Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives

2011 ◽  
Vol 89 (8) ◽  
pp. 575-585 ◽  
Author(s):  
Manassés Claudino Fonteles ◽  
Nilberto Robson Falcão do Nascimento
Keyword(s):  
Guanylate Cyclase ◽  
Disulfide Bonds ◽  
Ex Vivo ◽  
New Drugs ◽  
Sodium Balance ◽  
Target Cells ◽  
Erectile Tissue ◽  
Surface Receptors ◽  
Redundant Mechanism

The guanylin family of peptides has 3 subclasses of peptides containing either 3 intramolecular disulfide bonds found in bacterial heat-stable enterotoxins (ST), or 2 disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. These hormones are synthesized in the intestine and released both luminally and into the circulation, and are also produced within the kidney. Stimulation of renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis by both cGMP-dependent and independent mechanisms. Uroguanylin may act as a hormone in a novel endocrine axis linking the digestive system and kidney as well as a paracrine system intrarenally to increase sodium excretion in the postprandial period. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess sodium in the urine. In addition, small concentrations of the atrial natriuretic peptide (ANP) can synergize with low concentrations of both guanylin or uroguanylin, which do not induce natriuresis per se, to promote significant natriuresis. Interestingly, the activation of the particulate guanylate cyclase receptors by natriuretic peptides can promote relaxation of animal and human penile erectile tissue and increase intracavernosal pressure to induce penile erection. These peptides can be prototypes for new drugs to treat erectile dysfunction, especially in patients with endothelial and nitrergic dysfunction, such as in diabetes.

Guanylin peptides: renal actions mediated by cyclic GMP

2000 ◽  
Vol 278 (2) ◽  
pp. F180-F191 ◽  
Author(s):  
Leonard R. Forte ◽  
Roslyn M. London ◽  
Ronald H. Freeman ◽  
William J. Krause
Keyword(s):  
Ex Vivo ◽  
Physiological Mechanism ◽  
Intestinal Lumen ◽  
Sodium Balance ◽  
Target Cells ◽  
Dietary Salt ◽  
Natriuretic Hormone ◽  
Cgmp Production ◽  
Heat Stable

The guanylin family of cGMP-regulating peptides has three subclasses of peptides containing either three intramolecular disulfides found in bacterial heat-stable enterotoxins (ST), or two disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These small, heat-stable peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. Two receptor GC signaling molecules have been identified that are highly expressed in the intestine (GC-C) and/or the kidney (OK-GC) and are selectively activated by the guanylin peptides. Stimulation of cGMP production in renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis. Activation of GC-C receptors in target cells of intestinal mucosa markedly stimulates the transepithelial secretion of Cl−and[Formula: see text], causing enhanced secretion of fluid and electrolytes into the intestinal lumen. Bacterial ST peptides act as mimics of guanylin and uroguanylin in the intestine, which provide a cellular mechanism underlying the diarrhea caused by ST-secreting strains of Escherichia coli. Uroguanylin and guanylin may participate in a novel endocrine axis linking the digestive system and kidney as a physiological mechanism that influences Na+homeostasis. Guanylin, uroguanylin, and/or lymphoguanylin may also serve within intrarenal signaling pathways controlling cGMP production in renal target cells. Thus we propose that guanylin regulatory peptides participate in a complex multifactorial biological process that evolved to regulate the urinary excretion of NaCl when dietary salt levels exceed the body's physiological requirements. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess NaCl in the urine. Uroguanylin, in particular, may be a prototypical “intestinal natriuretic hormone.”

Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1823-1827 ◽  
Author(s):  
Bregje Mommaas ◽  
Janine A. Stegehuis-Kamp ◽  
Astrid G. van Halteren ◽  
Michel Kester ◽  
Jürgen Enczmann ◽  
...  
Keyword(s):  
T Cells ◽  
Cord Blood ◽  
Ex Vivo ◽  
Cytotoxic T Cells ◽  
Cord Blood Transplantation ◽  
Human Leukocyte ◽  
Leukemic Cells ◽  
Target Cells ◽  
Graft Versus Leukemia

AbstractUmbilical cord blood transplantation is applied as treatment for mainly pediatric patients with hematologic malignancies. The clinical results show a relatively low incidence of graft-versus-host disease and leukemia relapse. Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect. Here, we demonstrate the feasibility of ex vivo generation of minor H antigen HA-1-specific T cells from cord blood cells. Moreover, we observed pre-existing HA-1-specific T cells in cord blood samples. Both the circulating and the ex vivo-generated HA-1-specific T cells show specific and hematopoietic restricted lysis of human leukocyte antigen-A2pos/HA-1pos (HLA-A2pos/HA-1pos) target cells, including leukemic cells. The cord blood-derived HA-1-specific cytotoxic T cells are from child origin. Thus, the so-called naive cord blood can comprise cytotoxic T cells directed at the maternal minor H antigen HA-1. The apparent immunization status of cord blood may well contribute to the in vivo graft-versus-leukemia activity after transplantation. Moreover, since the fetus cannot be primed against Y chromosome-encoded minor H antigens, cord blood is an attractive stem cell source for male patients. (Blood. 2005;105:1823-1827)

scholarly journals In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

2019 ◽  
Vol 65 (1) ◽  
pp. 55-70 ◽  
Author(s):  
Marcin Ożarowski ◽  
Radosław Kujawski ◽  
Przemysław Ł. Mikołajczak ◽  
Karolina Wielgus ◽  
Andrzej Klejewski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Chemical Compounds ◽  
New Drugs ◽  
Future Application ◽  
Mediators Of Inflammation ◽  
And Function

Summary Flavonoids and their conjugates are the most important group of natural chemical compounds in drug discovery and development. The search for pharmacological activity and new mechanisms of activity of these chemical compounds, which may inhibit mediators of inflammation and influence the structure and function of endothelial cells, can be an interesting pharmacological strategy for the prevention and adjunctive treatments of hypertension, especially induced by pregnancy. Because cardiovascular diseases have multi-factorial pathogenesis these natural chemical compounds with wide spectrum of biological activities are the most interesting source of new drugs. Extracts from one of the most popular plant used in Traditional Chinese Medicine, Scutellaria baicalensis Georgi could be a very interesting source of flavonoids because of its exact content in quercetin, apigenin, chrysin and scutellarin as well as in baicalin. These flavonoids exert vasoprotective properties and many activities such as: anti-oxidative via several pathways, anti-in-flammatory, anti-ischaemic, cardioprotective and anti-hypertensive. However, there is lack of summaries of results of studies in context of potential and future application of flavonoids with determined composition and activity. Our review aims to provide a literature survey of in vitro, in vivo and ex vivo pharmacological studies of selected flavonoids (apigenin, chrysin and scutellarin, baicalin) in various models of hypertension carried out in 2008–2018.

scholarly journals Extracellular vesicles from symbiotic vaginal lactobacilli inhibit HIV-1 infection of human tissues

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Rogers A. Ñahui Palomino ◽  
Christophe Vanpouille ◽  
Luca Laghi ◽  
Carola Parolin ◽  
Kamran Melikov ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Viral Entry ◽  
Ex Vivo ◽  
Target Cells ◽  
Isolated Cells ◽  
Viral Attachment ◽  
Vaginal Lactobacilli ◽  
Male To Female ◽  
Hiv 1

AbstractThe vaginal microbiota, dominated by Lactobacillus spp., plays a key role in preventing HIV-1 transmission. Here, we investigate whether the anti-HIV effect of lactobacilli is mediated by extracellular vesicles (EVs) released by these bacteria. Human cervico-vaginal and tonsillar tissues ex vivo, and cell lines were infected with HIV-1 and treated with EVs released by lactobacilli isolated from vaginas of healthy women. EVs released by L. crispatus BC3 and L. gasseri BC12 protect tissues ex vivo and isolated cells from HIV-1 infection. This protection is associated with a decrease of viral attachment to target cells and viral entry due to diminished exposure of Env that mediates virus-cell interactions. Inhibition of HIV-1 infection is associated with the presence in EVs of several proteins and metabolites. Our findings demonstrate that the protective effect of Lactobacillus against HIV-1 is, in part, mediated by EVs released by these symbiotic bacteria. If confirmed in vivo, this finding may lead to new strategies to prevent male-to-female sexual HIV-1 transmission.

