C.E.R.A. safety profile: a pooled analysis in patients with chronic kidney disease.

BACKGROUND: C.E.R.A., a continuous erythropoietin receptor activator, is a long-acting erythropoiesis-stimulating agent (ESA) that is approved for the treatment of renal anemia. This analysis evaluated the safety profile of C.E.R.A. in comparison to that of other ESAs in patients with chronic kidney disease (CKD). METHODS: Safety parameters were analyzed in a pooled population comprising all patients with CKD on dialysis and not on dialysis from the completed Phase II and Phase III studies in the C.E.R.A. clinical program (Phase II/III population); patients were treated with either C.E.R.A. (n = 1,789) or comparator ESA (n = 948). Differences between treatment groups in safety parameters were identified by either a 2% difference in incidence between groups, or a statistically significant difference between groups (p < or = 0.05 with the Fisher's exact test, which was used as a conservative screening tool). To assess changes in safety findings over time, long-term safety data were analyzed from patients who were given the option to enter long-term safety studies upon completing their initial Phase II/III study (safety extension population). RESULTS: Compared with the C.E.R.A. group, the incidence of adverse events (AEs) was higher in the comparator ESA group in the Phase II/III population (C.E.R.A. vs. comparator ESA, 89.5% vs. 91.8%, p = 0.067), and significantly so in the safety extension population (93.0% vs. 95.8%, p = 0.003). The incidence of serious AEs was significantly higher in the comparator ESA group than in the C.E.R.A. group in both analysis populations (Phase II/III population, 37.8% vs. 42.4%, p = 0.021; safety extension population, 53.3% vs. 59.7%, p = 0.001). However, there was no consistent pattern of clinical events that could explain these differences between the treatment groups. CONCLUSION: Analysis of safety events in patients with renal anemia receiving long-term treatment with C.E.R.A. shows a safety profile comparable to that of other ESAs.

The continuous erythropoietin receptor activator (C.E.R.A.) corrects anemia at extended administration intervals in patients with chronic kidney disease not on dialysis: results of a phase II study.

AIM: This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naive patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose. METHODS: Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 microg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase > 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy. RESULTS: A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p < 0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p < 0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses > or = 0.30 microg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 microg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure. CONCLUSIONS: C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 microg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

Continuous Erythropoietin Receptor Activator (C.E.R.A.) administered at extended administration intervals corrects anaemia in patients with chronic kidney disease on dialysis: a randomised, multicentre, multiple-dose, phase II study.

This dose-finding, open-label study examined the potential of subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) to correct anaemia at extended administration intervals in 61 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) on dialysis. After a 4-week run-in, patients were randomised to C.E.R.A. 0.15, 0.30 and 0.45 microg/kg/week. Within these dose groups, patients were further randomised to once weekly, once every 2 weeks or once every 3 weeks treatment. Mean changes in haemoglobin (Hb) increased with increasing C.E.R.A. dose during a period of 6 weeks where no dose adjustments were permitted. The effect was independent of administration schedule. Erythropoietic responses were sustained until the end of the study (12 weeks) in all groups. In total, 90% of patients in the 0.30 microg/kg/week group and 79% in the 0.45 microg/kg/week group responded to treatment (Hb increase > or =1.0 g/dl), compared with 72% in the 0.15 microg/kg/week group. Faster median response time was associated with increasing dose (51, 38 and 31 days, respectively) and response was unrelated to administration frequency. C.E.R.A. was generally well tolerated. Our results suggest that 0.60 microg/kg twice monthly would be a suitable starting dose of C.E.R.A. for the initiation of anaemia correction in patients with CKD on dialysis. Phase III studies will confirm the feasibility of using C.E.R.A. at extended administration intervals in patients with CKD and anaemia.

MLYCD mutation analysis: evidence for protein mistargeting as a cause of MLYCD deficiency.

