Wild bank voles (Clethrionomys glareolus) may develop diabetes in laboratory captivity. The aim of this study was to test whether bank voles develop type 1 diabetes in association with Ljungan virus. Two groups of bank voles were analyzed for diabetes, pancreas histology, autoantibodies to glutamic acid decarboxylase (GAD65), IA-2, and insulin by standardized radioligand-binding assays as well as antibodies to in vitro transcribed and translated Ljungan virus antigens. Group A represented 101 trapped bank voles, which were screened for diabetes when euthanized within 24 hours of capture. Group B represented 67 bank voles, which were trapped and kept in the laboratory for 1 month before being euthanized. Group A bank voles did not have diabetes. Bank voles in group B (22/67; 33%) developed diabetes due to specific lysis of pancreatic islet beta cells. Compared to nondiabetic group B bank voles, diabetic animals had increased levels of GAD65 (P < .0001), IA-2 (P < .0001), and insulin (P = .03) autoantibodies. Affected islets stained positive for Ljungan virus, a novel picorna virus isolated from bank voles. Ljungan virus inoculation of nondiabetic wild bank voles induced beta-cell lysis. Compared to group A bank voles, Ljungan virus antibodies were increased in both nondiabetic (P < .0001) and diabetic (P = .0015) group B bank voles. Levels of Ljungan virus antibodies were also increased in young age at onset of newly diagnosed type 1 diabetes in children (P < .01). These findings support the hypothesis that the development of type 1 diabetes in captured wild bank voles is associated with Ljungan virus. It is speculated that bank voles may have a possible zoonotic role as a reservoir and vector for virus that may contribute to the incidence of type 1 diabetes in humans.

Hyperphosphatemia is common among patients with CKD stage 5D and is associated with morbidity and mortality. Current guidelines recommend lowering serum phosphate concentrations toward normal. Tenapanor is a minimally absorbed small molecule inhibitor of the sodium/hydrogen exchanger isoform 3 that functions in the gut to reduce sodium and phosphate absorption. This randomized, double-blind, placebocontrolled trial assessed the effects of tenapanor on serum phosphate concentration in patients with hyperphosphatemia receiving hemodialysis. After a 1-to 3-week washout of phosphate binders, we randomly assigned 162 eligible patients (serum phosphate =6.0 to ,10.0 mg/dl and a 1.5-mg/dl increase from before washout) to one of six tenapanor regimens (3 or 30 mg once daily or 1, 3, 10, or 30 mg twice daily) or placebo for 4 weeks. The primary efficacy end point was change in serum phosphate concentration from baseline (randomization) to end of treatment. In total, 115 patients (71%) completed the study. Mean serum phosphate concentrations at baseline (after washout) were 7.32-7.92 mg/dl for tenapanor groups and 7.87 mg/dl for the placebo group. Tenapanor provided dose-dependent reductions in serum phosphate level from baseline (least squares mean change: tenapanor =0.47-1.98 mg/dl; placebo =0.54 mg/dl; P=0.01). Diarrhea was the most common adverse event (tenapanor =18%-68%; placebo =12%) and frequent at the highest tenapanor doses. In conclusion, tenapanor treatment resulted in statistically significant, dose-dependent reductions in serum phosphate concentrations in patients with hyperphosphatemia receiving hemodialysis. Additional studies are required to clarify the optimal dosing of tenapanor in patients with CKD-related hyperphosphatemia. 28: 193328: -194228: , 201728: . doi: https://doi.org/10.1681 Disorders of mineral metabolism are common among persons with CKD. 1 Impaired kidney function reduces urinary phosphate excretion, the principal mechanism by which normal phosphate balance is maintained. 2 Modulation of tubular reabsorption of phosphate, mediated in large part by parathyroid hormone (PTH) and the phosphatonin fibroblast growth factor 23 (FGF23), allows for maintenance of serum phosphate concentrations within a physiologic range, despite wide variation in phosphate intake on a day to day basis. However, in advanced CKD, dietary phosphate intake generally exceeds excretory capacity; for patients on dialysis, even with dietary phosphate restriction, hyperphosphatemia is almost inevitable without specific treatment. 3 Among patients receiving dialysis, evidence from observational studies, 1,4 retrospective database analyses, 5,6 and to a lesser extent, prospective controlled trials 7,8 has shown that hyperphosphatemia is associated with mortality, 1,4-6 fractures, 5 and cardiovascular disease, including vascular calcification 8 and left ventricular hypertrophy. 7 J Am Soc Nephrol