A Non-Internalizing Anti-CD40 Antibody, CHIR-12.12, Blocks CD40L-Induced Cytokine Production and Mediates Greater ADCC Than Rituximab in Primary CLL Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2964-2964
Author(s):  
Xia Tong ◽  
Sharon Lea Aukerman ◽  
Karen Lin ◽  
Natasha Aziz ◽  
Cheryl Goldbeck ◽  
...  
Keyword(s):  
Cell Surface ◽  
B Cell ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Lymphocytic Leukemia ◽  
Target Cells ◽  
Adcc Activity ◽  
Effector Cells ◽  
Cells Cultured

Abstract CD40 is expressed on chronic lymphocytic leukemia (CLL) cells, and CD40 activation leads to signaling critical for cell survival and proliferation. We have previously described a novel, fully human IgG1 anti-CD40 antagonistic monoclonal antibody, CHIR-12.12, generated in XenoMouse® mice (Abgenix, Inc.), and have demonstrated that it inhibits normal human B cell proliferation and survival and mediates potent antibody-dependent cellular cytotoxicity (ADCC) against primary CLL and non-Hodgkin’s lymphoma cells. In this study, we examined the ability of CHIR-12.12 to modulate cytokine production by primary CLL cells and compared the ADCC activity of CHIR-12.12 with rituximab against primary CLL cells. Primary CLL cells stimulated with CD40L produced a variety of cytokines, including IL-10, TNF-α , IL-8, GM-CSF, IL-6, MCP-1, and MIP-1β. Addition of CHIR-12.12 to primary CLL cells inhibited CD40L-mediated production of these cytokines. Cytokine production by primary CLL cells cultured with CHIR-12.12 alone in the absence of CD40L did not exceed levels produced by CLL cells cultured in medium. These data suggest that CHIR-12.12 is a potent antagonist for CD40L-mediated cytokine production by primary CLL cells and shows no agonistic activity by itself. We next compared the relative ADCC activity of CHIR-12.12 and rituximab against ex vivo primary CLL cells from 8 patients. CHIR-12.12 exhibited greater ADCC than rituximab against CLL cells from all patients. The average percent of maximum lysis by CHIR-12.12 and rituximab were 49 ± 16% and 31 ± 14%, respectively. CHIR-12.12 was greater than 10-fold more potent than rituximab, as measured by ED50 values (14.1 pM versus 155.5 pM, respectively). Quantitative CD20 and CD40 density on CLL cells and the degree of antibody internalization were investigated as potential reasons for the difference in ADCC activity. The greater ADCC potency and efficacy of CHIR-12.12 was not dependent on a higher density of cell surface CD40 molecules, as there were 1.3 to 14-fold higher numbers of CD20 than CD40 molecules on the cell surface. Antibody internalization studies using primary CLL cells conducted by flow cytometry and confocal microscopy show that upon binding to CD40 at 37°C, CHIR-12.12 remains uniformly distributed on the cell surface, even after 3 hours. In contrast, after binding at 37°C, rituximab is redistributed into caps and internalized. These data suggest that the potent ADCC activity of CHIR-12.12 may be partly related to its ability to remain on the surface of target cells uniformly, allowing optimal interaction with effector cells. Taken together, these results suggest that CHIR-12.12 may be effective at mediating potent ADCC against CLL cells in vivo. CHIR-12.12 is currently in Phase I trials for B-cell malignancies.

