High Blood Concentrations Research Articles

Detecting low blood concentrations in joints using T1 and T2 mapping at 1.5, 3, and 7 T: an in vitro study

BackgroundIntra-articular blood causes irreversible joint damage, whilst clinical differentiation between haemorrhagic joint effusion and other effusions can be challenging. An accurate non-invasive method for the detection of joint bleeds is lacking. The aims of this phantom study were to investigate whether magnetic resonance imaging (MRI) T1 and T2 mapping allows for differentiation between simple and haemorrhagic joint effusion and to determine the lowest blood concentration that can be detected.MethodsSolutions of synovial fluid with blood concentrations ranging from 0 to 100% were scanned at 1.5, 3, and 7 T. T1 maps were generated with an inversion recovery technique and T2 maps from multi spin-echo sequences. In both cases, the scan acquisition times were below 5 min. Regions of interest were manually drawn by two observers in the obtained T1 and T2 maps for each sample. The lowest detectable blood concentration was determined for all field strengths.ResultsAt all field strengths, T1 and T2 relaxation times decreased with higher blood concentrations. The lowest detectable blood concentrations using T1 mapping were 10% at 1.5 T, 25% at 3 T, and 50% at 7 T. For T2 mapping, the detection limits were 50%, 5%, and 25%, respectively.ConclusionsT1 and T2 mapping can detect different blood concentrations in synovial fluid in vitro at clinical field strengths. Especially, T2 measurements at 3 T showed to be highly sensitive. Short acquisition times would make these methods suitable for clinical use and therefore might be promising tools for accurate discrimination between simple and haemorrhagic joint effusion in vivo.

A case of complete atrioventricular block with extremely high blood concentration of azelnidipine

BackgroundAzelnidipine, a dihydropyridine calcium channel blocker (CCB), has less adverse effects (e.g. hot flushes and reflex tachycardia) compared to other dihydropyridine CCBs. Azelnidipine has been reported to reduce heart rate as opposed to inducing tachycardia. No evidence of bradycardia or complete atrioventricular block (CAVB) with azelnidipine treatment has been reported.Case presentationIn the present study, a 92-year-old woman was diagnosed with CAVB while taking azelnidipine and simvastatin for an extended period of time, and referred to our medical center. It was thought that the CAVB may have been an adverse effect of azelnidipine treatment. Specifically, it was considered that in this patient, one of the causes might be the concomitant use of simvastatin inhibiting the metabolism of azelnidipine by cytochrome P450 enzyme 3A4. Consequently, it was suggested to the patient’s physician that the patient’s serum azelnidipine levels be measured and treatment with azelnidipine and simvastatin be discontinued. The patient’s serum concentration of azelnidipine at the time of her visit to our center was 63.4 ng/mL, higher than the normal acceptable level. There was no occurrence of CAVB for 4 weeks, to present, following discontinuation of azelnidipine and simvastatin treatment.ConclusionsAzelnidipine has a different mechanism of action that other CCBs. In very rare cases, it may cause CAVB when combined with CYP3A4 inhibitors. If a patient taking azelnidipine is diagnosed with CAVB, physicians should suspect that the condition may be an adverse effect of azelnidipine and should consider discontinuing azelnidipine. And, in the elderly, it is necessary to avoid concomitant use of CYP3A4 inhibitors.

Clinical, laboratory and radiological associations with extending of the intensive phase of treatment in patients with first diagnosed infiltrative pulmonary tuberculosis

