scholarly journals Lactobacillus rhamnosus attenuates Thai chili extracts induced gut inflammation and dysbiosis despite capsaicin bactericidal effect against the probiotics, a possible toxicity of high dose capsaicin

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0261189
Author(s):  
Wimonrat Panpetch ◽  
Peerapat Visitchanakun ◽  
Wilasinee Saisorn ◽  
Ajcharaporn Sawatpanich ◽  
Piraya Chatthanathon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tight Junction ◽  
Healthy Volunteers ◽  
Lactobacillus Rhamnosus ◽  
High Dose ◽  
Fluorescent Staining ◽  
Qrt Pcr ◽  
Junction Molecules ◽  
High Concentrations

Because of a possible impact of capsaicin in the high concentrations on enterocyte injury (cytotoxicity) and bactericidal activity on probiotics, Lactobacillus rhamnosus L34 (L34) and Lactobacillus rhamnosus GG (LGG), the probiotics derived from Thai and Caucasian population, respectively, were tested in the chili-extract administered C57BL/6 mice and in vitro experiments. In comparison with placebo, 2 weeks administration of the extract from Thai chili in mice caused loose feces and induced intestinal permeability defect as indicated by FITC-dextran assay and the reduction in tight junction molecules (occludin and zona occludens-1) using fluorescent staining and gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, the chili extracts also induced the translocation of gut pathogen molecules; lipopolysaccharide (LPS) and (1→3)-β-d-glucan (BG) and fecal dysbiosis (microbiome analysis), including reduced Firmicutes, increased Bacteroides, and enhanced total Gram-negative bacteria in feces. Both L34 and LGG attenuated gut barrier defect (FITC-dextran, the fluorescent staining and gene expression of tight junction molecules) but not improved fecal consistency. Additionally, high concentrations of capsaicin (0.02–2 mM) damage enterocytes (Caco-2 and HT-29) as indicated by cell viability test, supernatant cytokine (IL-8), transepithelial electrical resistance (TEER) and transepithelial FITC-dextran (4.4 kDa) but were attenuated by Lactobacillus condition media (LCM) from both probiotic-strains. The 24 h incubation with 2 mM capsaicin (but not the lower concentrations) reduced the abundance of LGG (but not L34) implying a higher capsaicin tolerance of L34. However, Lactobacillus rhamnosus fecal abundance, using qRT-PCR, of L34 or LGG after 3, 7, and 20 days of the administration in the Thai healthy volunteers demonstrated the similarity between both strains. In conclusion, high dose chili extracts impaired gut permeability and induced gut dysbiosis but were attenuated by probiotics. Despite a better capsaicin tolerance of L34 compared with LGG in vitro, L34 abundance in feces was not different to LGG in the healthy volunteers. More studies on probiotics with a higher intake of chili in human are interesting.

Evidence that gene expression of ovarian follicular tight junction proteins is regulated in vivo and in vitro in cattle

2017 ◽  
Vol 95 (3) ◽  
pp. 1313 ◽  
Author(s):  
L. Zhang ◽  
L. F. Schütz ◽  
C. L. Robinson ◽  
M. L. Totty ◽  
L. J. Spicer
Keyword(s):  
Gene Expression ◽  
Tight Junction ◽  
Tight Junction Proteins ◽  
Junction Proteins

scholarly journals Dose-response effects of omega-3 on platelet aggregation: an observational study

2018 ◽  
Vol 46 (12) ◽  
pp. 5074-5082 ◽  
Author(s):  
Thomas Kander ◽  
Erik Lindblom ◽  
Ulf Schött
Keyword(s):  
Fatty Acids ◽  
Platelet Aggregation ◽  
Healthy Volunteers ◽  
Dose Response ◽  
High Dose ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Positive Health ◽  
Inhibiting Effect

