MH_dev_141

Pharmacodynamics and pharmacokinetics of the novel P25116 REA antagonist vorapaxar ( formerly P35240 REA 530348 ) in healthy subjects . PURPOSE : The aim of our study was to evaluate the pharmacology of vorapaxar ( P35240 REA 530348 ) , an oral P25116 REA antagonist , in healthy volunteers . METHODS AND RESULTS : In two randomized , placebo-controlled studies , subjects received either single ascending doses of vorapaxar ( 0.25 , 1 , 5 , 10 , 20 , or 40 mg ; n = 50 ) , multiple ascending doses of vorapaxar ( 1 , 3 , or 5 mg / day for 28 days ; n = 36 ) , a loading dose ( 10 or 20 mg ) followed by daily maintenance doses ( 1 mg ) for 6 days ( n = 12 ) , or placebo . Single 20 - and 40 - mg doses of vorapaxar completely inhibited thrombin receptor activating peptide ( TRAP ) - induced platelet aggregation ( > 80 % inhibition ) at 1 h and sustained this level of inhibition for ≥ 72 h . Multiple doses yielded complete inhibition on Day 1 ( 5 mg / day ) and Day 7 ( 1 and 3 mg / day ) . Adverse events were generally mild , transient , and unrelated to dose . CONCLUSION : DB09030 SUB provided rapid and sustained dose-related inhibition of platelet aggregation without affecting bleeding or clotting times .

Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at DB00988 MEN D2 - and Serotonin - P08908 REA - receptors as well as an antagonism at Serotonin - 5 - Q13049 REA - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .

DB09030 SUB : first global approval . DB09030 SUB [ DB09030 SUB ( ® ) ( US ) ] , an orally active protease-activated receptor - 1 ( P25116 REA ) receptor antagonist , has been developed by Merck & Co for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction ( MI ) or peripheral arterial disease ( PAD ) . DB09030 SUB has received its first global approval for this indication in the US . This article summarizes the milestones in the development of vorapaxar leading to this first approval for the reduction of thrombotic cardiovascular events in patients with a prior MI or PAD .

Stage-dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4.3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3.4 and 4.5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . DB00622 MEN , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .

DB09030 SUB expands antiplatelet options . Which patients may benefit from thrombin receptor antagonism ? DB09030 SUB is the first substance of a new class of antiplatelet drugs that has been tested in large clinical trials . The protease-activated receptor 1 ( P25116 REA ) antagonist inhibits thrombin-induced platelet activation to prevent atherothrombosis . In the phase 3 trials TRACER ( acute coronary syndrome ) and TRA 2P - TIMI 50 ( stable atherosclerosis ) reducing ischemic events with vorapaxar came at the cost of bleeding . TRACER compared vorapaxar to placebo in 12,944 patients who had non-ST-segment elevation acute coronary syndromes on top of contemporary treatment including dual antiplatelet therapy ( aspirin and clopidogrel ) . DB09030 SUB reduced ischemic events non-significantly , but increased bleeding significantly , therefore not justifying triple antiplatelet therapy in this setting . Follow-up was stopped early because of bleeding . TRA 2P - TIMI 50 examined 26,449 patients who had a history of myocardial infarction , ischemic stroke , or peripheral arterial disease . DB09030 SUB reduced ischemic events and increased bleeding both significantly . Recruitment of patients with prior stroke was stopped early . Net clinical outcome and subgroup analyses suggested that vorapaxar could be beneficial for patients with prior myocardial infarction - but no history of stroke .

