Maintenance of Remission With Tofacitinib Therapy in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib in patients with moderate to severe UC, up to 1 year, have been reported. We investigated maintenance of efficacy in patients in remission after 52 weeks of maintenance treatment in the pivotal phase 3 study (OCTAVE Sustain); these patients received open-label, long-term treatment with tofacitinib 5 mg twice daily. METHODS: Patients with moderate to severe UC who completed a 52-week, phase 3 maintenance study (OCTAVE Sustain) were eligible to enroll into the ongoing, phase 3, multicenter, open-label, long-term extension (OCTAVE Open). We analyzed data from 142 patients who were in remission following tofacitinib treatment in OCTAVE Sustain who received tofacitinib 5 mg twice daily during OCTAVE Open. We assessed efficacy (including remission [based on total Mayo score], endoscopic improvement, clinical response, and partial Mayo score up to month 36 of OCTAVE Open) and safety data. RESULTS: After 12 months of tofacitinib 5 mg twice daily in OCTAVE Open, 68.3% of patients were in remission, 73.9% had endoscopic improvement, and 77.5% had a clinical response. At month 36, 50.4%, of the patients were in remission, 55.3% had endoscopic improvement, and 56.0% had a clinical response. The safety profile of tofacitinib 5 mg twice daily revealed no new safety risks associated with long-term exposure up to 36 months. CONCLUSIONS: Efficacy endpoints were maintained for up to 36 months, regardless of prior tofacitinib dose, including patients who reduced from tofacitinib 10 mg to 5 mg twice daily upon OCTAVE Open entry. No new safety risks were identified. ClinicalTrials.gov: OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Nonmelanoma Skin Cancer Rates From the Ulcerative Colitis Clinical Program.

BACKGROUND: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program. METHODS: Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis. RESULTS: Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors. CONCLUSIONS: For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management.

BACKGROUND: Patients with ulcerative colitis (UC) are at elevated risk of cardiovascular disease vs the general population, despite a lower prevalence of traditional risk factors, including hyperlipidemia. Mechanistic studies in patients with rheumatoid arthritis and psoriasis suggest that tofacitinib restores serum lipids to preinflammation levels by reversing inflammation-induced cholesterol metabolism changes. We reviewed data on lipid levels and cardiovascular events, alongside recommendations for managing lipid levels during tofacitinib treatment in patients with UC, based on up-to-date expert guidelines. METHODS: Data were identified from a phase 3/open-label, long-term extension (OLE) tofacitinib UC clinical program (cutoff May 27, 2019). Literature was identified from PubMed (search terms "lipid," "cholesterol," "lipoprotein," "cardiovascular," "inflammation," "atherosclerosis," "tofacitinib," "rheumatoid arthritis," "psoriasis," "inflammatory bowel disease," "ulcerative colitis," "hyperlipidemia," and "guidelines") and author knowledge. Data were available from 4 phase 3 clinical trials of 1124 patients with moderately to severely active UC who received ≥1 dose of tofacitinib 5 or 10 mg twice daily in induction (two identical trials), maintenance, and OLE studies (treatment duration ≤6.8 years; 2576.4 patient-years of drug exposure). RESULTS: In the OLE study, tofacitinib treatment was not associated with major changes from baseline in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, total cholesterol/high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol, with lipid levels and ratios generally remaining stable over time. The major adverse cardiovascular events incidence rate was 0.26/100 patient-years (95% confidence interval, 0.11-0.54). CONCLUSIONS: Lipid levels and ratios remained generally unchanged from baseline in the OLE study after tofacitinib treatment, and major adverse cardiovascular events were infrequent. Long-term studies are ongoing. CLINICALTRIALS.GOV IDENTIFIERS: NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme.

