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1.
Eur Respir J ; 57(6)2021 06.
Article in English | MEDLINE | ID: mdl-33334933

ABSTRACT

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.


Subject(s)
Pulmonary Arterial Hypertension , Scleroderma, Systemic , Biomarkers , Humans , Machine Learning , Natriuretic Peptide, Brain , Peptide Fragments , Proteomics
2.
Ann Rheum Dis ; 77(1): 128-132, 2018 Jan.
Article in English | MEDLINE | ID: mdl-29061853

ABSTRACT

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a severe complication of systemic sclerosis (SSc). In this longitudinal study, we aimed to identify factors associated with an unfavourable outcome in patients with SSc with early PAH (SSc-PAH) from the DETECT cohort. METHODS: Patients with SSc-PAH enrolled in DETECT were observed for up to 3 years. Associations between cross-sectional variables and disease progression (defined as the occurrence of any of the following events: WHO Functional Class worsening, combination therapy for PAH, hospitalisation or death) were analysed by univariable logistic regression. RESULTS: Of 57 patients with PAH (median observation time 12.6 months), 25 (43.9%) had disease progression. The following factors (OR (95% CI)) were associated with disease progression: male gender (4.1 (1.2 to 14.1)), high forced vital capacity % predicted/carbon monoxide lung diffusion capacity (DLCO)% predicted ratio (3.6 (1.2 to 10.7)), high Borg Dyspnoea Index (1.7 (1.1 to 2.6)) and low DLCO% predicted (non-linear relationship). CONCLUSION: More than 40% of early-diagnosed patients with SSc-PAH had disease progression during a short follow-up time, with male gender, functional capacity and pulmonary function tests at PAH diagnosis being associated with progression. This suggests that even mild PAH should be considered a high-risk complication of SSc.


Subject(s)
Disease Progression , Hypertension, Pulmonary/physiopathology , Scleroderma, Systemic/complications , Severity of Illness Index , Adult , Cross-Sectional Studies , Early Diagnosis , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/etiology , Logistic Models , Longitudinal Studies , Lung/physiopathology , Male , Risk Factors , Scleroderma, Systemic/physiopathology , Sex Factors , Total Lung Capacity
3.
Hum Mol Genet ; 22(21): 4349-56, 2013 Nov 01.
Article in English | MEDLINE | ID: mdl-23773996

ABSTRACT

Niemann-Pick disease type C (NP-C) is a rare, autosomal-recessive, progressive neurological disease caused by mutations in either the NPC1 gene (in 95% of cases) or the NPC2 gene. This observational, multicentre genetic screening study evaluated the frequency and phenotypes of NP-C in consecutive adult patients with neurological and psychiatric symptoms. Diagnostic testing for NP-C involved NPC1 and NPC2 exonic gene sequencing and gene dosage analysis. When available, results of filipin staining, plasma cholestane-3ß,5α,6ß-triol assays and measurements of relevant sphingolipids were also collected. NPC1 and NPC2 gene sequencing was completed in 250/256 patients from 30 psychiatric and neurological reference centres across the EU and USA [median (range) age 38 (18-90) years]. Three patients had a confirmed diagnosis of NP-C; two based on gene sequencing alone (two known causal disease alleles) and one based on gene sequencing and positive filipin staining. A further 12 patients displayed either single mutant NP-C alleles (8 with NPC1 mutations and 3 with NPC2 mutations) or a known causal disease mutation and an unclassified NPC1 allele variant (1 patient). Notably, high plasma cholestane-3ß,5α,6ß-triol levels were observed for all NP-C cases (n = 3). Overall, the frequency of NP-C patients in this study [1.2% (95% CI; 0.3%, 3.5%)] suggests that there may be an underdiagnosed pool of NP-C patients among adults who share common neurological and psychiatric symptoms.


