Endogenous arginine derivatives homoarginine, asymmetric dimethylarginine (ADMA) and symmetric dimethyarginine (SDMA) are independent mortality predictors in atherosclerotic cardiovascular disease ...(CVD). Our study reports the first analysis, whether homoarginine, ADMA and SDMA predict venous thromboembolism (VTE) recurrence and overall mortality in patients with suspected acute VTE. We assessed serum levels of homoarginine, ADMA and SDMA by LC-MS/MS in 865 individuals from a prospective consecutive cohort of patients with clinical suspicion of VTE. The median follow-up time for mortality was 1196 days. VTE was confirmed by imaging in 418 patients and excluded in 447 patients. Low levels of homoarginine and high levels of ADMA or SDMA independently predicted all-cause mortality after adjustment for sex, age, oral anticoagulants, body mass index, arterial hypertension, diabetes mellitus, smoking, dyslipidemia, chronic heart failure, history of stroke, creatinine and cancer both in patients with VTE and without VTE. Interestingly, none of those parameters was predictive for VTE recurrence. We provide the first report that low circulating levels of homoarginine and high circulating levels of ADMA and SDMA independently predict all-cause mortality in patients with suspected VTE. These parameters might serve as markers of "frailty" and should be considered for future risk stratification approaches in this clinical population. Taking into account that homoarginine supplementation is protective in animal models of CVD and safe in healthy human volunteers, our study provides the basis for future homoarginine supplementation studies in patients with suspected VTE to investigate possible direct protective effects of homoarginine in this population.
On April 17 2020, the United States Food and Drug Administration granted Coronavirus Disease 2019 (COVID‐19) emergency use authorizations for the Seraph 100 Microbind Affinity Blood Filter. The ...medical device is aimed to treat critically ill COVID‐19 patients with confirmed or imminent respiratory failure. The aim of this life size in vitro pharmacokinetic study was to investigate the in vitro adsorption of chloroquine and hydroxychloroquine from human plasma using equipment that is also used at the bedside. After start of the hemoperfusion, Pre (Cpre) Seraph plasma levels were obtained at 5 (C5), 10 (C10), 15 (C15), 30 (C30), 60 (C60), and 120 (C120) minutes into the procedure. At two timepoints (5 and 120 minutes) post (Cpost) Seraph plasma levels were determined that were used to calculate the plasma clearance of the Seraph. Both drugs were determined using a validated HPLC method. Median IQR plasma clearance of the Seraph for chloroquine/hydroxychloroquine was 1.71 0.51‐4.38 mL/min/1.79 0.21‐3.68 mL/min respectively. The lack of elimination was also confirmed by the fact that plasma levels did not change over the 120 minutes treatment. As neither chloroquine nor hydroxychloroquine were removed by the treatment with the Seraph dose adjustments in COVID‐19 patients undergoing this treatment are not necessary.
Background Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue-nonspecific alkaline ...phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low-density lipoprotein receptor mutation (wicked high cholesterol WHC allele). WHC and WHC -endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC -endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids ( P<0.01), increased left ventricular end-diastolic diameter ( P<0.0001), reduced ejection fraction ( P<0.05), and increased myocardial fibrosis ( P<0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC -endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P<0.01), preserved ejection fraction ( P<0.05), and reduced myocardial fibrosis ( P<0.001). Conclusions The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.
Endogenous methylarginines were proposed as cardiovascular risk factors more than two decades ago, however, so far, this knowledge has not led to the development of novel therapeutic approaches. The ...initial studies were primarily focused on the endogenous inhibitors of nitric oxide synthases asymmetric dimethylarginine (ADMA) and monomethylarginine (MMA) and the main enzyme regulating their clearance dimethylarginine dimethylaminohydrolase 1 (DDAH1). To date, all the screens for DDAH1 activators performed with the purified recombinant DDAH1 enzyme have not yielded any promising hits, which is probably the main reason why interest towards this research field has started to fade. The relative contribution of the second DDAH isoenzyme DDAH2 towards ADMA and MMA clearance is still a matter of controversy. ADMA, MMA and symmetric dimethylarginine (SDMA) are also metabolized by alanine: glyoxylate aminotransferase 2 (AGXT2), however, in addition to methylarginines, this enzyme also has several cardiovascular protective substrates, so the net effect of possible therapeutic targeting of AGXT2 is currently unclear. Recent studies on regulation and functions of the enzymes metabolizing methylarginines have given a second life to this research direction. Our review discusses the latest discoveries and controversies in the field and proposes novel directions for targeting methylarginines in clinical settings.
Purpose
Chronic β-alanine supplementation leads to increased levels of muscle histidine-containing dipeptides. However, the majority of ingested β-alanine is, most likely, degraded by two ...transaminases: GABA-T and AGXT2. In contrast to GABA-T, the in vivo role of AGXT2 with respect to β-alanine metabolism is unknown. The purpose of the present work is to investigate if AGXT2 is functionally involved in β-alanine homeostasis.
Methods
Muscle histidine-containing dipeptides levels were determined in AGXT2 overexpressing or knock-out mice and in human subjects with different rs37369 genotypes which is known to affect AGXT2 activity. Further, plasma β-alanine kinetic was measured and urine was obtained from subjects with different rs37369 genotypes following ingestion of 1400 mg β-alanine.
