Barry Ticho

Anti–JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy

The increased risk of progressive multifocal leukoencephalopathy (PML) with natalizumab treatment is associated with the presence of anti–JC virus (JCV) antibodies. We analyzed whether anti‐JCV antibody levels, measured as index, may further define PML risk in seropositive patients.

MS disease activity in RESTORE A randomized 24-week natalizumab treatment interruption study

Objective: RESTORE was a randomized, partially placebo-controlled exploratory study evaluating multiple sclerosis (MS) disease activity during a 24-week interruption of natalizumab. Methods: Eligible patients were relapse-free through the prior year on natalizumab and had no gadolinium-enhancing lesions on screening brain MRI. Patients were randomized 1:1:2 to continue natalizumab, to switch to placebo, or to receive alternative immunomodulatory therapy (other therapies: IM interferon β-1a [IM IFN-β-1a], glatiramer acetate [GA], or methylprednisolone [MP]). During the 24-week randomized treatment period, patients underwent clinical and MRI assessments every 4 weeks. Results: Patients (n = 175) were randomized to natalizumab (n = 45), placebo (n = 42), or other therapies (n = 88: IM IFN-β-1a, n = 17; GA, n = 17; MP, n = 54). Of 167 patients evaluable for efficacy, 49 (29%) had MRI disease activity recurrence: 0/45 (0%) natalizumab, 19/41 (46%) placebo, 1/14 (7%) IM IFN-β-1a, 8/15 (53%) GA, and 21/52 (40%) MP. Relapse occurred in 4% of natalizumab patients and in 15%–29% of patients in the other treatment arms. MRI disease activity recurred starting at 12 weeks (n = 3 at week 12) while relapses were reported as early as 4–8 weeks (n = 2 in weeks 4–8) after the last natalizumab dose. Overall, 50/167 patients (30%), all in placebo or other-therapies groups, restarted natalizumab early because of disease activity. Conclusions: MRI and clinical disease activity recurred in some patients during natalizumab interruption, despite use of other therapies. Classification of evidence: This study provides Class II evidence that for patients with MS taking natalizumab who are relapse-free for 1 year, stopping natalizumab increases the risk of MS relapse or MRI disease activity as compared with continuing natalizumab.

Anti‐JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti‐JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti‐JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two‐step anti‐JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti‐JCV antibodies in approximately 55% of multiple sclerosis (MS) patients. This study describes the prevalence of anti‐JCV antibodies in a large, multinational MS population.

Rationale and Design of the Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (THE BALANCE) Study

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V2‐receptor antagonist that improves hyponatremia by promoting electrolyte‐free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double‐blind, placebo‐controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital‐free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30‐day safety follow‐up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure. Clin Trans Sci 2010; Volume 3: 249–253.

Protective Effect of Tonapofylline (BG9928), an Adenosine A1 Receptor Antagonist, against Cisplatin-Induced Acute Kidney Injury in Rats

Background/Aims: Cisplatin (CIS) induces nephrotoxicity partly through renal vasoconstriction and decreased glomerular filtration effects thought to involve adenosine acting on adenosine A1 receptors (A1Rs). We studied the effect of the orally active, A1R antagonist tonapofylline (BG9928) on biochemical measures of renal function in CIS-induced acute kidney injury (AKI) in rats. Methods: Tonapofylline, 1 mg/kg b.i.d., p.o., was administered on days 0–1 or 0–6 to rats treated with CIS 5.5 mg/kg i.v. Prednisolone (PRED) 5 mg/kg s.c. (day 0) served as a positive control. Serum creatinine and urea nitrogen (BUN) were measured in serial blood samples taken over the 13-day study period. Results: CIS produced significant elevations in creatinine, reduction in body weight and marked proximal tubular injury throughout the renal cortex and outer medulla. Tonapofylline, days 0–1 or 0–6 and PRED all produced sustained reductions in post-CIS serum creatinine and BUN levels compared with controls, improved body weight recovery and significant attenuation of CIS-induced kidney pathology scores. Conclusion: These data support the involvement of A1Rs in CIS-induced AKI in rats. Tonapofylline may be useful in the clinical setting for the prevention of kidney failure induced by nephrotoxic agents such as CIS.

Effects of BG9928, an adenosine A1 receptor antagonist, in patients with congestive heart failure

Previous studies suggest that adenosine A1 receptor antagonists may promote natriuresis without deleterious effects on renal function. This study evaluated renal and hemodynamic effects as well as safety, pharmacokinetics, and tolerability of BG9928, a selective adenosine A1‐receptor antagonist, in patients with heart failure. In this multicenter, randomized, double‐blind, placebo‐controlled, dose‐escalation study, 33 patients received a single dose of BG9928 (0.03, 0.3, 1.0, or 3.0 mg/kg) or placebo intravenously. Change from baseline in urinary sodium excretion for the 8‐hour postdose interval was greater for all dosing groups versus placebo. The 0.03‐mg/kg and 0.3‐mg/kg groups had significant reductions in body weight versus placebo (−0.8 kg, −1.1 kg, 0.3 kg, respectively; P < 005). No changes in creatinine clearance or hemodynamic parameters were observed among any of the BG9928 groups versus placebo. However, pulmonary capillary wedge pressure tended to decrease and correlated with weight loss. Across the range of doses studied, pharmacokinetic parameters were linear and predictable. One patient who received the highest dose (3.0 mg/kg) developed seizures, and no further patients received that dose. Single intravenous BG9928 doses of up to 1.0 mg/kg were well tolerated and increased sodium excretion without worsening renal function. Further studies are needed to determine the clinical benefit of adenosine A1 receptor antagonism.

