Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects.

BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 inhibitors can modulate inflammation. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level >70 mg/dL on maximum tolerated statin therapy received subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were change in circulating immune cell transcriptional response, lipoproteins and blood viscosity at 2 weeks and 12 weeks. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects did not receive study medication consistently after the 2-week visit due to COVID-19 pandemic suspension of research activities. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p < 0.0001) and -52.8% (p < 0.0001) at 2 and 12 weeks, respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells with and without TLR4 stimulation ("Stress" transcriptomics). "Stress" transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of "stress" profiling of circulating immune cells that more clearly define immune contributions to ASCVD.

Investigation of Zinc on hemorheological parameters in a rat model of diabetes.

Diabetes mellitus (DM) is a complex, chronic metabolic disorder characterized by impaired regulation of blood glucose levels. Zinc (Zn) is an essential trace elements that plays a role in various physiological processes within the body, including those related to diabetes. The current study was investigated the effect of Zn supplementation on hemorheological parameters in a rat model of DM. After induction of DM, 32 male Wistar albino rats were divided into four groups: control, Zn, DM, and Zn+DM. Whole blood viscosity (WBV) was determined by using digital cone and plate viscometer and plasma viscosity (PV) was determined by a Coulter Harkness capillary viscometer. The rats in the DM Group showed a decrease in both Zn levels and body weight, as well as an increase in glucose levels when compared to the control group. Diabetic rats supplemented with Zn displayed lower blood glucose levels and higher concentrations of Zn compared to the DM Group. The higher PV and lower hematocrit level were measured in DM Group than control group and lower PV, higher hematocrit level were measured in Zn+DM group than DM Group. The WBV was measured at four different shear rates (57.6-115.2 - 172.8-230.4 s -1). A statistically significant increase was observed in the DM group compared to the control group. Additionally, a statistically significant decrease was observed in the Zn+DM Group compared to the DM Group at a shear rate of 230.4 s-1. Erythrocyte rigidity index (Tk) and oxygen delivery index (ODI) were computed under conditions of high shear rate. The rats in the DM group exhibited a reduction in ODI and an elevation in Tk in comparison to the control group. Conversely, the diabetic rats supplemented with Zn exhibited decreased Tk and increased ODI compared to the DM Group. Zn supplementation seems to have a potential beneficial effect for protecting adverse affect of diabetes on hemorheogical parameters and for maintaining vascular health.

Effects of Low-Dose Aspirin Combined with Vitamin E on the Incidence of Intrauterine Growth Restriction and Hemorheological Indexes of Pregnant Women in Patients with Gestational Hypertension.

OBJECTIVE: To investigate the effect of low-dose aspirin combined with vitamin E on the incidence of intrauterine growth restriction and hemorheological indexes of pregnant women in patients with gestational hypertension. METHOD: 134 elderly patients with chronic urticaria treated in our hospital from November 2017 to November 2020 were studied. According to the treatment methods, they were randomly divided into observation and control groups. There were 67 patients in the observation group, aged 20-37 years, with an average of (25.7 ± 2.75) years. There were 67 patients in the control group, aged 21-35 years, with an average of (26.3 ± 3.17) years. No significant difference was observed between the two groups (P > 0.05). RESULTS: The number of cases with postpartum hemorrhage and intrauterine growth restriction in the observation group was less than that in the control group. The total incidence rate was lower than that in the control group. There were significant differences in the above results (P < 0.05). The number of patients with preterm birth in the observation group was less than that in the control group, but there was no significant difference in the results (P > 0.05). The head circumference, abdominal circumference, biparietal diameter, and femoral length diameter in the control and observation groups increased significantly after treatment (P < 0.05). Compared with the control group, the head circumference, abdominal circumference, biparietal diameter, and femoral diameter in the observation group increased more after treatment, and the results were statistically poor (P < 0.05). The systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the control and observation groups decreased significantly after treatment, and the results were statistically different (P < 0.05). Compared with the control group, the systolic blood pressure, diastolic blood pressure, and mean arterial pressure in the observation group decreased more after treatment. The results were statistically different (P < 0.05). The plasma viscosity levels, whole blood high shear viscosity, and whole blood low shear viscosity in the control and observation groups decreased significantly after treatment, and the results were statistically different (P < 0.05). Compared with the control group, plasma viscosity levels, whole blood high shear viscosity, and whole blood low shear viscosity in the observation group decreased more after treatment, and the results were statistically different (P < 0.05). The control and observation groups' fetal systolic/diastolic pressure and pulsatile index decreased significantly after treatment, and the results were statistically different (P < 0.05). Compared with the control group, the fetal systolic/diastolic blood pressure and pulsatile index in the observation group decreased more after treatment, and the results were statistically poor (P < 0.05). CONCLUSION: Low-dose aspirin combined with vitamin E is effective in treating intrauterine growth restriction in patients with gestational hypertension. It can effectively control the blood pressure and blood flow of patients and newborns and improve pregnancy outcomes without increasing the incidence of adverse reactions. It is worthy of clinical promotion.