Subject(s)
Carrier Proteins/genetics , Genetic Testing , Glycoproteins/genetics , Membrane Glycoproteins/genetics , Niemann-Pick Disease, Type C/diagnosis , Niemann-Pick Disease, Type C/genetics , Adult , Age of Onset , Aged , Aged, 80 and over , Alleles , Female , Genetic Variation , Genotype , Humans , Intracellular Signaling Peptides and Proteins , Male , Middle Aged , Mutation , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/physiopathology , Niemann-Pick Disease, Type C/psychology , Phenotype , Sequence Analysis, DNA , Vesicular Transport Proteins , Young Adult
4.
Ann Rheum Dis ; 73(7): 1340-9, 2014 Jul.
Article in English | MEDLINE | ID: mdl-23687283

ABSTRACT

OBJECTIVE: Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. METHODS: In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. RESULTS: Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. CONCLUSIONS: The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.


Subject(s)
Algorithms , Cardiac Catheterization/methods , Echocardiography/methods , Hypertension, Pulmonary/diagnosis , Scleroderma, Systemic/complications , Adult , Aged , Breath Tests , Cross-Sectional Studies , Early Diagnosis , Evidence-Based Medicine , Familial Primary Pulmonary Hypertension , Female , Humans , Hypertension, Pulmonary/etiology , Logistic Models , Male , Middle Aged , Multivariate Analysis , Nomograms , Pulmonary Diffusing Capacity , Pulmonary Wedge Pressure , Risk Assessment , Sensitivity and Specificity , Severity of Illness Index
5.
J Inherit Metab Dis ; 37(1): 93-101, 2014 Jan.
Article in English | MEDLINE | ID: mdl-23793527

ABSTRACT

OBJECTIVE: The Suspicion Index (SI) screening tool was developed to identify patients suspected of having Niemann-Pick disease type C (NP-C). The SI provides a risk prediction score (RPS) based on NP-C manifestations within and across domains (visceral, neurological, and psychiatric). The aim of these subanalyses was to further examine the discriminatory power of the SI by age and manifestation-associations by NP-C suspicion-level and leading manifestations. METHODS: The original retrospectively collected data were split into three patient age groups, where NP-C-positive cases were >16 years (n = 30), 4-16 years (n = 18), and <4 years (n = 23), and patients' RPS were analyzed by logistic regression. Co-occurrence of manifestations within groups of suspicion level (low, medium, high) and leading manifestations (presence/absence of ataxia, cognitive decline, psychosis, and splenomegaly) were analyzed descriptively. RESULTS: NP-C-positive cases versus controls showed strong discriminatory power of RPS. Area under the receiver operating characteristic curve was 0.964 (>16 years) and 0.981 (4-16 years) but weaker 0.562 for infants (<4 years). Patients with RPS <70 were characterized by a lack of psychiatric manifestations and low levels of neurological involvement, suggestive of a preneurological phase of the disease. In patients >4 years, prominent leading manifestation-associations were ataxia with dystonia, dysarthria/dysphagia, and cognitive decline. Psychosis was associated with dysarthria/dysphagia but also with cognitive decline and treatment-resistant psychiatric symptoms. CONCLUSIONS: The SI tool maintains strong discriminatory power in patients >4 years but is not as useful for infants <4 years. The SI is also informative regarding the association and co-occurrence of manifestations in patients with NP-C.


Subject(s)
Niemann-Pick Disease, Type C/diagnosis , Adolescent , Age Factors , Ataxia/complications , Child , Child, Preschool , Cognition Disorders/complications , Data Collection , Decision Support Techniques , Female , Humans , Infant , Logistic Models , Male , Mass Screening/methods , Phenotype , Psychotic Disorders/complications , ROC Curve , Retrospective Studies , Risk , Splenomegaly/complications
6.
Mol Genet Metab ; 99(4): 351-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20045366

