sirolimus and Hypercholesterolemia

Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression.. To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM.. We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml.. Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV. Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

Topics: Adult; Disease Progression; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Hypercholesterolemia; Japan; Lung; Lymphangioleiomyomatosis; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Pneumonia; Quality of Life; Regression Analysis; Sirolimus; Vital Capacity

Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome.. The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS).. Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS.. The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS.. Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Hypercholesterolemia; Hyperglycemia; Hyperlipidemias; Male; Middle Aged; Neoplasms; Receptor, IGF Type 1; Sirolimus; Survival Analysis; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Bevacizumab and temsirolimus are active agents in gynecologic tumors. Temsirolimus attenuates upregulation of HIF-1α levels, a resistance mechanism for antiangiogenics, and targets the PI3-kinase/AKT/mTOR axis, commonly aberrant in these tumors.. We analyzed safety and responses in 41 patients with gynecologic cancers treated as part of a Phase I study of bevacizumab and temsirolimus.. Median age of the 41 women was 60 years (range, 33-80 years); median number of prior systemic therapies was 4 (1-11). Grade 3 or 4 treatment-related toxicities included: thrombocytopenia (10%), mucositis (2%), hypertension (2%), hypercholesterolemia (2%), fatigue (7%), elevated aspartate aminotransferase (2%), and neutropenia (2%). Twenty-nine patients (71%) experienced no treatment-related toxicity greater than grade 2. Full FDA-approved doses of both drugs (bevacizumab 15mg/kg IV Q3weeks and temsirolimus 25mg IV weekly) were administered without dose-limiting toxicity. Eight patients (20%) achieved stable disease (SD) > 6 months and 7 patients (17%), a partial response (PR) [total = 15/41 patients (37%)]. Eight of 13 patients (62%) with high-grade serous histology (ovarian or primary peritoneal) achieved SD > 6 months/PR.. Bevacizumab and temsirolimus was well tolerated. Thirty-seven percent of heavily-pretreated patients achieved SD > 6 months/PR, suggesting that this combination warrants further study.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bevacizumab; Carcinoma; Fatigue; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Mucositis; Neutropenia; Ovarian Neoplasms; Sirolimus; Thrombocytopenia; Uterine Cervical Neoplasms

The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR).. For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions.. Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months.. Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.

Topics: Cholesterol; Drug Therapy, Combination; Follow-Up Studies; Humans; Hypercholesterolemia; Immunosuppressive Agents; Mycophenolic Acid; Sirolimus; Tacrolimus; Triglycerides

Loss of PTEN, which is common in glioblastoma multiforme (GBM), results in activation of the mammalian target of rapapmycin (mTOR), thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression. CCI-779 is an inhibitor of mTOR. The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug.. CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs (EIAEDs). Patients not on EIAEDs were initially treated at 250 mg; however, the dose was reduced to 170 mg because of intolerable side effects. Treatment was continued until unacceptable toxicity, tumor progression, or patient withdrawal. The primary endpoint was 6-month progression-free survival.. Forty-three patients were enrolled; 29 were not on EIAEDs. The expected toxicity profile of increased lipids, lymphopenia, and stomatitis was seen. There were no grade IV hematological toxicities and no toxic deaths. One patient was progression free at 6 months. Of the patients assessable for response, there were 2 partial responses and 20 with stabilization of disease. The median time to progression was 9 weeks.. CCI-779 was well tolerated at this dose schedule; however, there was no evidence of efficacy in patients with recurrent GBM. Despite initial disease stabilization in approximately 50% of patients, the durability of response was short. Because of the low toxicity profile, CCI-779 may merit exploration in combination with other modalities.

Topics: Adult; Aged; Anemia; Anticonvulsants; Antineoplastic Agents; Brain Neoplasms; Disease-Free Survival; Drug Interactions; Female; Glioblastoma; Humans; Hypercholesterolemia; Infusions, Intravenous; Lymphopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Sirolimus

In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n = 42) or sirolimus (n = 41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. At 12 months, graft survival (98% sirolimus vs 93% CsA), patient survival (100% vs 98%), and incidence of biopsy-confirmed acute rejection (41% vs 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P

Topics: Adrenal Cortex Hormones; Azathioprine; Cyclosporine; Drug Therapy, Combination; France; Graft Rejection; Hospitals, University; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Transplantation; Methylprednisolone; Prednisolone; Prednisone; Sirolimus

