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Barbey F Hayoz D Widmer U Burnier M 《Current Medicinal Chemistry - Cardiovascular & Hematological Agents》2004,2(4):277-286
Enzyme replacement therapy has recently been introduced to treat Fabry disease, a rare X-linked lysosomal storage disorder. The disease occurs due to deficient activity of alpha-galactosidase A, leading to progressive accumulation of globotriaosylceramide in multiple organs and tissues. Renal, cardiac and cerebrovascular manifestations of the disease result in premature death in both hemizygous males and heterozygous females. This paper outlines the clinical signs, symptoms and diagnosis of Fabry disease, and the development of the two available enzyme replacement therapies -- agalsidase alfa and agalsidase beta. Agalsidase alfa and agalsidase beta are produced in a human cell line and in Chinese hamster ovary cells, respectively, resulting in products with the same amino acid sequence as the native human enzyme, but with different patterns of glycosylation. Correct post-translational glycosylation is important in terms of the pharmacokinetics, biodistribution, clinical efficacy and tolerability of genetically engineered protein therapeutics. Differences in glycosylation, which may affect immunogenicity and mannose-6-phosphate receptor-mediated cellular internalisation of administered enzyme, possibly account for the differences in dosing, clinical effects and safety profiles reported for agalsidase alfa and agalsidase beta. 相似文献
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Deegan PB 《Journal of inherited metabolic disease》2012,35(2):227-243
Fabry disease is an X-linked disorder caused by a deficiency of α-galactosidase A. This leads to a progressive accumulation
of globotriaosylceramide in tissues throughout the body. Cardiac, renal and neurological manifestations are common and life
expectancy is significantly reduced relative to the general population. Management of Fabry disease involves the administration
of intravenous enzyme replacement therapy (ERT). Two forms – agalsidase alfa and agalsidase beta – have been licensed in certain
jurisdictions and are generally well tolerated; however, some patients develop antibodies to the infused enzyme, which may
impair the efficacy and safety of treatment. Agalsidase alfa and agalsidase beta are produced in different systems; this leads
to certain differences in post-translational modification that may affect immunogenicity. Immunoglobulin (Ig) G antibodies
have frequently been reported in patients with Fabry disease receiving ERT; IgG responses are reported in a greater proportion
of patients receiving agalsidase beta than in patients receiving agalsidase alfa. IgE antibodies are less common than IgG
antibodies, and have not been observed in patients receiving agalsidase alfa. However, these data are difficult to interpret
due to methodological differences in the assessment of seropositivity, and in the doses of enzyme used. The clinical impact
of the development of IgG antibodies to ERT in patients with Fabry disease remains unclear, due to lack of data and to the
marked heterogeneity of patients both in terms of disease manifestations and response to therapy. Further studies that examine
the development of antibodies in patients with Fabry disease and the potential impact of such antibodies on the outcome of
ERT are necessary. 相似文献
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Jardim LB Gomes I Netto CB Nora DB Matte US Pereira F Burin MG Kalakun L Giugliani R Becker J 《Journal of inherited metabolic disease》2006,29(5):653-659
Summary
Aim To report the effect of enzyme replacement therapy (ERT) in sympathetic skin responses (SSR) of patients with Fabry disease.
Patients and methods Seven male patients were included in an open-label protocol using agalsidase-alfa, continued at regular intervals. Five patients
completed 24 months of ERT and two of them completed 18 months. Two main measurements were performed at baseline, as well
as 1 and 2 years after ERT: (1) a standard neurological examination (NE), with a detailed evaluation of the sensory perception
of light touch, pinprick, cold, hot, and vibratory stimuli; (2) the SSR amplitudes. Results Although there were no significant differences between NE in this time period, all patients reported general improvement
in their subjective reports of acroparaesthesia and sweating. Before starting ERT, the SSR amplitudes were either too small
(3/7 patients) or absent (4/7 patients): the average (range) amplitude of 122 μV (0 through 492) was statistically smaller
than that found in a control group, i.e. 1453.6 μV (619.7–2754) (p<0.0001, t-test). Mean ± SD SSR amplitude increased to 1088± 690 μV in the second year of ERT, reaching the range found in a normal
control group (p=0.004). Conclusion ERT improved SSR continuously in Fabry patients in 2 years of observation. Although the mechanism of the SSR improvement
is unknown, this response to ERT can be clinically significant if it reflects a normalization in sweating.