ABSTRACT

A randomized, controlled trial of miglustat indicated that miglustat (Zavesca) stabilized neurological disease over 12 months in adult and juvenile patients with Niemann-Pick disease type C (NP-C). We report data from a non-controlled, open-label extension to this initial randomized trial. All patients completing the randomized trial were allowed to continue treatment in a 12-month, non-controlled open-label extension. Those completing 12 months of extension therapy could continue further on miglustat in a 'continued extension' phase. From a total of 29 patients in the randomized phase (mean [+/-SD] age 24.6+/-9.1 ears; 52% female), 21 completed 12 months of therapy with miglustat (17 of whom received miglustat in the initial randomized phase, and four in the extension phase), and 15 patients (all from the miglustat-randomized group) completed 24 months on miglustat. Mean horizontal saccadic eye movement velocity (HSEM-alpha) indicated improvement in the 12-month miglustat group, and stabilization in the 24-month group; swallowing was improved or stable in 86% and in up to 93%, respectively. Ambulation was stabilized in both the 12- and 24-month groups. In an exploratory disease stability analysis of prospective data on key parameters of disease progression (HSEM-alpha, swallowing, ambulation and cognition), 13/19 (68%) patients receiving >or= 12 months' miglustat therapy had stable disease. Among all patients receiving >or= 1 dose of miglustat (n=28), the most frequent adverse events were diarrhoea, weight decrease, flatulence and tremor. Overall, these data suggest that long-term miglustat therapy stabilizes neurological disease and is well tolerated in adult and juvenile patients with NP-C.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Niemann-Pick Disease, Type C/drug therapy , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/therapeutic use , Adolescent , Adult , Child , Deglutition/drug effects , Diarrhea/chemically induced , Female , Humans , Walking , Weight Loss
7.
Clin Pharmacol Ther ; 80(3): 246-56, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16952491

ABSTRACT

OBJECTIVE: In patients with renal disease increased urotensin II plasma levels have been observed. We have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin II receptor, has effects in patients who are prone to the development of renal disease. METHODS: Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125 mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was determined twice at baseline and after 13.5 days of treatment. Plasma concentrations of palosuran were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured before and after 12.5 days of treatment. Tolerability and safety parameters were monitored. RESULTS: An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to 45.0) in the 24-hour urinary albumin excretion rate was observed (P = .014). No effect was observed on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean) (95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated. CONCLUSIONS: The good tolerability profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients with renal failure with regard to their disease progression. Larger placebo-controlled trials in this patient population are needed to investigate whether urotensin II receptor antagonists, given as monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.


Subject(s)
Albuminuria/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Quinolines/pharmacokinetics , Receptors, G-Protein-Coupled/antagonists & inhibitors , Urea/analogs & derivatives , Aged , Albuminuria/drug therapy , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Area Under Curve , Creatinine/blood , Creatinine/urine , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Diabetic Nephropathies/drug therapy , Fatigue/chemically induced , Female , Glomerular Filtration Rate/drug effects , Headache/chemically induced , Humans , Hypertension/complications , Hypertension/drug therapy , Male , Middle Aged , Nasopharyngitis/chemically induced , Quinolines/adverse effects , Quinolines/therapeutic use , Renal Circulation/drug effects , Treatment Outcome , Urea/adverse effects , Urea/pharmacokinetics , Urea/therapeutic use
8.
Arthritis Rheumatol ; 68(10): 2527-39, 2016 10.
Article in English | MEDLINE | ID: mdl-27111549

ABSTRACT

OBJECTIVE: To identify nailfold videocapillaroscopic features and other clinical risk factors for new digital ulcers (DUs) during a 6-month period in patients with systemic sclerosis (SSc). METHODS: In this multicenter, prospective, observational cohort study, the videoCAPillaroscopy (CAP) study, we evaluated 623 patients with SSc from 59 centers (14 countries). Patients were stratified into 2 groups: a DU history group and a no DU history group. At enrollment, patients underwent detailed nailfold videocapillaroscopic evaluation and assessment of demographic characteristics, DU status, and clinical and SSc characteristics. Risk factors for developing new DUs were assessed using univariable and multivariable logistic regression (MLR) analyses. RESULTS: Of the 468 patients in the DU history group (mean ± SD age 54.0 ± 13.7 years), 79.5% were female, 59.8% had limited cutaneous SSc, and 22% developed a new DU during follow-up. The strongest risk factors for new DUs identified by MLR in the DU history group included the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs (categorized as 0, 1, 2, or ≥3), and the presence of critical digital ischemia. The receiver operating characteristic (ROC) of the area under the curve (AUC) of the final MLR model was 0.738 (95% confidence interval [95% CI] 0.681-0.795). Internal validation through bootstrap generated a ROC AUC of 0.633 (95% CI 0.510-0.756). CONCLUSION: This international prospective study, which included detailed nailfold videocapillaroscopic evaluation and extensive clinical characterization of patients with SSc, identified the mean number of capillaries per millimeter in the middle finger of the dominant hand, the number of DUs at enrollment, and the presence of critical digital ischemia at enrollment as risk factors for the development of new DUs.


