Cardiorenal Effects of Long‐Term Phosphodiesterase V Inhibition in Pre–Heart Failure

Background Phosphodiesterase V (PDEV) is upregulated in heart failure, leading to increased degradation of cGMP and impaired natriuresis. PDEV inhibition improves the renal response to B‐type natriuretic peptide in animal models. We tested the hypothesis that long‐term PDEV inhibition would improve renal function and cardiorenal response after short‐term volume load in subjects with pre–heart failure. Methods and Results A total of 20 subjects with pre–heart failure (defined as an ejection fraction ≤45% without previous diagnosis of heart failure) and renal impairment were randomized in a 2:1 manner to tadalafil or placebo. Baseline echocardiography and renal clearance study were performed, followed by a short‐term saline load and repeated echocardiography and renal clearance study. Subjects then received either tadalafil at a goal dose of 20 mg daily or placebo, and the study day was repeated after 12 weeks. Long‐term tadalafil did not improve glomerular filtration rate (median increase of 2.0 mL/min in the tadalafil group versus 13.5 mL/min in the placebo group; P =0.54). There was no difference in urinary sodium or cGMP excretion with PDEV inhibition following short‐term saline loading. Conclusions Glomerular filtration rate and urinary sodium/cGMP excretion were not significantly different after 12 weeks of tadalafil compared with placebo. These results do not support the use of PDEV inhibition to improve renal response in patients with pre–heart failure. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01970176.

Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers

Background In patients with type 2 diabetes (T2D) sodium-glucose cotransporter 2 (SGLT-2) inhibitors improve glycaemic control as well as cardiovascular and renal outcomes. Their effects on l-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported. Methods Plasma and 24-h urine samples taken before and after 6 weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters. Results Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p < 0.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p < 0.001 and p < 0.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p < 0.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p < 0.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (− 15.5%, p < 0.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on l-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure. Conclusions Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors. Trial registrationhttp://www.clinicaltrials.gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.

Clinical Pharmacology of Levetiracetam in Infants and Children

Levetiracetam inhibits focal and secondary generalized tonic-clonic seizures. The mechanism of levetiracetam action is not fully understood, however the correlation between binding affinity of levetiracetam and its analogues and their potency toward audiogenic seizures suggest that the synaptic vesicle glycoprotein 2A mediates the anticonvulsant effects of levetiracetam. The neural function of the synaptic vesicle 2A protein is not fully understood, but binding of levetiracetam to synaptic vesicle glycoprotein 2A might affect neuronal excitability by modifying the release of glutamate GABA through an action on vesicular function. Synaptic vesicle glycoprotein 2A may plain a role in vesicle recycling following exocytosis of neurotransmitter. In addition, levetiracetam inhibits N-type Ca2+ channels and Ca2+ release from intracellular stores. Levetiracetam may be administered intravenously or orally to infants and children and in children the levetiracetam dose varies according to the child age and body-weight. Levetiracetam is almost completed absorbed after oral administration and levetiracetam is found efficacy and safe in infants and children but it may induce adverse-effects. The levetiracetam elimination half-life is about 6 hours in infants and children, and in children the renal clearance is similar to the non-renal clearance. The prophylaxis, treatment, and trials with levetiracetam have been extensively studied in infants and children. Levetiracetam freely crosses the human placenta and freely migrates into the breast-milk. The aim of this study is to review the levetiracetam dosing, efficacy, safety, adverse-effects, pharmacokinetics, prophylaxis, treatment, and trials and transfer of levetiracetam across the human placenta and levetiracetam migration into the breast-milk.

Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients.Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count.Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient.Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

Large-Scale Synthesis of Glutathione-Coated and 68Ga- Labeled Gold Nanoclusters for PET/CT Imaging of Tumors

Gold nanoclusters (AuNCs) have gained popular attention in recent years because of their efficient tumor accumulation through EPR effect and renal clearance. In this work, we put forward a new approach to prepare glutathione-coated, 68Ga-labeled AuNCs (68Ga-GHS@AuNCs) with ultrasmall sizes (< 2 nm) for PET/CT imaging of tumors. GHS@AuNCs has low cytotoxicity in vitro. PET/CT imaging revealed that the 68Ga-GHS@AuNCs could target tumor and be cleared by kidney efficiently. Our study demonstrates that 68Ga-GHS@AuNCs has great potential for detection of tumors.