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Joel Moss - One of the best experts on this subject based on the ideXlab platform.
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Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis
JCI insight, 2019Co-Authors: Wendy K. Steagall, Gustavo Pacheco-rodriguez, Mario Stylianou, Joel MossAbstract:A local renin-angiotensin system exists in the pulmonary nodules of lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate Sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected lymphangioleiomyomatosis disease progression. Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with Sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with Sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and Sirolimus versus Sirolimus alone. Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with lymphangioleiomyomatosis not treated with Sirolimus. These inhibitors may be an option or adjunct in the treatment of lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. NIH.
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retrospective review of combined Sirolimus and simvastatin therapy in lymphangioleiomyomatosis
Chest, 2015Co-Authors: Angelo M Taveiradasilva, Mario Stylianou, Amanda M Jones, Patricia Julienwilliams, Joel MossAbstract:BACKGROUND Combined simvastatin and Sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. METHODS To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of Sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus Sirolimus (n = 14), Sirolimus alone (n = 44), or simvastatin alone (n = 20). RESULTS Sirolimus-related adverse events in the simvastatin plus Sirolimus and Sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus Sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus Sirolimus therapy, FEV 1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, −1.4 ± 0.2 and −1.8 ± 0.2% predicted. After simvastatin plus Sirolimus therapy, these rates changed to +1.2 ± 0.5 ( P = .635) and +0.3 ± 0.4% predicted ( P = .412), respectively. In 44 patients treated with Sirolimus alone, FEV 1 and Dlco rates of change were −1.7 ± 0.1 and −2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment ( P CONCLUSIONS Therapy with Sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of Sirolimus.
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Retrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis
Chest, 2015Co-Authors: Angelo M. Taveira-dasilva, Mario Stylianou, Amanda M Jones, Patricia Julien-williams, Joel MossAbstract:Combined simvastatin and Sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of Sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus Sirolimus (n = 14), Sirolimus alone (n = 44), or simvastatin alone (n = 20). Sirolimus-related adverse events in the simvastatin plus Sirolimus and Sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus Sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus Sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, -1.4 ± 0.2 and -1.8 ± 0.2% predicted. After simvastatin plus Sirolimus therapy, these rates changed to +1.2 ± 0.5 (P = .635) and +0.3 ± 0.4% predicted (P = .412), respectively. In 44 patients treated with Sirolimus alone, FEV1 and Dlco rates of change were -1.7 ± 0.1 and -2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment (P < .001). Therapy with Sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of Sirolimus.
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sustained effects of Sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Jianhua Yao, Mario Stylianou, Angelo M Taveiradasilva, Amanda M Jones, Patricia Julienwilliams, Joel MossAbstract:Rationale: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. Objectives: To determine whether Sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether Sirolimus is well tolerated by patients. Methods: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on Sirolimus with studies done on Sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on Sirolimus. Measurements and Main Results: Sirolimus reduced yearly declines in FEV1 (−2.3 ± 0.1 vs. 1.0 ± 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (−2.6 ± 0.1 vs. 0.9 ± 0.2% predicted; P < 0.001). Cyst scores 1.2 ± 0.8 years (30.5 ± 11.9%) and 2.5 ± 2 years (29.7 ± 12.1%) after initiating Sirolimus were not significantly different from pretreatment values (28.4 ± 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (−1.4 ± 0.2 vs. 0.3 ± 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 ± 0.2 vs. 0.3 ± 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue Sirolimus therapy. Conclusions: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate Sirolimus therapy.
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Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis
The New England journal of medicine, 2011Co-Authors: Francis X. Mccormack, Joel Moss, Yoshikazu Inoue, Lianne G. Singer, Charlie Strange, Koh Nakata, Alan F. Barker, Jeffrey T. Chapman, Mark L. Brantly, James M. StocksAbstract:Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM. We conducted a two-stage trial of Sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of Sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)). During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the Sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the Sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of Sirolimus, the decline in lung function resumed in the Sirolimus group and paralleled that in the placebo group. Adverse events were more common with Sirolimus, but the frequency of serious adverse events did not differ significantly between the groups. In patients with LAM, Sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with Sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).
David W Holt - One of the best experts on this subject based on the ideXlab platform.