Malonyl-CoA decarboxylase (MLYCD) deficiency is an autosomal recessive disorder characterized by malonic aciduria, developmental delay, seizure disorder, hypoglycemia, and cardiomyopathy. Genomic sequencing of MLYCD in nine unrelated patients identified 16 of 18 pathogenic alleles, which are documented in the newly created Human MLYCD Allelic Variant Database (http://mlycd.hgu.mrc.ac.uk/). Fibroblast cell lines were available from eight of these patients and two previously reported patients with homozygous MLYCD mutations. Western blot analysis using antisera raised to a C-terminal peptide detected a 66-kDa band that was absent in six patients and substantially reduced in three patients. One patient showed an increase in protein levels with a prominent smeary 68-l83-kDa band. Immunocytochemical analysis of MLYCD-expressing patient cell lines showed apparent intracellular mislocalization. An extreme N-terminal mutation c.8G>A (p.G3D) mislocalized to the plasma membrane, suggesting that a novel targeting signal may reside in a four-amino acid conserved N-terminal motif. A 25-base deletion between the putative mitochondrial and peroxisomal initiating codons (M1 and M40) and a point mutation ablating the second of these (c.119T>C, p.M40T) both showed punctate perinuclear staining. As none of the three mislocalizing mutations are predicted to alter the catalytic function of the peptide, it seems likely that correct subcellular localization of MLYCD is critical for it to function normally.

Predictors of 90-day outcome in patients stabilized after acute coronary syndromes.

AIMS: We investigated predictors of 90-day risk among patients surviving the early period after an acute coronary syndrome (ACS). METHODS AND RESULTS: The study population included 15 904 stabilized ST-segment elevation or non-ST-segment elevation ACS patients randomized in SYMPHONY and 2nd SYMPHONY. We developed risk models for death, death or myocardial infarction (MI), and death, MI, or severe recurrent ischaemia (SRI) using Cox proportional-hazards techniques. Demographic, history, and pre-randomization clinical and medication variables were tested. Validation techniques included development of individual trial models, backward elimination and bootstrapping. Of 118 variables, 17 independently predicted mortality. The strongest associations included greater age (chi(2)=31.1), higher randomization heart rate (chi(2)=27.4), and heart failure (HF) variables (HF between qualifying event and randomization, chi(2)=21.8; history of HF, chi(2)=12.2). Higher creatinine clearance (chi(2)=17.7) and percutaneous coronary intervention between qualifying event and randomization (chi(2)=11.1) most strongly predicted lower risk. Similar characteristics entered the double and triple composite models, but HF variables and age less strongly predicted these end-points. CONCLUSIONS: In patients stabilized after ACS, those at highest risk over the next 90 days can be identified. Typical clinical markers are better at identifying risk of death than non-fatal MI or SRI. Novel risk markers are needed for these outcomes.

Harmonic analysis of perfusion pumps.

The controversy over the use of nonpulsatile versus pulsatile pumps for maintenance of normal organ function during ex vivo perfusion has continued for many years, but resolution has been limited by lack of a congruent mathematical definition of pulsatility. We hypothesized that the waveform frequency and amplitude, as well as the underlying mean distending pressure are all key parameters controlling vascular function. Using discrete Fourier Analysis, our data demonstrate the complexity of the pulmonary arterial pressure waveform in vivo and the failure of commonly available perfusion pumps to mimic in vivo dynamics. In addition, our data show that the key harmonic signatures are intrinsic to the perfusion pumps, are similar for flow and pressure waveforms, and are unchanged by characteristics of the downstream perfusion circuit or perfusate viscosity.

Metabolic testing in mitochondrial disease.

Mitochondrial oxidative phosphorylation (OXPHOS) disorders are a heterogeneous group of diseases with variable expression that often pose diagnostic dilemmas. Although definitive diagnosis of these disorders usually requires a muscle biopsy and mtDNA and enzymatic testing, standard metabolic studies including organic acid and amino acid analysis often provide useful findings that support an OXPHOS disease and the need for more invasive studies. In addition, the detection of possible metabolic derangements, such as elevated lactate levels, may lead to improved long-term outcomes for affected patients through the use of various treatment regimens. Similarly, long-term yearly monitoring of diagnosed OXPHOS patients with metabolic testing is also warranted.

Attenuation of histamine-induced endothelial permeability responses after pacing-induced heart failure: role for endogenous catecholamines.