Exposure, safety, and efficacy data from the two everolimus randomized, double-blind phase 3 trials were evaluated to identify a therapeutic concentration range applicable in de novo kidney transplantation.. A total of 695 evaluable everolimus-treated patients received either 0.75 or 1.5 mg bid in addition to corticosteroids and cyclosporine (troughs 150-400 ng/ml in month 1 and 100-300 ng/ml thereafter). A total of 3355 everolimus trough levels (Cmin) were obtained in weeks 1 and 2 and months 1, 2, 3, and 6 after transplantation. Each patient's average Cmin was calculated and the values were divided into quintiles: 1.0-3.4, 3.5-4.5, 4.6-5.7, 5.8-7.7, 7.8-15.0 ng/ml (139 patients per quintile). Efficacy was freedom from biopsy-confirmed acute rejection. Safety measures were maximum total cholesterol and triglyceride levels and minimum leukocyte and platelet counts. A sigmoid exposure-response model was used to test the significance of these Cmin-efficacy and Cmin-safety relationships.. Freedom from acute rejection was significantly related to Cmin with an incidence of 68% at 1.0-3.4 ng/ml, 81-86% at 3.5-7.7 ng/ml, and 91% at 7.8-15.0 ng/ml (P=0.03). The incidence of hypercholesterolemia, defined as >6.5 mmol/liter, ranged from 76 to 87% over the exposure range without a significant relation to Cmin (P=0.37). The incidence of hypertriglyceridemia, defined as >2.9 mmol/liter, rose from 59 to 77% across the exposure groups (P=0.02). Leukocytopenia, defined as <4x10(9)/liter, occurred in 11-19% of patients across the exposure quintiles showing no relationship to Cmin (P=0.76). The incidence of thrombocytopenia, defined as <100x10(9)/liter, occurred in

Topics: Adrenal Cortex Hormones; Cholesterol; Cyclosporine; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Everolimus; Follow-Up Studies; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Leukocyte Count; Leukopenia; Platelet Count; Safety; Sirolimus; Thrombocytopenia; Time Factors; Triglycerides

Our objective was to characterize the steady-state pharmacokinetics of everolimus and cyclosporine (INN, ciclosporin) when coadministered in de novo kidney allograft recipients during the first year after transplantation.. This study was a multicenter randomized double-blind study of 101 patients who were randomly assigned 1:1:1 to receive everolimus tablets at doses of 0.5 mg, 1 mg, or 2 mg twice daily with cyclosporine and prednisone. Blood sampling for the pharmacokinetics of everolimus and cyclosporine was performed on day 1, on weeks 1, 2, 3, and 4, and on months 2, 3, 6, 9, and 12. Everolimus dose-proportionality and stability over time were assessed in the context of linear regression and ANOVA models. Everolimus exposure-response relationships between area under the blood concentration-time curve (AUC) and changes in platelets, leukocytes, and lipids were explored with the median-effect model. Potential differences in cyclosporine dosing and pharmacokinetics at different levels of everolimus exposure were assessed in the context of ANOVA.. Everolimus steady state was reached on or before day 7, with a median 3-fold accumulation of drug exposure compared with that after the first postoperative dose. Both steady-state maximum concentration and AUC were dose proportional over the full dose range when assessed on day 1, as well as for the full duration of the study at steady state. There was evidence for longitudinal stability in AUC of everolimus during the course of the study. The interindividual pharmacokinetic variability for AUC was 85.4% and intraindividual, interoccasion variability was 40.8%. Age (range, 17-69 years), weight (range, 49-106 kg), and sex (65 men and 36 women) were not significant contributors to variability. There was an increasing incidence of transient thrombocytopenia (< or =100 x 10(9)/L) with increasing everolimus AUC (P = .03). Cyclosporine doses, trough concentrations, and AUC exhibited similar temporal patterns during the course of the study regardless of the co-administered everolimus dose level (P = .13, .82, and .76, respectively).. Everolimus exhibited dose-proportional, stable exposure during the first post-transplant year. For a 4-fold range of everolimus doses there were no differential effects on cyclosporine dosing or pharmacokinetics.

Topics: Administration, Oral; Adolescent; Adult; Aged; Area Under Curve; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Everolimus; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Sirolimus; Thrombocytopenia

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Cadaver; Cyclosporine; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Graft Survival; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Opportunistic Infections; Placebos; Postoperative Complications; Risk Factors; Sirolimus; Survival Rate; Thrombocytopenia; Time Factors; Tissue Donors; Transplantation, Homologous; Triglycerides

Hypercholesterolemia can aggravate contrast-induced acute kidney injury, and the exacerbation of renal tubular epithelial cell (RTEC) injury is a major cause. However, the exact mechanisms remain obscure. Mitophagy, a type of autophagy, selectively eliminates damaged mitochondria and reduces mitochondrial oxidative stress, which is strongly implicated in cell homeostasis and acute kidney injury. Oxidized low-density lipoprotein (Ox-LDL) is accumulated in hypercholesterolemia and has a cytotoxic effect. This study aimed to determine whether and how ox-LDL exacerbates contrast-induced injury in RTECs and to further explore whether PINK1/Parkin-dependent mitophagy is involved in this process. Iohexol and ox-LDL were used alone or in combination to treat HK-2 cells. Rapamycin pretreatment was utilized to enhance mitophagy. Cell viability, apoptosis, mitochondrial membrane potential (MMP) and mitochondrial reactive oxygen species (mtROS) were detected by cell counting kit-8, TUNEL staining, JC-1 kit and MitoSOX fluorescence, respectively. The expression of mitophagy-related proteins (including PINK1, Parkin, and so on) and cleaved caspase-3 was confirmed by western blot. Colocalization of MitoTracker-labeled mitochondria and LysoTracker-labeled lysosomes was observed by fluorescence microscopy to evaluate mitophagy. The results of our study showed that ox-LDL aggravated MMP decline, mtROS release and apoptosis in iohexol-treated HK-2 cells, accompanied by a further increased autophagy level. Enhancement of PINK1/Parkin-dependent mitophagy by rapamycin alleviated apoptosis and mitochondrial injury in HK-2 cells in response to iohexol under ox-LDL condition. Therefore, our findings indicate that ox-LDL aggravates contrast-induced injury of RTECs by increasing mitochondrial damage and mitochondrial oxidative stress, which may be associated with the relative insufficiency of PINK1/Parkin-dependent mitophagy.