Objective This study aimed to evaluate the dose-response effects of supplemental omega-3 fatty acids on platelet function in healthy volunteers. Methods Twelve healthy volunteers ingested a normal supplemental dose of 1260 mg omega-3 fatty acids daily for 5 days, followed by a high dose of 2520 mg daily for another 5 days. Multiple electrode aggregometry (MEA) with four different agonists was used to measure platelet aggregation before and after the normal- and high-dose regimes. In vitro spiking using physiological doses of omega-3 fatty acids was also performed to determine whether MEA is capable of detecting a platelet-inhibiting effect due to omega-3 fatty acids. Results There were no differences in platelet aggregation measured by the MEA assay in healthy volunteers after intake of either the normal or high dose of omega-3 fatty acids. In the in vitro experiment, a platelet-inhibiting effect of omega-3 fatty acids was shown by an arachidonic acid agonist in MEA . Conclusions Supplemental omega-3 fatty acids do not evoke their positive health effects through inhibition of platelet aggregation measurable with MEA.

scholarly journals 2'-Deoxycytidine protects normal human bone marrow progenitor cells in vitro against the cytotoxicity of 3'-azido-3'-deoxythymidine with preservation of antiretroviral activity

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 1923-1928 ◽  
Author(s):  
K Bhalla ◽  
M Birkhofer ◽  
GR Li ◽  
S Grant ◽  
W MacLaughlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
High Dose ◽  
Normal Bone Marrow ◽  
Normal Bone ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor ◽  
High Concentrations ◽  
Anti Hiv

Abstract Bone marrow cytotoxicity of 3′-azido-3′-deoxythymidine (AZT), an anti- human immunodeficiency virus (anti-HIV) drug, has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined, in vitro, the effect of high, but clinically achievable and nontoxic, concentrations of 2′-deoxycytidine (dCyd) (greater than or equal to 100 mumol/L) on high-dose AZT mediated growth inhibition and intracellular biochemical perturbations in normal bone marrow progenitor cells. Colony formation by bone marrow progenitor cells in semisolid medium was significantly protected by dCyd against the inhibitory effects of co-administered, high concentrations of AZT (10 mumol/L). Also, dCyd significantly corrected AZT mediated depletion of intracellular thymidine triphosphate (dTTP) and dCyd triphosphate (dCTP) levels in normal bone marrow mononuclear cells (BMMC). Moreover, dCyd reduced the intracellular accumulation of AZT triphosphate (AZT-TP) and its DNA incorporation in BMMC. In contrast, co-administration of dCyd (100 mumol/L to 1 mmol/L) did not reverse AZT (10 mumol/L) mediated suppression of HIV infectivity in HUT-102 cells in culture, although a partial reduction in intracellular AZT-TP pools and its DNA incorporation as well as a correction of AZT mediated depletion of dTTP and dCTP pools was observed in these cells. These studies suggest that dCyd at high concentrations might ameliorate the bone marrow cytotoxicity of high-dose AZT without impairing its anti-HIV effect.

scholarly journals Bioinformatics-Based Identification of lncRNA-miRNA-mRNA Network in Dilated Cardiomyopathy and Drug Prediction

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Wei Liu ◽  
Jinqiang Cai ◽  
Mengjie Tang ◽  
QinJing Yang
Keyword(s):  
Gene Expression ◽  
Dilated Cardiomyopathy ◽  
Protein Interactions ◽  
Unknown Etiology ◽  
Pathway Enrichment Analysis ◽  
Blood Samples ◽  
Qrt Pcr ◽  
Cerna Network ◽  
Potential Biomarkers

