Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort

IntroductionRecent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb3) and related analogues, deacylated forms of globotriaosylceramide (Gb3), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease.MethodsWe evaluated Gb3, lyso-Gb3 and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb3 and analogues at m/z (−28), (−2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb3 and lyso-Gb3 analogues at m/z (−12) and (+14) were evaluated in urine while the analogue at m/z (+18) was evaluated in plasma.ResultsA strong correlation between plasma and urine lyso-Gb3 and analogue levels was revealed. Plasma and urine lyso-Gb3 and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb3 and analogues at m/z (−28), (−2), (+16), (+34) and the seven urinary lyso-Gb3 analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb3 and five analogues, as well as urine Gb3 and six lyso-Gb3 analogues, but not lyso-Gb3 and lyso-Gb3 at m/z (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa.ConclusionWomen with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb3 and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.

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Clinical event status of patients with Fabry disease after long-term treatment with agalsidase beta and follow-up from The Fabry Registry

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2012.11.092 ◽

2013 ◽

Vol 108 (2) ◽

pp. S42

Author(s):

Dominique P. Germain ◽

Gabor E. Linthorst ◽

William R. Wilcox ◽

Frank Weidemann ◽

Marta Cizmarik ◽

...

Keyword(s):

Fabry Disease ◽

Term Treatment ◽

Clinical Event ◽

Agalsidase Beta ◽

Long Term Treatment

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MO035HISTORICAL CONTROL ANALYSIS DEMONSTRATES SUPERIOR REDUCTION OF PLASMA GLOBOTRIAOSYLCERAMIDE BY VENGLUSTAT COMPARED WITH PLACEBO OR AGALSIDASE BETA IN CLASSIC FABRY DISEASE PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa140.mo035 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Dominique P Germain ◽

William Wilcox ◽

Patrick Deegan ◽

Kejian Liu ◽

Eric Hailman ◽

...

Keyword(s):

Fabry Disease ◽

Term Treatment ◽

Historical Control ◽

Agalsidase Beta ◽

Phase 2 ◽

Phase 3 ◽

Glucosylceramide Synthase ◽

Phase 2 Study ◽

Long Term Treatment

Abstract Background and Aims Fabry disease (FD) is a rare, X-linked, genetic disorder caused by pathogenic variants in the gene for the lysosomal enzyme alpha-galactosidase A (αGal-A). The progressive accumulation of glycosphingolipids, most notably globotriaosylceramide (GL-3), leads to renal, cardiovascular, and other clinical manifestations over decades. In a single-arm phase 2 study, glucosylceramide synthase inhibition with venglustat led to a reduction in lysosomal GL-3 inclusions in skin capillary endothelial cells, as well as a progressive reduction in plasma GL-3 to normal levels by 26 weeks, with a continued decrease to low-normal levels after 3 years of therapy. We used patient data from a previously completed placebo-controlled phase 3 study of agalsidase beta (Fabrazyme) as historical control to compare the effect of venglustat treatment with placebo over 6 months and with agalsidase beta over 3 years. Methods In the venglustat phase 2 study, previously untreated classic FD patients were treated with daily venglustat for up to 3 years (NCT02228460, NCT02489344). For comparison to placebo, change in plasma GL-3 levels after 26 weeks of venglustat treatment was compared with matched historical control data from previously untreated classic FD patients who were treated for 20 weeks with placebo in the phase 3 agalsidase beta study (Eng et al, N Engl J Med 345:9, 2001). For comparison to agalsidase beta, the historical control arm was matched patients treated with agalsidase beta in the phase 3 study; change in plasma GL-3 was compared at multiple time points up to 3 years. Entry criteria and baseline characteristics were similar between the two studies. Due to the much larger numbers of patients in the phase 3 agalsidase beta study, venglustat patients were matched 1:X (variable match) with control (placebo or agalsidase beta) patients based on propensity scores using baseline variables of age, plasma GL-3, gender, UPCR (< 500 vs 500-1000 vs >1000 mg/g), and eGFR (<80 vs >= 80 mL/min/1.73m2) as matching variables. Plasma GL-3 was measured at Sanofi Genzyme by LC/MS/MS, using the same method for the two studies, with controls in place to assure assay consistency. Results Venglustat patients (N=11) were matched to 19 patients for the placebo comparison and to 28 patients for comparison to Fabrazyme. All patients in all 3 groups were male and had elevated plasma GL-3, UPCR <500 mg/g, and eGFR ≥80 mL/min/1.73m2 at baseline. Mean ages in the 3 groups were 26.6, 25.7, and 26.5 years after matching, respectively. Venglustat treatment for ∼6 months led to a highly significant reduction in plasma GL-3 compared to placebo of 3.62 vs 1.06 µg/mL (p <0.0001). Long-term treatment with venglustat yielded similar reductions in plasma GL-3 compared to agalsidase beta for the first year of treatment, but while GL-3 levels reached a plateau with agalsidase beta, the reduction with venglustat continued with longer treatment and was significantly greater than that of agalsidase beta after 2 years (p=0.0351) or 3 years (p=0.0081) (Figure). Plasma GL-3 levels after 3 years of treatment were 1.90 and 4.44 µg/mL for venglustat and agalsidase beta, respectively (normal range ≤7.02 µg/mL). Conclusions Glucosylceramide synthase inhibition with venglustat led to a significantly greater reduction in plasma GL-3 compared to placebo after 6 months, and treatment for 2-3 years led to a significantly greater reduction in plasma GL-3 compared with agalsidase beta. These results highlight the potential of long-term treatment venglustat to reverse the accumulation of GL-3 in classic FD.