Improved Erythrocyte Deformability Induced by Sodium-Glucose Cotransporter 2 Inhibitors in Type 2 Diabetic Patients.

PURPOSE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors are antidiabetic drugs that improve cardiovascular outcomes. Hemoglobin and hematocrit values increase after SGLT-2 inhibitor administration. Although these factors increase blood viscosity and the risk of cardiovascular disease, SGLT-2 inhibitors have protective effects on the cardiovascular system. The mechanisms for this paradoxical phenomenon remain unclear, and the effect of SGLT-2 inhibitors on hemorheology has not been studied. METHODS: We evaluated the hemorheological parameters of 63 patients of whom 38 received metformin with a dipeptidyl peptidase 4 (DPP-4) inhibitor, while 25 received metformin with SGLT-2 inhibitor. Blood viscosity was measured using a cone-and-plate viscometer, erythrocyte aggregation was measured using a modified erythrocyte sedimentation rate method, and erythrocyte membrane fluctuation was measured as deformability, using a diffraction optical tomography. RESULTS: Both blood viscosity and erythrocyte aggregation increased in the SGLT-2 inhibitor group, although erythrocyte deformability was significantly improved compared with that of the DPP-4 inhibitor group (DPP-4 inhibitor 43.71 ± 5.13 nm; SGLT-2 inhibitor 53.88 ± 4.88 nm; p < 0.001). When the two groups were compared after propensity score matching, no differences in blood viscosity at high shear rates and erythrocyte aggregation were observed, although erythrocyte deformability was significantly improved in the SGLT-2 inhibitor group (DPP-4 inhibitor 45.01 ± 5.28 nm; SGLT-2 inhibitor 53.14 ± 4.72 nm; p = 0.001). CONCLUSION: This study demonstrates that erythrocyte deformability was improved in the SGLT-2 inhibitor group compared with that in the DPP-4 inhibitor group. This improvement in erythrocyte deformability is expected to have a protective effect on the cardiovascular system.

Oxidative stress, inflammation, blood rheology, and microcirculation in adults with sickle cell disease: Effects of hydroxyurea treatment and impact of sickle cell syndrome.

Inflammation and oxidative stress play a key role in the pathophysiology of sickle cell disease (SCD). However, the potential influence of different sickle genotypes, or hydroxyurea (HU) treatment, on these factors remains poorly documented. The present study compared several plasma markers of inflammation and oxidative stress, as well as microvascular function, between patients with sickle SC disease (HbSC, n = 19) and patients with sickle cell anemia (HbSS) under hydroxyurea (HU) treatment (n = 16), or not (n = 13). Hemorheological parameters and levels of inflammatory (IL-6, IL-8, IFN-γ, MCP-1, MIP-1ß, TNF-α) and oxidative stress (AOPP, MDA, MPO) markers were determined. Peripheral microcirculatory cutaneous blood flow and immediate microvascular response to local heat were evaluated using laser Doppler flowmetry. Oxidative stress and inflammation were lower in HbSC patients and HbSS patients under HU therapy compared to HbSS patients not treated with HU. Blood viscosity was higher in HbSC than in HbSS patients treated with or not with HU. Vasodilation response of the cutaneous microcirculation to heat stress was higher in HbSS patients receiving HU treatment. Our results clearly established that both sickle cell genotype and HU treatment modulate inflammation and oxidative stress.

