Endoscopic band ligation for postpolypectomy gastric bleeding

We report a case of a patient in whom endoscopic band ligation was achieved for postpolypectomy gastric bleeding. A 76‐year‐old man visited our hospital because of anemia. Endoscopy revealed a gastric polyp, approximately 12 mm in diameter, on the lesser curvature in the distal gastric body. The polyp was considered to be the source of chronic anemia and was therefore removed by using standard careful snare‐cautery polypectomy technique. Four days later, follow‐up endoscopy was performed to evaluate the postpolypectomy site, and an active bleeding postpolypectomy ulcer was identified. Initial attempts to achieve hemostasis with ethanol injection were unsuccessful. Immediate hemostasis was obtained with a subsequent endoscopic band ligation device. There has been no recurrent bleeding. Endoscopic band ligation might be a good treatment modality for the treatment of a postpolypectomy gastric bleeding lesion.     

The Preclinical Safety Evaluation of Human Monoclonal Antibody against Cytomegalovirus

The human monoclonal antibody against cytomegalovinis (Mab C23)was examined pharmacokinetically and toxicologically as partof the preclinical studies prior to approval for human use.Rats given repeated intravenous administrations of Mab C23 producedno antibodies against Mab C23 and maintained a blood Mab C23level in a dose-dependent manner. However, pregnant rabbitsproduced antibodies against Mab C23. The half-life of Mab C23in plasma was 15.9 days in rats, which was similar to that ofnormal human serum -globulin (NHSG). Neither behavioral effectsnor circulatory disturbance was found in mice, rats, and dogseven after a single intravenous injection of 100 or 200 mg/kg,which corresponds to 50 or 100 times the intended clinical dosage.The repeated doses of 2, 10, or 20 mg/kg of Mab C23 on six occasionswith 1- or 2-week intervals elicited a transient decrease inleukocyte counts in rats given 10 or 20 mg/kg, but no adverseeffects in cynomolgus monkeys. Mab C23 did not cause any reproductiveor developmental toxicity when administered to rats and rabbitsat dose levels of 20 mg/kg or less. However, pregnant animalsshowed lower plasma levels of Mab C23 than non-pregnant animals.The chromosomal aberration test disclosed no clastogenicityin human lymphocytes. An immunostaining for Mab C23 revealedno localizations in several tissues of cynomolgus monkeys givenintravenous doses of Mab C23. The preclinical safety evaluationin animals other than rabbits, which produced no antibodiesagainst Mab C23, showed that the behavior of Mab C23 is pharmacokineticallysimilar to that of NHSG and is as safe as NHSG, which has longbeen used as a biological agent. However, because there wasa difference in blood levels of Mab C23 between pregnant andnonpregnant animals, its clinical administration to pregnantpatients should differ from that to non-pregnant patients.     

Removal of a Large Common Bile Duct Stone Using Endoscopic Balloon Sphincter Dilation and Extracorporeal Shock Wave Lithotripsy

Abstract: Although endoscopic balloon sphincter dilation (EBSD) appears to be an attractive treatment modality, the rate of bile duct clearance is apparently reduced due to limited enlargement of the bile duct opening when the stones are large and/or numerous. We present the case of an 87-year-old woman who developed an extremely large bile duct stone. To crush the stone sufficiently to allow grasping by a mechanical lithotriptor or a basket catheter with the EBSD procedure, extracorporeal shock wave lithotripsy was performed and the fragments were removed successfully.     

Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptor

Summary. Background: Thromboxane A₂ receptor (TXA₂R) abnormality appears to dominantly disturb platelet function. Objectives: To reveal a molecular genetic defect in a patient with TXA₂R abnormality and investigate the mechanism for the impaired response to TXA₂. Patient: The proband (OSP‐2, PT) was a 7‐year‐old Japanese girl, suffering from repeated mucocutaneous bleeding. Methods and results: U46619 (2.5 and 10 μm )‐induced platelet aggregation was remarkably impaired in the proband and her father. Immunoblots showed that TXA₂R expression levels in their platelets were approximately 50% of controls, and nucleotide sequence analysis revealed that they were heterozygous for a novel mutation, c.167dupG in the TXA₂R cDNA. Expression studies using Chinese hamster ovary (CHO) cells indicated that the mutation is responsible for the expression defect in TXA₂R. We then examined α_IIbβ₃ activation by employing an initial velocity analysis and revealed that U46619 failed to induce a sustained α_IIbβ₃ and Rap1B activation in the proband. In addition, platelet secretion as monitored by P‐selectin expression was markedly impaired in response to U46619 but not to ADP. The interaction between secreted ADP and P2Y₁₂ has been shown to play a critical role in the sustained α_IIbβ₃ activation (Kamae et al. J Thromb Haemost 2006; 4 : 1379). As expected, small amounts of exogenous ADP (0.5 μm ) partially restored the sustained α_IIbβ₃ activation induced by U46619. Conclusion: Our present data strongly suggest that the impaired platelet activation in response to U46619 in the heterozygous subject for the TXA₂R mutation is, at least in part, as a result of the decrease in ADP secretion.     

