) replacing azathioprine (AZA) as a basis immunosuppressant, reduced rates of rejection have been reported. This study investigates the frequency and clinical relevance of allograft rejection in SPK patients receiving antithymocyte globulin (ATG) or Basiliximab induction therapy and cyclosporine Neoral (CyA), MMF, steroid basis immunosuppression. Between December 1996 and October 1999, 21 consecutive patients (15 males, 6 females) received a SPK transplant at our institution with a mean +/- standard deviation (SD) age of 42 +/- 6 yr. Of these, 14 patients were treated with anti-thymocyte globulin (ATG) Fresenius (rabbit) 3-5 mg/kg for 6 +/- 2 d, cyclosporine Neoral (CyA) (trough levels 350-400 ng/mL), MMF 3 g/d and low dose steroid therapy. Seven SPK patients were treated with Basiliximab (Simulect, Novartis 20 mg on d 0 and d 4 post-transplant) instead of ATG. The patients had an average human leucocyte antigen (HLA) mismatch of 3.9/6 and a negative cross match. All patients remained on triple drug therapy. Three patients were switched to tacrolimus instead of Neoral for CyA intolerance. The mean +/- SD cold ischemia time (CIT) of the organs was 10.1 +/- 2.4 h for the pancreas and 10.5 +/- 2.6 h for the kidney. RESULTS: Biopsy-proven rejection occurred in the kidney of 1 ATG patient (8%), which responded to steroid bolus therapy. One of the patients (14%) with Basiliximab induction developed renal allograft rejection, which was resolved after a 6-d course of anti-CD3 mAb (OKT3) treatment. All patients (100%) were free from rejection in the pancreas, as measured by urine amylase levels and glycemic control without the need for exogenous insulin with a mean glycosylated hemoglobin (HBA1C) of 5.1 +/- 0.7%, and serum creatinine with a mean of 1.24 +/- 0.24 mg/dL in a mean follow-up period of 17 +/- 15 months (median 12, range 2 37). CONCLUSION: Triple drug immunosuppression including cyclosporine, MMF and low dose steroids with ATG or interleukin 2 (IL2) receptor antibodies induction therapy appears to be a very suitable immunosuppressive regimen for combined pancreas-kidney transplant (PKT) with a marked reduction in the incidence of rejection.

Adult↗
PubMed1999

A review of interleukin-2 receptor antagonists in solid organ transplantation.

Daclizumab and basiliximab, engineered human IgG monoclonal antibodies to the interleukin-2 (IL-2) receptor alpha-subunit, were approved to prevent acute rejection after renal transplantation. Daclizumab was studied in adult and pediatric renal allograft recipients, liver allograft recipients, and calcineurin-sparing protocols in renal transplant recipients. Basiliximab was studied in renal allograft recipients and subgroups of recipients of living-related and cadaveric transplants, and in patients with diabetes mellitus. Both agents reduced acute rejection and were associated with few adverse effects. However, information regarding their long-term effects on infection, malignancy, chronic rejection, and patient survival must be available before a final decision is made regarding their proper administration. We propose that a likely role the drugs will play in the field of solid organ transplantation is in new protocols that allow sparing of other more toxic immunosuppressive agents.

Adult↗
PubMed2000

Successful hand transplantation. One-year follow-up. Louisville Hand Transplant Team.

BACKGROUND: On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite tissue transplantation, we developed a protocol for human hand transplantation. METHODS: After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy. RESULTS: The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient had regained the ability to perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces. CONCLUSIONS: Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs.

Adult↗
PubMed2000

Immunosuppression for pediatric cardiac transplantation in the modern era.

With the advent of the T cell activation inhibitors such as cyclosporine, heart transplant success rates for pediatric patients have improved to the point that the initially restricted ages and indications have expanded considerably. Currently the half-life (50% still alive) for children transplanted in the early 1980s is approximately 12-14 years. Decades-long survival seems likely. Components and functions of the immune system are naïve and change during postnatal development. Maturation occurs not only in the first years of life, but well through adolescence and even into adult life. These age-dependent changes within the immune system greatly complicate any attempt to assess immune implications for the use of immunosuppression in children. Since the introduction of cyclosporine, immunosuppression regimens have been virtually unchanged through the 1990s. Recently, there have been significant new immune pharmacological agents which are now commercially available, or still in investigational stages of development. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The newer inhibitors of de novo nucleotide synthesis include mycophenolate mofetil, mizoribine, brequinar and leflunomide. The immunophilin-binding drugs are cyclosporine, tacrolimus and rapamycin. Antibody preparations such as ATG, ATGAM and OKT3, as well as the newer biological agents, which specifically bind to the IL-2 receptor, basiliximab and daclizumab, are discussed. The potential for biologicals which inhibit co-stimulation are also discussed. There may be dramatic changes in protocols used clinically as a result of these new agents over the next decade. The increasing understanding of the alloimmune response as well as the clinical use of these newer drugs promise even better long-term results.

Journal Article↗
PubMed2000

Drug therapy for acute graft-versus-host disease prophylaxis.

The mechanisms of many immunosuppressive drugs have been defined, allowing for a rational approach to the use of these agents in GVHD prophylaxis. In addition to standard drugs such as methotrexate, cyclosporine, tacrolimus, and glucocorticoids, new agents-mycophenolate mofetil, tresperimus, rapamycin, basiliximab, and daclizumab-are now part of the immunosuppressive armamentarium. Improved understanding of tolerance has resulted in new approaches to prevention of GVHD. Anti-CD40L, CTLA-4-Ig, tresperimus, and rapamycin are agents that are being explored in this area and have shown impressive results in animal models. Currently, the standard therapy for acute GVHD prophylaxis in matched sibling transplants remains cyclosporine and methotrexate. Lower dose methotrexate, particularly in combination with tacrolimus, has shown good results in single arm studies with low toxicity, but this has not been tested in a randomized study. For unrelated donor transplants there is less GVHD when tacrolimus, rather than cyclosporine, is combined with methotrexate; there seems little reason to use cyclosporine in this setting. GVHD is still the major barrier to more widespread use of unrelated donor transplants and improved regimens are needed. In vivo T-cell depletion using Campath-1 or ATG is being used in high-risk patients. Data on its efficacy are so far anecdotal. Due to the variation in grading of GVHD between centers, randomized studies are needed to quantify the relative merits of different regimens, and participation in such studies is encouraged.

Acute Disease↗
PubMed2024

Network proximity analysis as a theoretical model for identifying potential novel therapies in primary sclerosing cholangitis.

Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.

Cholangitis, Sclerosing↗