Apolipoprotein E Receptor 2′ Mediates Pathogenic Effects of Dimeric β2glycoprotein I and of Anti- β2glycoprotein I Antibodies in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 408-408
Author(s):  
Zurina Romay-Penabad ◽  
Rolf T Urbanus ◽  
Elizabeth Pappalardo ◽  
Yong Hwang ◽  
Ronald H.W.M. Derksen ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Laser Scanning ◽  
Carotid Arteries ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Peritoneal Macrophages ◽  
Laser Scanning Microscopy ◽  
Target Cells ◽  
Pathogenic Effects

Abstract Antiphospholipid antibodies (aPL) recognize β2Glycoprotein (β2GPI)-bound to receptor (s) in target cells and trigger a pro-coagulant/pro-inflammatory phenotype [i e.:expression of tissue factor (TF), vascular cell adhesion molecule-1 (VCAM-1)] that lead to thrombosis. The interaction of β2GPI with target cells may involve more than one protein. Investigators have shown that dimeric β2GPI binds to apolipoprotein E receptor 2′ (apoER2′) in platelets, in the absence of anti-β2GPI antibodies, increases their activation and induces enhanced thrombosis and TF activity in mice. However, the role of apoER2′ in vivo in Antiphospholipid Syndrome (APS) is not completely understood. Here, we examined the in vivo effects of dimeric β2GPI and of anti-β2GPI antibodies (IgG-APS) in apoER2′ deficient (−/−) mice and in normal mice pre-treated with recombinant soluble domain 1 of apoER2′ (BD1). In vivo, dynamics of thrombus formation (thrombus sizes), TF activities in carotid artery homogenates and in peritoneal macrophages and ex vivo expression of VCAM-1 in aortas and of TF activity in peritoneal macrophages were examined in the various types of mice after two i.p. injections with 40 μg of recombinant dimeric β2GPI – or with the corresponding monomer control – or with 500 μg IgG-APS (isolated from a patient with APS by protein G Sepharose) or with control IgG (IgG-NHS). Mice injected with IgG-APS had significant titers of anticardiolipin (aCL) and anti-β2GPI antibodies in their sera. In vivo, IgG-APS increased significantly the size of the induced thrombi as well as the TF activities in carotid arteries and in peritoneal macrophages in C57BL/6J (wild type) mice when compared to same type of mice treated with IgG-NHS. Similarly, ex vivo expression of VCAM-1 in mouse aortas and of TF in peritoneal macrophages, detected by two photon excitation laser scanning microscopy were increased in normal mice treated with IgG-APS when compared to control mice. The pre-treatment with 40 μg of BD1 i.p., significantly reduced those effects. Importantly, dimeric β2GPI (in the absence of anti-β2GPI antibodies) or IgGAPS did not increase significantly thrombus size, TF activities in homogenates of carotid arteries or in peritoneal macrophages, or ex vivo expression of VCAM-1 and TF in mice lacking apoER2′. Conclusions: Altogether these data show that dimers of β2GPI mimic pathogenic effects of anti-β2GPI antibodies in mice. Most importantly, apoER2′ is a mediator of those effects in vivo. These findings may provide insights not only for a better understanding of the pathophysiology of APS but may be important in the development of new targeted therapies, by means of interfering with the binding of β2GPI-aPL complexes with their receptor(s) in target cells in vivo.

T-cell redirected killing and cure of pancreatic and gastric cancer xenografts by targeting Trop-2.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 262-262
Author(s):  
David M. Goldenberg ◽  
Edmund A. Rossi ◽  
Diane L Rossi ◽  
Thomas M. Cardillo ◽  
Chien-Hsing Chang
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Control Group ◽  
Calcium Signal ◽  
Target Cells ◽  
Normal Tissues