Despite the availability of medical services, timely detection of pulmonary tuberculosis, before the appearance of destructive changes, is often difficult. The management of patients with an infiltrative form in a hospital setting does not always guarantee the same positive effect and sometimes requires prolongation of therapy. The effectiveness of therapy can be associated with various factors and is of interest to study. The aim of this work was to study the effectiveness of standard therapy in patients with first diagnosed infiltrative pulmonary tuberculosis, clinical laboratory and radiological associations with prolongation of the intensive phase of treatment. Materials and methods. The study involved 109 men from 18 to 53 years old with first diagnosed infiltrative pulmonary tuberculosis with preserved MBT sensitivity to 1-st line anti-tuberculosis drugs. Patients were examined before and after 60 doses of the intensive phase of treatment, after which two groups were formed. Group 1 included patients with pronounced positive clinical and radiological dynamics, who entered the continuation phase of therapy. Group 2 included patients with insufficient clinical and radiological dynamics, for whom the intensive phase of treatment was extended to 90 doses. Results. Weak dynamics in patients who needed prolongation of treatment was associated with the characteristics of the initial data of patients in this group compared with similar indicators in Group 1. These were a reliably higher frequency of symptoms of intoxication and coughing, a reliably greater number of patients excreting mycobacterium tuberculosis in large quantities in sputum, with reliably high blood concentrations of haptoglobin and ceruloplasmin levels. Conclusions. Patients requiring prolongation of the intensive phase of treatment are characterized by an initially higher prevalence of infiltrative changes in the lungs, a small number of lung lesions limited to 2 segments, the presence of destructive changes in 100 % of cases, and a significant increase in the factors of the systemic inflammatory response

Therapeutic effects of an innovative BS-HH-002 drug on pancreatic cancer cells via induction of complete MCL-1 degradation

BS-HH-002 is a newly developed drug with excellent antitumor activity, which resulted from the modification and optimization of the side structure of the homoharringtonine (HHT). It is particularly efficient in treatment for acute myeloid leukemia and myelodysplastic syndromes. Here we tested whether BS-HH-002 also had anti-cancer effects on solid tumors, especially pancreatic cancer. The results showed that BS-HH-002 treatment resulted in the complete degradation of the anti-apoptosis protein MCL-1, thereby inhibiting proliferation and inducing apoptosis of pancreatic cancer cells. In contrast, BCL-2 and BCL-XL protein levels were still detected in apoptotic cells. Further, we compared HHT and BS-HH-002 in terms of PK and heart toxicity in animals. Compared to HHT, BS-HH-002 quickly reached high blood concentration after intravenous injection or oral administration, without causing obvious cardiac toxicity. These results indicate that BS-HH-002 is a promising new anti-cancer drug to treat pancreatic and other solid tumors.

In silico Analysis of a Novel Peptide Vaccine against Hepatitis B Virus (HBV)

Background : Hepatitis B is a potentially life-threatening liver infection caused by the Hepatitis B virus (HBV). It is a major global health problem and the most serious type of viral hepatitis. It can cause chronic liver disease and puts people at high risk of death from cirrhosis of the liver and liver cancer. HBV is found in highest concentrations in blood and in lower concentrations in other body fluids.
 Methods: Target protein was retrieved from the swissprot database. Epitopes were predicted using the BCEPRED server. After running the BLAST algorithm for the target protein, the template with the best identity was selected. After modeling, target protein is verified by using the swiss model workspace and after this process the obtained target protein is allowed to interact with the MHC which is studied by using patchdock, finally these results were viewed by using the deepview tool.
 Results: The target protein for vaccine development was downloaded from the SwissProt database. Its SwissProt ID was p29178. The protein was isolated from hepatitis B virus genotype G. The virus was isolated from the United States of America. The length of the target protein was found to be 195 amino acids. To confirm that the target protein could be used for vaccine development, the Presence of epitopes in the protein was confirmed using the BCEPRED tool. Results from the SAVS server showed 95.80 of the residues of the protein had an average 3D-1D score greater than 0.2. The protein attained a pass with an ERRAT value of 90.299.
 Conclusion: The present investigation recognized the promising complex formed between the HBV peptide and MHC molecules. All the downloaded MHC molecules were found to interact with the target protein through the formation of hydrogen bonds. Since these interactions are necessary during an immune response to invading pathogens, the target protein would ultimately trigger an immune response if it is administered as a vaccine for Hepatitis B virus genotype G.

