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Background: Cardiac manifestation of COVID-19 has been reported during the COVID pandemic. The role of cardiac arrhythmias in COVID-19 is insufficiently understood. This study assesses the incidence of cardiac arrhythmias and their prognostic implications in hospitalized COVID-19-patients. Methods: A total of 166 patients from eight centers who were hospitalized for COVID-19 from 03/2020&ndash, 06/2020 were included. Medical records were systematically analyzed for baseline characteristics, biomarkers, cardiac arrhythmias and clinical outcome parameters related to the index hospitalization. Predisposing risk factors for arrhythmias were identified. Furthermore, the influence of arrhythmia on the course of disease and related outcomes was assessed using univariate and multiple regression analyses. Results: Arrhythmias were detected in 20.5% of patients. Atrial fibrillation was the most common arrhythmia. Age and cardiovascular disease were predictors for new-onset arrhythmia. Arrhythmia was associated with a pronounced increase in cardiac biomarkers, prolonged hospitalization, and admission to intensive- or intermediate-care-units, mechanical ventilation and in-hospital mortality. In multiple regression analyses, incident arrhythmia was strongly associated with duration of hospitalization and mechanical ventilation. Cardiovascular disease was associated with increased mortality. Conclusions: Arrhythmia was the most common cardiac event in association with hospitalization for COVID-19. Older age and cardiovascular disease predisposed for arrhythmia during hospitalization. Whereas in-hospital mortality is affected by underlying cardiovascular conditions, arrhythmia during hospitalization for COVID-19 is independently associated with prolonged hospitalization and mechanical ventilation. Thus, incident arrhythmia may indicate a patient subgroup at risk for a severe course of disease.

Introduction Traumatic and non-traumatic spinal cord injury bears a high risk for thromboembolism in the first few months after injury. So far, there is no consented guideline regarding diagnostic and prophylactic measures to prevent thromboembolic events in spinal cord injury. Based on a Pubmed research of related original papers and review articles, international guidelines and a survey conducted in German-speaking spinal cord injury centers about best practice prophylactic procedures at each site, a consensus process was initiated, which included spinal cord medicine experts and representatives from medical societies involved in the comprehensive care of spinal cord injury patients. The recommendations comply with the German S3 practice guidelines on prevention of venous thromboembolism. Recommendations Specific clinical or instrument-based screening methods are not recommended in asymptomatic SCI patients. Based on the severity of neurological dysfunction (motor completeness, ambulatory function) low dose low molecular weight heparins are recommended to be administered up to 24 weeks after injury. Besides, mechanical methods (compression stockings, intermittent pneumatic compression) can be applied. In chronic SCI patients admitted to the hospital, thromboembolism prophylactic measures need to be based on the reason for admission and the necessity for immobilization. Conclusions Recommendations for thromboembolism diagnostic and prophylactic measures follow best practice in most spinal cord injury centers. More research evidence needs to be generated to administer more individually tailored risk-adapted prophylactic strategies in the future, which may help to further prevent thromboembolic events without causing major side effects. The present article is a translation of the guideline recently published online (https://www.awmf.org/uploads/tx_szleitlinien/179-015l_S1_Thromboembolieprophylaxe-bei-Querschnittlaehmung_2020-09.pdf).

Aims A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms. Methods In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg kg−1 digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay. Results Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration–time curve [mean AUC(0,24) ± SD 23 ± 5.2 vs. 14 ± 2.9 µg L−1 h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) ± SD 34 ± 39 vs. 57 ± 41 mL min−1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin. Conclusions Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

Background The antineoplastic compound paclitaxel (Taxol) causes an increased assembly of extraordinarily stable microtubules. The present study was designed to characterize the effects of paclitaxel on proliferation and migration of human arterial smooth muscle cells (haSMCs) in vitro and on neointima formation in an in vivo experimental rabbit model. Methods and Results Both monocultures of haSMCs and cocultures with human arterial endothelial cells (haECs) were used. Cell growth after 4, 8, and 14 days was determined in the absence or presence of platelet-derived growth factor-AB (PDGF-AB), basic fibroblast growth factor (bFGF), or thrombin. Nonstop paclitaxel exposure, as well as single-dose applications of paclitaxel for 24 hours or even 20 minutes (0.1 to 10.0 μmol/L), caused a complete and prolonged inhibition of haSMC growth up to day 14, with an IC 50 of 2.0 nmol/L. Mitogens or cocultures with stimulating haECs did not significantly attenuate paclitaxel-induced effects. Immunohistochemistry showed characteristic cytoskeletal changes predominantly in the microtubule network. Additionally, in 20 male New Zealand White rabbits, intimal plaques were produced by electrical stimulation. In 10 animals, paclitaxel was locally applied by use of microporous balloons. Histologically, the intima wall area, wall thickness, and degree of stenosis were reduced significantly in paclitaxel-treated animals compared with controls. Conclusions Our data show that paclitaxel inhibits haSMC proliferation and migration in a dose-dependent manner in monocultures and cocultures even in the presence of mitogens. Furthermore, paclitaxel prevents neointima formation in rabbits after balloon angioplasty. The long-lasting effect after just several minutes’ exposure time makes this lipophilic substance a promising candidate for local antiproliferative therapy of restenosis.