Background. Dilated cardiomyopathy (DCM) is a cardiovascular disease of unknown etiology with progressive aggravation. More and more studies have shown that long noncoding RNAs (lncRNAs) play an essential role in dilated cardiomyopathy formation and development. The mechanism of action of competitive endogenous RNA (ceRNA) networks formed based on the principle that lncRNAs affect mRNAs’ expression level by competitively binding microRNAs (miRNAs) in dilated cardiomyopathy has rarely been reported. Objective. This study is aimed at constructing a lncRNA-miRNA-mRNA ceRNA network by bioinformatics analysis methods, discovering, and validating potential biomarkers of DCM in the ceRNA network and determining possible therapeutic targets from them for drug prediction. Methods. A lncRNA dataset and a mRNA microarray dataset were downloaded from the Gene Expression Omnibus Database (GEO). Gene expression was compared between blood samples from patients with dilated cardiomyopathy and blood samples from normal subjects to identify differential expression of lncRNAs and mRNAs. The lncRNA-miRNA-mRNA network was constructed using bioinformatics tools, and functional and pathway enrichment analysis and protein-protein interactions were performed. The mRNAs in the network and the proteins they encode are then used as targets for predicting drugs. Besides, the expression of lncRNAs in the ceRNA network was validated by real-time quantitative PCR (qRT-PCR) experiments in vitro. Results. The differentially expressed lncRNA-miRNA-mRNA ceRNA network in dilated cardiomyopathy was successfully established. Two differentially overexpressed key lncRNAs were found from the network: AC093817 and AC091062, and qRT-PCR experiments further validated the overexpression of AC093817 and AC091062. The mRNAs in the network and the proteins encoded by the mRNAs were used for drug prediction to get related drugs. Conclusion. This study supports a possible mechanism and drug development of dilated cardiomyopathy, AC093817 and AC091062 being potential biomarkers of dilated cardiomyopathy.

Efficacy of β-D-Mannuronic Acid [M2000] on the Pro-Apoptotic Process and Inflammatory-Related Molecules NFκB, IL-8 and Cd49d using Healthy Donor PBMC

2020 ◽  
Vol 17 (2) ◽  
pp. 225-232
Author(s):  
Atousa Khalatbari ◽  
Mehdi Mahdavi ◽  
Fahimeh Jafarnezhad ◽  
Sanaz Afraei ◽  
Farzaneh Tofighi Zavareh ◽  
...  
Keyword(s):  
Gene Expression ◽  
Healthy Volunteers ◽  
Illicit Drugs ◽  
Mononuclear Cells ◽  
Venous Blood ◽  
Untreated Group ◽  
High Dose ◽  
Peripheral Blood Mononuclear ◽  
Expression Levels ◽  
Mannuronic Acid

Objective: This investigation evaluates the pro-apoptotic and anti-inflammatory effects of β-D-mannuronic acid [M2000] compared to diclofenac, based on gene expression involved in apoptosis and inflammation process [including Bcl2, NFκB, IL-8 and Cd49d] in Peripheral Blood Mononuclear Cells [PBMCs] of healthy donors under exvivo conditions. Material: The venous blood samples of twelve healthy volunteers with aged 25-60 years were collected in heparinized tubes. The healthy volunteers were selected from no smoking group and without using illicit drugs and suffering from diabetes. The PBMCs were separated and divided into untreated and treated groups. Methods: The PBMCs of each sample were cultured in 5 wells of culture plate, so that the first well consisted of 2×106 cells exposed by LPS-EB [1μg/ml] to stimulate PBMCs and absence of M2000 [untreated well]. The second, third, fourth and fifth wells containing 2×106 cells/well and LPS-EB, after 4 hours incubation at 37ºC, received 5, 25 and 50 μg/well of M2000 and 5 μg/well of diclofenac, respectively as treated group. Results: The PBMCs were separated and RNAs were then extracted and cDNAs synthesized and gene expression levels were assessed by qRT-PCR. Furthermore, we studied whether M2000 is able to facilitate apoptosis in PBMCs. Our findings represent that the high dose of M2000 could significantly decrease the expression level of NFκB gene compared to untreated group (p < 0.0002). On the other hand, no significant change was observed in treated cells with diclofenac. All doses of M2000 could significantly augment apoptosis compared to untreated group [p < 0.0001]. Additionally, we observed the same apoptotic effects between the medium dose of M2000 and diclofenac. Besides, no significant reduction was shown in expression levels of IL8, Bcl2 and Cd49d genes in all doses of M2000 and diclofenac compared to untreated group. This experiment demonstrates M2000 as a new effective NSAID with immunosuppressive characteristics capable of stimulating apoptosis through lowering expression levels of NFκB gene, which might be probably considered as an appropriate drug for reducing the risk of developing inflammatory diseases and cancer.