P25116 REA antagonists : current state of evidence . DB09030 SUB ( P35240 REA 530348 ) and atopaxar ( E5555 ) are oral protease-activated receptor - 1 ( P25116 REA ) antagonists with high bioavailability . They inhibits thrombin induced platelet aggregation by competitively inhibiting P25116 REA . We systematically evaluated the evidence for the efficacy and safety of all P25116 REA antagonists as well as for the individual drugs vorapaxar and atopaxar in different databases-PubMed , EMBASE , Scopus , and Cochrane register of Controlled Clinical Trials ( CENTRAL ) . We selected randomized controlled trials of P25116 REA antagonists that reported on cardiovascular mortality as a clinical outcome . The random-effects Mantel-Haenszel model was used to evaluate the effect of P25116 REA antagonists on cardiovascular mortality . Seven trials were selected ( N = 42,355 ) for analysis . P25116 REA antagonists as a class , as well as individually , were associated with a non-significant numerically lower risk of cardiovascular mortality than that seen with agents used in the control group ; RR , 0.93 ; 95 % CI , 0.83- 1.04 ; P = 0.20 ) . No heterogeneity was noted . However , P25116 REA antagonists also appeared to increase the risk of bleeding significantly . P25116 REA antagonists appear to be associated with some reduction in the risk of cardiovascular mortality ; however the significantly higher bleeding risk noted with P25116 REA antagonists appear to mandate a very careful selection of patients that may benefit without a substantially increased risk of bleeds .

DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 REA expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression , and increased P38936 REA expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .

DB09030 SUB , an oral P25116 REA receptor antagonist , does not affect the pharmacokinetics and pharmacodynamics of warfarin . PURPOSE : DB09030 SUB is an orally active protease-activated receptor 1 ( P25116 REA ) antagonist that inhibits thrombin-induced platelet aggregation . This open-label study assessed the pharmacokinetics and pharmacodynamics of single-dose warfarin in the presence / absence of multiple-dose vorapaxar in 12 healthy men . METHODS : Subjects received two treatments separated by ≥ 7 - day washout : Treatment A warfarin 25 mg ( Day 1 ) ; Treatment B vorapaxar 2.5 mg / day on Days 1-6 and vorapaxar 40 mg coadministered with warfarin 25 mg ( Day 7 ) . R-warfarin , S-warfarin , and prothrombin time ( PT ) were assayed predose and up to 120 h postdose . RESULTS : The geometric mean ratio ( GMR ) as a percentage ( warfarin + vorapaxar / warfarin ) was calculated . The GMR ( 90 % CIs ) estimates of C ( max ) were 105 ( 99 , 111 ) and 105 ( 99 , 112 ) for R - and S-warfarin , respectively . The GMR ( 90 % CIs ) estimates of AUC ( 0 - ∞ ) were 108 ( 101 , 116 ) and 105 ( 96 , 115 ) for R - and S-warfarin , respectively . The GMR ( 95 % CIs ) estimates of AUC ( 0-120 h ) for PT and INR were 97 ( 95 , 98 ) and 96 ( 94 , 98 ) , respectively . CONCLUSION : Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin , suggesting that the coadministration of these two drugs or vorapaxar coadministered with other P11712 REA / P33261 REA substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction .

Inhibition of c-kit receptor tyrosine kinase activity by DB00619 MEN , a selective tyrosine kinase inhibitor . DB00619 MEN ( formerly known as CGP 57148B ) is a known inhibitor of the c-abl , bcr-abl , and platelet-derived growth-factor receptor ( P09619 REA ) tyrosine kinases . This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia . We sought to extend the activity profile of DB00619 MEN by testing its ability to inhibit the tyrosine kinase activity of c-kit , a receptor structurally similar to P09619 REA . We treated a c-kit expressing a human myeloid leukemia cell line , M - 07e , with DB00619 MEN before stimulation with Steel factor ( SLF ) . DB00619 MEN inhibited c-kit autophosphorylation , activation of mitogen-activated protein ( Q96HU1 ) kinase , and activation of Akt without altering total protein levels of c-kit , Q96HU1 kinase , or Akt . The concentration that produced 50 % inhibition for these effects was approximately 100 nmol / L . DB00619 MEN also significantly decreased SLF-dependent growth of M - 07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF . In contrast , the compound had no effect on Q96HU1 kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor . We also tested the activity of DB00619 MEN in a human mast cell leukemia cell line ( HMC - 1 ) , which has an activated mutant form of c-kit . DB00619 MEN had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor . These findings show that DB00619 MEN selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival . This compound may be useful in treating cancers associated with increased c-kit kinase activity .