Relationship of Edoxaban Plasma Concentration and Blood Coagulation in Healthy Volunteers Using Standard Laboratory Tests and Viscoelastic Analysis.

The capability of viscoelastic measurement parameters to screen anticoagulation activity of edoxaban in relation to its plasma concentrations was evaluated in 15 healthy male volunteers. Blood samples were drawn before the oral administration of edoxaban 60 mg and 2, 4, 6, 8, and 24 hours after administration. At each time, standard coagulation tests were performed, blood viscoelastic properties were measured with a thromboelastometry device ROTEM delta analyzer (Instrumentation Laboratory, Werfen, Barcelona, Spain), and edoxaban plasma concentrations were measured. Our primary interest was the possible correlation between edoxaban plasma concentrations and values for ROTEM ExTEM, and FibTEM. We also studied the correlation of edoxaban plasma concentrations with the results of standard coagulation tests. We saw the effect of a single dose of edoxaban most clearly in clotting time (CT) of ROTEM ExTEM and FibTEM. Changes in these parameters correlated significantly with edoxaban plasma concentrations up to 6 hours from the ingestion of the drug. Activated partial thromboplastin time, prothrombin time, and anti-factor Xa were also affected. Peak changes were observed 2 and 4 hours after administration of edoxaban. The changes were mostly reversed after 8 hours. In conclusion, ROTEM CT correlates significantly with edoxaban plasma concentrations and can be used to estimate the effect of edoxaban. ROTEM should be considered as part of the assessment of coagulation, with the big advantage of being readily available on site.

Effects of total saponins from Panacis majoris Rhizoma and its degradation products on myocardial ischemia-reperfusion injury in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Panacis majoris Rhizoma, which is a member of herbal medicine, is known for many years to remove blood stasis, promote blood circulation, and enrich the blood. The active ingredients of this plant are mainly attributed to saponins. AIM OF THE STUDY: The total saponins from Panacis majoris Rhizoma (TSPJ), and the degradation products of TSPJ (DTSPJ), were designed in this study to compare the protective effects on myocardial ischemia-reperfusion injury, and the aim of this approach is to discover more effective agents for the treatment of ischemic heart diseases. We analyzed the main constituents of TSPJ and DTSPJ, aiming to make clear which saponins played important roles in this protective effect, and also investigated the possible mechanisms. MATERIALS AND METHODS: DTSPJ was prepared by the method of alkaline hydrolysis. High performance liquid chromatography (HPLC) were used to analyze the main chemical constituents of TSPJ and DTSPJ, which were isolated by chromatographic techniques and identified by comparison with the Nuclear Magnetic Resonance (NMR) data in reported literature. Male Wistar rats were randomized to sham-operated group, ischemia-reperfusion group, three TSPJ (50, 100 and 200 mg/kg) groups, three DTSPJ (50, 100 and 200 mg/kg) groups, and isosorbide dinitrate tablet (5.0 mg/kg) group. The rats in all groups were intragastrically administrated once per day for three successive days. The establishment of the model of myocardial ischemia-reperfusion injury was used the following method: firstly, the left coronary artery of experimental rat was ligated for 30 min and then reperfused for 120 min. Then the myocardial infarct size, hemorheological and biochemical parameters, whole blood viscosity, plasma viscosity, platelet adhesion rate, platelet aggregation and histopathology changes were assessed. RESULTS: Five C3,C28-bidesmosidic oleanane-type saponins and ginsenoside Rd were the main constituents of TSPJ, and their total content in TSPJ was 79.2 %. The main constituents of DTSPJ were five C3-monodesmosidic oleanane-type saponins and ginsenoside Rd, and their total content in DTSPJ was 72.6 %. The HPLC analysis revealed that the five C3,C28-bidesmosidic oleanane-type saponins in TSPJ were completely turned into five C3-monodesmosidic oleanane-type saponins in DTSPJ through the method of alkaline hydrolysis, but ginsenoside Rd remained unchanged. Both TSPJ and DTSPJ could significantly reduced myocardial infarct size, and improved heart function, and lowered the activities of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase isoenzymes (CK-MB), and malonyldialdehyde (MDA) content, as well as the levels of whole blood viscosity, plasma viscosity, platelet adhesion rate, and platelet aggregation; on the contrary, both the level of glutathione peroxidase (GSH-Px) and the activity of superoxide dismutase (SOD) were notablely increased. The results of histopathological examination further supported the cardioprotective effects of TSPJ and DTSPJ. CONCLUSION: Both TSPJ and DTSPJ can guard cardiomyocytes against myocardial ischemia-reperfusion injury. The underlying mechanisms may be closely related to its enhancing anti-oxidative properties, modifying blood viscosity, and inhibiting platelet aggregation and platelet adhesion. As a whole, the protection of DTSPJ against myocardial ischemia-reperfusion injury was a little stronger than those of TSPJ. The results display the prospect of DTSPJ as a drug candidate for treating ischemic heart disease.