Subject(s)
Fingers , Microscopic Angioscopy , Peripheral Vascular Diseases/epidemiology , Scleroderma, Systemic/diagnostic imaging , Skin Ulcer/epidemiology , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Peripheral Vascular Diseases/diagnostic imaging , Peripheral Vascular Diseases/etiology , Peripheral Vascular Diseases/physiopathology , Prospective Studies , ROC Curve , Risk Factors , Scleroderma, Limited/complications , Scleroderma, Limited/diagnostic imaging , Scleroderma, Systemic/complications , Skin Ulcer/diagnostic imaging , Skin Ulcer/etiology , Skin Ulcer/physiopathology
9.
Orphanet J Rare Dis ; 10: 81, 2015 Jun 19.
Article in English | MEDLINE | ID: mdl-26084276

ABSTRACT

BACKGROUND: Gastrointestinal (GI) disturbances such as diarrhea and flatulence are the most frequent adverse effects associated with miglustat therapy in type 1 Gaucher disease (GD1) and Niemann-Pick disease type C (NP-C), and the most common recorded reason for stopping treatment during clinical trials and in clinical practice settings. Miglustat-related GI disturbances are thought to arise from the inhibition of intestinal disaccharidases, mainly sucrase isomaltase. We report the effects of a co-administered dietary probiotic, S. boulardii, on the GI tolerability of miglustat in healthy adult subjects. METHODS: In a double-blind, placebo-controlled, two-period, two-treatment cross-over trial, healthy adult male and female subjects were randomly allocated to treatment sequences, A-B and B-A (treatment A - miglustat 100 mg t.i.d. + placebo; treatment B - miglustat 100 mg t.i.d. + S. boulardii [500 mg, b.i.d.]). GI tolerability data were collected in patient diaries. The primary endpoint was the total number of 'diarrhea days' (≥3 loose stools within a 24-h period meeting Bristol Stool Scores [BSS] 6-7) based on WHO criteria. Secondary endpoints comprised numerous other diarrhea and GI tolerability indices. RESULTS: Twenty-one subjects received randomized therapy in each treatment sequence (total N = 42), and overall, 37 (88 %) subjects completed the study. The total number of diarrhea days was <1.5 for both treatment sequences, and approximately 60 % of subjects did not experience diarrhea during either treatment period. The mean (SD) number of diarrhea days was lower with miglustat + S. boulardii (0.8 [2.4] days) than with miglustat + placebo (1.3 [2.4] days), but the paired treatment difference was not statistically significant (-0.5 [2.4] days; p = 0.159). However, a significant treatment difference (-0.7 [1.9]; p < 0.05) was identified after post hoc exclusion of a clear outlier who had a very high number of diarrhea days (n = 13) and inconsistent GI tolerability reporting. The incidence of the GI AEs was higher with miglustat + placebo (82 %) than with miglustat + S. boulardii (73 %). There were no between-treatment differences in miglustat pharmacokinetics. CONCLUSIONS: Although the primary endpoint was not met, the results of the post-hoc analysis suggest that co-administration of miglustat with S. boulardii might improve GI tolerability.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Gastrointestinal Tract/drug effects , Saccharomyces , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/pharmacokinetics , 1-Deoxynojirimycin/therapeutic use , Adult , Cross-Over Studies , Double-Blind Method , Enzyme Inhibitors , Female , Humans , Male , Middle Aged , Placebos
10.
Arthritis Res Ther ; 16(6): 493, 2014 Dec 10.
Article in English | MEDLINE | ID: mdl-25491468