BACKGROUND AND AIMS: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis. We report integrated analyses of infections in the Phase [P]2 and P3 OCTAVE programmes. METHODS: Three cohorts were analysed: Induction [P2/3 induction studies]; Maintenance [P3 maintenance study]; and Overall [all tofacitinib-treated patients in induction, maintenance, or ongoing, open-label, long-term extension studies; as of May 2019]. Proportions and incidence rates [IRs; unique patients with events/100 patient-years] of serious infections [SIs], herpes zoster [HZ] [non-serious and serious], and opportunistic infections [OIs] are reported [censored at time of event]. RESULTS: In the Induction Cohort [N = 1220], no patients receiving placebo and eight [0.9%] receiving tofacitinib 10 mg twice daily [BID] developed SIs. Maintenance Cohort [N = 592] SI IRs (95% confidence interval [CI]) were 1.94 [0.23-7.00] for placebo and 1.35 [0.16-4.87] and 0.64 [0.02-3.54] for tofacitinib 5 and 10 mg BID, respectively; HZ IRs were 0.97 [0.02-5.42], 2.05 [0.42-6.00], and 6.64 [3.19-12.22], respectively. In the Overall Cohort [N = 1157; 82.9% predominantly received tofacitinib 10 mg BID], SI, HZ, and non-HZ OI IRs were 1.70 [1.24-2.27], 3.48 [2.79-4.30], and 0.15 [0.04-0.38], respectively. No SIs resulted in death. CONCLUSIONS: During induction, SIs were more frequent with tofacitinib versus placebo. SIs were generally infrequent in the Maintenance and Overall Cohorts, with rates comparable between treatment groups. Maintenance Cohort HZ IR was numerically higher with tofacitinib 10 mg BID versus 5 mg BID. Overall Cohort HZ IRs remained stable over time. Non-HZ OIs and viral infections were rare.

A Biomarker-Centric Approach to Drug Discovery and Development: Lessons Learned from the Coronavirus Disease 2019 Pandemic.

Faced with the health and economic consequences of the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the biomedical community came together to identify, diagnose, prevent, and treat the novel disease at breathtaking speeds. The field advanced from a publicly available viral genome to a commercialized globally scalable diagnostic biomarker test in less than 2 months, and first-in-human dosing with vaccines and repurposed antivirals followed shortly thereafter. This unprecedented efficiency was driven by three key factors: 1) international multistakeholder collaborations, 2) widespread data sharing, and 3) flexible regulatory standards tailored to meet the urgency of the situation. Learning from the remarkable success achieved during this public health crisis, we are proposing a biomarker-centric approach throughout the drug development pipeline. Although all therapeutic areas would benefit from end-to-end biomarker science, efforts should be prioritized to areas with the greatest unmet medical needs, including neurodegenerative diseases, chronic lower respiratory diseases, metabolic disorders, and malignant neoplasms. SIGNIFICANCE STATEMENT: Faced with the unprecedented threat of the severe acute respiratory syndrome coronavirus 2 pandemic, the biomedical community collaborated to develop a globally scalable diagnostic biomarker (viral DNA) that catalyzed therapeutic development at breathtaking speeds. Learning from this remarkable efficiency, we propose a multistakeholder biomarker-centric approach to drug development across therapeutic areas with unmet medical needs.

Use of biomarkers to improve immunosuppressive drug development and outcomes in renal organ transplantation: A meeting report.

On September 27-28, 2018 the Food and Drug Administration (FDA) and the Critical Path Institute's Transplant Therapeutics Consortium convened a public workshop titled "Evidence-Based Treatment Decisions in Transplantation: The Right Dose & Regimen for the Right Patient/Individualized Treatment." The workshop facilitated cooperative engagement of transplant community stakeholders, including pharmaceutical industry, academic researchers, clinicians, patients, and regulators to discuss methods to advance the development of novel immunosuppressive drugs for use in solid organ transplantation. Day 1 focused on the utility of biomarkers in drug development, with considerations for seeking regulatory endorsement for use in clinical trials. Biomarkers add value to drug development by improving patient selection criteria, safety monitoring, endpoint selection, and more. Regulatory endorsement through the FDA Biomarker Qualification Program encourages the use of biomarkers in drug development by instilling confidence and consistency in biomarker interpretation across trials. Public-private partnerships or consortia allow stakeholders to share expertise, resources, and data in pursuit of biomarker qualification. Biomarkers relevant to pretransplant risk assessment, early posttransplant care, and assessment of immune response, immunosuppressive drug efficacy, and graft function as discussed on day 1 of the workshop are described.