Objective Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. Methods In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. Results Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. Conclusions 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.

To investigate the effect of acute hypoxia and concomitant changes in portal blood flow on the disposition of drugs mainly metabolized by the cytochrome P(450) enzymes (CYP) 3A4 (verapamil) and CYP1A2 (theophylline).Twenty healthy male participants were studied on two 14-h study days in a normobaric hypoxic chamber and were allocated randomly to one of two groups receiving short infusions of either theophylline (6 mg kg (-1) body weight) or verapamil (5 mg) intravenously. According to a randomized, cross-over design, participants were once exposed to normoxia and once to hypoxia (12% oxygen corresponding to the ambient( P)O(2) at an altitude of 4,500 m above sea level). The concentrations of theophylline, 1,3-dimethyluric acid, verapamil, and norverapamil were determined in serial blood samples by means of liquid chromatography-mass spectrometry (LC/MS/MS). Portal blood flow was assessed by transabdominal duplex ultrasonography.Acute hypoxia did not alter the pharmacokinetics of theophylline [half-life+/-SD: 9.29+/-1.77 versus 9.39+/-1.40 (hypoxia)], 1,3-dimethyluric acid (12.9+/-4.72 versus 15.1+/-8.59), verapamil (2.00+/-0.98 versus 1.79+/-0.58), or norverapamil (7.98+/-2.94 versus 9.91+/-6.40). Individual changes of elimination half-life and changes in capillary oxygen saturation,( P)O(2), or portal vein flow were not correlated. Portal vein flow was unaffected by hypoxia.Acute hypoxia corresponding to hypoxia at altitudes of 4,500 m does not impair the metabolism mediated by CYP1A2 or CYP3A4. At rapid ascent to and short-term stay at altitudes up to 4,500 m, the doses of drugs metabolized by these CYPs do therefore not require dose modification, and major changes in the disposition of already administered drugs are not to be expected.

A clinically important interaction between the cardiac glycoside digoxin and the antibiotic clarithromycin has been suggested in earlier reports. The aim of this study was to investigate the extent of the interaction and the relative contribution of different mechanisms.In a randomized, placebo-controlled, double-blind cross-over design single oral doses of 0.75 mg digoxin with oral coadministration of placebo or 250 mg clarithromycin twice daily for 3 days were administered to 12 healthy men. Additionally, three of the subjects received single intravenous doses of 0.01 mg x kg(-1) digoxin with oral placebo or clarithromycin. Digoxin plasma and urine concentrations were determined by a highly sensitive radioimmunoassay.Oral coadministration of clarithromycin resulted in a 1.7-fold increase of the area under the digoxin plasma concentration-time curve [mean AUC(0,24) +/- SD 23 +/- 5.2 vs. 14 +/- 2.9 microg x L(-1) x h; 95% confidence interval (CI) on the difference 7.0, 12; P = 0.002] and in a reduction of the nonglomerular renal clearance of digoxin [mean ClRng(0, 24) +/- SD 34 +/- 39 vs. 57 +/- 41 mL min-1; 95% CI on the difference 7.2, 45; P = 0.03]. The ratios of mean digoxin plasma concentrations with and without clarithromycin were highest during the absorption period of clarithromycin. After intravenous administration digoxin AUC(0,24) increased only 1.2-fold during coadministration of clarithromycin.Increased oral bioavailability and reduced nonglomerular renal clearance of digoxin both contribute to the interaction between digoxin and clarithromycin, probably due to inhibition of intestinal and renal P-glycoprotein.

5-fluorouracil (5-FU), widely used for chemotherapy of colorectal carcinoma, requires intracellular anabolic conversion to cytotoxic nucleotides and exhibits a narrow therapeutic range with dose-dependent and concentration-dependent effects. 5-FU undergoes extensive metabolic degradation to several catabolites, which are excreted mainly by the kidneys. Alteration of the pharmacokinetics of 5-FU and its catabolites as a result of renal dysfunction might augment systemic toxicity. Because no data are available for patients with severe renal failure, the pharmacokinetic parameters of 5-FU and its catabolites were determined for a patient with colorectal carcinoma and end-stage renal disease on maintenance hemodialysis therapy. Plasma was analyzed by 19F nuclear magnetic resonance spectroscopy for the first 5-day treatment cycle (daily bolus injections of 5-FU for 5 days in combination with low-dose folinic acid). On days 1 and 5, the pharmacokinetic parameters for 5-FU (total area under the plasma concentration-time curve, terminal half-life, total plasma clearance, volume of distribution based on the terminal phase) and its initial catabolite dihydrofluorouracil (total area under the plasma concentration-time curve, terminal half-life) were in the ranges reported in the literature for patients with normal renal function, implying no need for primary dose adjustment. In contrast, the final 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) accumulated to a concentration of 276 micromol/L on day 5 (approximately twofold higher than expected from the literature) despite good removal by hemodialysis with extraction ratios of 0.6 to 0.85 over the filter membrane. Negative effects of FBAL or enhancement of 5-FU-related toxicity could not be judged in this individual case, but further study is warranted to determine the possible benefits of more intensive dialysis treatment.