A Successful Management of Hyperuricaemia Through Ayurveda Medications: A Case Series

Uric acid is a heterolytic compound of Carbon, Nitrogen, Oxygen and Hydrogen which is produced by the metabolism breakdown of purine nucleotides. Elevated level of uric acid in blood is called hyperuricemia. This condition arises due to over production or under secretion of uric acid. High blood concentration of uric acid can lead to Gout and are associated with other medical conditions. In Ayurveda science Vaatarkta disease is described which having similarities to the conditions of hyperuricemia, So hyperuricaemia can be corelated with Vaatarakta as Ayurveda perspective. In this case series, three cases of Hyperuricaemia were treated with Navakarshika ghana vati - 250 mg x2 TID after meal for one month with Kashyam and Amrutadi tailam-10ml OD with 100ml lukewarm water or milk on empty stomach for one month, gets very effective & quick response in hyperuricaemia. Both are pacified and normalised the level of uric acid. Also didn’t found any adverse drug reaction of both medicines.

68P High blood concentration of circulating cancer stem cell-derived extracellular vesicles is associated with poor survival in advanced colorectal cancer patients

Extracellular vesicles (EVs) are lipid membrane-enclosed, nanosized particles secreted by cells to regulate intercellular communication. EVs released by cancer cells are valuable carriers of tumor information and are considered as having promising potential as biomarkers in cancer diagnosis, prognostication, and surveillance. In our study, we investigated the diagnostic and prognostic value of blood circulating EV expressing cancer stem cell markers in a cohort of advanced cancer patients.

Pharmacokinetics, plasma protein binding, and metabolism of a potential natural chemosensitizer from Marsdenia tenacissima in rats

Ethnopharmacological relevanceMarsdenia tenacissima (Roxb.) Wight et Arn is a medicinal plant mainly distributed in southwest China. It is used in folk medicine for the treatment of tumors and is synergistic with chemotherapies. In our previous study, 11α-O-2-methybutyryl-12β-O-tigloyl-tenacigenin B (MT2), a main steroid aglycone isolated from the total aglycones of M. tenacissima, significantly enhanced the in vivo antitumor effect of paclitaxel in mice bearing human tumor xenografts, showing its potential as a chemosensitizer. However, the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 remain unclear. Aim of the studyTo elucidate the pharmacokinetic characteristics, plasma protein binding rate, and metabolic profile of MT2 in rats. Materials and methodsMT2 in rat plasma and phosphate-buffered saline was quantified using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method, while the MT2 metabolites in rat liver microsomes were analyzed using UPLC-triple time-of-flight MS/MS. ResultsFor intravenously administered MT2, the maximum plasma concentration and the area under the plasma concentration-time curve indicated dose dependency, while the elimination half-life time, the mean residence time, apparent volume of distribution and total apparent clearance values remained relatively unchanged in both the 5 mg/kg and 10 mg/kg groups. For orally administered MT2, the bioavailability was 1.08–1.11%. In rat plasma, MT2 exhibited a protein binding rate of 93.84–94.96%. In rat liver microsomes, MT2 was metabolized by oxidation alone or in combination with demethylation, and five MT2 metabolites were identified. ConclusionMT2 has low oral bioavailability and a high plasma protein binding rate in rats. After administration, MT2 is transformed into oxidative metabolites in the liver. To achieve a high blood concentration of MT2, it should be administered intravenously. These findings would serve as a reference for further MT2-based pharmacological study and drug development.

Expert consensus on the use of human serum albumin in critically ill patients.

Expert consensus on the use of human serum albumin in critically ill patients.

Bisphenol a Exposure and Kidney Diseases: Systematic Review, Meta-Analysis, and NHANES 03-16 Study.

Bisphenol A (BPA) is a compound that is especially widespread in most commonly used objects due to its multiple uses in the plastic industry. However, several data support the need to restrict its use. In recent years, new implications of BPA on the renal system have been discovered, which denotes the need to expand studies in patients. To this end, a systematic review and a meta-analysis was performed to explore existing literature that examines the BPA-kidney disease paradigm and to determine what and how future studies will need to be carried out. Our systematic review revealed that only few relevant publications have focused on the problem. However, the subsequent meta-analysis revealed that high blood concentrations of BPA could be a factor in developing kidney disease, at least in people with previous pathologies such as diabetes or hypertension. Furthermore, BPA could also represent a risk factor in healthy people whose urinary excretion is higher. Finally, the data analyzed from the NHANES 03-16 cohort provided new evidence on the possible involvement of BPA in kidney disease. Therefore, our results underline the need to carry out a thorough and methodologically homogeneous study, delving into the relationship between urinary and blood BPA, glomerular filtration rate, and urine albumin-to-creatinine ratio, preferably in population groups at risk, and subsequently in the general population, to solve this relevant conundrum with critical potential implications in Public Health.