Tofacitinib Treatment Is Associated With Modest and Reversible Increases in Serum Lipids in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We analyzed inflammation, lipid concentrations, and incidence rates of major adverse cardiovascular (CV) events (MACEs) in patients who received tofacitinib in worldwide studies. METHODS: We collected data from 1157 patients who participated in 3 8-week induction studies (1 phase-2 study and 2 phase-3 studies; patients received tofacitinib 10 mg twice daily or placebo), a 52-week phase-3 maintenance study of responders (patients received tofacitinib 5 or 10 mg twice daily or placebo), and an ongoing long-term extension study of patients who did and did not respond to induction or maintenance therapy (patients received tofacitinib 5 or 10 mg twice daily). Lipid concentrations were assessed from induction baseline to week 61 (week 52 of maintenance therapy). We calculated MACE incidence rates (patients with ≥1 event per 100 patient-years of exposure) and Reynolds risk score (RRS; a composite score used to determine CV risk) for patients given tofacitinib vs placebo. RESULTS: The mean RRS was <5% at baseline and week 8 of treatment with tofacitinib. At week 8, there were greater increases from baseline in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol in patients given tofacitinib compared with placebo. There were correlations between reduced levels of high-sensitivity C-reactive protein and increased serum concentrations of lipid in patients given tofacitinib or placebo (P < .001). Lipid concentrations were increased in patients given tofacitinib vs patients given placebo through week 61. Overall, ratios of low-density lipoprotein cholesterol to HDL-c and total cholesterol to HDL-c did not change significantly over the 61-week period. Four MACEs were reported; the incidence rate was 0.24 (95% CI, 0.07-0.62) and 3 of these patients had 4 or more CV risk factors. CONCLUSIONS: In an analysis of data from 5 trials of patients with UC who received tofacitinib, we found reversible increases in lipids with treatment and inverse correlations with reduced levels of high-sensitivity C-reactive protein. We did not find clinically meaningful changes in lipid ratios or RRS. MACEs were infrequent and not dose-related. Clinicaltrials.gov: A3921063 (NCT00787202); OCTAVE Induction 1 (NCT01465763); OCTAVE Induction 2 (NCT01458951); OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Kidney Safety Assessment: Current Practices in Drug Development.

The kidney's role as a major route of metabolism and clearance of xenobiotics and its ability to concentrate the glomerular filtrate make it particularly vulnerable to drug-induced toxicity. Improving kidney safety is an active area of research and there is a need in early stages of drug development for strategies and model systems to reliably identify nephrotoxic compounds and sufficiently characterize mechanisms to support drug pipeline decision making. In later stages of drug development the value of sensitive translational biomarkers to monitor kidney toxicity across species in nonclinical and clinical settings is gaining realization. Various tools and strategies for kidney safety assessment have emerged over the past decade; however, there is currently no clear consensus on best practices for their use across different phases of drug development. Here, we provide perspective on the scope of this problem in drug development, and an overview of progress in the field of kidney safety including several informative case examples of kidney toxicity de-risking scenarios encountered in the pharmaceutical industry. The results of a survey of pharmaceutical companies conducted through the Innovation and Quality Drug Safety consortium provides additional insight into recent experiences with compound attrition and different de-risking approaches across the industry.

The Impact of Raising the Bar for Clinical Trials in Ulcerative Colitis.

In order to identify the practical implications for both health care practitioners and patients in understanding differences between the results of trials assessing therapies for ulcerative colitis [UC], we reviewed clinical trials of therapies for moderate to severe UC, with a focus on trial design. Over time, patient populations in UC trials have become more refractory, reflecting that patients are failing treatment with additional and different classes of drug, including conventional therapies, immunosuppressant drugs, and anti-tumour necrosis factor therapies. Outcomes used to measure efficacy have become increasingly stringent in order to meet the expectations of patients and physicians, and the requirements of regulatory bodies. Trial design has also evolved to integrate induction and maintenance therapy phases, so as to facilitate patient recruitment and to answer clinically important questions such as how efficacious therapies are in specific subpopulations of patients and during long-term use. As UC clinical trial design continues to evolve, and with limited head-to-head trials and real-world comparative effectiveness studies evaluating UC therapies, careful judgment is required to appreciate the differences and similarities in trial designs, and to understand how these variances may affect the observed efficacy and safety outcomes.

Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule inhibitor of JAK for the treatment of ulcerative colitis (UC). We evaluated the onset of symptom improvement in post-hoc analyses of data from 2 phase 3 trials of induction therapy with tofacitinib in patients with UC (OCTAVE Induction 1 and 2). METHODS: The studies comprised patients with moderate to severe active UC who were intolerant to, or failed by previous treatment with, corticosteroids, thiopurines, and/or tumor necrosis factor (TNF) antagonists. Patients received tofacitinib (10 mg twice daily, n = 905) or placebo (n = 234) for 8 weeks. Daily Mayo stool frequency and rectal bleeding subscores were calculated using diary data from the first 15 days of therapy. We analyzed data from subgroups including failure of prior anti-TNF therapy, baseline corticosteroid use, and baseline serum levels of C-reactive protein. RESULTS: Mean changes were significantly greater in patients given tofacitinib vs placebo in reductions from baseline stool frequency subscore (tofacitinib: -0.27 vs placebo: -0.11; P < .01), total number of daily bowel movements (-1.06 vs -0.27; P < .0001), and rectal bleeding subscore (-0.30 vs -0.14; P < .01) by day 3. Compared with placebo, more tofacitinib-treated patients had reductions from baseline in stool frequency subscore (by ≥1 point for tofacitinib, 241/837, 28.8% vs placebo, 39/218, 17.9%) (P < .01) and rectal bleeding subscore (by ≥1 point for tofacitinib, 266/830, 32.0% vs placebo, 43/214, 20.1%) (P < .01) by day 3. A consistent effect of tofacitinib was observed in all subgroups. CONCLUSIONS: In a post-hoc analysis of data from phase 3 trials of induction therapy with tofacitinib in patients with UC, we found significant improvements in symptoms among patients given tofacitinib compared with placebo within 3 days. These findings indicate the rapid onset of effect of this drug in patients with UC. ClinicalTrials.gov no: NCT01465763 and NCT01458951.

Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of Data From Global Clinical Trials.

BACKGROUND & AIMS: Tofacitinib is an oral, small-molecule inhibitor of JAK approved in several countries for the treatment of ulcerative colitis (UC). We report integrated safety analyses of tofacitinib-treated patients with moderate to severe UC. METHODS: Patients receiving placebo or tofacitinib (5 or 10 mg) twice daily were analyzed as 3 cohorts: induction (phase 2 and 3 induction studies, n = 1220), maintenance (phase 3 maintenance study, n = 592), and overall (patients receiving tofacitinib 5 or 10 mg twice daily in phase 2, phase 3, or open-label, long-term extension studies, n = 1157; 1613 patient-years' exposure). Incidence rates (IRs; patients with events per 100 patient-years of exposure) were evaluated for select adverse events. RESULTS: In the maintenance cohort, IRs for select adverse events were similar among treatment groups, except for a numerically higher IR of herpes zoster infection among patients who received tofacitinib 5 mg twice daily (2.1; 95% CI, 0.4-6.0) and statistically higher IR among patients who received tofacitinib 10 mg twice daily (IR, 6.6; 95% CI, 3.2-12.2) vs placebo (IR, 1.0, 95% CI, 0.0-5.4). For the overall cohort (84% received average dose of tofacitinib 10 mg twice daily), IRs were: death, 0.2 (95% CI, 0.1-0.6); serious infections, 2.0 (95% CI, 1.4-2.8); opportunistic infections, 1.3 (95% CI, 0.8-2.0); herpes zoster infection, 4.1 (95% CI, 3.1-5.2); malignancy (excluding non-melanoma skin cancer), 0.7 (95% CI, 0.3-1.2); non-melanoma skin cancer, 0.7 (95% CI, 0.3-1.2); major adverse cardiovascular events, 0.2 (95% CI, 0.1-0.6); and gastrointestinal perforations, 0.2 (95% CI, 0.0-0.5). CONCLUSIONS: In safety analyses of patients with moderate to severe UC treated with tofacitinib, we observed a dose relationship with herpes zoster infection. Although follow-up time was relatively short, the safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher IR of herpes zoster infection. ClinicalTrials.gov, no: NCT00787202, NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

The pharmacodynamic effects of sirolimus and sirolimus-calcineurin inhibitor combinations on macrophage scavenger and nuclear hormone receptors.