Research on the Mechanism of Asiaticoside Inhibiting Osteoclast Differentiation and Promoting the Recovery of Steroid-Induced Osteonecrosis of the Femoral Head (SIONFH)

2021 ◽  
Vol 11 (8) ◽  
pp. 1606-1611
Author(s):  
Meijing Miao ◽  
Liping Guo ◽  
Pengfei Su ◽  
Jinshan Ji ◽  
Baoli Li
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Femoral Head ◽  
Protein Expression ◽  
Western Blot ◽  
Osteoclast Differentiation ◽  
Culture Fluid ◽  
Qrt Pcr

Our study aims to assess whether asiaticoside promotes the recovery of SINOFH by inhibiting bone marrow stem cells (BMSCs) differentiation into osteoclasts (OC). BMMs were induced to form OC system by dexamethasone in vitro and ELISA detected the expression of OC-related genes formation by asiaticoside. BMSCs were cultured followed by analysis of BMSCs morphology under microscope, gene expression by qRT-PCR. TRACP and c-Src level by western blot, RANKL, OPG and TRACP5b level by ELISA. Asiaticoside inhibited the expression of OC formation in SIONFH. The expression of OC-related genes increased with the induction days. With the increasing of induction days, asiaticoside level in culture fluid was decreased. While after asiaticoside interference, OCrelated genes and proteins levels were significantly down-regulated. Aasiaticoside can significantly increase the RANKL signaling protein expression. In conclusion, asiaticoside promotes the recovery of SINOFH by inhibiting BMSCs differentiation into OC.

Abstract P107: Hypertension Enhances the Differentiation of Cardiac Fibroblasts Into Myofibroblasts After TGF-beta1 Treatment

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Gianluca L Perrucci ◽  
Maria Corlian!ò ◽  
Delfina Tosi ◽  
Patrizia Nigro ◽  
Gaetano Bulfamante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Expression ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Smooth Muscle Actin ◽  
Pcr Analysis ◽  
Alpha Smooth Muscle Actin ◽  
Qrt Pcr ◽  
Gene And Protein Expression

Objectives: In cardiac fibrosis associated with hypertension, TGF-beta1 plays a key role by acting on differentiation of cardiac fibroblasts (CF) into alpha-smooth muscle actin (alpha-SMA)-positive myofibroblasts. In this study, we tested the effect of TGF-beta1 during the myofibroblast differentiation process of CF from normotensive and hypertensive rats. Methods: CF were obtained by enzymatic digestion of hearts isolated from Spontaneously Hypertensive (hCF) and normotensive Wistar Kyoto (nCF) rats (n=5 rat/group). Gene and protein expression in CF was evaluated by Western blot and qRT-PCR analyses, respectively. Immunohistochemistry analysis for integrin alpha-v beta-5 was performed on rat cardiac tissue (n=5 rat/group). Results: Cultured hCF showed an enhanced SMAD2/3 activation and alpha-SMA protein expression after treatment with TGF-beta1 (5 ng/ml) in comparison with nCF. Alpha-SMA up-regulation was further confirmed by qRT-PCR analysis that showed a significant increase in alpha-SMA gene expression in hCF after TGF-beta1 treatment (2.78±0.25 vs 2.01±0.21 fold increase, p <0.05). Moreover, immunostaining on cardiac tissues revealed a higher expression of integrin alpha-v beta-5 in hypertensive vs normotensive rat hearts (345.3±170.0 vs 48.2±22.3 mm 2 of integrin-positive area, p <0.05). This result was also confirmed in vitro ; indeed, integrin alpha-v beta-5 gene expression in hCF increased 2.8-fold in basal condition and 5.12-fold after TGF-beta1 treatment when compared to untreated nCF. Conclusions: Taken together, these results suggest that hCF are more prone to upregulate integrin alpha-v beta-5 and consequently differentiate into myofibroblasts in vitro under TGF-beta1 treatment. Thus, targeting alpha-v beta-5 might open a novel prospective for the treatment of fibrosis in hypertensive hearts likely reducing integrin-mediated TGF-beta1 activation.