Topics: Acute Kidney Injury; Apoptosis; Epithelial Cells; Humans; Hypercholesterolemia; Iohexol; Lipoproteins, LDL; Protein Kinases; Reactive Oxygen Species; Sirolimus; Ubiquitin-Protein Ligases

The FLEX-LONG study assessed the safety and clinical outcomes of ultra-long (44 mm/48 mm) biodegradable polymer-coated Supraflex (Sahajanand Medical Technology Pvt. Ltd., Surat, India) sirolimus-eluting stents (SES) in real-world patients with complex, long coronary artery lesions.. It was an investigator-initiated, retrospective, non-randomized, observational and single-center study, which evaluated one-year results of 141 patients who had undergone implantation of at least one ultra-long (44 mm/48 mm) Supraflex SES. The incidence of major adverse cardiac events (MACE), a composite of cardiac death, myocardial infarction (MI) and target lesion revascularization (TLR), at one-year follow-up was considered as primary outcome. Stent thrombosis was analyzed as a safety outcome.. The mean age of the study population was 56.2±9.6 years and 78.0% (110/141) patients were male. The study analyzed high risk patients, including 62 (44.0%) hypertensive and 60 (42.6%) diabetic patients. Total 147 target lesions were treated, including 25 (17.0%) total occlusions. Total 51 (34.7%) and 96 (65.3%) Supraflex SES of 44 mm and 48 mm were implanted, respectively. Average stent length and diameter were 46.6±1.9 mm and 3.4±0.2 mm, respectively. One-year follow-up was obtained in 100% of patients. There was one probable stent thrombosis after three weeks. At one-year follow-up, 99.3% of patients remained event free.. The results of the FLEX-LONG study support the use of ultra-long (44 mm/48 mm) Supraflex SES, in the treatment of high-risk real-world patients. The stent appeared to be safe and effective at one-year with low clinical events in complex, long coronary artery lesions.

Topics: Absorbable Implants; Coronary Artery Disease; Diabetes Mellitus; Drug-Eluting Stents; Female; Humans; Hypercholesterolemia; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Prosthesis Design; Retrospective Studies; Sirolimus; Smokers; Thrombosis; Treatment Outcome

Topics: Allografts; Heart Transplantation; Humans; Hypercholesterolemia; Immunosuppression Therapy; Lipids; Sirolimus

Sirolimus (SRL) attenuates cardiac allograft vasculopathy (CAV) progression after heart transplantation (HT) but often results in hyperlipidemia. In this study we investigated the differential effects of SRL-based and calcineurin inhibitor (CNI)-based immunosuppression on CAV progression and clinical outcomes in HT recipients.. CAV progression was assessed by coronary intravascular ultrasound (IVUS) as changes in volumetric measurements after correction to time between the first and last follow-up IVUS exams. CAV progression rate and CAV-associated events were compared between patients with mean follow-up low-density lipoprotein (LDL) <100 mg/dl (lower level or LL) and ≥100 mg/dl (higher level or HL) in the SRL and CNI groups.. We identified 227 patients on SRL (LL: 118; HL: 109) and 96 on CNI (LL: 56; HL: 40), with a median follow-up of 6.7 years. Clinical characteristics did not differ between the LL and HL groups and all patients were on statins. In the SRL arm, there were no significant differences in CAV progression rate and there were no differences in all-cause mortality and CAV-associated events between the LL and HL groups. In the CNI arm, the Δ change in plaque volume normalized to segment length and time of follow-up (PV/SL/year) (0.55 ± 0.53 vs 1.53 ± 2.32, p = 0.003) and Δ change in plaque index per year (defined as PV/vessel volume ratio) (3.1 ± 3.7% vs 6.3 ± 10.4%; p = 0.034) were significantly lower in the LL than the HL group. After adjusting for patient characteristics, HL was associated with higher rates of advanced CAV requiring coronary angioplasty (hazard ratio [HR] 3.0, 95% confidence interval [CI] 1.05 to 9.40, p = 0.040) and higher rates of all CAV-associated events (HR 2.2, 95% CI 1.10 to 4.54, p = 0.026) in these CNI-treated subjects.. Unlike CNI-based immunosuppression, the effects of SRL on attenuating CAV progression are independent of LDL cholesterol levels post-HT.