BACKGROUND: Sirolimus (SIR) alone or in combination with cyclosporine (CsA) or tacrolimus (TAC) are used in solid organ transplantation, but uncertainty remains regarding their respective atherogenic potentials. METHODS: THP-1 cells were cultured as macrophages and then treated with plasma trough and peak concentration doses of SIR, SIR/CsA or SIR/TAC to assess the time- and dose-dependent mRNA or protein expression of selected atherogenic genes. The selected atherogenic genes included: the macrophage scavenger receptors (MSRs) CD36, CD68, scavenger receptor (SR)-A, SR-BII, and LOX-1; the nuclear hormone receptors peroxisome proliferator activated receptor gamma (PPARgamma) and liver-X-receptor alpha (LXRalpha); and the cholesterol efflux transporter (ABCA-1). RESULTS: SIR-mediated changes in mRNA included the upregulation of ABCA1, downregulation of CD68, SR-A and SR-BII, and concentration- and/or time-dependent effects on CD36, LOX-1, PPARgamma, and LXRalpha that did not translate into significant protein changes. With SIR/CsA, the protein expressions of PPARgamma and ABCA-1 were downregulated at 8 h. In contrast, with SIR/TAC, PPARgamma, and ABCA-1 protein expressions were upregulated at 8 h. CONCLUSIONS: Combination results differed from findings with SIR alone, supporting the observed clinical phenotype with calcineurin inhibitors. These findings may provide a rationale for the development of novel drug delivery strategies to mitigate adverse pharmacodynamic responses.

Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation.

Clinical monitoring of organ-transplant recipients suggests that administration of cyclosporine (CsA) may increase the risk of atherosclerosis when compared with the general population. The purpose of this work is to demonstrate the utility of the in vitro Tamm-Horsfall protein (THP)-1 human monocyte cell culture model for determining drug-related atherosclerotic potential in macrophages. The effect of CsA on the mRNA expression of macrophage scavenger receptor genes including CD36, CD68, scavenger receptor (SR)-A, SR-BII, and lectin-like oxidized low-density lipoprotein receptor (LOX-1); the nuclear hormone receptors, including peroxisome-proliferator activated receptor (PPAR)gamma and liver-X-receptor (LXR)alpha; and the cholesterol efflux pump ABCA1 were investigated as markers of atherosclerotic progression. The THP-1 cells were cultured and differentiated into macrophages. The macrophages were then treated with CsA to assess gene expression. Time- (1, 2, 4, 8, and 24 hours) and dose- (concentrations [mg/L] corresponding to the trough [0.5], peak [1.25] and 4x peak [5]) dependency of CsA was assessed. The treated macrophage mRNA gene expression of CD36, CD68, and PPARgamma were up-regulated in the presence of CsA. Interestingly, SR-A, SR-BII, LOX-1, and LXRalpha expression appeared to be slightly down-regulated, and ABCA1 was relatively unchanged. Immunoblotting studies demonstrated that the protein expression of CD36 was unchanged or increased, PPARgamma was unchanged, and ABCA1 was unchanged or decreased at 4 and 8 hours. The results document CsA-induced mRNA and protein changes in receptors relevant to lipid-laden foam cell formation and demonstrate the utility of THP-1 macrophages for screening of atherosclerotic risk potential.

Effect of tacrolimus on the expression of macrophage scavenger and nuclear hormone receptors in THP-1-derived human macrophages.

BACKGROUND: Data indicate that tacrolimus and cyclosporine A (CsA) differentially affect the risk of atherosclerosis. The results of our recent in vitro studies of clinically relevant CsA concentrations demonstrated the modulation of macrophage scavenger receptors (MSRs) involved in atherogenesis. This work evaluated the effects of clinically relevant tacrolimus concentrations on the expression of the MSR genes CD36 and CD68, SR-A and SR-BII, lectin-like oxidized low-density lipoprotein receptor-1, the nuclear hormone receptors peroxisome proliferator-activated receptor (PPAR)gamma and liver-X-receptor-alpha, and the cholesterol efflux pump ABCA1 in the in vitro human THP-1 macrophage model. METHODS: The cells were cultured and differentiated into macrophages. Macrophages were treated with the tacrolimus to assess gene expression in a time-dependent (1, 2, 4, 8, and 24 hr) and dose-dependent (concentrations [micrograms/liter] corresponding to the trough [15], peak [30], and 4 x peak [120]) manner using reverse-transcriptase polymerase chain reactions. The gene expression levels of interest were normalized to GAPDH expression in each sample to provide semiquantitative reverse-transcriptase polymerase chain reaction results. Additional immunoblotting studies demonstrated protein expression of CD36, PPARgamma, and ABCA1. RESULTS.: The gene expression of CD36, SR-BII, and lectin-like oxidized low-density lipoprotein receptor-1 were down-regulated, and ABCA1 was up-regulated. CD68, SR-AI, liver-X-receptor-alpha, and PPARgamma were regulated in a dose-dependent manner. Protein expression of CD36 was down-regulated, and PPARgamma and ABCA1 were relatively unchanged. CONCLUSIONS: Tacrolimus seems to regulate MSRs, nuclear hormone receptors, and ABCA1 in THP-1 macrophages. These results differ from previous findings with CsA and may provide insight into the mechanisms of posttransplant atherosclerosis.