Dual A1/A2B Receptor Blockade Improves Cardiac and Renal Outcomes in a Rat Model of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is prevalent and often accompanied by metabolic syndrome. Current treatment options are limited. Here, we test the hypothesis that combined A1/A2B adenosine receptor blockade is beneficial in obese ZSF1 rats, an animal model of HFpEF with metabolic syndrome. The combined A1/A2B receptor antagonist 3-[4-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)-1-bicyclo[2.2.2]octanyl]propanoic acid (BG9928) was administered orally (10 mg/kg/day) to obese ZSF1 rats (n = 10) for 24 weeks (from 20 to 44 weeks of age). Untreated ZSF1 rats (n = 9) served as controls. After 24 weeks of administration, BG9928 significantly lowered plasma triglycerides (in mg/dl: control group, 4351 ± 550; BG9928 group, 2900 ± 551) without adversely affecting plasma cholesterol or activating renin release. BG9928 significantly decreased 24-hour urinary glucose excretion (in mg/kg/day: control group, 823 ± 179; BG9928 group, 196 ± 80) and improved oral glucose tolerance, polydipsia, and polyuria. BG9928 significantly augmented left ventricular diastolic function in association with a reduction in cardiac vasculitis and cardiac necrosis. BG9928 significantly reduced 24-hour urinary protein excretion (in mg/kg/day: control group, 1702 ± 263; BG9928 group, 1076 ± 238), and this was associated with a reduction in focal segmental glomerulosclerosis, tubular atrophy, tubular dilation, and deposition of proteinaceous material in the tubules. These findings show that, in a model of HFpEF with metabolic syndrome, A1/A2B receptor inhibition improves hyperlipidemia, exerts antidiabetic actions, reduces HFpEF, improves cardiac histopathology, and affords renal protection. We conclude that chronic administration of combined A1/A2B receptor antagonists could be beneficial in patients with HFpEF, in particular those with comorbidities such as obesity, diabetes, and dyslipidemias.

Clinical Pharmacokinetics of Tonapofylline: Evaluation of Dose Proportionality, Oral Bioavailability, and Gender and Food Effects in Healthy Human Subjects

Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single‐dose tonapofylline (0.2–375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in a multiple phasic manner. Based on a power model, dose proportionality of peak concentration (Cmax), area under the time‐concentration curve for all values (AUCall), and area under the time‐concentration curve to infinity (AUCinf) was concluded in a clinical setting. The bioavailability of tonapofylline was 81.2% (90% confidence interval, 70.6%–93.5%). Following intravenous administration, the steady‐state volume of distribution of tonapofylline was estimated to be 756 mL/kg. The total clearance of tonapofylline was low (64.8 mL/h/kg), approximately 5% of hepatic blood flow. The terminal half‐life was variable within groups and ranged from 11.2 to 24.2 hours across the dose range. Female subjects showed significantly higher Cmax, AUCall, and AUCinf than male subjects (P < .05). Food decreased Cmax by approximately 39%, whereas it did not appear to affect AUCall and AUCinf. The intersubject variability of the pharmacokinetic parameters of tonapofylline was generally less than 30%. In these studies, a single dose of tonapofylline was safe and well tolerated.

Consultants for the American Journal of Nephrology 2009

Glenn Chertow Robert Chevalier Monique Cho Kai-Ming Chow Felix Claverie-Martin Mark Cooper Fernando Cordido Daniel Coyne Farhad Danesh Robert Danziger John Daugirdas Prasad Devarajan Francis Dumler Thomas Easterling Tevfik Ecder Paul Eggers Randa El Zein Kathrin Eller Murray Epstein Sahar Fathallah-Shaykh Gal Finer Jeffrey Fink Michael Fischer Agnes Fogo Barry Freedman Eli Friedman Verica Garaj-Vrhovac Richard Glassock Glenda Gobe Stuart Goldstein Harvest Gu Krishnamurthy Gudehithlu Martha Gulati Michael Haase Melisha Hanna Peter Hart Kitamura Harumi Marion Hofmann-Bowman Yao Huang Adrian Iaina Narita Ichiei Zaid Abassi Kevin Abbott Rajiv Agarwal Adesuyi Ajayi Charambolos Antoniades Natarajan Aravindan Gema Ariceta Jose Arruda Arif Asif John Asplin Jonas Axelsson Mindy Banks Vinod Bansal Amy Barton Pai David Basile Alexei Basnakian Srinivasan Beddhu Enrico Benedetti Carsten Bergmann Daniel Berlowitz Judith Beto Rajendra Bhimma Erhard Bieberich Geoffrey Block Amy Bobrowski Neil Boudville Michael Braun Carolyn Brecklin Ellen Brooks Rebecca Brown Steve Brunelli Nigel Brunskill Emmanuel Burdmann Michel Burnier Hui Cai David Calhoun Niels Camara Vito Campese Thomas Carpenter Tak Mao Chan Arelene Chapman