Protease-activated receptor - 1 and platelet-derived growth factor in spinal cord neurons are implicated in neuropathic pain after nerve injury . Recently , it has been reported that both thrombin-sensitive protease-activated receptor 1 ( P25116 REA ) and platelet-derived growth factor ( PDGF ) are present not only in platelets , but also in the CNS , which indicates that they have various physiological functions . In this study , we evaluated whether P25116 REA / PDGF in the spinal cord could contribute to the development of a neuropathic pain-like state in mice . Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were significantly suppressed by repeated intrathecal injection of hirudin , which is characterized as a specific and potent thrombin inhibitor . Furthermore , a single intrathecal injection of thrombin produced long-lasting hyperalgesia and allodynia , and these effects were also inhibited by hirudin in normal mice . In nerveligated mice , the increase in the binding of [ 35S ] GTPgammaS to membranes of the spinal cord induced by thrombin and P25116 REA - like immunoreactivity ( IR ) in the spinal cord were each greater than those in sham-operated mice . Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were also suppressed by repeated intrathecal injection of either the PDGF alpha receptor ( PDGFRalpha ) / Fc chimera protein or the P09619 REA - dependent tyrosine kinase inhibitor AG17 [ ( 3,5- di-tert-butyl - 4 - hydroxybenzylidene ) - malononitrile ] . Moreover , thermal hyperalgesia and tactile allodynia induced by thrombin in normal mice were virtually eliminated by intrathecal pretreatment with PDGFRalpha / Fc . In immunohistochemical studies , P25116 REA - like IR-positive cells in the spinal dorsal horn were mostly colocated on PDGF-like IR-positive neuronal cells . These data provide novel evidence that P25116 REA and PDGF-A-mediated signaling pathway within spinal cord neurons may be directly implicated in neuropathic pain after nerve injury in mice .

P10275 REA rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration-resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen-androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with DB08899 MENMAX DB08899 MEN , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .

Mass spectrometry and hydrogen / deuterium exchange measurements of alcohol-induced structural changes in cellular retinol-binding protein type I . To bind and release its ligand , cellular retinol-binding protein type I ( P09455 REA ) needs to undergo conformational and dynamic changes to connect the inner , solvent-shielded cavity , where retinol is found to bind , and the outside medium . DB00162 dissociation in vitro is favoured by water / alcohol mixtures whose moderately low dielectric constants mimic a property characteristic of the membrane microenvironment where this process occurs in vivo . Apo - and holo - P09455 REA , in either water / methanol or water / trifluoroethanol ( TFE ) mixtures , were analyzed at equilibrium by electrospray ionization with orthogonal quadrupole time-of-flight mass spectrometry ( P19957 REA - Q-TOFMS ) to identify the alcohol-induced species . The questions were asked whether the presence of alcohols affects protein dynamics , as reflected by hydrogen / deuterium ( H / D ) exchange monitored by continuous-labelling experiments , and to which extent retinol dissociation influences the process . With increasing methanol , at pH near neutrality , apo - P09455 REA exhibits a progressively more compact conformation , resulting in reduced H / D exchange with respect to the native protein in water . DB00162 dissociation from the holo-protein did not promote hydrogen replacement . Similarly , in the presence of the low TFE concentration sufficient to cause retinol dissociation , the hydrogen exchange of the resulting apo-protein was not exalted . However , in contrast with the alkanol , higher TFE concentrations induced a transition of apo - P09455 REA to a new alpha-helix conformation capable of exchanging all available hydrogen atoms .