Comparison of Blood Lead Concentrations in Mothers of Children with Congenital Heart Disease and Mothers of Healthy Children.

Congenital heart disease (CHD) is the most prevalent congenital defect that causes several problems for patients and their families and medical specialists. It is important to investigate CHD risk factors due to their significantly destructive load on society. This study aims to determine the association between maternal lead exposure and conceiving a child with CHD. This case-control study was performed on a total of 246 mothers in the pediatric clinic of Vali-e-Asr Hospital in Birjand, Iran. One hundred forty-six mothers with CHD children were defined as the case group, and 100 age-matched mothers with healthy children were considered the control group. All the mothers were between 20 and 40years old, and their children were under the age of 6months. Demographic data was collected from mothers using a well-designed questionnaire. In addition, all mothers were referred to the laboratory for measuring blood lead concentrations. The mean blood lead concentration (BLC) of mothers in the group of children with heart problems was 4.11 ± 10.02 with a median of 2.50μg/dL and in the control group was 2.66 ± 2.06 with a median of 2.30μg/dL. The Mann-Whitney test results showed that mothers' lead concentration in the group of children with heart problems was significantly higher than the control group (z = 2.13, p = 0.03). The chi-square test results showed that lead concentrations in the two groups were significantly different from each other (χ2 = 9.11, p = 0.01). The results of our study showed that mothers of children with CHD had higher blood concentrations than mothers of healthy children.

Unexpected overdose of oral cyclosporine in a kidney transplant patient: a case report

Cyclosporine is a widely used immunosuppressive agent to prevent rejection of solid organ transplant. Here, we describe the case of a 71-year-old man who received the prescribed dose of cyclosporine...

Predictive potential of cardiovascular risk factors and their associations with arterial stiffness in people of European and Korean ethnic groups

Aim. To compare the effect of cardiovascular risk factors on aortic stiffness in people of European and East Asian ethnic groups.Material and methods. A total of 266 patients aged 18-60 years of European (n=133) and Korean (n=133) ethnic groups were examined. Clinical assessment was carried, Also, following blood parameters was evaluated: total cholesterol (TC), low- (LDL-C) and high- (HDL-C) density lipoprotein cholesterol, apolipoproteins A (apo-A) and B (apo-B), triglycerides (TG), uric acid, creatinine, glucose, adiponectin, resistin. The aortic pulse wave velocity (PWV) and central blood pressure (CBP) were determined using a Tensiomed arteriograph (Hungary). The study design included 3 stages. The first stage included statistical analysis using Mann-Whitney, χ2, Fisher tests, while the second one — determination of weighing coefficients of individual risk factors on aortic PWV. The third stage consists of verification of the relationship between ethnicity and aortic PWV using multivariate logistic regression and stochastic gradient boosting (SGB).Results. In Europeans, the median values of growth, body mass index (BMI), waist circumference (WC) and waist-to-height ratio were significantly higher, while the levels of apo-B, TC, HDL-C, LDL-C, TG was significantly lower than in Asians. Koreans had higher blood concentrations of UA, creatinine, glucose, while the resistin concentration was 1,8 times lower. Among Europeans, the odds ratio of developing hypertension (HTN) was significantly higher. The level of aortic PWV in people of different ethnic groups did not differ significantly. Univariate logistic regression showed a dominant influence of age, CPP and waist-to-height ratio on aortic PWV. A less noticeable significant relationship with aortic PWV had HTN, female sex, BMI, levels of systolic, diastolic and pulse BP. Multivariate logistic regression and SGB showed the maximum prediction accuracy when 5 predictors were combined in one model: age, height, HTN, LDL-C, and ethnicity. Comparable accuracy was demonstrated by a model where glucose level was used instead of LDL-C. The results indicate a nonlinear relationship between the ethnic factor and aortic PWV. Its predictive potential was realized only in combination with functional and metabolic status parameters of patients. In Koreans, the threshold values of these factors can be significantly higher than in Europeans.Conclusion. Developed using modern machine learning technologies, the assessment aortic PWV models taking into account the ethnic factor can be a useful tool for processing and analyzing data in predictive studies.