Communicating editor: Verena Peters
Competing interests: None declared
Databases: Fabry disease, OMIM 301500; enzyme α-galactosidase NM 000169 相似文献
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Fabry disease patients have increased risk of vascular disease despite cardioprotective increased HDL-cholesterol. Enzyme therapy does not significantly alter the lipid profile in the short term. 相似文献
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Undas A Ryś D Brzeńziiska-Kolarz B Padjas A Musiał J 《Polskie Archiwum Medycyny Wewn?trznej》2004,112(6):1479-1486
We report here the course and outcomes of 18-month enzyme replacement therapy in two 43 and 41-year-old brothers with Fabry disease. At 18 months of recombinant alpha-galactosidase A (Fabrazyme) infusions, we observed in the older patient: weight gain, decreased proteinuria (from 4 to 1.5 g/d), stabilization of creatinine clearance, much lower frequency and intensity of angina, and in the younger brother: weight gain, stabilization of creatinine clearance and proteinuria, prolongation of PQ interval and improvement of hearing. However, neurologic manifestations deteriorated over treatment period in both patients. No serious infusion-related side effects were observed. 相似文献
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Summary Background. Fabry disease is an X-linked genetic disorder resulting in the accumulation of glycosphingolipids in various organs, leading
to exercise intolerance and early mortality. Enzyme replacement therapy (ERT) has recently been approved for use in Fabry
patients. Goals of study. To assess baseline cardiopulmonary exercise characteristics in both invasive and noninvasive tests and to study the impact
of ERT on exercise. Methods. A total of 15 patients with Fabry disease underwent baseline cardiopulmonary exercise tests. Six patients were randomized
2:1 to receive either ERT or placebo. We performed serial cardiopulmonary exercise tests at baseline and every 3 months over
a period of at least 18 months. The baseline test was compared to the last two exercise tests for each patient. Results. Mean age was 32 years. Mean VO2 max was 1.680 ± 0.67 L/min and increased by 0.459 ± 0.64 L/min in the patients receiving ERT. Mean VO2 max was 1.462 ± 0.25 L/min and decreased by 0.116 ± 0.44 L/min in patients on placebo. Mean oxygen pulse (VO2/HR) increased by 1.71 with enzyme, but increased only 0.025 in patients taking placebo. Estimated stroke volume (SV) increased
by 10 ml in patients on ERT. Conclusions. In this small cohort, exercise tolerance increased in patients receiving enzyme replacement therapy. Cardiopulmonary exercise
testing is a useful test in measuring the response to therapy in Fabry disease patients.
Competing interests: W. R. Wilcox is a paid consultant of Genzyme Corp. and is on the Genzyme Speakers Bureau. Neither he
nor his relations own Genzyme stock. Genzyme Corp. provided a research grant for the study 相似文献
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Dehout F Roland D Treille de Granseigne S Guillaume B Van Maldergem L 《Journal of inherited metabolic disease》2004,27(4):499-505
Gastrointestinal symptoms, including diarrhoea and abdominal pain, are one of the earliest and most frequently reported signs of Fabry disease, a rare X-linked lipid storage disorder. As the disease progresses, renal, cardiac and cerebrovascular complications develop, resulting in more serious symptoms and early mortality. The present study evaluated the effects of enzyme replacement therapy (ERT) with agalsidase alfa on the gastrointestinal symptoms of Fabry disease. Following 6 months of treatment, both the severity ( p < 0.02) and frequency ( p < 0.02) of abdominal pain decreased. For those patients who had received agalsidase alfa for more than 6 months, the observed improvement was generally maintained. This is the first study indicating a significant beneficial effect of ERT on gastrointestinal symptoms in a group of patients treated for Fabry disease. 相似文献
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Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients 下载免费PDF全文
Balázs Odler Áron Cseh Tamás Constantin György Fekete György Losonczy Lilla Tamási Kálmán Benke Bálint Szilveszter Veronika Müller 《The clinical respiratory journal》2017,11(6):942-950
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《Nefrología : publicación oficial de la Sociedad Espa?ola Nefrologia》2021,41(6):652-660
Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT.Study designMulticentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24–120).ResultsIn 69 patients (42 males, 27 females, mean age 44.6 ± 13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242–128 mg/g (p = 0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤ 60 ml/min/1.73 m2 (log Rank 12.423, p = 0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p = 0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models.ConclusionsGFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. 相似文献
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L. J. Anderson K. M. Wyatt W. Henley V. Nikolaou S. Waldek D. A. Hughes G. M. Pastores S. Logan 《Journal of inherited metabolic disease》2014,37(6):969-978
Objectives
To determine the effectiveness of enzyme replacement therapy (ERT) for adults and children with Fabry disease.Design
Cohort study including prospective and retrospective clinical data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment and untreated patients contributed natural history data.Participants
Consenting adults (N?=?289) and children (N?=?22) with a confirmed diagnosis of Fabry disease attending a specialist Lysosomal Storage Disorder treatment centre in England. At recruitment 211 adults and seven children were on ERT (range of treatment duration, 0 to 9.7 and 0 to 4.2 years respectively).Outcome measures
Clinical outcomes chosen to reflect disease progression included left ventricular mass index (LVMI); proteinuria; estimated glomerular filtration rate (eGFR); pain; hearing and transient ischaemic attacks (TIA)/stroke.Results
We found evidence of a statistically significant association between time on ERT and a small linear decrease in LVMI (p?=?0.01); a reduction in the risk of proteinuria after adjusting for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (p?0.001) and a small increase in eGFR in men and women without pre-treatment proteinuria (p?=?0.01 and p?0.001 respectively). The same analyses in children provided no statistically significant results. No associations between time on ERT and pain, risk of needing a hearing aid, or risk of stroke or TIAs, were found.Conclusions
These data provide some further evidence on the long-term effectiveness of ERT in adults with Fabry disease, but evidence of effectiveness could not be demonstrated in children. 相似文献16.