Topics: Adult; Calcineurin Inhibitors; Cholesterol, LDL; Coronary Artery Disease; Disease Progression; Drug Substitution; Female; Follow-Up Studies; Heart Transplantation; Humans; Hypercholesterolemia; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Survival Rate; Ultrasonography, Interventional

Sirolimus used in transplantation is often associated with hypercholesterolemia. We measured serum lipid and PCSK9 levels in 51 heart transplant recipients who had their immunosuppressive therapy switched from calcineurin inhibitors to sirolimus. The switch resulted in a 23% increase in LDL cholesterol, and 46% increase in triglycerides and PCSK9 levels increased from 316 ± 105 ng/mL to 343 ± 107 ng/mL (p = 0.04), however the change in PCSK9 levels did not correlate with an increase in lipid levels (p = 0.2). To investigate the mechanism for the variability in the change in PCSK9 levels, lymphoblastoid cell lines were incubated with both sirolimus and everolimus, resulting in a 2-3 fold increase in PCSK9 expression and protein levels in mTOR inhibitor sensitive but not in mTOR inhibitor resistant cell lines. This first in human study demonstrates that sirolimus therapy is associated with elevation in PCSK9 levels which is not associated with sirolimus-induced hypercholesterolemia.

Topics: Adult; Aged; Biomarkers; Cell Line, Tumor; Cholesterol, LDL; Drug Substitution; Female; Heart Transplantation; Humans; Hypercholesterolemia; Immunosuppressive Agents; Male; Middle Aged; Proprotein Convertase 9; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Up-Regulation

Metastatic renal cell carcinoma (mRCC) develops in approximately 33% of all renal cancer patients. First line treatment of mRCC includes drugs such as sunitinib, temsirolimus and pazopanib, with overall survival now reaching up to 43,6months in patients with favorable-risk metastatic disease. Several side-effects in mRCC treatment, such as hypothyroidism, can be used as positive prognostic factors and indicate good response to therapy. Hypercholesterolemia and hypertriglyceridemia independent of hypothyroidism are reported as side-effects in temsirolimus treatment and recently in sunitinib treatment, but the exact mechanism and significance of the changes remains elusive. Most likely, metabolic changes are caused by inhibition of mechanistic target of rapamycin (mTOR), a positive target of tumor growth suppression, but also a regulator of iron homeostasis. There are no clinical studies reporting changes in iron and ferritin levels during mRCC biotherapy, but we hypothesize that inhibition of mTOR will also affect iron and ferritin levels. If both lipid and iron changes correlate, there is a high possibility that both changes are primarily caused by mTOR inhibition and the level of change should correlate with the inhibition of mTOR pathway and hence the efficacy of targeted treatment. We lastly hypothesize that mRCC biotherapy causes hypercholesterolemia with a possibly improved cholesterol profile due to increase HDL/LDL ratio, so statins might not have a role as supplementary treatment, whereas a sharp rise in triglyceride levels seems to be the primary target for additional therapy.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Renal Cell; Cholesterol; Ferritins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypertriglyceridemia; Hypothyroidism; Indazoles; Indoles; Iron; Kidney Neoplasms; Lipids; Metabolome; Models, Theoretical; Neoplasm Metastasis; Prognosis; Pyrimidines; Pyrroles; Sirolimus; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Triglycerides

To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry.. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both).. This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Constriction, Pathologic; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hypercholesterolemia; Hyperplasia; Iliac Artery; Inflammation; Male; Metals; Neointima; Plaque, Atherosclerotic; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Time Factors

Proliferation signal inhibitors/mTOR-inhibitors have been shown to reduce de novo development of hypercholesterolemic atherosclerosis in animal models. However, their effect on pre-existing atherosclerosis has not yet been studied.. Feeding LDL-R-KO mice a high cholesterol diet for 12 weeks resulted in formation of moderate fibroatheroma (induction phase). Sixty mice received either everolimus (1 or 5 mg/kg) or no everolimus for further 12 weeks (treatment phase). Everolimus significantly enhanced hypercholesterolemia (plasma cholesterol +45%, p<0.001). Atherosclerosis progressed obstructively in treated and non-treated mice. Everolimus (5 mg/kg) tended to reduced progression in aortic root lesions (0.28±0.02 vs. 0.33±0.03 mm(2), p=ns) and brachiocephalic lesions (0.044±0.006 vs. 0.066±0.012 mm(2), p=ns) but without significance. Everolimus (5mg/kg) resulted in an arrest of CD68 positive plaque area (p=0.03) and nearly halved CD68 fraction (p=0.05) in aortic root lesions but not in brachiocephalic lesions. Taken together, despite a trend to reduced progression and inflammatory cell content there was less conclusive net effect of everolimus treatment than expected.. A higher potential of everolimus in the treatment of atherosclerosis might be obscured by its concomitant hypercholesterolemia. Considering stronger effects in previous studies we suggest that everolimus might exert more potent anti-atherogenic properties in earlier stages of atherogenesis than in advanced atherosclerosis.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Aorta; Atherosclerosis; Biomarkers; Brachiocephalic Trunk; Cholesterol; Disease Models, Animal; Everolimus; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Protein Kinase Inhibitors; Receptors, LDL; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

A 70-year-old man with metastatic renal cell carcinoma developed progressive liver metastases after 8 weeks of treatment with the multitargeted tyrosine kinase inhibitor (TKI) sunitinib. He then participated in the phase III placebo-controlled clinical trial of the oral mammalian target of rapamycin (mTOR) inhibitor everolimus, initially randomized to placebo (but had disease progression after 3 months) and crossed over to everolimus at time of unblinding. The patient had stable disease after 8 weeks (two cycles) of everolimus that was maintained until 28 months of therapy, at which time the patient had achieved a partial response. This case illustrates the potential for patients with metastatic renal cell carcinoma, a malignancy with historically poor prognosis, to derive long-term benefit from everolimus when used in a manner consistent with its approved indication (after TKI therapy with sunitinib or sorafenib).