As ximelagatran did not exert a significant effect on the hepatic CYP isoenzymes responsible for the metabolism of diclofenac, diazepam and nifedipine, it is reasonable to expect that it would have no effect on the metabolism of other drugs metabolised by these isoenzymes. Furthermore, the pharmacokinetics of melagatran after oral administration of ximelagatran are not expected to be altered by inhibition or induction of CYP2C9, CYP2C19 or CYP3A4. Together, the in vitro and in vivo studies indicate that metabolic drug-drug interactions involving the major human CYP enzymes should not be expected with ximelagatran.

Ljungan virus (LV) is a suspected human pathogen recently isolated from bank voles (Clethrionomys glareolus).In the present study, it is revealed through comparative sequence analysis that three newly determined Swedish LV genomes are closely related and possess a deviant picornavirus-like organization: 5 untranslated region-VP0-VP3-VP1-2A1-2A2-2B-2C-3A-3B-3C-3D-3 untranslated region. The LV genomes and the polyproteins encoded by them exhibit several exceptional features, such as the absence of a predicted maturation cleavage of VP0, a conserved sequence determinant in VP0 that is typically found in VP1 of other picornaviruses, and a cluster of two unrelated 2A proteins. The 2A1 protein is related to the 2A protein of cardio-, erbo-, tescho-, and aphthoviruses, and the 2A2 protein is related to the 2A protein of parechoviruses, kobuviruses, and avian encephalomyelitis virus. The unprecedented association of two structurally different 2A proteins is a feature never previously observed among picornaviruses and implies that their functions are not mutually exclusive. Secondary polyprotein processing of the LV polyprotein is mediated by proteinase 3C (3C pro ) possessing canonical affinity to Glu and Gln at the P1 position and small amino acid residues at the P1 position. In addition, LV 3C pro appears to have unique substrate specificity to Asn, Gln, and Asp and to bulky hydrophobic residues at the P2 and P4 positions, respectively. Phylogenetic analysis suggests that LVs form a separate division, which, together with the Parechovirus genus, has branched off the picornavirus tree most closely to its root. The presence of two 2A proteins indicates that some contemporary picornaviruses with a single 2A may have evolved from the ancestral multi-2A picornavirus.

BackgroundTenapanor (RDX5791, AZD1722), a small molecule with minimal systemic availability, is an inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3). Tenapanor acts locally in the gut to reduce absorption of sodium and phosphate. It is being developed for the treatment of patients with hyperphosphatemia in CKD requiring dialysis and patients with constipation-predominant irritable bowel syndrome. We report the safety, pharmacodynamics, and pharmacokinetics of tenapanor in Japanese volunteers.MethodsIn this phase 1, double-blind study (NCT02176252), healthy Japanese adults (aged 20–45 years) received single-dose tenapanor 180 mg (n = 6), repeated-dose tenapanor 15, 30, 60, or 90 mg twice daily (n = 12 each) for 7 days, or placebo (n = 14). All participants received a standardized diet.ResultsSingle and repeated doses of tenapanor resulted in higher mean stool sodium content vs. placebo (single dose, 41.9 mmol/day; repeated dose, range of means 21.3–32.2 mmol/day; placebo, 4.1 mmol/day) accompanied by lower urinary sodium content (single dose, 110 mmol/day; repeated dose, 101–112 mmol/day; placebo, 143 mmol/day). Additionally, stool phosphorus content was increased (single dose, 31.0 mmol/day; repeated dose, 17.6–24.8 mmol/day; placebo, 16.8 mmol/day) and urinary phosphorus content decreased (single dose, 18.7 mmol/day; repeated dose, 15.3–19.4 mmol/day; placebo, 25.5 mmol/day). Tenapanor had minimal systemic exposure, provided a softer stool consistency, and was well tolerated.ConclusionsTenapanor treatment reduced absorption of intestinal sodium and phosphate from the gut in Japanese adults. Tenapanor had minimal systemic exposure and was well tolerated. Further research into the clinical benefits of tenapanor is warranted.Electronic supplementary materialThe online version of this article (doi:10.1007/s10157-016-1302-8) contains supplementary material, which is available to authorized users.