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Long-Term Treatment Outcomes for Heroin Dependence: The 11-Year Follow-Up of the ATOS Study

PsycEXTRA Dataset ◽

10.1037/e612192013-001 ◽

2013 ◽

Author(s):

Christina Marel ◽

Maree Teesson ◽

Shane Darke ◽

Katherine Mills ◽

Joanne Ross ◽

...

Keyword(s):

Treatment Outcomes ◽

Term Treatment ◽

Heroin Dependence ◽

Long Term Treatment

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Faculty Opinions recommendation of Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726126988.793518505 ◽

2016 ◽

Author(s):

Adlette Inati ◽

Hussein Abbas

Keyword(s):

Sickle Cell Disease ◽

Sickle Cell ◽

Transcranial Doppler ◽

Term Treatment ◽

Cell Disease ◽

Long Term Treatment

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Globotriaosylsphingosine (Lyso-Gb) and analogues in plasma and urine of Fabry disease patients and relation to long-term treatment in a nationwide female Danish cohort: A retrospective study of a prospective cohort

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2019.11.115 ◽

2020 ◽

Vol 129 (2) ◽

pp. S52

Author(s):

Grigorios Effraimidis ◽

Ulla Feldt-Rasmussen ◽

Åse Krogh Rasmussen ◽

Pamela Lavoie ◽

Christiane Auray-Blais

Keyword(s):

Retrospective Study ◽

Fabry Disease ◽

Prospective Cohort ◽

Term Treatment ◽

Long Term Treatment ◽

Danish Cohort

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The changes of corneal biomechanical properties with long-term treatment of prostaglandin analogue measured by Corvis ST

10.21203/rs.3.rs-22280/v3 ◽

2020 ◽

Author(s):

Na Wu ◽

Yuhong Chen ◽

Yaping Yang ◽

Xinghuai Sun

Keyword(s):

