Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to ...identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.
Cigarette smoke, specifically the nicotine contained within, has been shown to cause ultrastructural changes in vascular endothelium resulting in the development of atherosclerosis. Our study ...examines the effects of nicotine on vascular smooth muscle cell (VSMC) migration and attempts to eludicidate the cellular mechanisms governing those effects.
Bovine aortic VSMC were cultured in 10% fetal bovine serum (FBS) growth media and exposed to 10
−8 nicotine for varying periods of time. Boyden chamber chemotaxis assays and a scrape injury model using confluent cells were used to assess cell motility. Activation of the mitogen-activated protein kinases (MAPK), p38 and p44/42, was assessed using Western blotting methods.
Nicotine, itself, did not cause significant VSMC migration. However, augmented migration was seen in nicotine-treated VSMCs (16.6
±
3-fold) and media (17.0
±
4-fold) with 10% FBS as chemoattractant. Inhibitors of p38 and p44/42 diminished this migration by 48.5
±
6% and 29.4
±
2%, respectively. Immunoblotting verified p38 and p44/42 activation with nicotine and inhibition with inhibitors of p38 and p44/42. Nicotine-treated endothelial cell (EC) conditioned media (CM) was shown to increase migration 20.3
±
l.l-fold. This chemotactic effect was diminished both with heat treatment and serial dilution.
In conclusion, nicotine enhances the chemotactiveness of VSMC. This migration is mediated via the MAPKs p38 and p44/42. Nicotine causes EC production of a chemoattractant molecule that enhances VSMC migration.
OBJECTIVEUntil recently, attention has been directed to disseminated intravascular coagulation as a cause of multiple organ failure (MOF). On the other hand, it has now become clear that humoral ...mediators play important roles in the pathogenesis of MOF. Therefore, we performed the present study in patients with thrombocytopenic MOF to investigate the relationship between various humoral mediators and vascular endothelial damage reported to be triggered by such humoral mediators in the pathogenesis of MOF.
DESIGNA retrospective clinical study.
SETTINGIntensive care unit of a university hospital.
PATIENTSThe study included 18 thrombocytopenic patients whose conditions progressed to septic MOF (MOF group) and 20 others who did not progress to MOF (non-MOF group). The MOF group and non-MOF group were also presented with infection and with platelet counts of <100,000/mm.
MEASUREMENTS AND MAIN RESULTSThe MOF group had fibrinolysis abnormality, as indicated by increased plasminogen activator inhibitor-1 level. On the other hand, the MOF group had increased polymorphonuclear elastase and polymorphonuclear-mediated fibrinogen degradation product levels with consequent prolonged elevation of thrombomodulin. In addition, both polymorphonuclear elastase and polymorphonuclear-fibrinogen degradation products were significantly positively correlated with thrombomodulin in the MOF group, but no such positive correlation was observed between interleukin-6 or plasminogen activator inhibitor-1 and thrombomodulin. In the non-MOF group, on the other hand, thrombomodulin exhibited no significant positive correlation with polymorphonuclear elastase, polymorphonuclear-fibrinogen degradation products, interleukin-6, or plasminogen activator inhibitor-1.
CONCLUSIONSOur study provided evidence that vascular endothelial damage was the primary cause of organ failures in patients with thrombocytopenic MOF and that humoral mediators played a major role in the development of vascular endothelial damage in such patients. These results suggest that it is important to treat thrombocytopenic MOF as a condition of vascular endothelial damage, with weight placed on countermeasures against disorders of humoral mediators.
Treatment of the 1,1-diiodo-1-alkenes
8
, prepared from the corresponding aldehydes with CI
4/PPh
3, with ZnCu/AcOH in THF–MeOH gave the (
Z)-1-iodo-1-alkenes
9
, selectively, in good yields.
Graphic
: Continuous hemodiafiltration (CHDF) is an essential procedure in critical care. However, application of this therapy to pediatric patients is associated with several problems derived from their ...smaller body size and weight compared with adults. We have successfully conducted CHDF in pediatric patients including newborns by taking such problems into consideration and carefully coping with them. The present study consisted of 60 pediatric patients treated with CHDF. Clinical efficacy and safety of CHDF in pediatric patients were assessed in these patients by reviewing patient clinical records. The 60 patients treated with CHDF included 27 males and 33 females. Their body weight ranged from 700 g to 53.0 kg. The mean CHDF duration was 6.80 ± 6.94 days. Blood access was provided in a veno‐venous mode in 42 patients, and an arterio‐venous mode in 18 patients. Of the 60 pediatric patients receiving CHDF, 31 patients survived without serious complications, achieving a survival rate of 51.7%. Successful CHDF in pediatric patients was achieved by careful and exact execution of the following countermeasures to overcome problems specific to application of this therapy to pediatric patients: minimization of the priming volume; use of colloid solutions or whole blood as priming solution; maintaining secure blood access; selection of an appropriate anticoagulant; temperature control of both the patient's body and components of the hemofiltration circuit. In pediatric critical care, CHDF is safely applicable to the critically ill and expected to produce a wide spectrum of clinical efficacy just as in adults.
Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly ...enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (C av,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.
The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine–piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 ...binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
Investigation into the etiology of atherosclerosis has identified cigarette smoking as a major risk factor. Although it has been established that cellular adhesion molecule expression on endothelial ...cells is stimulated by nicotine, the mechanism by which this occurs is not clear. The aim of this study was to determine the effect of nicotine on the expression of the adhesion molecules, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 inendothelial cells and to determine the involvement of imporcule tank known intermediaries, protein kinase C (PKC), p38 mitogen-activated protein kinase (p38 MAPK), and the transcription factors NF- Kappa B and AP-1. Human umbilical vein endothelial cells (HUVEC) were exposed to 10 super(-8) M nicotine for up to 24 h. Expression of ICAM-1 and VCAM-1 and phosphorylation of p38 were examined by immunoblot. Electrophoretic mobility shift assay was performed to determine NF- Kappa B and AP-1 activation. We observed that nicotine increased the expression of ICAM-1 and VCAM-1 with a peak at 6h.p38 MAPK was activated after 5 min exposure to 10 super(-8) mol/L nicotine and returned to baseline levels by 30 min. Exposure of HUVEC to nicotine resulted in a 4.1-fold increase of PKC activity at 5 min, which subsequently returned to control levels by 15 min. Nicotine (10 super(-8) mol/L) also increased NF- Kappa B and AP-1 activity. Inhibitors of p38 MAPK, PKC, and NF- Kappa B suppressed nicotine-stimulated expression of ICAM-1 and VCAM-1. Our results indicate that nicotine enhances the expression of ICAM-1 and VCAM-1 on the endothelial cell surface via a second messenger pathway which involves PKC and p38 MAPK-mediated activation of NF- Kappa B and AP-1, resulting in increased expression of these cellular adhesion molecules.
A convergent synthesis of the FGHI ring segment of yessotoxin was achieved via the intramolecular allylation of an α-chloroacetoxy ether and subsequent ring-closing metathesis.
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