Exploration in the mechanism of rhubarb for the treatment of hyperviscosity syndrome based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperviscosity syndrome (HVS) is a major risk factor for thrombotic diseases. Rhubarb, well-known as a traditional Chinese medicine, exhibits multiple pharmacological activities, especially for promoting blood circulation to remove blood stasis (PBRB), which has been become a functional health food for decreasing the risk of cardiovascular diseases. However, due to the complexity of rhubarb components, it is still difficult to clarify the specific targets of effective substances in PBRB, and the pharmacodynamic mechanism needs to be further probed. MATERIALS AND METHODS: The "compound-target-cell-disease" network analysis was initially used to predict potential targets and bioactive compounds. The effect of rhubarb for the treatment of HVS was examined by histopathology and biochemical assays based on the HVS rat model. RESULTS: Through the "compound-target-cell-disease" network analysis, eight potential therapeutic targets were eventually screened out, and platelets were predicted as the main effector cells of rhubarb in PBRB. Among targets coagulation factor II (prothrombin, F2) and fibrinogen gamma chain (FGG) were closely related to platelets, and five compounds associated with F2 and FGG were predicted including emodin-8-O-beta-D-glucopyranoside (Emo), physcion-8-O-beta-D-glucopyranoside (Phy), procyanidin B-5,3'-O-gallate, torachrysone-8-O-beta-D-(6'-oxayl)-glucoside and epicatechin. Furthermore, thoracic aorta histopathology and biochemical examinations showed middle dose of rhubarb (0.42 g/kg/day) significantly ameliorated pathological changes, hemorheology parameters, as well as levels of representative biomarkers such as plasma P-selectin (P-sel) and thromboxane (TXB2) in platelet activation compared to HVS rat model, whose effects were comparable to the positive drug aspirin or even better. Finally, it was further validated F2 and FGG as the major effective targets of rhubarb as well as its two active ingredients Emo and Phy in PBRB. CONCLUSIONS: This study may provide an innovative way and scientific information to further understand the main effective components of rhubarb and its mechanisms about targets of F2 and FGG in PBRB, especially the new therapeutic target FGG, which also provide a basis for establishing a quality control for rhubarb by bioassays that could correlate the clinical efficacy and its mechanism.