Hyaluronic Acid-Based Nanocapsules as Efficient Delivery Systems of Garlic Oil Active Components with Anticancer Activity.

Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are garlic oil compounds exhibiting beneficial healthy properties including anticancer action. However, these compounds are sparingly water-soluble with a limited stability that may imply damage to blood vessels or cells after administration. Thus, their encapsulation in the oil-core nanocapsules based on a derivative of hyaluronic acid was investigated here as a way of protecting against oxidation and undesired interactions with blood and digestive track components. The nuclear magnetic resonance (1H NMR) technique was used to follow the oxidation processes. It was proved that the shell of the capsule acts as a barrier limiting the sulfur oxidation, enhancing the stability of C=C bonds in DADS and DATS. Moreover, it was shown that the encapsulation inhibited the lysis of the red blood cell membrane (mainly for DADS) and interactions with serum or digestive track components. Importantly, the biological functions and anticancer activity of DADS and DATS were preserved after encapsulation. Additionally, the nanocapsule formulations affected the migration of neoplastic cells—a desirable preliminary observation concerning the inhibition of migration. The proposed route of administration of these garlic extract components would enable reaching their higher concentrations in blood, longer circulation in a bloodstream, and thus, imply a better therapeutic effect.

Propionate alleviates palmitic acid–induced endoplasmic reticulum stress by enhancing autophagy in calf hepatic cells

Negative energy balance-induced high blood concentrations of free fatty acids during the early postpartum period in dairy cows is a major cause of liver injury. Cows in severe negative energy balance often have suboptimal intakes of feed, which contributes to shortfalls in production of ruminal propionate and circulating glucose. Although increasing propionate production by the rumen through feed additives such as propylene glycol is effective in helping cows alleviate the shortfall in dietary energy supply, mechanisms whereby propionate affects liver function beyond gluconeogenesis are unknown. Therefore, the objective of this study was to investigate whether propionate could protect calf hepatic cells from palmitic acid (PA)-induced lipotoxicity and the underlying mechanisms. Calf hepatic cells were isolated from 5 healthy calves (1 d old, female, 30-40 kg, fasting) and treated with various concentrations of PA (0, 100, 200, or 400 μM) and propionate (0, 1, 2, or 4 mM) after being administered with or without autophagic inhibitor. Propionate enhanced autophagic activity in calf hepatic cells, as indicated by elevated expression of autophagy markers LC3-II (microtubule-associated protein 1 light chain 3-II, encoded by MAP1LC3) and decreased expression of SQSTM1 (sequestosome-1, also called p62). Conversely, PA suppressed autophagic activity and decreased cell viability, which was improved by propionate in calf hepatic cells. In addition, propionate decreased the phosphorylation of proteins EIF2AK3 (kinase R/PKR like ER kinase) and ERN1 (inositol-requiring enzyme 1α) and cleaved ATF6 (activating transcription factor 6) in PA-treated calf hepatic cells, indicating the suppression effect of propionate on endoplasmic reticulum (ER) stress. However, inhibition of autophagic activity by chloroquine or bafilomycin A1 impede the beneficial effects of propionate on ER stress and cell viability. These results demonstrated that propionate alleviates ER stress and elevates cell viability in PA-treated calf hepatic cells by enhancing autophagy, which implies that autophagy may be a promising target in improving liver injury of dairy cows during transition period.