Result
Overexpression of AGXT2 decreased circulating and muscle histidine-containing dipeptides (> 70% decrease;
p
< 0.05), while AGXT2 KO did not result in altered histidine-containing dipeptides levels. In both models, β-alanine remained unaffected in the circulation and in muscle (
p
> 0.05). In humans, the results support the evidence that decreased AGXT2 activity is not associated with altered histidine-containing dipeptides levels (
p
> 0.05). Additionally, following an acute dose of β-alanine, no differences in pharmacokinetic response were measured between subjects with different rs37369 genotypes (
p
> 0.05). Interestingly, urinary β-alanine excretion was 103% higher in subjects associated with lower AGXT2 activity, compared to subjects associated with normal AGXT2 activity (
p
< 0.05).
Conclusion
The data suggest that in vivo, β-alanine is a substrate of AGXT2; however, its importance in the metabolism of β-alanine and histidine-containing dipeptides seems small.
Although intravenous thrombolysis (IVT) with recombinant tissue-plasminogen-activator represents a highly effective treatment in acute ischemic stroke patients, not every patient benefits. We ...hypothesized that pretreatment levels of mediators of hemostasis (VWF and ADAMTS13) and dimethylarginines (ADMA and SDMA) are associated with early neurological improvement and outcome after IVT in ischemic stroke. Moreover we aimed to investigate the link between ADAMTS13 and markers of inflammation (CRP, IL-6, MMP-9 and MCP-1). In 43 patients with acute ischemic stroke treated with IVT blood samples for determination of the different markers were strictly taken before treatment, as well as at 24 h, 3, 7 and 90 days after symptom onset. Early neurological improvement was assessed using the shift between National Institutes of Health Stroke Scale (NIHSS) at baseline and at 24 h. Outcome at 90 days was assessed using the modified Rankin Scale. The lowest quartile of ADAMTS13 activity was independently associated with less improvement in NIHSS (baseline-24 h) (OR 1.298, p = 0.050). No independent association of ADMA or SDMA levels at baseline with outcome could be shown. Furthermore, IL-6, MCP-1 and CRP levels at 90 days significantly differed between patients with low and high ADAMTS13 activity. Thus, ADAMTS13 might indicate or even influence efficacy of IVT.
Aim: Increased levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been observed in patients with cardiovascular risk factors and atherosclerosis and ...in patients with a history of stroke. The role of ADMA and its analogue symmetric dimethylarginine (SDMA) in acute ischemic stroke is yet unclear. We hypothesized that plasma dimethylarginine levels increase in the hyper-acute phase after ischemic stroke and that their time course is related to stroke outcome. Methods: Plasma dimethylarginines ADMA and SDMA and L-arginine levels were measured in 67 patients at 6, 12, 24 hours, as well as 3 and 7 days after stroke onset using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). Data were compared to control data from 32 age-adjusted healthy volunteers. Clinical outcome was assessed using the modified Rankin Scale (mRS) at 90 days after stroke. Results: At baseline, plasma ADMA levels were higher in stroke patients than in controls, whereas plasma SDMA and L-arginine levels did not differ from control subjects. The time courses of ADMA and SDMA were related to the clinical outcome. Binary logistic regression analysis showed that ADMA levels of ≥ 0.566 µmol/L at day 3, ≥ 0.530 µmol/L at day 7 and SDMA levels of ≥ 0.59 µmol/L at 24 hours predicted an unfavorable clinical outcome.Conclusions: An increase of both ADMA and SDMA plasma levels within the first 72 hours after the onset of ischemic stroke predicts a poor outcome.
For treatment of ventriculitis, vancomycin and meropenem are frequently used as empiric treatment but cerebrospinal fluid (CSF) penetration is highly variable and may result in subtherapeutic ...concentrations. Fosfomycin has been suggested for combination antibiotic therapy, but data are sparse, so far. Therefore, we studied CSF penetration of fosfomycin in ventriculitis.
Adult patients receiving a continuous infusion of fosfomycin (1 g/h) for the treatment of ventriculitis were included. Routine therapeutic drug monitoring (TDM) of fosfomycin in serum and CSF was performed with subsequent dose adaptions. Demographic and routine laboratory data including serum and CSF concentrations for fosfomycin were collected. Antibiotic CSF penetration ratio as well as basic pharmacokinetic parameters were investigated.
Seventeen patients with 43 CSF/serum pairs were included. Median fosfomycin serum concentration was 200 159-289 mg/L and the CSF concentration 99 66-144 mg/L. Considering only the first measurements in each patient before a possible dose adaption, serum and CSF concentrations were 209 163-438 mg/L and 104 65-269 mg/L. Median CSF penetration was 46 36-59% resulting in 98% of CSF levels above the susceptibility breakpoint of 32 mg/L.
Penetration of fosfomycin into the CSF is high, reliably leading to appropriate concentrations for the treatment of gram positive and negative bacteria. Moreover, continuous administration of fosfomycin appears to be a reasonable approach for antibiotic combination therapy in patients suffering from ventriculitis. Further studies are needed to evaluate the impact on outcome parameters.
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