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multi center evaluation of analytical performance of the microparticle enzyme immunoassay for Sirolimus
Clinical Biochemistry, 2006Co-Authors: D. Wilson, F Johnston, M Moreton, J Engelmayer, Jm Gaulier, Hilmar Luthe, D Moscato, Pascal Marquet, David W Holt, Michael OellerichAbstract:OBJECTIVES: This study evaluated the analytical characteristics of the new Abbott microparticle enzyme immunoassay (MEIA) for Sirolimus. DESIGN AND METHODS: The protocol consisted of nine sections: evaluation of antibody specificity, linearity, detection limit, quantification limit, endogenous interferents, exogenous interferents, precision, proficiency testing panel, and method comparison. RESULTS: The mean analytical detection limit was 0.68 microg/L. The Sirolimus concentration corresponding to a total CV of 20% was 1.5 microg/L. Linearity of response was demonstrated across the dynamic range of the assay. Total precision (CVs) at QC control levels from 5 to 22 microg/L ranged from 5.7 to 12.6%. Assay standardization was found to be in good agreement with LC/MS/MS as compared with target values for spiked Sirolimus proficiency samples from an international Sirolimus proficiency testing program. Good correlations (R values) of the immunoassay were observed in comparisons to LC/MS/MS. R values tended to be lower in comparisons with LC/UV methods. Across both LC-based methods and all study sites, there was approximately 25% overall positive slope bias due to cross reactivity of the MEIA antibody to metabolites of Sirolimus. The assay cross-reactivity to metabolites of Sirolimus parent drug ranged from 6 to 63%. Assay interferences were minimal with the exception of hematocrit, which presented a negative relationship to measured Sirolimus concentration. CONCLUSIONS: The MEIA demonstrated acceptable analytical characteristics for use for routine monitoring of Sirolimus immunosuppressive therapy, and is a viable alternative to HPLC-based methods for Sirolimus monitoring.
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HPLC Assay with Ultraviolet Detection for Therapeutic Drug Monitoring of Sirolimus
Clinical chemistry, 2001Co-Authors: Daniel C. French, Michael Saltzgueber, David Hicks, Annabel L. Cowper, David W HoltAbstract:Sirolimus (Rapamune®; rapamycin) is a macrocyclic lactone produced by Streptomyces hygroscopicus (1)(2). Studies in a variety of animal transplant models (3)(4)(5) and human clinical trials (6)(7)(8)(9) have shown that Sirolimus is a potent immunosuppressive agent. Sirolimus is metabolized in humans by hepatic and intestinal cytochrome P450 3A4, primarily leading to demethylated and hydroxylated metabolites (10). When Sirolimus is given in the presence of cytochrome P450 3A4 inducers or inhibitors or to patients with hepatic insufficiency, Sirolimus blood concentrations may be affected and dose adjustments may be required. Therefore, therapeutic drug monitoring (TDM) of Sirolimus concentrations plays an important role in the selection of the optimum dose of Sirolimus; in Europe, the license for this drug stipulates that concentrations must be monitored. Sirolimus binds to the immunophilin FK506 binding protein and is sequestered in red blood cells, leading to whole-blood/plasma ratios of ∼38 (11)(12). Because of low Sirolimus concentrations in plasma and limited stability in that matrix, whole blood is the matrix of choice for determining Sirolimus concentrations (13)(14). An excellent correlation has been reported between Sirolimus 24-h whole-blood trough concentrations ( c min) and Sirolimus area under the concentration-time curve (12)(15). A strong correlation between Sirolimus c min values and the evidence of efficacy and adverse events has also been reported (15). Therefore, the TDM of Sirolimus c min values provides a useful prediction of inadequate immunosuppression or potential adverse events. When Sirolimus is given with full-dose cyclosporine, the recommended therapeutic range for Sirolimus whole-blood trough concentrations is 5–15 μg/L (15). For an analytical method to be suitable for the TDM of Sirolimus, it should be simple, sensitive (lower limit of quantification,
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An immunoassay for the measurement of Sirolimus.