Antihypertensive activity of a new c-Jun N-terminal kinase inhibitor in spontaneously hypertensive rats.

c-Jun N-terminal kinases (JNKs) are involved in the myocardial and aortic remodeling, increased arterial tone, and arterial blood pressure elevation associated with hypertension. The aim of the present study was to investigate the antihypertensive effect of a new JNK inhibitor, 1H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), on spontaneously hypertensive rats (SHRs). Experiments were performed using normotensive Wistar-Kyoto (WKY) rats and SHRs. Experimental groups of SHRs received IQ-1S intragastrically for 6 weeks in daily doses of 5 and 50 mg/kg; experimental groups of WKY rats received 50 mg/kg IQ-1S according to the same regimen. The IQ-1S administration regimen induced decreases in systolic blood pressure, mean arterial blood pressure, total peripheral resistance, blood viscosity, hematocrit, myocardial cell cross-sectional area, and aortic wall thickness in SHRs vs untreated SHRs. There were no significant differences in systolic blood pressure values between the control and experimental groups of WKY rats during the treatment period. A concentration-dependent decrease in the tone of carotid arterial rings isolated from SHRs was observed after JNK inhibitor application in vitro. Application of the JNK inhibitor diminished endothelin-1 secretion by human umbilical vein endothelial cells in vitro. The main mechanisms of the antihypertensive effect of IQ-1S included the attenuation of blood viscosity due to decreased hematocrit, a vasodilatory effect on arterial smooth muscle cells, and a decrease in endothelin-1 production by endothelial cells.

Embolization using warmed glue via the triaxial microballoon occlusion system for various vascular disorders.

PURPOSE: We aimed to illustrate the benefits of using warmed glue for viscosity reduction via the triaxial microballoon system for the treatment of various vascular disorders. METHODS: Seven patients who underwent 10 treatment sessions for hemoptysis, type II endoleak, post-pancreatic surgical bleeding, spontaneous retroperitoneal bleeding, or ovarian tumor bleeding were evaluated based on technical and clinical outcomes. In the procedure, the triaxial system, consisting of a 4.5-Fr guiding catheter, a 2.8-Fr microballoon catheter, and a 1.9-Fr no-taper microcatheter, was advanced into the target lesion. Glue (33% n-butyl cyanoacrylate mixed with Lipiodol) warmed to 40°C was injected under balloon occlusion. RESULTS: The common hepatic, right bronchial, intercostals, internal mammary, costocervical, lateral thoracic, superior thoracic, thoracoacromial, inferior thyroid, iliolumbar, lumbar, internal pudendal arteries, and branch of the inferior mesenteric artery were successfully embolized; 100% technical success and 100% clinical success were obtained after each session. CONCLUSION: Our modified balloon-occluded glue embolization may lead to better handling with more distal glue penetration capability.

Evaluation Procoagulant Activity and Mechanism of Astragalin.

Astragalin, isolated from flowers of Rosa chinensis Jacq., is a kind of flavonoid, with anti-inflammatory, antioxidant, antiviral, analgesic, antibacterial, antiallergic, and antihepatotoxic effects. However, no studieson the procoagulant effect of astragalin have been reported. This study aimed to investigate the procoagulant activity of astragalin and its mechanism. Its procoagulant effect was investigated by activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT), and fibrinogen (FIB) in vitro, and a rat model established by heparin sodium was used to evaluate the mechanism for the procoagulant effect in vivo. The results showed that astragalin had good procoagulant effects compared with the control group in vitro. Compared with the model group in vivo, astragalin could shorten the coagulation time and significantly increase the number of platelets. Meanwhile, astragalin could significantly reduce the effectual time of PT and APTT and increase the content of FIB. The contents of 6-keto-PGF1α and eNOS significantly decreased. Astragalin could increase whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte sedimentation rate (ESR) and packedcell volume (PCV). All of the above revealed that astragalin had good procoagulant effects by promoting the intrinsic and extrinsic coagulation system.

Erythrocytes morphology and hemorheology in severe bacterial infection.