262 Background: Trop-2 [also called tumor-associated calcium signal transducer 2 (TACSTD2), EGP-1 (epithelial glycoprotein-1), GA733-1, or M1S1]is a 35 kDa transmembrane glycoprotein that is overexpressed relative to normal tissues in a variety of human cancers, including pancreatic and gastric carcinomas, where increased expression correlates with poor prognosis. Trop-2 appears to be more tumor-specific than the related molecule, EpCAM (Trop-1). MT110, the EpCAM antibody x CD3 bispecific T-cell engager (BiTE), is currently undergoing a Phase I study in various solid tumors, including lung, gastric, colorectal, breast, prostate, and ovarian cancers. We produced a similar T-cell redirecting bispecific tandem scFv, E1-3, using the variable domains of hRS7 (humanized anti-Trop-2 mAb) and Okt-3 (anti-CD3 mAb). Methods: T-cell activation, cytokine induction and cytotoxicity were evaluated ex vivo using PBMCs or purified T cells with human pancreatic (Capan-1 and BxPC3) and gastric (NCI-N87) cancer cell lines as target cells. In vivo activity was assayed with NCI-N87 xenografts that were inoculated s.c. in a mixture with twice the number of human PBMCs and matrigel. Results: In the presence of target cells and PBMCs, E1-3 potently induced T-cell activation, proliferation, and dose-dependent cytokine production of IL-2 (>2 ng/mL), IL-6 (>1 ng/mL), IL-10 (>7 ng/mL), TNF-α (>1 ng/mL) and IFN-γ (>50 ng/mL). In vitro, E1-3 mediated a highly potent T-cell lysis of BxPC3 [IC50=0.09(±0.04) pM], Capan-1 [IC50=1.2(±1.1) pM] and NCI-N87 [IC50=1.2(±1.2) pM] target cells. In vivo, two 50-µg doses of E1-3 given three days apart cured all of the mice (N=8) bearing NCI-N87 xenografts (P=0.0005; Log-Rank). Tumors in the control group (PBMCs only) reached the endpoint (TV>1 cm3) with a median of 39.5 days. All mice remained tumor-free in the E1-3 group at 78 days. Conclusions: Trop-2 is an attractive target for T-cell-mediated killing of pancreatic, gastric and other epithelial cancers.

Rapid S-nitrosothiol metabolism by platelets and megakaryocytes

2003 ◽  
Vol 31 (6) ◽  
pp. 1450-1452 ◽  
Author(s):  
C.M. Shah ◽  
I.C. Locke ◽  
H.S. Chowdrey ◽  
M.P. Gordge
Keyword(s):  
Critical Role ◽  
Cellular Responses ◽  
Blocking Agent ◽  
Target Cells ◽  
Pharmacological Effects ◽  
Surface Receptors ◽  
Nitrobenzoic Acid ◽  
Short Time ◽  
Glutamyl Transpeptidase

RSNOs (S-nitrosothiols) regulate platelet and megakaryocyte function, and may act in vivo as a nitric oxide reservoir. There is a discrepancy between the spontaneous rate of NO release from different RSNO compounds and their pharmacological effects, implying that target cells may mediate biological activity either by metabolism of RSNOs or by displaying cell surface receptors. In the present study, we sought evidence for rapid cell-mediated metabolism of RSNOs. Exposure of platelets to GSNO (S-nitrosoglutathione) for as little as 5 s inhibited thrombin-induced platelet aggregation by >95%; however, AlbSNO (S-nitrosoalbumin) was much less effective over these short time periods. Incubation of 1 μM GSNO or AlbSNO with platelets and megakaryocytes resulted in a 25–34% loss of RSNO recoverable from the supernatant (P<0.02) within 30 s. This rapid cell-mediated RSNO decay did not progress further over 5 min, and could not be accounted for by release of free NO. The γ-glutamyl transpeptidase inhibitor acivicin (100 μM) partially decreased GSNO decay, whereas the membrane-impermeable thiol-blocking agent 5,5´-dithiobis-(2-nitrobenzoic acid) (100 μM) completely blocked cell-mediated GSNO decay and partially blocked AlbSNO decay. Our results highlight differences between high- and low-molecular-mass RSNOs with regard to their rapid metabolism/uptake and subsequent cellular responses, and indicate a critical role for extracellular thiols in RSNO metabolism by platelets and megakaryocytes.