OBJECTIVE: After congestive heart failure (CHF), lung endothelial permeability responses to a number of perturbations, including acute barotrauma, angiotensin II, and thapsigargin are blunted. Our hypothesis was that similar attenuation of permeability responses occurs in peripheral vascular beds after CHF. We compared peripheral microvascular permeability responses to the autacoid histamine in control dogs and in dogs paced to heart failure (245 bpm for approximately 36 days). Since catecholamines attenuate autacoid-induced increases in microvascular permeability in skin and muscle in normal animals, we also tested whether the known elevation in catecholamines in CHF was involved in any downregulation of permeability responses in this group. METHODS: Control and paced dogs were anesthetized, intubated, and ventilated, and a hindpaw lymphatic cannulated. The reflection coefficient for total proteins (sigma) was measured at baseline and during one-hour, local intra-arterial histamine infusion. RESULTS: In controls, sigma fell from 0.83 +/- 0.02 to 0.73 +/- 0.04 after histamine (p < 0.05), while in the paced group sigma was no different from that at baseline (0.77 +/- 0.02). To test whether this difference was due to endogenous catecholamines, dogs were pretreated with propranolol (controls only) or the specific beta 2-antagonist ICI 118,551 prior to histamine infusion. After beta-blockade, histamine significantly reduced sigma in both control (0.83 +/- 0.01 to 0.55 +/- 0.05) and paced (0.83 +/- 0.01 to 0.57 +/- 0.07) groups (p < 0.05). CONCLUSION: We conclude that endogenous catecholamines, acting via beta 2-adrenergic receptors, attenuate the permeability response to histamine in pacing-induced heart failure.

Spectrum of phenotypic variability in Niemann-Pick type C disease: A cause of delayed diagnosis.

BACKGROUND: Niemann-Pick type C (NP-C) disease exhibits marked heterogeneity in its phenotype. This can pose diagnostic dilemmas and even delayed recognition of this condition. OBJECTIVE: To highlight the phenotypic variations and distinctive pathological and biochemical findings in this disorder. DESIGN: Descriptive case studies. SETTING: Tertiary care children's hospital and clinic. POPULATION STUDIED: Three cases of NP-C disease where diagnosis was delayed. RESULTS: In each of the three cases the clinical presentation was varied, one as neonatal hepatitis, the second with megaloblastic anemia, chronic hepatitis and short stature, and the third with neonatal hepatitis and chronic respiratory failure. Definitive diagnosis was established in each case by demonstration of defective cholesterol esterification in skin fibroblasts. CONCLUSIONS: In the clinical setting of neonatal hepatitis, hepatosplenomegaly and undiagnosed neurological symptoms, NP-C disease should be considered in the differential diagnosis. Electron microscopic examination of skin biopsy is an effective screening test, although the definitive diagnosis should be made by the cholesterol esterification assay and filipin staining.

Familial recurrence of atypical symptoms in an extended pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).

We report a clinically heterogeneous, multigenerational pedigree with the syndrome of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) associated with a mutation at nucleotide 3243 in the mitochondrial DNA tRNA(Leu)(UUR) gene. Our findings suggest that the mutation at nucleotide 3243 is not always associated with the classic MELAS phenotype and that other symptoms (notably cardiac and gastrointestinal abnormalities) should raise the suspicion of a mitochondrial disorder.

Imaging of acute myocardial infarction by magnetic resonance tomography (MRT) using the paramagnetic relaxation substance gadolinium-DTPA.

Twenty-six patients admitted to the Free University of Berlin University Hospital catheterization laboratory with acute myocardial infarction were studied. The diagnosis was confirmed by angiography, but acute revascularization was unsuccessful in every case. MR imaging was performed within 7 days of the acute event in 11 patients with uncomplicated clinical courses after acute infarction. Imaging was performed within 3 weeks in three additional cases, while the remaining 12 patients underwent studies more than 3 weeks after infarction. We determined signal intensity at three points within the area of infarction and at three other points in adjacent myocardial tissue. Decreased signal intensity within the area of infarction was found in native scans in 60% of all cases. Administration of gadolinium-DTPA 0.1 mmol/kg body weight was followed by a mean 70% increase in signal intensity within the zones of acute infarction, as compared to a 20% increase in surrounding myocardial tissue. In cases of subacute and chronic infarction, there was no significant signal enhancement after administration of gadolinium-DTPA. Uptake of the substance in the area of acute infarction may be a positive marker of acute myocardial necrosis and as such may prove useful in the clinical setting.

Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty.

