Dasatinib inhibits coated-platelet generation in patients with chronic myeloid leukemia

Since the introduction of tyrosine kinase inhibitors, the overall survival of patients with chronic myeloid leukemia has markedly improved. However long term use of these drugs results in various adverse events. Treatment with second generation dasatinib is often complicated by hemorrhagic events. Previous lumi-aggregometry studies have shown impaired platelet function in patients on dasatinib therapy. Dual agonist activated platelets (coated-platelets) are also sensitive indicators of platelet function. We hypothesized that dual activation with convulxin and thrombin of platelets in a flow cytometric assay could be a more sensitive method for detecting platelet dysfunction as compared to single agonist studies used in lumi-aggregometer. Platelets of healthy volunteers incubated with dasatinib as well as platelets from patients on dasatinib therapy were investigated. Low therapeutic plasma level dasatinib concentrations at which a considerable reduction in coated-platelet generation was observed in vitro, did not cause detectable change in platelet aggregation response. Coated-platelet assay and lumi-aggregometry were also investigated at 0, 1 and 4 hours after drug administration in dasatinib treated CML patients. Significant decrease was observed at 1 hour in maximal aggregation by collagen. Although the aggregation curves became normalized by 4 hours, coated-platelet generation was still inhibited in dasatinib treated patients. Nilotinib, another second generation tyrosine kinase inhibitor, had no effect on aggregation and on coated-platelet formation neither in vitro nor in ex vivo samples. At therapeutic plasma levels coated-platelet assay is more sensitive than lumi-aggregometry studies for the demonstration of the inhibitory effect of dasatinib on platelet function.     

Three years' experience with the sorin pericarbon stentless prosthesis: mid-term results with three different implantation techniques

BACKGROUND AND AIM OF THE STUDY: Sorin Pericarbon stentless pericardial valves were implanted using three different surgical techniques, and early and mid-term clinical and hemodynamic results were analyzed according to the method used. METHODS: Between January 2000 and December 2002, 102 Pericarbon stentless valves were implanted in 101 patients (55 females, 46 males; mean age 67.6+/-7.1 years). Among these patients, 63 had isolated aortic valve replacement and 39 underwent a combined procedure. The inflow portion of a matching-size prosthesis was fixed to the aortic annulus either by semi-continuous Prolene suture (n = 48), interrupted simple Ethibond (n = 29) or interrupted Ethibond mattress stitches (n = 25). Valve sizes were not significantly different in the three subgroups. The aortic cross-clamp and cardiopulmonary bypass times were 145+/-31 min and 171+/-39 min, respectively, with interrupted stitches; these times were significantly longer than in the continuous suture group (115+/-27 min and 143+/-45 min) or with interrupted mattress stitches (111+/-28 min and 137+/-34 min). RESULTS: Early mortality was 6.8% (n = 7) for the entire patient group. None of the deaths was valve-related. Postoperatively, all patients were followed up (mean 26.6+/-9.4 months). There were two late deaths (both non-valve-related). One patient developed early endocarditis, and the infected valve was re-replaced with another Pericarbon stentless valve. During the follow up period the mean and peak transvalvular gradient was decreased from 12.8+/-8.5 mmHg to 9.1+/-2.3 mmHg and from 22.5+/-13.9 mmHg to 16.1+/-4.3 mmHg respectively, and left ventricular wall thickness from 15.5+/-2.1 mm to 12.8+/-1.4 mm. Regurgitation was not more than trivial for any of the implanted valves. The implantation technique did not significantly affect the hemodynamic performance of the Pericarbon stentless valve. CONCLUSION: The Sorin Pericarbon stentless pericardial prosthesis showed excellent hemodynamic performance, even if implanted in a matching-size aortic root. The implantation technique used had no significant influence on valve performance.     

Application of the modified vaccination technique for the prevention and cure of chronic ailments

Over the years vaccination has proven to be the most successful health protection program for large populations, to prevent them from acquiring serious infectious and contagious diseases caused by exogenous antigens (ags) such as bacteria and viruses. Protection is generally achieved by an active immunization program, though passive immunization has also been employed, especially in the past, to combat diseases caused by certain bacterial infections (e.g. tetanus, diphtheria, etc.).Most recently, encouraging research data suggests that therapeutic approaches employing vaccination techniques can also be used to correct or deal with mishaps induced by or involving endogenous ags. However, most attempts at employing conventional vaccination techniques to do so have proven less than successful. In the case of cancer, one of the reasons for this is that the presentation of cancer related ags in presently available immunization frameworks is unable to evoke a powerful, specific cancer killing response. Therefore, drug treatments have been required in order to achieve additional beneficial effects.Recently, the Barabas group has developed a new vaccination technique (the third vaccination method, after active and passive immunization) called Modified Vaccination Technique (MVT). In experiments the MVT has been able to prevent-and with equal effectiveness, terminate-mishaps induced by or involving endogenous ags, e.g. in an experimental autoimmune kidney disease called slowly progressive Heymann nephritis (SPHN).The MVT is safe, and is able to initiate a specific immune response in the injected host (provided the injected components are in pure form). The MVT promises to provide the next generation of vaccines for the prevention, treatment, and termination of chronic disorders in humans, such as autoimmune diseases, cancer, and chronic infections.