ABSTRACT

INTRODUCTION: Patients with mean pulmonary artery pressures (mPAP) of 21 to 24 mm Hg have a so-called borderline elevation of mPAP (BoPAP)--a condition thought to represent early-stage pulmonary arterial vasculopathy. Based on the DETECT study, this post-hoc analysis examined patient characteristics of systemic sclerosis (SSc) patients with normal mPAP, BoPAP and elevated mPAP, fulfilling pulmonary arterial hypertension (PAH) criteria. METHODS: Adult patients with a duration of SSc more than 3 years, a diffusing capacity of the lung for carbon monoxide less than 60% predicted, and no previous diagnosis of any form of pulmonary hypertension (PH) underwent screening tests followed by right heart catheterization. Subjects were divided into three groups: normal mPAP, BoPAP, and PAH. Exploratory comparative and binary logistic regression analyses were performed for the BoPAP versus normal mPAP and PAH versus BoPAP groups. RESULTS: Of 244 patients evaluated, 148 (60%) had normal mPAP, 36 (15%) had BoPAP, and 60 (25%) had definite PAH. Univariable logistic regression (ULR) showed the mean tricuspid regurgitation velocity in patients with BoPAP to be intermediate between normal mPAP and PAH. In the ULR analyses BoPAP versus normal mPAP and PAH versus BoPAP, the statistically significant predictors were, amongst others: demographic, clinical, pulmonary function, echocardiographic and hemodynamic variables. CONCLUSIONS: In this exploratory post-hoc analysis of the DETECT study population patients with BoPAP could be distinguished from patients with normal mPAP and PAH, and it appears that BoPAP may be an intermediate stage on the continuum between normal PA pressures and PAH.


Subject(s)
Arterial Pressure , Hypertension, Pulmonary/diagnosis , Hypertension, Pulmonary/physiopathology , Pulmonary Artery/physiopathology , Scleroderma, Systemic/diagnosis , Scleroderma, Systemic/physiopathology , Adult , Aged , Arterial Pressure/physiology , Cross-Sectional Studies , Female , Humans , Male , Middle Aged
11.
J Child Neurol ; 25(3): 300-5, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19822772

ABSTRACT

Niemann-Pick disease type C is a rare, genetic disease associated with impaired intracellular lipid trafficking and progressive neurological symptoms. Miglustat slowed disease progression in a 12-month randomized trial in juveniles and adults with Niemann-Pick disease type C, and in a parallel, noncontrolled study in affected children. Here, the authors report the open-label extension to the pediatric study. Patients aged 4 to 12 years received open-label miglustat (dose adjusted for body surface area) for an initial 12 months, during a further 12-month extension, and a long-term, continued extension phase. Efficacy assessments included horizontal saccadic eye movement, swallowing, and ambulation. Ten children completed 24 months' treatment. Horizontal saccadic eye movement, ambulation, and swallowing were stabilized at 24 months. Analysis of key parameters of disease progression showed disease stability in 8 of 10 patients (80%). Miglustat stabilized neurological disease progression in pediatric patients with Niemann-Pick disease type C, with comparable safety and tolerability to that observed in adults and juveniles.


Subject(s)
1-Deoxynojirimycin/analogs & derivatives , Enzyme Inhibitors/therapeutic use , Niemann-Pick Disease, Type C/drug therapy , 1-Deoxynojirimycin/administration & dosage , 1-Deoxynojirimycin/adverse effects , 1-Deoxynojirimycin/therapeutic use , Child , Child, Preschool , Deglutition/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/adverse effects , Female , Humans , Male , Motor Activity/drug effects , Prospective Studies , Saccades/drug effects , Time Factors , Treatment Outcome
12.
Hypertension ; 55(5): 1206-9, 2010 May.
Article in English | MEDLINE | ID: mdl-20231521

ABSTRACT

The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.


Subject(s)
Antihypertensive Agents/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Hypertension/complications , Hypertension/drug therapy , Quinolines/therapeutic use , Urea/analogs & derivatives , Adult , Aged , Albuminuria/prevention & control , Blood Pressure/drug effects , Blood Pressure/physiology , Creatinine/urine , Cross-Over Studies , Female , Humans , Hypertension/urine , Male , Middle Aged , Placebos , Receptors, G-Protein-Coupled/antagonists & inhibitors , Renin-Angiotensin System/drug effects , Urea/therapeutic use , Urotensins/drug effects , Urotensins/metabolism
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