scholarly journals Prolonged Adherence of Human Immunodeficiency Virus-Derived Vector Particles to Hematopoietic Target Cells Leads to Secondary Transduction In Vitro and In Vivo

2006 ◽  
Vol 81 (2) ◽  
pp. 639-649 ◽  
Author(s):  
Yung-Wei Pan ◽  
Jarrad M. Scarlett ◽  
Tammy T. Luoh ◽  
Peter Kurre
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cell Biology ◽  
Germ Line ◽  
Ex Vivo ◽  
Critical Parameters ◽  
Target Cells ◽  
Hematopoietic Stem ◽  
Immunodeficiency Virus ◽  
Vector Particles

ABSTRACT Human immunodeficiency virus type 1-derived lentivirus vectors bearing the vesicular stomatitis virus G (VSV-G) envelope glycoprotein demonstrate a wide host range and can stably transduce quiescent hematopoietic stem cells. In light of concerns about biosafety and potential germ line transmission, they have been used predominantly for ex vivo strategies, thought to ensure the removal of excess surface-bound particles and prevent in vivo dissemination. Studies presented here instead reveal prolonged particle adherence after ex vivo exposure, despite serial wash procedures, with subsequent transduction of secondary target cells in direct and transwell cocultures. We explored the critical parameters affecting particle retention and transfer and show that attachment to the cell surface selectively protects virus particles from serum complement-mediated inactivation. Moreover, studies with nonmyeloablated murine recipients show that transplantation of vector-exposed, washed hematopoietic cells results in systemic dissemination of functional VSV-G/lentivector particles. We demonstrate genetic marking by inadvertent transfer of vector particles and prolonged expression of transgene product in recipient tissues. Our findings have implications for biosafety, vector design, and cell biology research.

PHARMACOLOGICAL STUDIES OF PLATELET ANTIAGGREGANTS USING AN IN VITRO MODEL OF PRIMARY HEMOSTASIS.

1987 ◽  
Author(s):  
S Bellucci ◽  
E Cambau ◽  
B Candalot ◽  
J P Caen
Keyword(s):  
Ex Vivo ◽  
Repeated Measurements ◽  
New Drugs ◽  
Type Iii Collagen ◽  
Type I ◽  
Glass Capillary ◽  
New Device ◽  
Primary Hemostasis

We used a new device simulating in vitro primary haemostasis : more precisely the reactivity of blood to collagen and ADP. Thus an artificial vessel was created consisting of two main parts : a glass capillary (ID 140 um, length 16 mm, siliconized) simulating the haemodynamic resistance of an arteriole and an aperture (ID 150 um) reflecting the injured part of a cut arteriole. This aperture was performed in a cellulose acetate filter covered with collagen type I (3 mg/ml) to provide a defined surface for the adhesion of platelets and soaked with ADP in a concentration similar to that of injured endothelial cells (2 x 10-2 M). The mean - sd control values were 110 ± 24 s, 156 -± 40 ul (n = 25) and correlated well with in vivo bleeding time values (p< 0.01). We studied the effect on this test of classical antiaggregant drugs which act on primary hemostasis by different mechanisms of action. Acetylsalycilic acid (Egic laboratories) prolonged this test for concentrations above 10−5 M, ticlopidine (Millot-Solac laboratories) above 3 × 10−4 M, prostacyclin (Wellcome laboratories) above 5 Õ 10−9 M, the synthetic octapeptide LYS-PRO-GLY-GLU-PRO-GLY-PR0-LYS derived from type III collagen (gift from Y. Legrand) above 5 × 10−4 M. We evidenced a synergistic action between collagen octapeptide and ticlopidine. Thus this device permits the screening of new drugs for their effects on primary hemostasis and the study of ex vivo repeated measurements for the monitoring of antiaggregant therapy.

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