Clinical Therapeutics, 2000Co-Authors: Kirsty Jones, David Hicks, Soha Saadat-lajevardi, Terry Lee, Ruth Horwatt, Atholl Johnston, David W HoltAbstract:Abstract Objective This study assessed the performance characteristics of a new microparticle enzyme immunoassay (MEIA) for the determination of Sirolimus in whole blood. Background In clinical investigatory studies, dose adjustments of the immunosuppressive drug Sirolimus have been carried out using either high-performance liquid chromatography (HPLC) or, more recently, this investigational immunoassay kit based on the MEIA technique. Methods Calibration was made over the linear range 0 to 30 ng/mL. Inaccuracy and imprecision were assessed by means of 3 control samples supplied with the kit (5, 11, and 22 ng/mL) and dilution of an above-quantitation-limit sample (154 ng/mL). Specificity was determined by the addition of 2 Sirolimus metabolites to Sirolimus-free human whole blood or to I of the control samples supplied with the kit. In addition, whole-blood samples from patients receiving either cyclosporine or tacrolimus (N = 24) were analyzed for Sirolimus. A comparison of the MEIA and a validated HPLC/MS/MS assay analyzed both pooled samples from patients receiving Sirolimus and spiked samples (Sirolimus 2–60 ng/mL). In a more extensive comparison of patient samples measured by the MEIA assay, a validated HPLC assay with UV detection (HPLC-UV) was used (HPLC-UV Sirolimus 7–64 ng/mL). Results Inaccuracy (between-run) was ≤ 16.2% at all 4 concentrations (N = 5). Withinassay imprecision (repeatability) was Conclusion The MEIA showed suitable precision across a clinically relevant concentration range. In terms of patient management, the practical significance of cross-reactivity with Sirolimus metabolites remains to be assessed.
D Durand - One of the best experts on this subject based on the ideXlab platform.
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Sirolimus rapamycin based therapy in human renal transplantation similar efficacy and different toxicity compared with cyclosporine Sirolimus european renal transplant study group
Transplantation, 1999Co-Authors: Carl G Groth, Henri Kreis, Josep Maria Campistol, Roy Calne, Lars Backman, Josemaria Morales, Philippe Lang, J L Touraine, Kerstin Claesson, D DurandAbstract:Background. Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. Methods. 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. Results. At 12 months, graft survival (98% Sirolimus vs. 90% 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<0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with Sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the Sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with Sirolimus. No gingival hyperplasia was seen with Sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with Sirolimus. Conclusions. Results at 12 months suggest that Sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.
Christopher J.e. Watson - One of the best experts on this subject based on the ideXlab platform.
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Sirolimus‐induced pneumonitis following liver transplantation
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation S, 2007Co-Authors: Rebecca J. Roberts, Antonia C. Wells, Esther Unitt, Meryl Griffiths, A.d. Tasker, Michael Allison, J. Andrew Bradley, Christopher J.e. WatsonAbstract:Sirolimus-induced pneumonitis has emerged as a potentially serious complication in renal transplantation but only single case reports of this condition have been described after liver transplantation (LT), where experience with Sirolimus is relatively limited. We report our experience, the largest to date, of Sirolimus-induced pneumonitis following LT. Between 1999 and 2006, 186 liver transplant patients received Sirolimus-based immunosuppression, after initial therapy with calcineurin inhibitors (CNIs). All cases of Sirolimus-induced pneumonitis were recorded and a retrospective review of the case notes of such patients was undertaken for the purpose of this analysis. Of 186 liver transplant patients receiving Sirolimus, 4 (2.2%) developed pneumonitis that was attributed to the drug; the time from starting Sirolimus to presentation was varied (1.5-30 months). The most common presenting symptoms were dyspnea, cough and fatigue. The median Sirolimus level at the time of diagnosis was 9.7 ng/mL (range, 7-19.5 ng/mL). All patients in the series underwent thoracic computed tomography, which showed similar changes in all patients, and lung biopsy, which revealed features consistent with a drug-induced pneumonitis. In all 4 patients, Sirolimus-induced pneumonitis resolved following cessation of therapy but took weeks to months for complete recovery. In conclusion, Sirolimus-induced pneumonitis occurred in at least 2% of liver transplant recipients and should be suspected in patients who develop respiratory symptoms while on Sirolimus. Although it may be life threatening, early recognition and cessation of Sirolimus can lead to complete resolution of pneumonitis.