Comparative Study of the Biochemical Response Behavior of Some Highly Toxic Minerals on Selenosis in Rats

Many researchers have studied the metabolism of toxics including selenium (Se) in biological medium in rats and defined some correlations between selenium and other minerals as arsenic (As), cadmium (Cd), mercury (Hg), and thallium (Tl). An investigation of the potential influences of As, Hg, Tl and Pb on Se metabolism, which can suggest new drugs to cope the poisonousness of Se. The current study also has looked into the potential use of As(III)/As(V) toxic in the treatment of essential mineral Se in the animals (as rats) based on sequestration of these toxic elements into biologically inert complexes, reflecting the enormous interest in this subject. The acute studies have been initially achieved by shaping the pulmonary and biliary excretions of the volatile Se in neonatal masculine Holtzman rats which were injected with selenite subcutaneously in the hind flank, then the volatile Se was trapped in 8N HNO3 and the radioselenate detected in a scintillation counter. The chronic cases were carried out with the nursing of rats with a purified diet of water-soluble vitamin mix, fat-soluble vitamin mix, saccharides, oil, and salts. One week after the basic diet, the rats taken Se have received diets containing 10 ppm of the element as sodium selenite (Na2SeO3) or selenate (Na2SeO4) added in the salts. The calorimeter was used to analyze Se in the frozen tissue specimens. As, Hg, and Tl were repressed the volatized Se excreted from the lungs. As has assisted the biliary excretion of Se and inhibited the chronic selenosis. Tl has increased the retention of Se in the liver and kidney, but, had no chronic effect on the amount of Se deposited in all the studied tissues. Similarly, Hg has increased the retention of Se but in the spleen and carcass of rats indicating to the high Se concentration in blood. Hg and Tl have inhibited the Se in urine. No effects of the doses rich in As, Hg, and Tl on the Se excretion in fecal. Even though, we suggest As as a possible medication to chronic selenosis.

Diuretic therapy as prognostic enrichment factor for clinical trials in patients with heart failure with reduced ejection fraction.

Loop diuretics are the mainstay of congestion treatment in patients with heart failure (HF). We assessed the association between baseline loop diuretic use and outcome. We also compared the increment in risk related to diuretic dose with conventional prognostic enrichment criteria used in the EMPHASIS-HF trial, which included patients with systolic HF and mild symptoms, such as prior hospitalization and elevated natriuretic peptides. Individual analyses were performed according to baseline loop diuretic usage (furosemide-equivalent dose > 40mg, 1-40mg, and no furosemide), and according to enrichment criteria adopted in the trial [i.e. recent hospitalization (< 30days or 30 to 180days prior to randomization) due to HF or other cardiovascular cause, or elevated natriuretic peptides]. The primary endpoint was a composite of cardiovascular death or HF hospitalization. Loop diuretic usage at baseline (HR for > 40mg furosemide-equivalent dose = 3.16, 95% CI 2.43-4.11; HR for 1-40mg = 2.06, 95% CI 1.60-2.65) was significantly associated with a higher risk for the primary endpoint in a stepwise manner when compared to no baseline loop diuretic usage. In contrast, the differences in outcome rates were more modest when using history of hospitalization and/or BNP: all HR ranged from 1 (reference, non-HF related CV hospitalization > 30days) to 2.04 (HF hospitalization < 30days). The effect of eplerenone on the primary endpoint was consistent across subgroups in both analyses (P for interaction ≥ 0.2 for all). Loop diuretic usage (especially at doses > 40mg) identified patients at higher risk than history of HF hospitalization and/or high BNP blood concentrations.

Methadone overdose in patients following methadone mainte- nance treatment:A three years overview in the district of Bari (South-Italy).

Methadone maintenance treatment (MMT) is reco-gnized as a reference treatment for opioid dependence. According to Italian Law, at the beginning of the treatment patients must receive medication under the supervision of a physician, to avoid overdose. After a period of stability, patients could be allowed to take methadone at home in pre-arranged and personalized concentrations, in order to empower their self-responsibility. The aim of the present investigation is to underline the presence of a "glitch in the system" of the MMT. In the last three years, 7 forensic autopsies and toxi-cological analysis on corpses of regular opioid users were performed into the Institute of Legal Medicine of Bari. Therefor an improvement of the MMT's guideline is needed to reduce methadone overdose deaths in future. In all these cases very high methadone concentration in blood were found. All the 7 subjects were following a MMT in a Public Health Institute and the cause of death was respiratory depression by overdose of methadone in 6 cases.