A lower starting dose of eltrombopag is efficacious in Japanese patients with previously treated chronic immune thrombocytopenia

Background:  Eltrombopag is an oral, non‐peptide thrombopoietin receptor agonist that has shown efficacy and safety in chronic immune thrombocytopenia (ITP). However, ethnic differences in eltrombopag exposure have been reported: area under the curve exposure to eltrombopag was 87% greater among ITP patients of East Asian descent than among ITP patients of non‐East Asian ITP descent. Objectives:  To evaluate the efficacy and safety of eltrombopag by using, in Japanese ITP patients, lower starting (12.5 mg) and maximum (50 mg) doses of eltrombopag than the standard starting (50 mg) and maximum (75 mg) doses approved in the USA and Europe. Patients:  We examined 23 Japanese patients with previously treated chronic ITP with a platelet count of < 30 000 μL^?1 in a multicenter study comprising a randomized, double‐blind, placebo‐controlled phase for 6‐week evaluation (15 eltrombopag, and eight placebo) and an open‐label phase for 6‐month evaluation (23 eltrombopag). Results and Conclusions:  The response rate (platelet count of ≥ 50 000 μL^?1) at week 6 of the 6‐week double‐blind phase was 60% in eltrombopag‐treated patients and 0% in placebo‐treated patients. Ten of 23 patients (43.5%) responded for ≥ 75% of predefined assessment visits during the 6‐month open‐label phase. Notably, 22% (5/23) of patients responded to 12.5 mg of eltrombopag, which was administered within the first 3 weeks of eltrombopag treatment. Bleeding decreased with eltrombopag treatment as compared with baseline. Eltrombopag was generally well tolerated; one patient experienced a transient ischemic attack on day 9. Eltrombopag (12.5–50 mg) is effective for the management of Japanese patients with chronic ITP (NCT00540423).     

Critical role of ADP interaction with P2Y12 receptor in the maintenance of αIIbβ3 activation: association with Rap1B activation

OBJECTIVE: Platelet integrin alpha(IIb)beta3 plays a crucial role in platelet aggregation, and the affinity of alpha(IIb)beta3 for fibrinogen is dynamically regulated. Employing modified ligand-binding assays, we analyzed the mechanism by which alpha(IIb)beta3 maintains its high-affinity state. METHODS AND RESULTS: Washed platelets adjusted to 50 x 10(3) microL(-1) were stimulated with 0.2 U mL(-1) thrombin or 5 microm U46619 under static conditions. After the completion of alpha(IIb)beta3 activation and granule secretion, different kinds of antagonists were added to the activated platelets. The activated alpha(IIb)beta3 was then detected by fluorescein isothiocyanate (FITC)-labeled PAC1. The addition of 1 mum AR-C69931MX (a P2Y12 antagonist) or 1 mm A3P5P (a P2Y1 antagonist) disrupted the sustained alpha(IIb)beta3 activation by approximately 92% and approximately 38%, respectively, without inhibiting CD62P or CD63 expression. Dilution of the platelet preparation to 500 microL(-1) also disrupted the sustained alpha(IIb)beta3 activation, and the disruption by such dilution was abrogated by the addition of exogenous adenosine 5'-diphosphate (ADP) in a dose-dependent fashion. The amounts of ADP released from activated platelets determined by high-performance liquid chromatography were compatible with the amounts of exogenous ADP required for the restoration. We next examined the effects of antagonists on protein kinase C (PKC) and Rap1B activation induced by 0.2 U mL(-1) thrombin. Thrombin induced long-lasting PKC and Rap1B activation. AR-C69931MX markedly inhibited Rap1B activation without inhibiting PKC activation. CONCLUSIONS: Our data indicate that the continuous interaction between released ADP and P2Y12 is critical for the maintenance of alpha(IIb)beta3 activation.     

Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon

In this study, we have identified a patient (OSP-1) with a congenital P2Y12 deficiency showing a mild bleeding tendency from her childhood and examined the role of P2Y12 in platelet function. At low concentrations of agonists OSP-1 platelets showed an impaired aggregation to several kinds of stimuli, whereas at high concentrations they showed a specifically impaired platelet aggregation to adenosine diphosphate (ADP). ADP normally induced platelet shape change and failed to inhibit PGE1-stimulated cAMP accumulation in OSP-1 platelets. Molecular genetic analysis revealed that OSP-1 was a homozygous for a mutation in the translation initiation codon (ATG to AGG) in the P2Y12 gene. Heterologous cell expression of wild-type or mutant P2Y12 confirmed that the mutation was responsible for the deficiency in P2Y12. OSP-1 platelets showed a markedly impaired platelet spreading onto immobilized fibrinogen. Real-time observations of thrombogenesis under a high shear rate (2000 s(-1)) revealed that thrombi over collagen were small and loosely packed and most of the aggregates were unable to resist against high shear stress in OSP-1. Our data suggest that secretion of endogenous ADP and subsequent P2Y12-mediated signaling are critical for platelet aggregation, platelet spreading, and as a consequence, for stabilization of thrombus.