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Sirolimus (rapamycin) in clinical transplantation
Transplantation Reviews, 2001Co-Authors: Christopher J.e. WatsonAbstract:Sirolimus (rapamycin) is a newly licensed immunosuppressant that ushers in a new era of immunosuppression. Unlike tacrolimus and cyclosporin, Sirolimus is not a calcineurin inhibitor (CNI) and shares few side effects associated with CNI therapy. Most importantly, it is not nephrotoxic, neurotoxic, or diabetogenic. Sirolimus binds to the 12-kd member of the FK506 binding protein immunophilin family; this complex interacts with the target of rapamycin, a key step in coreceptor- and cytokine-mediated stimulation, resulting in growth arrest late in the G-phase. Thus, Sirolimus does not inhibit cytokine gene transduction like cyclosporin, but acts later in the cell cycle to inhibit cytokine-stimulated proliferation of T cells. Its adverse effects include bone marrow suppression, increased serum lipid levels, and impaired wound healing. It is synergistic with cyclosporin and tacrolimus and has been shown to be as potent as cyclosporin in the immunosuppression of renal allografts. Its principal role likely will be in combination with CNIs in the early treatment phase after transplantation, possibly with a CD25 monoclonal antibody and no steroids, and as the principal agent for maintenance therapy after CNI withdrawal. Everolimus, a derivative of Sirolimus, shares many of the properties of Sirolimus and is being developed along similar lines.
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Sirolimus: a potent new immunosuppressant for liver transplantation.
Transplantation, 1999Co-Authors: Christopher J.e. Watson, Peter J. Friend, Neville V. Jamieson, Thomas W. Frick, Graeme J. M. Alexander, Alexander E. S. Gimson, Roy CalneAbstract:Sirolimus (rapamycin) is a new immunosuppressant that appears to be synergistic with cyclosporine in kidney transplantation, but with a different side-effect profile. This pilot study evaluated Sirolimus in liver transplantation. Patients undergoing orthotopic liver transplantation for primary tumors (8), and later for nonmalignant disease (7), received one of three Sirolimus-based immunosuppressive regimens. Protocol A comprised Sirolimus, microemulsion cyclosporine (target whole blood concentration: 100 ng/ml), and prednisolone; protocol B omitted prednisolone; and protocol C was Sirolimus alone. By 3 months after transplantation, all patients were receiving Sirolimus as monotherapy. Fifteen patients were treated with a follow-up of 117-806 days. Rejection was more common on monotherapy than double therapy, and absent on triple therapy. The drug was generally well tolerated, with only three patients discontinuing Sirolimus: one for hyperlipidemia, one for pneumocystis pneumonia, and one for inability to tolerate the taste of the drug. Two patients discontinued cyclosporine early, both as a result of neurological complications; they continued on Sirolimus monotherapy. Five patients died; one suffered a cardiac arrest, and four died from sepsis in association with graft-versus-host disease, recurrent tumor, a paralyzed right hemidiaphragm, and primary nonfunction. Sirolimus combined with cyclosporine provided potent immunosuppression of liver allografts, and Sirolimus monotherapy was adequate and well tolerated as maintenance therapy. Side effects of Sirolimus over the short period of follow-up were uncommon and reversible with dose reduction or cessation of therapy.
Amanda M Jones - One of the best experts on this subject based on the ideXlab platform.
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retrospective review of combined Sirolimus and simvastatin therapy in lymphangioleiomyomatosis
Chest, 2015Co-Authors: Angelo M Taveiradasilva, Mario Stylianou, Amanda M Jones, Patricia Julienwilliams, Joel MossAbstract:BACKGROUND Combined simvastatin and Sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. METHODS To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of Sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus Sirolimus (n = 14), Sirolimus alone (n = 44), or simvastatin alone (n = 20). RESULTS Sirolimus-related adverse events in the simvastatin plus Sirolimus and Sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus Sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus Sirolimus therapy, FEV 1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, −1.4 ± 0.2 and −1.8 ± 0.2% predicted. After simvastatin plus Sirolimus therapy, these rates changed to +1.2 ± 0.5 ( P = .635) and +0.3 ± 0.4% predicted ( P = .412), respectively. In 44 patients treated with Sirolimus alone, FEV 1 and Dlco rates of change were −1.7 ± 0.1 and −2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment ( P CONCLUSIONS Therapy with Sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of Sirolimus.