Topics: Aged; Antineoplastic Agents; Arthritis, Rheumatoid; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Everolimus; Humans; Hypercholesterolemia; Hypertension; Indoles; Kidney Neoplasms; Lung Neoplasms; Male; Pyrroles; Randomized Controlled Trials as Topic; Salvage Therapy; Sirolimus; Sunitinib

The introduction of cyclosporine revolutionized the practice of immunosuppression for solid organ transplant recipients, and has resulted in a significant increase in survival. While CNI use has been the mainstay of immunosuppressive therapy in pediatric heart transplantation, CNIs have been associated with an increased risk of nephropathy leading to significant morbidity and mortality. We evaluated the effect on renal function of a CNI minimization protocol using SRL in pediatric heart transplant patients with CNI induced renal insufficiency. An IRB approved retrospective chart review and case control study was performed. There were 20 patients identified with renal insufficiency who had been converted to SRL (target 5-8 ng/mL) and cyclosporine (target 50-75 vs. 125-150 ng/mL). Renal insufficiency was defined as isotopic (Indium 111 DTPA) GFR <60 mL/min per 1.73 m(2) or sCr >1 mg/dL. Outcome variables evaluated were GFR and sCr at time of conversion and at two yr post conversion. Comparison was made with case control subjects matched for age at Tx, time from Tx to conversion, and initial GFR. The median age at Tx = 81 days (S.D. ±26), median time of conversion after Tx = 10 yrs (s.d. ±0.65). Self-limited/treatable side effects included hypercholesterolemia (10), neutropenia (6), aphthous ulcer (3), edema (2), anemia (2), and tremor (1). One patient rejected in the two yr prior to conversion, and one patient had two rejection episodes following conversion. GFR at conversion for study group was 51 ± 14 vs. 60 ± 2 at two yr, p = 0.018. GFR at inclusion for control group was 56 ± 20 vs. 53 ± 21, p = 0.253. This report demonstrates that minimizing CNI exposure by addition of SRL to the immunosuppressant regimen in pediatric heart transplant recipients result in improved renal function in comparison to historically managed patients. Furthermore, immunotherapy with SRL and lower-dose CNI can effectively prevent rejection with an acceptable side-effect profile.

Topics: Calcineurin Inhibitors; Child; Cyclosporine; Glomerular Filtration Rate; Heart Transplantation; Humans; Hypercholesterolemia; Immunosuppressive Agents; Immunotherapy; Infant; Infant, Newborn; Kidney; Neutropenia; Retrospective Studies; Risk; Sirolimus; Time Factors

Among the adverse effects of different calcineurin inhibitors (CIs), nephrotoxicity is the most common (incidence: 18.1% at 13 y from liver transplantation) and depends on a variable degree of tubular-interstitial injury accompanied by focal glomerular sclerosis. A new immunosuppressive drug was introduced in solid organ transplant management, Sirolimus (SRL). It is a nonnephrotoxic immunosuppressor.. Twenty-six patients who developed nephrotoxicity owing to CIs, showing an increment of serum creatinine levels (>1.8 mg/dL) were switched to SRL monotherapy, initially at a dosage between 3 and 5 mg/d, and subsequently adapted to achieve trough level between 8 to 10 ng/mL.. Patients were followed-up for a mean period of 40.3 months (range, 8.4 to 76.7) from liver transplantation. Mean follow-up after switch was 27.5 months (range, 2 to 71.2). Immunosuppression therapy was converted after a mean period of 12.8 months (range, 0.2 to 43.4). Serum creatinine, urea, and estimated glomerular filtration rate were significantly improved.. Patients developing renal dysfunction after liver transplantation may be successfully treated by conversion from CI to SRL. Hypertriglyceridemia and hypercholesterolemia represent the principal side effects from SRL, but are treatable. Furthermore, SRL can significantly improve glucose tolerance.