BACKGROUND: Severe bacterial infections initiate inadequate inflammation that leads to disseminated intravascular coagulation and death. OBJECTIVES: To evaluate the influence of bacterial infection on blood viscosity and red blood cells (RBCs) morphology, and the ability of Calotropis procera proteins (CpLP) to prevent the patho-hemorheology in infected animals. METHODS: Rheology of blood, atomic force microscopy measurements on specific blood elements and blood count were performed to examine changes in blood viscosity, RBCs morphology, platelets activation, and RBCs indices. FINDINGS: Infected mice hold their blood rheological behaviour as compared to that of the control group. However, they presented hyperactivated platelets, RBCs at different stages of eryptosis, and variation on RBCs indices. CpLP administration in healthy animals altered blood behaviour from pseudoplastic to Bingham-like fluid. Such effect disappeared over time and by inhibiting its proteases. No alterations were observed in RBCs morphology or platelets. Treatment of infected animals with CpLP prevented the changes in RBCs indices and morphology. MAIN CONCLUSIONS: The inflammatory process triggered by bacterial infection induced pathological changes in RBCs and platelets activation. Treatment of infected animals with CpLP prevented the emergence of RBCs abnormal morphology and this may have implications in the protective effect of CpLP, avoiding animal death.

Possible anti-oxidative effects of long-term administration of Juzen-taiho-to in dogs.

It is known that oxidative stress is related to disease in humans and dogs. Many traditional Chinese medicines have been reported to have anti-oxidative effects, but there are no reports that they have anti-oxidative effects in dogs. In this study, we examined the anti-oxidative effects of Juzen-taiho-to, a traditional Chinese medicine, in dogs. Five healthy female beagle dogs (38-41 months of age weighing 8.6-10.7 kg) were orally administered Juzen-taiho-to at 450 mg/kg with food for 28 days. Blood samples were taken from all five dogs on days 0, 7, 14, 21, and 28. Using the blood samples, improvement of the antioxidant level as assessed by the biological antioxidant potential (BAP), reduced oxidative stress level as assessed by derivatives of reactive oxygen metabolites (d-ROMs), and improvement of blood fluidity were examined. Regarding the antioxidant level and blood fluidity, no significant difference was observed, but the oxidative stress level on days 14, 21, and 28 was significantly lower than that on day 0. Thus, Juzen-taiho-to may have anti-oxidative effects in dogs by reducing oxidative stress and be useful for oxidative stress-related diseases in dogs.

1,25(OH)2D3 improves blood lipid metabolism, liver function, and atherosclerosis by constraining the TGF-ß/Smad signaling pathway in rats with hyperlipidemia.

1,25(OH)2D3 has already been reported to function in some diseases. However, its role in hyperlipidemia (HLP) remains unknown. This study aims to investigate the effect of 1,25(OH)2D3 on HLP rats. Rat models were established by high-fat diet feeding, perfusion of different doses of 1,25-(OH)2D3 and injection of TGF-ß1 siRNA. Whole blood viscosity, plasma viscosity, hematocrit, and erythrocyte aggregation index were detected, together with levels of biochemical indexes, 6-keto-PGF1α, and TXB2 in serum. Levels of oxidative stress indexes and inflammatory factors in serum and liver tissues were determined. TGF-ß1 and Smad3 expression in serum, liver tissues, and aorta was detected. 1,25(OH)2D3 lowered HLP-induced rise of whole blood viscosity, red blood cell aggregation index, plasma viscosity, and hematocrit, TC, TG, LDL-C, apoB, ALT, AST, TXB2, MDA, IL-1ß, TNF-α, and increased HLP-induced decrease of HDL-C, apoAI, 6-keto-PGF1α, SOD, GSH-Px, CAT, and T-AOC. TGF-ß1 and Smad3 expression in serum, liver tissue, and aorta of 1,25(OH)2D3-treated rats reduced. High 1,25(OH)2D3 dose and inhibited TGF-ß/Smad signaling pathway alleviated lipid metabolism, liver function, and atherosclerotic injury in HLP rats. Our study found that 1,25(OH)2D3 improves blood lipid metabolism, liver function, and atherosclerosis injury by constraining the TGF-ß/Smad signaling pathway in rats with HLP.