A Uremic Goat Model Created by Subtotal Renal Artery Embolization and Gentamicin.

Simple SummaryTo improve the treatment of patients with kidney disease, new renal replacement therapies are being developed. Prior to their use in humans with end-stage kidney disease (ESKD), these therapies need to be tested in animals with kidney disease. Goats seem particularly suitable because they are docile, have bodyweights comparable to humans and easily accessible neck veins to obtain blood access and tolerate frequent blood sampling, allowing for repeated monitoring. To obtain high blood concentrations of waste solutes that accumulate in patients with kidney disease and allow for the evaluation of solute removal by the new renal replacement therapies, we established kidney failure in five goats by partially blocking the blood supply of the kidneys via radiographic embolization. This resulted in stable moderate kidney disease. The administration of high-dose gentamicin caused a temporary further decline in kidney function. Although the response varied with animal, blood concentrations of waste solutes were representative of those found in ESKD patients. These animals can survive for more than ten months in good condition, allowing for the repetitive testing of new therapies in one animal, and therefore limiting the use of laboratory animals.A large animal model of (end-stage) kidney disease (ESKD) is needed for the preclinical testing of novel renal replacement therapies. This study aimed to create stable uremia via subtotal renal artery embolization in goats and induce a temporary further decline in kidney function by administration of gentamicin. Renal artery embolization was performed in five Dutch white goats by infusing polyvinyl alcohol particles in branches of the renal artery, aiming for the embolization of ~80% of one kidney and complete embolization of the contralateral kidney. Gentamicin was administered to temporarily further increase the plasma concentrations of uremic toxins. After initial acute kidney injury, urea and creatinine plasma concentrations stabilized 1.5 ± 0.7 months post-embolization and remained elevated (12 ± 1.4 vs. 5.6 ± 0.8 mmol/L and 174 ± 45 vs. 65 ± 5.6 µmol/L, resp.) during follow-up (16 ± 6 months). Gentamicin induced temporary acute-on-chronic kidney injury with a variable increase in plasma concentrations of small solutes (urea 29 ± 15 mmol/L, creatinine 841 ± 584 µmol/L, phosphate 2.2 ± 0.3 mmol/L and potassium 5.0 ± 0.6 mmol/L) and protein-bound uremic toxins representative of patients with ESKD. A uremic goat model characterized by stable moderate uremia was established via subtotal renal artery embolization with the induction of temporary severe acute-on-chronic kidney injury by the administration of gentamicin, allowing preclinical in vivo validation of novel renal replacement technologies.

Edoxaban Dosing Time Affects Blood Coagulation Inhibition in Rats.

Coagulation–fibrinolytic system activity shows daily rhythmicity, with hypercoagulability in the morning and hypocoagulability in the evening. Consequently, the efficacy of anticoagulants may be influenced by their dosing time. Edoxaban, a selective inhibitor of the active form of coagulation factor X (FXa), is taken orally once daily, but the optimal dosing time is unknown. This study evaluated the dosing time-dependent effects of edoxaban on coagulation activity and thrombus formation in rats. Edoxaban (10 mg/kg) or vehicle was administered to Wistar rats at zeitgeber time (ZT)-2 (beginning of the light phase) or ZT14 (beginning of the dark phase), followed by blood collection at ZT4, ZT10, ZT16, or ZT22, to measure the activity of coagulation factors and edoxaban concentrations, or followed by inferior vena cava ligations at ZT4 or ZT16, to assess the efficacy of edoxaban against thrombus formation. Coagulation FX activity was high during the light phase, and a single dose of edoxaban administered at ZT2 inhibited FX activity and thrombus formation more potently compared with the same dose administered at ZT14. The inhibitory effects during the light phase could be attributed, at least in part, to the high blood concentration of edoxaban achieved by dosing at ZT2. Morning dosing of edoxaban leads to a high blood concentration of the drug during the morning hours and thus may better counteract the hypercoagulability and hypofibrinolytic activity characteristic of the morning hours. Optimizing the dosing time may contribute to improving the efficacy of edoxaban.