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Retrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis
Chest, 2015Co-Authors: Angelo M. Taveira-dasilva, Mario Stylianou, Amanda M Jones, Patricia Julien-williams, Joel MossAbstract:Combined simvastatin and Sirolimus therapy reduces tuberous sclerosis complex 2-null lesions and alveolar destruction in a mouse model of lymphangioleiomyomatosis (LAM), suggesting that therapy with both drugs may benefit patients with LAM. To determine whether simvastatin changed the prevalence of adverse events or altered the therapeutic effects of Sirolimus, we recorded adverse events and changes in lung function in patients with LAM treated with simvastatin plus Sirolimus (n = 14), Sirolimus alone (n = 44), or simvastatin alone (n = 20). Sirolimus-related adverse events in the simvastatin plus Sirolimus and Sirolimus-only groups were 64% and 66% for stomatitis, 50% and 52% for diarrhea, 50% and 45% for peripheral edema, 36% and 61% for acne, 36% and 30% for hypertension, 29% and 27% for proteinuria, 29% and 27% for leukopenia, and 21% and 27% for hypercholesterolemia. The frequency of simvastatin-related adverse events in the simvastatin-only and simvastatin plus Sirolimus groups were 60% and 50% for arthralgias and 35% and 36% for myopathy. Before simvastatin plus Sirolimus therapy, FEV1 and diffusing capacity of the lung for carbon monoxide (Dlco) yearly rates of change were, respectively, -1.4 ± 0.2 and -1.8 ± 0.2% predicted. After simvastatin plus Sirolimus therapy, these rates changed to +1.2 ± 0.5 (P = .635) and +0.3 ± 0.4% predicted (P = .412), respectively. In 44 patients treated with Sirolimus alone, FEV1 and Dlco rates of change were -1.7 ± 0.1 and -2.2 ± 0.1% predicted before treatment and +1.7 ± 0.3 and +0.7 ± 0.3% predicted after treatment (P < .001). Therapy with Sirolimus and simvastatin does not increase the prevalence of drug adverse events or alter the therapeutic effects of Sirolimus.
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sustained effects of Sirolimus on lung function and cystic lung lesions in lymphangioleiomyomatosis
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Jianhua Yao, Mario Stylianou, Angelo M Taveiradasilva, Amanda M Jones, Patricia Julienwilliams, Joel MossAbstract:Rationale: Sirolimus therapy stabilizes lung function and reduces the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis. Objectives: To determine whether Sirolimus has beneficial effects on lung function, cystic areas, and adjacent lung parenchyma; whether these effects are sustained; and whether Sirolimus is well tolerated by patients. Methods: Lung function decline over time, lung volume occupied by cysts (cyst score), and lung tissue texture in the vicinity of the cysts were quantified with a computer-aided diagnosis system in 38 patients. Then we compared cyst scores from the last study on Sirolimus with studies done on Sirolimus therapy. In 12 patients, we evaluated rates of change in lung function and cyst scores off and on Sirolimus. Measurements and Main Results: Sirolimus reduced yearly declines in FEV1 (−2.3 ± 0.1 vs. 1.0 ± 0.3% predicted; P < 0.001) and diffusing capacity of carbon monoxide (−2.6 ± 0.1 vs. 0.9 ± 0.2% predicted; P < 0.001). Cyst scores 1.2 ± 0.8 years (30.5 ± 11.9%) and 2.5 ± 2 years (29.7 ± 12.1%) after initiating Sirolimus were not significantly different from pretreatment values (28.4 ± 12.5%). In 12 patients followed for 5 years, a significant reduction in rates of yearly decline in FEV1 (−1.4 ± 0.2 vs. 0.3 ± 0.4% predicted; P = 0.025) was observed. Analyses of 104 computed tomography scans showed a nonsignificant (P = 0.23) reduction in yearly rates of change of cyst scores (1.8 ± 0.2 vs. 0.3 ± 0.3%; P = 0.23) and lung texture features. Despite adverse events, most patients were able to continue Sirolimus therapy. Conclusions: Sirolimus therapy slowed down lung function decline and increase in cystic lesions. Most patients were able to tolerate Sirolimus therapy.