Gene Expression Profiling in Multiple Myeloma Cells Treated with the Novel Anti-Myeloma Agents Zoledronate and Fluvastatin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5078-5078
Author(s):  
Timothy J. Molloy ◽  
Baulch-Brown Cindy ◽  
Yi-Mo Deng ◽  
Andrew Spencer ◽  
David F. Ma
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Real Time ◽  
Real Time Pcr ◽  
Mevalonate Pathway ◽  
Annexin V ◽  
Quantitative Real Time Pcr ◽  
Myeloma Cells ◽  
Qrt Pcr

Abstract We have shown in vitro that multiple myeloma (MM) cells can be destroyed by treating them with the mevalonate pathway inhibitors zoledronate and fluvastatin. While the efficacy of these compounds singly and combination have been demonstrated, their exact modes of action remain largely unknown. The present study aimed to use microarray and quantitative real-time PCR (QRT-PCR) techniques to analyse gene expression in treated myeloma cells to identify novel genes and pathways involved in the anti-myeloma action of these compounds. The human MM cell line NCI-H929 was treated with zoledronate and fluvastatin singly and in combination, and RNA was extracted and used to interrogate oligonucleotide microarrays consisting of 19,000 features representing known and unknown genes. Quantitative real-time PCR was subsequently used to confirm the expression of several genes of interest. Flow cytometry with Annexin V FITC staining was used to detect apoptosis. It was observed that genes related to apoptosis (caspases and p53-related genes), cell cycle control (cyclins), GTPase signalling (Rabs), and growth and proliferation (growth factors) were particularly affected by zoledronate and fluvastatin, and some of these genetic effects were synergistic when a combination of zoledronate and fluvastatin was used. QRT-PCR confirmed the effects on the caspase- and p53-related apoptotic pathways, and these effects were correlated with increased apoptosis in the myeloma cells. The mevalonate pathway inhibitors fluvastatin and zoledronate are highly efficient at killing MM cells, and their effects appear to be synergistic. Our microarray and QT-PCR analyses demonstrated that the expression of specific groups of genes important to the survival and proliferation of myeloma cells are affected by these compounds. p53 and caspase-dependent pathways appear to be the key apoptotic cascades stimulated. Insights into the mechanisms of these novel therapeutics are important as they might help to define their roles in the treatment of multiple myeloma.

Downregulation of CD30, Resistance to MMAE, and Upregulation of MDR1 Are All Associated with Resistance to Brentuximab Vedotin

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3643-3643
Author(s):  
Robert Chen ◽  
Jessie Hou ◽  
Edward Newman ◽  
Young Kim ◽  
Cecile Donohue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
Gene Expression Profiling ◽  
Western Blotting ◽  
Primary Tumor ◽  
Expression Profiling ◽  
Primary Tumors ◽  
Qrt Pcr ◽  
Mts Assay