Pharmacokinetics and hemorheology of phosphocreatine and creatine in rabbits: A directly comparative study between parent drug and active metabolite.

This study is to investigate pharmacokinetics (PK) and hemorheology (HR) of exogenous phosphocreatine (PCr), a cardio-protective agent, and its active metabolite creatine (Cr), with particular focus on the PK and PD comparison between PCr and Cr. A specific ion-pair reversed-phase HPLC-UV assay was used to simultaneously measure PCr, Cr and ATP concentrations in plasma and red blood cells (RBC) samples of rabbits. PK and HR parameters were calculated based on concentration-time (C-T) curves and effect-time (E-T) curves, respectively, obtained after i.v. dosing. Meanwhile the apparent pharmacological activity ratio (Rapp) and real pharmacological activity ratio (Rreal) of Cr to PCr were calculated. The PCr disappeared from plasma rapidly and in a biphasic manner; plasma PCr was converted to Cr fast and largely with the elimination rate limited metabolite disposition in vivo (Km < K). The i.v. administration of PCr led to a markedly elevated and long-lasting ATP level in RBC. After i.v. administration of preformed Cr, plasma Cr displayed similar elimination kinetics behaviors to that of Cr generated metabolically after i.v. PCr. The Cr could also raise ATP level in RBC, but to less extent than PCr. Approximately 43% of PCr-derived ATP came from Cr-derived ATP in RBC. PCr could significantly reduce whole blood viscosity and RBC osmotic fragility and Cr could do so, but weakly with estimated Rapp of 0.53-0.68 and Rreal of 0.38-0.48. PCr also inhibited platelet aggregation significantly, as opposed to Cr. The PCr-caused improvement of HR is related to the rise in ATP level in RBC. Cr is likely to partially mediate HR effect of PCr.

Microfluidics-based device for the measurement of blood viscosity and its modeling based on shear rate, temperature, and heparin concentration.

Blood viscosity measurements are crucial for the diagnosis and understanding of a range of hematological and cardiovascular diseases. Such measurements are heavily used in monitoring patients during and after surgeries, which necessitates the development of a highly accurate viscometer that uses a minimal amount of blood. In this work, we have designed and implemented a microfluidic device that was used to measure fluid viscosity with a high accuracy using less than 10 µl of blood. The device was further used to construct a blood viscosity model based on temperature, shear rate, and anti-coagulant concentration. The model has an R-squared value of 0.950. Finally, blood protein content was changed to simulate diseased conditions and blood viscosity was measured using the device and estimated using the model constructed in this work. Simulated diseased conditions were clearly detected when comparing estimated viscosity values using the model and the measured values using the device, proving the applicability of the setup in the detection of rheological anomalies and in disease diagnosis.

CXCR4 mutations affect presentation and outcomes in patients with Waldenström macroglobulinemia: A systematic review.

Introduction: The genomic landscape of Waldenström macroglobulinemia (WM) is characterized by recurrent MYD88 (MYD88L265P) and CXCR4 mutations (CXCR4MUT), detected in 90% and 30% of cases, respectively. The role of CXCR4MUT in clinical features and outcomes to therapy in WM patients is evolving. Areas covered: We performed a systematic review aimed at evaluating the prevalence of CXCR4MUT in WM patients, and at assessing differences in clinical features and outcomes to therapy between WM patients with and without CXCR4MUT. Seventeen studies were included in our analysis. The pooled prevalence of CXCR4MUT in WM patients was 31%; 34% in MYD88L265P and 5% in MYD88WT patients. CXCR4MUT were associated with higher serum IgM levels and higher risk of hyperviscosity than CXCR4WT patients. Very good partial response (VGPR) and progression-free survival (PFS) rates to ibrutinib, with and without rituximab, appeared lower in CXCR4MUT than in CXCR4WT patients. Response and PFS rates were not affected by CXCR4MUT status on patients treated with proteasome inhibitors. Expert opinion: Our systematic review shows that WM patients with CXCR4MUT have specific clinical features and have lower response and PFS rates to BTK inhibitors. Our findings support standardization of CXCR4 testing and development of CXCR4-directed therapy.

Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial.

BACKGROUND: Microvascular blood flow (MBF) impairment in patients with lower extremity arterial disease (LEAD) is associated with more severe major adverse limb events (MALE). The contribution of ticagrelor, a P2Y12 antagonist and an adenosine enhancer, on blood viscosity (BV) and BV-dependent MBF in LEAD is unknown. The aim of the trial is to investigate the effects of ticagrelor on BV, and explore the association of BV-dependent MBF in participants with LEAD and type 2 diabetes (T2DM). METHODS: Randomized, double-blind, double-dummy, crossover trial design that compares treatment with aspirin 81 mg/ticagrelor placebo, aspirin 81 mg/ticagrelor 90 mg twice daily and aspirin placebo/ticagrelor 90 mg twice daily on high-shear (300 s-1) and low-shear (5 s-1) BV, and laser Doppler flowmetry (LDF) in the dorsum of the feet of participants with T2DM. RESULTS: We randomized 70 (45% female) participants aged (mean ± SD) 72 ± 9 years. The duration of LEAD was 12.3 ± 10.3 years, and 96.9% reported intermittent claudication symptoms. Use of statins was 93% (high-intensity 43%, moderate intensity 49%), renin-angiotensin-aldosterone system inhibitors (75%) and beta-blockers (61%). Treatment with ticagrelor with or without aspirin reduced high-shear BV by 5%, in both cases, while aspirin monotherapy increased high-shear BV by 3.4% (p < 0.0001). Ticagrelor with or without aspirin reduced low-shear BV by 14.2% and 13.9% respectively, while aspirin monotherapy increased low-shear BV by 9.3% (p < 0.0001). The combination of ticagrelor and aspirin increased MBF in the left foot compared to the other two treatments (p = 0.02), but not in the right foot (p = 0.25). CONCLUSIONS: Ticagrelor should be considered in the treatment of microvascular disease in patients with LEAD and T2DM. Trial registration Registration number: NCT02325466, registration date: December 25, 2014.

UPLC-Q-TOF/MS-Based Plasma Metabolomics to Evaluate the Effects of Aspirin Eugenol Ester on Blood Stasis in Rats.

Aspirin eugenol ester (AEE) is a novel compound that is formed from the esterification of aspirin (acetylsalicylic acid (ASA)) and eugenol. This study aimed to investigate the effects of AEE on blood stasis in rats and to characterize the underlying mechanisms using a plasma metabolomic study. The results indicate that AEE and ASA could modulate whole blood viscosity (WBV), plasma viscosity (PV), blood coagulation parameters, platelet count, platelet aggregation, lactate dehydrogenase (LDH), creatinine (CR) and the levels of thromboxane A2 (TXA2) and 6-keto prostaglandin F1α (6-keto-PGF1α). The metabolic profiles of the plasma samples from all groups were clearly separated in the score plots. Nineteen potential metabolites were selected and identified, and disordered levels of these metabolites could be regulated by AEE and ASA. Pathway analysis showed that the mechanism of action of AEE on blood stasis might be principally related to the metabolism of amino acid, fatty acid, energy and glycerophospholipid. The above results indicate that AEE protected the rats against blood stasis, and that this effect might have been caused by the anticoagulation activity of AEE and its abilities to maintain a balance between TXA2 and PGI2, reduce blood viscosity, inhibit platelet aggregation and normalize the plasma metabolic profile.