Kalliokoski RJ Kantola I Kalliokoski KK Engblom E Sundell J Hannukainen JC Janatuinen T Raitakari OT Knuuti J Penttinen M Viikari J Nuutila P 《Journal of inherited metabolic disease》2006,29(1):112-118
Summary Fabry disease (McKusick 301500) is an X-linked lysosomal storage disorder secondary to deficient α-galactosidase A activity
which leads to the widespread accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, especially in vascular smooth-muscle and endothelial cells. We have recently shown that
the myocardial perfusion reserve of Fabry patients is significantly decreased. Thus, in the present study we investigated,
whether it can be improved with enzyme replacement therapy (ERT). Ten patients (7 male, 3 female; mean age 34, range 19–49
years) with confirmed Fabry disease were approved for this uncontrolled, open-label study. Myocardial perfusion was measured
at rest and during dipyridamole-induced hyperaemia by positron emission tomography and radiowater. Myocardial perfusion reserve
was calculated as the ratio between maximal and resting perfusion. Perfusion measurements were performed before and after
6 and 12 months of ERT by recombinant human α-galactosidase A (Fabrazyme, Genzyme). Plasma Gb3 concentration decreased significantly and the patients reported that they felt better and suffered less pain after the ERT.
However, neither resting or dipyridamole-stimulated myocardial perfusion nor myocardial perfusion reserve changed during the
ERT. Pretreatment relative wall thickness correlated negatively with posttreatment changes in flow reserve (r = −0.76, p = 0.05) and positively with posttreatment changes in minimal coronary resistance (r = 0.80, p = 0.03). This study shows that 12 months of ERT does not improve myocardial perfusion reserve, although the plasma Gb3 concentration decreases. However, individual variation in the response to therapy was large and the results suggest that
the success of the therapy may depend on the degree of cardiac hypertrophy.
Communicating editor: Guy Besley
Competing interests: None declared 相似文献
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Wendt S Whybra C Kampmann C Teichmann E Beck M 《Journal of inherited metabolic disease》2005,28(5):787-788
Summary Fabry disease is an inherited lysosomal storage disease caused by deficiency of α-galactosidase A. Enzyme replacement therapy
for this multisystem progressive disease has been available only since 2001. We here report the first known successful pregnancy
of a female patient receiving such therapy. 相似文献
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Saskia M. Rombach Bouwien E. Smid Gabor E. Linthorst Marcel G. W. Dijkgraaf Carla E. M. Hollak 《Journal of inherited metabolic disease》2014,37(3):341-352
Objective
Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage.Design
Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages.Data extraction
Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis.Results
Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR?>?60 ml/min/1.73 m2, decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR?<?60 ml/min/1.73 m2 had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT.Conclusion
ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease. 相似文献20.
CNS involvement in Fabry disease: Clinical and imaging studies before and after 12 months of enzyme replacement therapy 总被引:1,自引:0,他引:1
Jardim L Vedolin L Schwartz IV Burin MG Cecchin C Kalakun L Matte U Aesse F Pitta-Pinheiro C Marconato J Giugliani R 《Journal of inherited metabolic disease》2004,27(2):229-240
We report the clinical and radiological central nervous system (CNS) findings of 8 Fabry disease patients, before (8/8) and after (7/8) 12 months of enzyme replacement therapy (ERT) with agalsidase-alpha. Eight biochemically proven Fabry disease patients (from four families) were included. Patients were evaluated at baseline and at regular intervals during 12 months of ERT. Evaluations included a thorough, standardized neurological examination, and magnetic resonance imaging (MRI) and angiography (MRA). Brain proton magnetic resonance spectroscopy (MRS) was also performed in 5/8 patients. The presence and location of grey- and white-matter lesions, the presence of vascular occlusion or ectasia on MRA and the metabolite ratios on MRS were determined, as well as their relation to age, symptoms and neurological examination. Neurological examination showed few abnormalities in these patients: scores varied (on a 0-100 scale) from zero to 5, at baseline and in the 12th month of ERT. The most consistent findings on MRI were asymmetric, widespread patterns of deep white-matter (WM) lesions, hyperintense on T2 and FLAIR-weighted images, found in 4/8 patients at baseline, predominantly in frontal and parietal lobes. These lesions did not correlate with other clinical variables, although there was a trend towards an association of the lesions with age and hearing loss. The youngest patient with MRI lesions was 24 years old. After 12 months of ERT, MRI was normal in 3/7, showed the same WM lesions in 2/7, and showed worsening of WM lesions in 2/7 patients (from the same family). Abnormal MRS metabolite ratios were detected at baseline in 4/5 patients. While neurological examination remained almost normal during the 12 months of ERT, new small-vessel CNS involvement still appeared in 2/7 patients. We do not know why ERT was not able to prevent this in these two related male patients. This could be due either to their older ages (46 and 36 years), or to a more pathogenic mutation. We conclude that MRI was more sensitive than neurological examination in detecting CNS involvement and progression in Fabry disease in the time interval studied. 相似文献