Drug-related dyslipidemia after renal transplantation.

PURPOSE: The frequency, onset, mechanisms, and causes of dyslipidemia after renal transplantation are reviewed in the context of the adverse impact of lipid alterations, recent guidelines, and the available treatment options. SUMMARY: At least 60% of adult renal transplant recipients develop dyslipidemia, which occurs within one month of the initiation of immunosuppressive therapy and continues indefinitely unless treated. Cyclosporine, sirolimus, and prednisone are mainly implicated, and the lipid profile differs between individual agents. In recognition that lipid alterations in these patients are linked with development of ischemic heart disease, vascular mortality, and graft deterioration, the National Kidney Foundation has recently released guidelines suggesting a low-density-lipoprotein (LDL) cholesterol goal of < 100 mg/dL for these patients. Statins and diet therapy are recommended as first-line agents for achieving goal LDL cholesterol levels in this population. Recent evidence proved a reduction in adverse cardiovascular events when fluvastatin was utilized in one large-scale trial. Care should be taken with aggressive dosage adjustment because of the potential for a pharmacokinetic interaction with cyclosporine and a resultant increase in the risk of myopathy or rhabdomyolysis. Other options for improving the lipid profile include modifications in the immunosuppressive regimen, the addition of other lipid-modifying agents, and using alternative lipid-modifying agents. CONCLUSION: Statins and diet therapy should be used as first-line treatments in renal transplant recipients with dyslipidemia. Other strategies, including modification of the immunosuppressive regimen, and the addition of other lipid-modifying agents, have also yielded positive results.

Bleeding and thrombosis in high-risk renal transplantation candidates using heparin.

BACKGROUND: Heparin can reduce the risk of renal artery/vein thrombosis in renal transplant patients with hypercoagulable states (HCS), but is associated with a high bleeding risk. Little is known about risk factors for this bleeding risk or the optimal anticoagulation target. OBJECTIVE: To determine factors associated with this bleeding risk and determine the optimal partial thromboplastin time (PTT) ratio. METHODS: We retrospectively reviewed medical records of consecutive adult renal transplant recipients administered heparin for perioperative renal thrombosis prevention (1998-2002). RESULTS: Twenty-eight (3.86%) of 725 consecutive renal transplant recipients received heparin to prevent renal thrombosis. Eighteen patients (64.3%) had clinically important bleeding (14 major bleeding). Patients with and without bleeding were similar in baseline demographic characteristics and overall mean PTT. Bleeding occurred at a mean PTT ratio of 2.5 +/- 1, higher than the overall mean in bleeders and nonbleeders (p = 0.001). Among postoperative characteristics, higher maximum PTT (p = 0.052) and prolonged surgical antibiotic prophylaxis (p = 0.053), particularly with cefotetan (p = 0.091), trended toward a significant association with bleeding. Two renal thrombotic episodes occurred, both at PTT ratios <1.5. A PTT ratio of 1.5-1.9 resulted in no thrombosis and < or = 4.2% bleeding. CONCLUSIONS: The benefits and risks of therapeutic heparin anticoagulation in renal transplant patients with HCSs were confirmed. Higher PTTs and cefotetan antibiotic surgical prophylaxis could contribute to bleeding. The optimal PTT ratio appeared to be 1.5-1.9 to prevent thrombosis and limit bleeding risk.

Levofloxacin-associated Achilles tendon rupture.

OBJECTIVE: To describe a case of levofloxacin-induced partial Achilles tendon rupture; this occurred in the presence of known risk factors and acute renal failure. CASE SUMMARY: A 79-year-old white man received levofloxacin for presumed pneumonia, developed acute renal failure in the setting of dehydration, and began having ankle pain on the 12th day of admission. Levofloxacin was discontinued, and magnetic resonance imaging revealed a 6-cm partial tear and degenerative changes. DISCUSSION: The Naranjo probability scale indicates a possible association between levofloxacin and tendon rupture because the event occurred in the setting of known risk factors such as steroid use, renal failure, older age, and male gender. CONCLUSIONS: Levofloxacin, like other fluoroquinolones, may cause Achilles tendon rupture, and this may be particularly likely with known risk factors.