Topics: Adult; Aged; Blood Glucose; Calcineurin Inhibitors; Cohort Studies; Creatinine; Cyclosporine; Glomerular Filtration Rate; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Sirolimus; Tacrolimus; Treatment Outcome

Topics: Adaptor Proteins, Signal Transducing; Dyslipidemias; Hypercholesterolemia; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus (SRL) is an immunosuppressive drug increasingly used in children undergoing solid organ transplantation. SRL does not cause glucose intolerance, hypertension, nephrotoxicity or neurotoxicity offering significant potential advantages over calceneurin inhibitors (CM).. To report five children treated with SRL.. A retrospective review of four children undergoing orthotopic liver transplantation (OLT) and one undergoing renal transplantation with recurrent acute rejection (RAR), chronic rejection (CR) or toxicity due to CM, treated with SRL between June 2001 and November 2006.. As primary immunosuppressive therapy, all patients received 3 drugs: CM (Tacrolimus (FK) or Cyclosporine), mycophenolate mofetil and steroids. Mean age at treatment with SRL was 98 months. Children undergoing OLT had a late introduction of SRL (mean time after OLT: 37 months), and mean follow-up was 24 months. In this group rescue indications of SRL were RAR in one, CR in one, thrombotic thrombocytopenic purpura (TTP) in one, food allergy in one and other CM toxicity in three. Only one did not experience adverse events due to SRL, but no one required discontinuation of SRL. There were remissions of RAR, CR, TTP and food allergy. The patient with RT was switched from FK to SRL at day 18th after RT, but he had severe neutropenia that led to discontinuation of SRL.. SRL may be useful in pediatric solid organ transplant recipients suffering from RAR, CR, TTP, food allergy and CM toxicity. Careful attention should be directed to detect side effects and avoid severe complications.

Topics: Calcineurin; Calcineurin Inhibitors; Child; Child, Preschool; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Male; Retrospective Studies; Secondary Prevention; Sirolimus

raptor is a specific and essential component of mammalian TOR complex 1 (mTORC1), a key regulator of cell growth and metabolism. To investigate a role of adipose mTORC1 in regulation of adipose and whole-body metabolism, we generated mice with an adipose-specific knockout of raptor (raptor(ad-/-)). Compared to control littermates, raptor(ad-/-) mice had substantially less adipose tissue, were protected against diet-induced obesity and hypercholesterolemia, and exhibited improved insulin sensitivity. Leanness was in spite of reduced physical activity and unaffected caloric intake, lipolysis, and absorption of lipids from the food. White adipose tissue of raptor(ad-/-) mice displayed enhanced expression of genes encoding mitochondrial uncoupling proteins characteristic of brown fat. Leanness of the raptor(ad-/-) mice was attributed to elevated energy expenditure due to mitochondrial uncoupling. These results suggest that adipose mTORC1 is a regulator of adipose metabolism and, thereby, controls whole-body energy homeostasis.

Topics: 3T3-L1 Cells; Adaptor Proteins, Signal Transducing; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Carrier Proteins; Cell Respiration; Dietary Fats; Energy Metabolism; Hypercholesterolemia; Insulin; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Mitochondria; Multiprotein Complexes; Obesity; Organ Specificity; Proteins; Regulatory-Associated Protein of mTOR; Sirolimus; TOR Serine-Threonine Kinases; Transcription Factors

Everolimus inhibits the mammalian target of rapamycin (mTOR) in proliferating cells. It is widely used in transplant patients and has also been exploited by drug-eluting stents for the treatment of cardiovascular disease. However, there is only limited data on the pathophysiological effects of mTOR-inhibitors on the vascular wall. We aimed to unravel the effects of everolimus on cholesterol-induced atherosclerosis and on circulating cell mediators in LDL-receptor-deficient (LDLR(-/-)) mice. Male hypercholesterolemic LDLR(-/-) mice received either solvent (group A; n=28) or everolimus at 0.05 mg/kg (group B, n=22) and 1.5 mg/kg (group C, n=29) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks. Group B showed 44% reduction of atherosclerotic lesions at the brachiocephalic artery (BCA). In group C atherosclerotic lesions were reduced by 85% in the BCA and by 60% at the aortic root. This was associated with a significantly lower complexity of lesions in both treated groups (p<0.001) and despite a 40% increase of plasma cholesterol. Everolimus caused a significant reduction of circulating cell mediators such as interleukin-1alpha, interleukin-5, GM-CSF and interleukin-12p40. Everolimus increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied. Everolimus strongly inhibits atherosclerosis development in LDL-receptor(-/-) mice despite severe hypercholesterolemia. Everolimus application had only small effects on circulating cell mediators. The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques.

Topics: Animals; Atherosclerosis; Body Weight; Cholesterol, LDL; Cytokines; Everolimus; Hypercholesterolemia; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Kinases; Receptors, LDL; Severity of Illness Index; Sirolimus; TOR Serine-Threonine Kinases

Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels. We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo- and hypercholesteraemic conditions to explain these findings.. Shear stress levels were varied over a large range of values in carotid arteries of transgenic mice expressing human eNOS fused to enhanced green fluorescence protein. The mice were divided into control, low-dose rapamycin (3 microg/kg/day), and high-dose rapamycin (3 mg/kg/day) groups and into normocholesteraemic and hypercholesteraemic (ApoE-/- on high cholesterol diet for 3-4 weeks) groups. The effect of rapamycin treatment on eNOS was evaluated by quantification of eNOS expression and of intracellular protein levels by en face confocal microscopy. A sigmoid curve fit was used to described these data. The efficacy of treatment was confirmed by measurement of rapamycin serum levels (2.0 +/- 0.5 ng/mL), and of p27kip1 expression in vascular tissue (increased by 2.4 +/- 0.5-fold). In control carotid arteries, eNOS expression increased by 1.8 +/- 0.3-fold in response to rapamycin. In the treated vessels, rapamycin reduced maximal eNOS expression at high shear stress levels (>5 Pa) in a dose-dependent way and shifted the sigmoid curve to the right. Hypercholesteraemia had a tendency to increase the leftward shift and the reduction in maximal eNOS expression (P = 0.07).. Rapamycin is associated with high eNOS in low shear regions, i.e. in atherogenic regions, protecting these regions against atherosclerosis, and is associated with a reduction of eNOS at high shear stress affecting vasomotion in these regions.