Q03135 REA interacts with 5 - Q13049 REA serotonin receptors and profoundly modulates the signaling of selected Galphaq-coupled protein receptors . 5 - Hydroxytryptamine 2A ( 5 - HT ( 2A ) ) serotonin receptors are important for a variety of functions including vascular smooth muscle contraction , platelet aggregation , and the modulation of perception , cognition , and emotion . In a search for 5 - HT ( 2A ) receptor-interacting proteins , we discovered that caveolin - 1 ( Cav - 1 ) , a scaffolding protein enriched in caveolae , complexes with 5 - HT ( 2A ) receptors in a number of cell types including P13671 REA glioma cells , transfected P29320 REA - 293 cells , and rat brain synaptic membrane preparations . To address the functional significance of this interaction , we performed RNA interference-mediated knockdown of Cav - 1 in P13671 REA glioma cells , a cell type that endogenously expresses both 5 - HT ( 2A ) receptors and Cav - 1 . We discovered that the in vitro knockdown of Cav - 1 in P13671 REA glioma cells nearly abolished 5 - HT ( 2A ) receptor-mediated signal transduction as measured by calcium flux assays . RNA interference-mediated knockdown of Cav - 1 also greatly attenuated endogenous Galpha ( q ) - coupled P2Y purinergic receptor-mediated signaling without altering the signaling of P25116 REA thrombin receptors . Cav - 1 appeared to modulate 5 - HT ( 2A ) signaling by facilitating the interaction of 5 - HT ( 2A ) receptors with Galpha ( q ) . These studies provide compelling evidence for a prominent role of Cav - 1 in regulating the functional activity of not only 5 - HT ( 2A ) serotonin receptors but also selected Galpha ( q ) - coupled receptors .

Role of SCH 79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage . BACKGROUND AND PURPOSE : Plasma thrombin concentration is increased after subarachnoid hemorrhage ( Q53FZ2 ) . However , the role of thrombin receptor ( protease-activated receptor - 1 [ P25116 REA ] ) in endothelial barrier disruption has not been studied . The aims of this study were to investigate the role of P25116 REA in orchestrating vascular permeability and to assess the potential therapeutics of a P25116 REA antagonist , SCH 79797 , through maintaining vascular integrity . METHODS : SCH 79797 was injected intraperitoneally into male Sprauge-Dawley rats undergoing Q53FZ2 by endovascular perforation . Assessment was conducted at 24 hours after Q53FZ2 for brain water content , Evans blue content , and neurobehavioral testing . To explore the role of P25116 REA activation and the specific mechanism of SCH 79797 ' s effect after Q53FZ2 , Western blot , immunoprecipitation , and immunofluorescence of hippocampus tissue were performed . A P38936 REA - activated kinase - 1 ( PAK 1 ) inhibitor , IPA - 3 , was used to explore the underlying protective mechanism of SCH 79797 . RESULTS : At 24 hours after Q53FZ2 , animals treated with SCH 79797 demonstrated a reduction in brain water content , Evans blue content , and neurobehavioral deficits . SCH 79797 also attenuated P25116 REA expression and maintained the level of vascular endothelial-cadherin , an important component of adherens junctions . Downstream to P25116 REA , c-Src-dependent activation of P38936 REA - activated kinase - 1 led to an increased serine / threonine phosphorylation of vascular endothelial-cadherin ; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial-cadherin with endocytosis orchestrator β-arrestin - 2 . These pathological states were suppressed after SCH 79797 treatment . CONCLUSIONS : P25116 REA activation after Q53FZ2 increases microvascular permeability , at least , partly through a P25116 REA - c-Src - P38936 REA - activated kinase - 1 - vascular endothelial-cadherin phosphorylation pathway . Through suppressing P25116 REA activity , SCH 79797 plays a protective role in maintaining microvascular integrity after Q53FZ2 .

P35367 REA occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 REA occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . ( + ) - DB01114 MEN , a selective and classical antihistamine , occupied 76.8 + / - 4.2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg ( + ) - chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98.2 + / - 1.2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17.2 + / - 14.2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea-pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea-pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second-generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .

No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects . BACKGROUND : DB09030 SUB , a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease , is a potent , orally bioavailable thrombin receptor antagonist selective for the protease-activated receptor 1 ( P25116 REA ) . METHODS : Since race / ethnicity may affect the safety , efficacy and dosage of drugs , this study was conducted to evaluate potential differences in the pharmacodynamics , pharmacokinetics and safety of vorapaxar after single ( 5 , 10 , 20 , or 40 mg ) or multiple ( 0.5 , 1 , or 2.5 mg once daily ) doses in healthy Japanese and matched ( gender , age , height , and weight ) Caucasian volunteers . RESULTS : DB09030 SUB was well tolerated in both Japanese and Caucasian subjects . Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial / ethnic groups were similar . In both racial groups , complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2.5 mg daily maintenance dose . CONCLUSION : There were no substantial differences in the safety , pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects .

Internet resources in GPCR modelling . G-Protein coupled receptors ( GPCRs ) , one of the most important families of drug targets , belong to the super family of integral membrane proteins characterized by seven transmembrane helices . Because they are difficult to crystallize , the three dimensional structure of these receptors have not yet been determined by X-ray crystallography , except one . In the absence of a 3 - D structure , in-silico approaches for solving the structure of this class of proteins are widely used and provide valuable information for structure based drug design . There are several web servers and computer programs available that automate the modelling process of GPCRs . Some of these include Modeller , Swiss-Model server , Homer , etc . Using these tools reliable homology models of human histamine H1 receptor ( P35367 REA ) and thrombin receptor ( P25116 REA ) have been generated which explain the binding mode of the standard antagonists of these receptors and may be useful in designing their novel antagonists .

Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 REA . DB01259 MEN is a potent dual inhibitor of HER - 2 and P00533 REA . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side-effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab-refractory metastatic breast cancer . DB01259 MEN may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .

Augmentation by citalopram of risperidone-induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : DB00734 MEN ( 1.0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 REA antagonist , WAY 100635 ( 0.2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment-resistant depression may be due , at least in part , to potentiation of SSRI-induced increases in cortical DA and NE . The contributions of P08908 REA receptor stimulation and 5 - Q13049 REA and alpha 2 adrenergic receptor antagonism to this augmentation are discussed .

Clinical potential of vorapaxar in cardiovascular risk reduction in patients with atherosclerosis . DB09030 SUB ( ZONTIVITY ™ , formerly known as P35240 REA 530348 ) is a specific , orally active antagonist of the protease-activated receptor - 1 ( P25116 REA ) on platelets . It inhibits thrombin-induced platelet activation by binding to the ectodomain of P25116 REA . After animal studies and Phase II studies showed that vorapaxar sufficiently inhibits platelet activation without significantly increasing bleeding complications , safety and efficacy of vorapaxar were assessed in two large multicenter trials in patients with coronary artery disease and atherosclerosis . The Thrombin-Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndromes ( TRACER ) trial investigated safety and efficacy of vorapaxar in patients with an acute coronary syndrome without ST-segment elevation . The Trial to Assess the Effects of DB09030 SUB in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50 ( TRA 2 ° P-TIMI 50 ) investigated atherothrombotic events in patients with stable atherosclerosis . Results of both studies suggested that vorapaxar given in addition to standard antiplatelet therapy can reduce atherothrombotic events , but increases the risk of mild and moderate bleeding complications . This review article summarizes the main results of TRACER and TRA 2 ° P-TIMI 50 and suggests patient cohorts that might benefit from treatment with vorapaxar in addition to standard antiplatelet therapy .

Safety of the novel protease-activated receptor - 1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke . BACKGROUND : DB09030 SUB , formerly P35240 REA 530348 , is a novel , orally active , potent thrombin receptor inhibitor selective for the protease-activated receptor - 1 ( P25116 REA ) . Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events , particularly myocardial infarction , without increasing bleeding risk . The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin . METHODS : Ninety patients with previous ischemic stroke ( ≥ 14 days to < 1 year before randomization ) were randomized to receive vorapaxar ( 1 or 2.5 mg ) or placebo once daily for 60 days . All patients received aspirin ( 75-150 mg / day ) . The primary endpoint was overall incidence of adverse events during the protocol-defined treatment phase ( 60 days ) . RESULTS : Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events , including serious adverse events . None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo . Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar . CONCLUSIONS : DB09030 SUB used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke .

Store-operated Ca2 + entry ( SOCE ) induced by protease-activated receptor - 1 mediates Q13586 REA protein phosphorylation to inhibit SOCE in endothelial cells through AMP-activated protein kinase and p38β mitogen-activated protein kinase . The Ca ( 2 + ) sensor Q13586 REA is crucial for activation of store-operated Ca ( 2 + ) entry ( SOCE ) through transient receptor potential canonical and Orai channels . Q13586 REA phosphorylation serves as an " off switch " for SOCE . However , the signaling pathway for Q13586 REA phosphorylation is unknown . Here , we show that SOCE activates AMP-activated protein kinase ( AMPK ) ; its effector p38β mitogen-activated protein kinase ( p38β MAPK ) phosphorylates Q13586 REA , thus inhibiting SOCE in human lung microvascular endothelial cells . Activation of AMPK using 5 - aminoimidazole - 4 - carboxamide - 1 - β-d-ribofuranoside ( AICAR ) resulted in Q13586 REA phosphorylation on serine residues and prevented protease-activated receptor - 1 ( P25116 REA ) - induced Ca ( 2 + ) entry . Furthermore , AICAR pretreatment blocked P25116 REA - induced increase in the permeability of mouse lung microvessels . Activation of SOCE with thrombin caused phosphorylation of isoform α1 but not α2 of the AMPK catalytic subunit . Moreover , knockdown of AMPKα 1 augmented SOCE induced by thrombin . Interestingly , SB203580 , a selective inhibitor of p38 MAPK , blocked Q13586 REA phosphorylation and led to sustained Q13586 REA - puncta formation and Ca ( 2 + ) entry . Of the three p38 MAPK isoforms expressed in endothelial cells , p38β knockdown prevented P25116 REA - mediated Q13586 REA phosphorylation and potentiated SOCE . In addition , inhibition of the SOCE downstream target P62158 kinase kinase β ( CaMKKβ ) or knockdown of AMPKα 1 suppressed P25116 REA - mediated phosphorylation of p38β and hence Q13586 REA . Thus , our findings demonstrate that SOCE activates CaMKKβ-AMPKα 1 - p38β MAPK signaling to phosphorylate Q13586 REA , thereby suppressing endothelial SOCE and permeability responses .

DB09030 SUB : a novel protease-activated receptor - 1 inhibitor . INTRODUCTION : Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences . AREAS COVERED : Only 20 % relative risk ( ∼ 2 % absolute risk ) reduction associated with newer P2Y ( 12 ) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy . Therefore , inhibition of the thrombin-protease-activated receptor ( PAR ) - 1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients . There are two major P25116 REA blockers are under investigations - vorapaxar and atopaxar . In preclinical and Phase I - II studies , inhibition of thrombin-mediated platelet activation by a P25116 REA inhibitor , in general , has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding . However , intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns . EXPERT OPINION : At this time , the specific role of P25116 REA inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome , both during the acute setting and as a long-term therapeutic agent , is not clear . Although the P25116 REA inhibitors are associated with less bleeding , its effectiveness as an antithrombotic agent and also side effects are major concerns . Future large-scale trials with goals addressing these concerns are needed to define the specific role of P25116 REA receptor inhibitor .

Pharmacokinetics of the novel P25116 REA antagonist vorapaxar in patients with hepatic impairment . PURPOSE : To determine whether hepatic impairment has an effect on the pharmacokinetics ( PK ) of vorapaxar or M20 , its main pharmacologically active metabolite . METHODS : This was an open-label study in which a single 40 - mg oral dose of vorapaxar was administered to patients with mild ( n = 6 ) , moderate ( n = 6 ) , and severe ( n = 4 ) hepatic impairment and healthy controls ( n = 16 ) matched for age , gender , weight , and height . Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose . RESULTS : Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls . Group mean values for vorapaxar C ( max ) and AUC ( tf ) were 206-279 ng / mL and 14,200- 18,200 ng · h / mL , respectively , with the lowest values observed in patients with severe impairment . DB09030 SUB median T ( max ) and mean t ( 1/2 ) values were 1.00- 1.75 h and 298-366 h , respectively . There was no apparent correlation between vorapaxar or M20 exposure or t ( 1/2 ) values and disease severity . DB09030 SUB was generally well tolerated ; one serious adverse event ( gastrointestinal bleeding secondary to ruptured esophageal varices ) was reported in a patient with severe hepatic impairment . CONCLUSIONS : Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20 . No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment . Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment , administration of vorapaxar to such patients is not recommended given their bleeding diathesis .

