Keywords asymmetric dimethylarginine, L-arginine, L-homoarginine, nitric oxide, vascular function AIMSLow blood concentrations of the naturally occurring amino acid L-homoarginine (L-hArg) are related to impaired cardiovascular outcome and mortality in humans and animals. L-hArg is a weak substrate of nitric oxide synthase and an inhibitor of arginases in vitro. The aim of our study was to obtain kinetic and dynamic data after oral L-hArg supplementation. METHODSIn a double-blind, randomized, placebo-controlled crossover study, 20 young volunteers received 125 mg L-hArg once daily for 4 weeks. Kinetic parameters (C max , T max and AUC 0-24h ) were calculated after ingestion of single and multiple doses of oral supplementation as primary endpoint. Secondary endpoints that were evaluated were routine laboratory, L-arginine, asymmetric dimethylarginine (ADMA), pulse wave velocity (PWV), augmentation index (AIx), flow-mediated vasodilatation (FMD), corticospinal excitability, i.e. motor threshold (MT), and cortical excitability, i.e. intracortical inhibition (ICI) and facilitation (ICF). RESULTSOne hour after ingestion (T max ), L-hArg increased the baseline L-hArg plasma concentration (2.87 ± 0.91 μmol l À1 , mean ± SD) by 8.74 ± 4.46 [95% confidence intervals 6.65; 10.9] and 17. 3 ± 4.97 [14.9; 19.6] μmol l À1 (C max ), after single and multiple doses, respectively. Once-only and 4 weeks of supplementation resulted in AUCs 0-24h of 63. 5 ± 28.8 [50.0; 76.9] and 225 ± 78.5 [188; 2624] μmol l À1 *h, for single and multiple doses, respectively. Routine laboratory parameters, L-arginine, ADMA, PWV, AIx, FMD, MT, ICI and ICF did not change by L-hArg supplementation compared to baseline. CONCLUSIONOnce daily orally applied 125 mg L-hArg raises plasma L-hArg four-and sevenfold after single dose and 4 weeks of supplementation, respectively, and is safe and well tolerated in young volunteers. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• L-Homoarginine (L-hArg) is an amino acid found in pea pulses (Lathyrus sativus and cicera). It is a weak substrate for nitric oxide (NO) synthases (NOS) and an inhibitor of arginases.• In clinical and epidemiological studies, low circulating L-hArg is associated with impaired cerebrovascular and cardiovascular outcome.• Orally administered L-hArg is readily absorbed in rats and pigs with a recovery of >95% of unmetabolized L-hArg in urine. WHAT THIS STUDY ADDS• Our data show that oral supplementation with 125 mg L-hArg raises plasma L-hArg concentrations four-and sevenfold after single and multiple dosing in humans, respectively.• Four weeks of supplementation did not change vascular and neuronal function in young volunteers, nor did any toxic side-effects occur.

A set of 31 items drawn from the German PRO-CTCAE item library demonstrated favourable measurement properties. These findings add to the body of evidence that PRO-CTCAE provides a rigorous method to capture patient self-reports of symptomatic toxicity for use in cancer clinical trials.

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Background To evaluate medication-related risks in older patients with cancer and their association with severe toxicity during antineoplastic therapy. Methods This is a secondary analysis of two prospective, single-center observational studies which included patients ≥ 70 years with cancer. The patients’ medication lists were investigated regarding possible risks: polymedication (defined as the use of ≥ 5 drugs), potentially inappropriate medication (PIM), and relevant potential drug-drug interactions (rPDDI). The risks were analyzed before and after start of cancer therapy. Severe toxicity during antineoplastic therapy was captured from medical records according to the Common Terminology Criteria for Adverse Events (CTCAE). The association between grade ≥ 3 toxicity and medication risks was evaluated by univariate as well as multivariate regression adjusted by ECOG and age. Results The study cohort comprised 136 patients (50% female, mean age 77 years, 42% hematological malignancies). Before the start of cancer therapy, patients took on average 5 drugs as long-term medication and 52% of patients were exposed to polymedication. More than half of patients used at least one PIM. Approximately one third of patients exhibited rPDDI. The prevalence of medication risks increased after start of cancer therapy. rPDDI were significantly associated with severe overall toxicity (OR, 5.07; p = 0.036; 95% Confidence Interval (CI) 1.11–23.14; toxicity in patients with rPDDI 94.1% (32/34) vs 75.9% (60/79) in patients without rPDDI) and hematological toxicity (OR, 3.95; p = 0.010; 95% CI 1.38–11.29; hematological toxicity in patients with rPDDI 85.3% (29/34) vs 59.5% (47/79) in patients without rPDDI). In the multivariate analysis adjusted by ECOG and age, only the association for rPDDI with hematological toxicity remained statistically significant (OR, 4.51; p = 0.007; 95% CI 1.52–13.38). These findings should be further investigated in larger studies. Conclusion Medication risks are common in older patients with cancer and might be associated with toxicity. This raises the need for tailored interventions to ensure medication safety in this patient cohort.

AIMS OF THE STUDY Our aim was to explore drug-induced liver injury (DILI) in Switzerland using the real-world data of the global pharmacovigilance database VigiBase™, with a special focus on the new drug class of checkpoint inhibitors. This is the first study investigating drug-related hepatic disorders in Switzerland in a global pharmacovigilance database. METHODS This was a retrospective study analysing the ICSRs (individual case safety reports) of the global pharmacovigilance database VigiBase™. We explored all ICSRs submitted in Switzerland within the last 10 years (1 July 2010 to 30 June 2020). For data extraction, the standardised MedDRA query (SMQ) “narrow drug-related hepatic disorders – severe events only” was applied. The ICSRs, drug-reaction pairs and adverse drug reactions were analysed descriptively, including a special focus on checkpoint inhibitors. For comparing the hepatic adverse drug reactions of pembrolizumab, nivolumab and ipilimumab, the reporting odds ratios (RORs) were calculated in a disproportionality analysis. RESULTS In total, 2042 ICSRs could be investigated, comprising 10,646 drugs and 6436 adverse drug reactions. Gender was equally distributed between male and female. Patients were on average 57 years old. The mortality rate was high, with fatal adverse reactions in over 10% of cases. On average, patients used five drugs including two suspected drugs. Paracetamol, amoxicillin/clavulanic acid, esomeprazole and atorvastatin ranked among the most frequently suspected drugs for severe drug-related hepatic disorders. However, Vigibase™ data are not appropriate for judging causality and these results should be interpreted with caution owing to the possible influences of comedication or comorbidity. An average of three adverse drug reactions per ICSR were reported, most frequently including hepatocellular injury, cholestatic liver injury, and liver injury. For checkpoint inhibitors, hepatitis was the most frequently reported hepatic adverse drug reaction. In comparison with nivolumab and ipilimumab, pembrolizumab had a significantly higher ROR for hepatitis (2.41, p = 0.016), but also a lower ROR for autoimmune hepatitis (0.11, p = 0.009). CONCLUSION Our findings highlight the importance for healthcare providers in Switzerland to pay special attention to possible drug-induced liver injuries because of their high mortality rate. The analysis of real-world data confirms the previous assumption that hepatitis is the most frequent hepatic adverse event for checkpoint inhibitors. Further clinical studies are warranted to directly compare hepatic adverse drug reactions to different checkpoint inhibitors.