Topics: Animals; Apolipoproteins E; Cardiovascular Agents; Carotid Arteries; Carotid Artery Diseases; Cyclin-Dependent Kinase Inhibitor p27; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Green Fluorescent Proteins; Humans; Hypercholesterolemia; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Nitric Oxide Synthase Type III; Pulsatile Flow; Recombinant Fusion Proteins; Sirolimus; Stress, Mechanical

Nephrotoxicity caused by CNI may adversely affect long-term graft outcomes. For this reason, we have adopted a protocol for withdrawing TAC and converting to SRL at three months post-renal transplantation. All recipients received basiliximab induction and TAC, MMF, and prednisone. Patients without acute rejection by surveillance biopsy at three months were eligible for SRL conversion.. From August 2004 to September 2006, TAC was withdrawn and replaced by SRL in 30 first transplant recipients, who were followed for six to 39 months (mean 18 +/- 8). Renal function did not improve significantly after SRL conversion (p = 0.25). Acute rejection occurred in three patients (10%) at five to 12 months after CNI withdrawal. There were no occurrences of wound healing problems, pneumonitis or post-transplant lymphoproliferative disease. Thrombocytopenia and diabetes each occurred in one patient. Four patients received treatment for hypercholesterolemia. CNI withdrawal and replacement with SRL was an effective regimen in children who did not display biopsy evidence of acute rejection at three months post-transplant. While these early results are promising, the ultimate benefit of this protocol to enhance the long-term renal function and graft survival requires ongoing follow-up.

Topics: Biopsy; Child; Child, Preschool; Female; Graft Rejection; Humans; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Male; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Statins offer a strategy to address dyslipidemia commonly experienced by immunosuppressed transplant recipients.. This single-center, retrospective study of 325 recipients (mean posttransplant follow-up of over 6 years; 75.0+/-26.0 months) correlated four adverse outcomes-biopsy-confirmed acute rejection episodes, biopsy-confirmed chronic rejection/allograft nephropathy, graft loss, or death-with demographic and posttreatment variables. Patients were treated with a combination of sirolimus (SRL), cyclosporine (CsA), and various durations of steroids. Statins were prescribed for 259/325 (79%) recipients whose serum cholesterol exceeded 240 mg/dL and discontinued when the creatine phosphokinase increased fivefold (3.4%) or the liver function, threefold (3.0%) above normal.. Upon univariate (hazard ratio [HR] 0.16; P<.001) and multivariate analysis (HR 0.38; P=.02), statins were markedly protective against acute rejection episodes. They reduced occurrence of chronic nephropathy/chronic rejection (HR 0.60; P=.03 and HR 0.52; P=.01, respectively). Incidences of graft loss were diminished (HR 0.26; P<.001 and HR 0.49; P=.01, respectively). Finally, the mortality rate was decreased (HR 0.21, P=.001 and HR 0.26, P=.01, respectively). Upon multivariate analysis, a reduced incidence of acute rejection was correlated with greater exposure to SRL (HR 0.78, P=.016) and CsA (HR 0.39; P=.006).. This study demonstrated compelling effects of statins against all adverse outcomes among patients treated with SRL-based, CsA-containing regimens. The profoundly dyslipidemic properties of SRL may explain these unique findings compared with previous studies on patients treated with CsA-based regimens.

Topics: Aged; Cholesterol; Cyclosporine; Drug Prescriptions; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Retrospective Studies; Sirolimus

As a possible explanation for everolimus/cyclosporine-induced hypercholesterolemia seen in transplant recipients, we investigated the interactions of the immunosuppressants everolimus and cyclosporine on bile flow and biliary excretion of bile salts and cholesterol in a subchronic bile fistula model in rats because biliary excretion is a main elimination route of cholesterol. After 2 weeks of daily treatment, everolimus (1 mg/kg i.p.) and cyclosporine (5 mg/kg i.p) decreased bile flow (-45 and -36%) and biliary excretion of bile salts (-34 and -54%) and cholesterol (-25 and -39%) and increased serum concentrations of cholesterol (+40 and +17%) and triglycerides (+220 and +110%). Bile salt serum concentration was elevated only by cyclosporine (+100%), and not by everolimus. Everolimus/cyclosporine slightly enforced the cyclosporine-induced hyperlipidemia but not reduction of bile parameters, while the cyclosporine-induced increase in bile salts in serum was totally prevented. From these results we conclude that bile salt synthesis could be impaired by everolimus, which could be one reason for everolimus-induced hypercholesterolemia.