Open Angle Glaucoma ◽

Corneal Thickness ◽

Biomechanical Properties ◽

Term Treatment ◽

Prostaglandin Analogue ◽

Corvis St ◽

Long Term Treatment ◽

Corneal Biomechanical Properties

Abstract Background: To investigate the corneal biomechanical changes in primary open angle glaucoma (POAG) patients treated with long-term prostaglandin analogue (PGA). Methods: 111 newly diagnosed POAG patients, including 43 high tension glaucoma (HTG) and 68 normal tension glaucoma (NTG), were measured by Corvis ST to obtain intraocular pressure (IOP), central corneal thickness (CCT) and corneal biomechanical parameters at baseline and at each follow-up visit after initiation of PGA treatment. The follow-up measurements were analyzed by the generalized estimate equation model with an exchangeable correlation structure. Restricted cubic spline was employed to estimate the dose-response relation between follow-up time and corneal biomechanics．Results: The mean follow-up time was 10.3 ± 7.02 months. Deformation amplitude (β=-0.0015, P=0.016), the first applanation velocity (AV1, β=-0.0004, P=0.00058) decreased and the first applanation time (AT1, β=0.0089, P<0.000001) increased statistically significantly with PGA therapy over time after adjusting for age, gender, axial length, corneal curvature, IOP and CCT. In addition, AT1 was lower (7.2950 ± 0.2707 in NTG and 7.5889 ± 0.2873 in HTG, P=0.00011) and AV1 was greater (0.1478 ± 0.0187 in NTG and 0.1314 ± 0.0191 in HTG, P=0.00002) in NTG than in HTG after adjusting for confounding factors.Conclusions: Chronic use of PGA probably influences the corneal biomechanical properties directly, which is to make cornea less deformable. Besides, corneas in NTG tended to be more deformable compared to those in HTG with long-term treatment of PGA.

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Long term dual antiplatelet therapy after myocardial infarction: retrospective analysis in an outpatient population

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2021.1881 ◽

2021 ◽

Author(s):

Gennaro Ratti ◽

Antonio Maglione ◽

Emilia Biglietto ◽

Cinzia Monda ◽

Ciro Elettrico ◽

...

Keyword(s):

Myocardial Infarction ◽

Term Treatment ◽

Multivessel Disease ◽

Coronary Syndrome ◽

Anticoagulant Drugs ◽

Long Term Treatment ◽

Risk Condition ◽

History Of

Long term treatment with ticagrelor 60 mg and low-dose aspirin are indicated after acute coronary syndrome (ACS). We retrospectively reviewed aggregate data of 187 patients (155 M and 38 F) (mean age 63.8±9 years) in follow up after ACS with at least one high risk condition (Multivessel disease, diabetes, GFR<60 mL/min, history of prior myocardial infarction, age >65 years) treated with ticagrelor 60 mg twice daily (after 90 mg twice daily for 12 months). The results were compared with findings (characteristics of the patients at baseline, outcomes, bleeding) of PEGASUS-TIMI 54 trial and Eu Label. The highrisk groups were represented as follows: multivessel disease 105 pts (82%), diabetes 63 pts (33%), GFR< 60 mL/min 27 pts (14%), history of prior MI 33 pts (17%), >65 year aged 85 pts (45%). Treatment was withdrawn in 7 patients: 3 cases showed atrial fibrillation and were placed on oral anticoagulant drugs, one developed intracranial bleeding, in three patients a temporary withdrawal was due to surgery (1 colon polyposis and 2 cases of bladder papilloma). Chest pain without myocardial infarction occurred in 16 patients (revascularization was required in 9 patients). Dyspnea was present in 15 patients, but was not a cause for discontinuation of therapy. Long term treatment with ticagrelor 60 mg twice daily plus aspirin 100 mg/day showed a favourable benefit/risk profile after ACS. In this study all patients had been given ticagrelor 90 mg twice daily for 12 months and the 60 mg twice daily dosage was started immediately thereafter, unlike PEGASUS-TIMI 54 trial in which it was prescribed within a period ranging from 1 day to 1 year after discontinuation of the 90 mg dose. This makes our results more consistent with current clinical practice. However, a careful outpatient follow-up and constant counseling are mandatory to check out compliance to therapy and adverse side effects.

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