Therapy with a synthetic retinoid - - ( Ro 10-1670 ) etretin - - increases the cellular retinoic acid-binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 REA ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , DB00459 MEN ( Ro 10-1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 REA levels were not altered during therapy . The results show that P09455 REA and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .

Distinct signaling functions for Shc isoforms in the heart . Thrombin activates protease-activated receptor - 1 ( P25116 REA ) and engages signaling pathways that influence the growth and survival of cardiomyocytes as well as extracellular matrix remodeling by cardiac fibroblasts . This study examines the role of Shc proteins in P25116 REA - dependent signaling pathways that influence ventricular remodeling . We show that thrombin increases p46Shc / p52Shc phosphorylation at DB00135 ( 239 ) / DB00135 ( 240 ) and DB00135 ( 317 ) ( and p66Shc - DB00133 ( 36 ) phosphorylation ) via a pertussis toxin-insensitive epidermal growth factor receptor ( P00533 REA ) transactivation pathway in cardiac fibroblasts ; p66Shc - DB00133 ( 36 ) phosphorylation is via a MEK-dependent mechanism . In contrast , cardiac fibroblasts express beta ( 2 ) - adrenergic receptors that activate P29323 REA through a pertussis toxin-sensitive P00533 REA transactivation pathway that does not involve Shc isoforms or lead to p66Shc - DB00133 ( 36 ) phosphorylation . In cardiomyocytes , thrombin triggers MEK-dependent p66Shc - DB00133 ( 36 ) phosphorylation , but this is not via P00533 REA transactivation ( or associated with Shc - DB00135 ( 239 ) / DB00135 ( 240 ) and / or DB00135 ( 317 ) phosphorylation ) . Importantly , p66Shc protein expression is detected in neonatal , but not adult , cardiomyocytes ; p66Shc expression is induced ( via a mechanism that requires protein kinase C and MEK activity ) by Pasteurella multocida toxin , a Galpha ( q ) agonist that promotes cardiomyocyte hypertrophy . These results identify novel regulation of individual Shc isoforms in receptor-dependent pathways leading to cardiac hypertrophy and the transition to heart failure . The observations that p66Shc expression is induced by a Galpha ( q ) agonist and that P25116 REA activation leads to p66Shc - DB00133 ( 36 ) phosphorylation identifies p66Shc as a novel candidate hypertrophy-induced mediator of cardiomyocyte apoptosis and heart failure .

Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 REA - activated endothelial cells by Q9UNN8 and P25116 REA dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 REA ) - alpha up-regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 REA ) down-regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 ) - IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 REA and thrombin on the expression of sPLA ( 2 ) - IIA and extracellular signal-regulated kinase ( P29323 REA ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 ) - IIA was quantitatively measured by an enzyme-linked-immunosorbent-assay following stimulation of HUVECs with either thrombin or P01375 REA in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 REA - kinase ) inhibitor LY294002 and the cholesterol-depleting drug methyl-beta-cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 ) - IIA in HUVECs , however , P01375 REA potently induced its expression . The prior treatment of cells with P25054 REA inhibited expression of sPLA ( 2 ) - IIA through the Q9UNN8 - dependent cleavage of P25116 REA . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 REA - mediated expression of sPLA ( 2 ) - IIA through the cleavage of P25116 REA . The Q9UNN8 - dependent cleavage of P25116 REA by both P25054 REA and thrombin increased the phosphorylation of P29323 REA 1/2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 REA and thrombin against sPLA ( 2 ) - IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 REA - kinase dependent protective activity for thrombin such that its cleavage of the lipid-raft localized P25116 REA inhibits the P01375 REA - mediated expression of sPLA ( 2 ) - IIA in HUVECs .