Topics: Animals; Bile; Cholesterol; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Everolimus; Hypercholesterolemia; Immunosuppressive Agents; Injections, Intraperitoneal; Male; Rats; Rats, Wistar; Sirolimus; Triglycerides

We evaluated the clinical and angiographic outcomes of patients presenting with restenosis after sirolimus-eluting stent (SES) implantation treated with repeated percutaneous intervention.. A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, 1 (4%) was re-treated with a bare stent, 3 (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated drug-eluting stent implantation (SES in 12 lesions [44%], paclitaxel-eluting stents in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42.9%. The risk of recurrent restenosis was increased for patients with hypercholesterolemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with drug-eluting stents was 18.2%.. Even though de novo lesions treated with SES at baseline and re-treated with drug-eluting stents had reasonably better outcomes than other lesion types and strategies, our study shows that the treatment of post-SES restenosis is currently suboptimal and warrants further investigation.

Topics: Aged; Angioplasty, Balloon, Coronary; Brachytherapy; Cohort Studies; Combined Modality Therapy; Coronary Restenosis; Coronary Stenosis; Disease-Free Survival; Drug Implants; Female; Follow-Up Studies; Humans; Hypercholesterolemia; Incidence; Male; Middle Aged; Paclitaxel; Radiography; Recurrence; Sirolimus; Stents; Treatment Outcome

This retrospective study compared the incidence, severity, and predisposing factors for dyslipidemia among renal transplant patients treated for up to 6 years with a cyclosporine +/- prednisone-based concentration-controlled regimen without (n=118) or with (n=280) ascending exposures to sirolimus.. The diagnosis of dyslipidemia was established when the serum cholesterol value (CHO) was more than 240 mg/dL or serum triglycerides (TG) were more than 200 mg/dL. Generalized estimating equations and mixed-modeling procedures were used for statistical analyses.. Hypercholesterolemia was observed in 46% to 80% and hypertriglyceridemia in 43% to 78% of sirolimus-treated patients during the first 6 posttransplantation months. The mean peak serum lipid levels among patients in the sirolimus group (CHO=285.5 mg/dL; TG=322.4 mg/dL) were significantly higher than those in the nonsirolimus group (CHO=250.2 mg/dL and TG=267.6 mg/dL; both P<0.01). The lipid values, which were persistently elevated during the first posttransplantation year, decreased slowly thereafter but remained significantly higher than the pretransplantation levels beyond 4 years after transplantation. The two forms of hyperlipidemia tended to occur in parallel (Pearson's coefficient of correlation, r=0.5, P<0.001), showing a positive predictive value of 0.67 and a negative predictive value of 0.65. However, there was no significant difference in the incidence of cardiovascular events within 4 years after transplantation among patients treated with versus without sirolimus.. The dyslipidemia associated with sirolimus therapy, albeit persistent, does not seem to represent a major risk factor for the early emergence of cardiovascular complications.

Topics: Adult; Anti-Inflammatory Agents; Cardiovascular Diseases; Cohort Studies; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Prednisolone; Prognosis; Retrospective Studies; Risk Factors; Severity of Illness Index; Sirolimus

We sought to examine the potential benefits of therapeutic drug monitoring of sirolimus, a potent immunosuppressive agent that displays a pleiotropic array of side effects.. A high-performance liquid chromatography (LC) procedure combined with ultraviolet detection (UV) was used to measure serial concentrations of parent compound sirolimus in 150 renal transplant recipients over a period of 4 yr. Drug concentrations in whole blood at trough time, as well as within pharmacokinetic profiles, were correlated with clinical events using contingency tables, logistic regression analysis, and receiver operating characteristic (ROC) curves.. The LC/UV method showed an excellent correlation with detection of LC-resolved components by tandem mass spectrometry, demonstrating that the LC/UV method selectively detected parent compound. Sirolimus displayed the characteristics of a critical-dose drug: Its concentration could not be predicted by a standard body or demographic measure, or by dose, and it showed high degrees of intra- and inter-individual variability. However, there was a good correlation between trough and area-under-the-curve measurements. There was a significant association between trough values expressed as either observed ( < 5 ng/mL) or dose-corrected parameter ( < 1.7 ng/mL per mg administered drug) and the occurrence and severity of acute rejection episodes - despite the low overall incidence of 23 episodes among the cohort of 150 patients. Similarly, ROC functions showed a correlation of the occurrence of hypertriglyceridemia, thrombocytopenia, and leukopenia, but not hypercholesterolemia, with trough concentrations above 15 ng/mL.. Due to its behavior as a critical-dose drug, therapeutic monitoring to measure sirolimus concentrations by a LC/UV method may provide clinicians with a tool to optimize outcomes.

Topics: Adolescent; Adult; Aged; Area Under Curve; Chromatography, High Pressure Liquid; Cohort Studies; Drug Monitoring; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Kidney Transplantation; Leukopenia; Logistic Models; Male; Mass Spectrometry; Middle Aged; ROC Curve; Sensitivity and Specificity; Sirolimus; Thrombocytopenia; Treatment Outcome; Ultraviolet Rays