Abstract Background: Both Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) express surface CD30. Brentuximab vedotin (BV) is an antibody-drug conjugate that delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), specifically to cells expressing surface CD30. Although BV elicits a high response rate (75% in HL and 86% in ALCL), the majority of patients who do not attain complete response (CR) will eventually develop resistance to BV. It is not known whether resistance to BV is through a) CD 30 alterations b) resistance to cytotoxic agent MMAE or c) overexpression of drug exporters. We developed 2 BV-resistant cell models and obtained primary lymphoma samples from patients with relapsed/progressive disease post BV therapy. We examined CD30 expression, MMAE resistance, drug exporter expression, and gene expression profiles in vitro and in vivo to determine mechanisms of resistance to BV. Methods: HL cell line(L428) and ALCL cell line (KARPAS 299) were used for in vitro experiments. The selection of BV resistant cell model (L428R and KARPAS 299R) used two different approaches (pulsatile or constant exposure). Both BV resistance and MMAE resistance were confirmed by MTS assays. CD30 expression was measured by flow cytometry,qRT-PCR, and Western blotting. Drug exporter expression was measured using qRT-PCR to MDR1, MRP1, and MRP3. In vivo experiments utilized primary tumor samples from 15 HL and 4 ALCL patients who had developed relapsed/progressive disease post BV treatment. CD30 expression was assessed by immunohistocytochemistry (IHC). Gene expression profiling was performed in both parental and resistant HL and ALCL cells, and in 4 ALCL primary tumor samples using Affymetrix whole genome GeneChip® Human Genome U133 2.0 Plus. Results: MTS assay showed the IC50 of KARPAS 299R to BV shifted from 24 +/- 10 ng/ml to 28 +/- 9 ug/ml, an 1183-fold increase. MTS assay also showed the IC50 of KARPAS 299R to MMAE only increased 2-fold when compared to KARPAS 299. Flow cytometry showed downregulation of surface CD30 expression in KARPAS 299R as compared to KARPAS 299 parental (59% vs. 96%, median intensity 78 +/- 17 vs. 591 +/- 51). This downregulation was confirmed by qRT-PCR and Western blotting for CD30. As KARPAS 299R is a mixed cell population, we sorted them into CD30+ and CD30- subpopulations. We then analyzed for BV sensitivity based on CD 30 expression status in KARPAS 299R. MTS assay showed that KARPAS 299R CD30+ cells were equally as resistant to BV as KARPAS 299R CD30- cells (figure 1A). IHC performed in 4 ALCL primary tumor samples showed persistent CD 30 expression in relapsed/progressive tumor specimens post BV treatment. Gene expression profiling on KARPAS 299R showed downregulation of CD30 as compared to KARPAS 299. Gene expression profiling on pre- and post-treatment ALCL samples (8) did not show significant differences in CD30 expression. The top four upregulated genes in relapsed/progressive samples as compared to pretreatment samples were LCE3D, WNT3, TNNT, CITED2. The top four downregulated genes in relapsed/progressive samples as compared to pretreatment samples were CXCL13, C4orf7, MS4A1, and IGJ. MTS assay showed that the IC50 of L428R to BV has shifted from 32 +/- 11 ug/ml to 391 +/- 92 ug/ml, a 12-fold increase. MTS assays showed the IC50 of L428R to MMAE has increased 99-folds when compared to L428 (figure 1B). No difference was seen in CD 30 expression by flow cytometry, qRT-PCR, or western blotting between L428R vs. L428. IHC performed in 15 HL primary tumors show persistent CD30 expression in relapsed/progressive tumor specimen post-BV treatment. qRT-PCR showed upregulation of MDR1mRNA in L428R as compared to L428. Gene expression profiling on L428R showed upregulation of MDR1 as compared to L428. Conclusion: Downregulation of CD30 is seen in BV-resistant ALCL cell model. However, sensitivity to BV did not depend solely on the level of CD30 expression as CD30+ cell subpopulations still exhibited resistance to BV in vitro. Upregulation of MDR-1 and resistance to MMAE were seen in BV-resistant HL cells, rather than downregluation of CD30. Downregulation of CD30 was not seen in HL or ALCL primary tumors. Further work is ongoing to explore/validate potential targets derived from gene expression profiling in ALCL primary tumors. Figure 1A Sensitivity to BV is not related to CD30 expression Figure 1A. Sensitivity to BV is not related to CD30 expression Figure 1B. Figure 1B. Viability of L-428 parental versus BV-resistant cells Disclosures Chen: Seattle Genetics, Inc.: Consultancy, Research Funding, Speakers Bureau, Travel expenses Other.

Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue

2011 ◽  
Vol 105 (02) ◽  
pp. 302-312 ◽  
Author(s):  
Thijs van Iersel ◽  
Heimo Stroissnig ◽  
Peter Giesen ◽  
Johan Wemer ◽  
Karin Wilhelm-Ogunbiyi
Keyword(s):  
Healthy Volunteers ◽  
Clinical Investigation ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Human Study ◽  
Bleeding Risk ◽  
High Dose ◽  
Multiple Dosing ◽  
Relevant Dose

SummarySolulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.

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