Chest
Original Research: Diffuse Lung DiseaseRetrospective Review of Combined Sirolimus and Simvastatin Therapy in Lymphangioleiomyomatosis
Section snippets
Patient Population
Patients were referred to the National Institutes of Health for participation in an LAM natural history and pathogenesis protocol, which was approved by the National Heart, Lung, and Blood Institute Institutional Review Board (NHLBI Protocol 95-H-0186). In addition to self-referral and referral by individual physicians, patients were informed of the studies by the LAM Foundation and the Tuberous Sclerosis Alliance. All patients gave written informed consent before enrollment. Clinical,
Patients Characteristics
Fourteen patients were treated with sirolimus (mean dose, 2.7 ± 0.9 mg/d) and simvastatin (mean dose, 23.3 ± 11.6 mg/d), 20 received simvastatin alone (mean dose, 32.0 ± 16.1 mg/d), and 44 were treated with sirolimus alone (mean dose, 2.4 ± 0.8 mg/d). The initial prevalence of hypercholesterolemia in the simvastatin plus sirolimus group was 64%. Simvastatin was prescribed for the treatment of preexisting hypercholesterolemia or hypercholesterolemia that worsened or developed after beginning
Discussion
Because mTORC1, mTORC2, and RhoGTPase activity are all required for cell proliferation and survival,25 inhibition of mTORC1, mTORC2, and RhoGTPase may be more effective in abrogating LAM cell growth and proliferation than mTORC1 blockade with mTOR inhibitors alone.25, 30 In the only human study evaluating changes in lung function in patients with LAM treated with statins, the rate of decline in lung diffusion capacity was found to be greater than that of matched off-statin-therapy control
Conclusions
Combined therapy with sirolimus plus simvastatin does not result in a greater prevalence of adverse events beyond those expected from the use of each drug alone. Within the limitations of this study and because of the small numbers of patients treated with sirolimus plus simvastatin, we found no evidence that simvastatin enhances or diminishes the beneficial effects of sirolimus therapy in LAM. Because there is good evidence that simvastatin and sirolimus act synergically to abrogate the
Acknowledgments
Authors contributions: A. M. T.-D. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. A. M. T.-D. and J. M. contributed to the study design, data analysis, and writing of the manuscript; A. M. J. and P. A. J.-W. contributed to the data collection and review; M. S. contributed to the statistical analysis; and A. M. T.-D., A. M. J., P. A. J.-W., M. S., and J. M. reviewed and approved the manuscript.
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A phase II clinical trial of the Safety Of Simvastatin (SOS) in patients with pulmonary lymphangioleiomyomatosis and with tuberous sclerosis complex
2020, Respiratory MedicineCitation Excerpt :In addition, although the mean FEV1 (68.7% predicted) at baseline was consistent with a moderate degree of obstruction in enrolled subjects, there was a significant dichotomy in lung function impairment with 5 patients having an FEV1>80% predicted and 4 patients with an FEV1<55% predicted. Consistent with a prior retrospective review of LAM patients treated with sirolimus with the subsequent addition of simvastatin for hypercholesterolemia, both drugs were tolerated well in combination [24]. Because only one subject had TSC-LAM and only one was on everolimus, our direct conclusions about adverse events in these populations are limited.
Evidence Supporting a Lymphatic Endothelium Origin for Angiomyolipoma, a TSC2<sup>−</sup> Tumor Related to Lymphangioleiomyomatosis
2016, American Journal of PathologyCitation Excerpt :We found that transfection of hyperactive mTOR down-regulated LEC markers in TSC2+ cells, suggesting that TSC2 correction promotes LEC differentiation through the inactivation of mTOR rather than through a noncanonical mechanism. Clinical trials with the mTORC1 inhibitor rapamycin, the only US Food and Drug Administration–approved drug for the treatment of LAM and AML, have revealed only partial efficacy in the treatment of both conditions22,37,81,82; therefore, combined therapies with rapamycin followed by surgery,83 in the case of AML, or including an adjuvant drug in addition to rapamycin, particularly in the case of LAM, are currently the focus of much attention.25,84,85 On the basis of the results obtained with NCTD in the treatment of TSC2− cells, we treated these cells with a combination of rapamycin and NCTD and observed additive benefit.
Lymphangioleiomyomatosis (LAM): Molecular Insights into mTOR Regulation Lead to Targeted Therapies
2016, Molecules to Medicine with mTOR: Translating Critical Pathways into Novel Therapeutic StrategiesEfficacy and Safety of Sirolimus for Blue Rubber Bleb Nevus Syndrome: A Prospective Study
2021, American Journal of GastroenterologyDiagnosis and treatment of lymphangioleiomyomatosis (LAM) from the PEComa group
2021, Oncology in Clinical Practice
FUNDING/SUPPORT: This study was supported by the Intramural Research Program, National Institutes of Health, National Heart, Lung, and Blood Institute.
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