A randomised trial of 367 patients with acute myocardial infarction was performed to determine whether an invasive strategy combining thrombolysis with recombinant tissue-type plasminogen activator (rTPA), heparin, and acetylsalicylic acid, and immediate percutaneous transluminal coronary angioplasty (PTCA) would be superior to a noninvasive strategy with the same medical treatment but without immediate angiography and PTCA. Intravenous infusion of 100 mg rTPA was started within 5 h after onset of symptoms (median 156 min). Angiography was performed 6-165 min later in 180 out of 183 patients allocated to the invasive strategy; 184 patients were allocated to the non-invasive strategy. Immediate PTCA reduced the percentage stenosis of the infarct-related segment, but this was offset by a high rate of transient (16%) and sustained (7%) reocclusion during the procedure and recurrent ischaemia during the first 24 h (17%). The clinical course was more favourable after non-invasive therapy, with a lower incidence of recurrent ischaemia within 24 h (3%), bleeding complications, hypotension, and ventricular fibrillation. Mortality at 14 days was lower in patients allocated to non-invasive treatment (3%) than in the group allocated to invasive treatment (7%). No difference between the treatment groups was observed in infarct size estimated from myocardial release of alpha-hydroxybutyrate dehydrogenase or in left ventricular ejection fraction after 10-22 days. Since immediate PTCA does not provide additional benefit there seems to be no need for immediate angiography and PTCA in patients with acute myocardial infarction treated with rTPA.

Intraoperative, two-dimensional echocardiography-guided removal of retained intracardiac air.

The removal of intracardiac air after cardiotomy may be simplified with the use of two-dimensional echocardiography. This technique can be used to readily identify retained pockets of air and can function as a guide to needle aspiration of the ventricular chambers. With a valve prosthesis in place, de-airing can be accomplished with minimal displacement of the heart. The technique is easy to use and the images are simple to interpret.

Use of nuclear magnetic resonance imaging to show regression of hypertrophy with ramipril treatment.

Thirty-two patients with arterial hypertension (diastolic blood pressure greater than 95 mm Hg) were treated with ramipril for 3 months. The aim of the study was to achieve an effective decrease in blood pressure and demonstrate reliably and reproducibly that regression of left ventricular hypertrophy takes place with ramipril treatment. Nuclear magnetic resonance images and echocardiographic measurements of the left ventricle were therefore made before treatment started, 4 hours after the first dose, 14 days after the start of treatment and after 3 months of treatment. The thickness of the septum decreased from 19.57 to 15.20 mm on magnetic resonance scans and from 18.78 to 14.57 mm on echocardiograms. The values were reproduced 3 times at the same measuring point and means were calculated. The septum and posterior wall of the left ventricle were also measured at 3 different points. With negligible scatter, the values obtained were reproducible and the differences were highly significant (p = 0.001). A parallel decrease in blood pressure to levels 15% below baseline was also observed. The therapeutic aim of achieving diastolic blood pressure levels of less than or equal to 90 mm Hg was achieved in all patients. In addition to reducing the blood pressure significantly, the angiotensin converting enzyme inhibitor ramipril caused a significant regression of pathologic left ventricular hypertrophy, which was demonstrated clearly using magnetic resonance imaging and echocardiography.

Magnetic resonance imaging (MRI) in different stages of myocardial infarction using the contrast agent gadolinium-DTPA.

We investigated 26 patients admitted to our catheterization laboratory with a diagnosis of acute myocardial infarction. In each case acute revascularization was unsuccessful, but the diagnosis was confirmed by angiography. In 11 patients with an uncomplicated course of acute myocardial infarction magnetic resonance imaging was carried out within 7 days of the acute event. In three additional cases imaging was performed within 3 weeks, while a remaining 12 patients underwent studies more than 3 weeks after the onset of symptoms. We determined signal intensity at three points within the area of infarction and at three other points in adjacent myocardial tissue. Decreased signal intensity within the area of infarction was present in native scans in 60% of all cases. Application of 0.1 mmol/kg body weight gadolinium-DTPA was followed by an average 70% increase in signal intensity within zones of acute infarction, as compared to a 20% increase in surrounding myocardial tissue. In cases of subacute and chronic infarction there was no significant signal enhancement after administration of gadolinium-DTPA. Uptake of gadolinium-DTPA in the area of acute myocardial infarction may be a positive marker of acute myocardial necrosis, which may be of potential clinical benefit.