Prognostic impact of blast cell counts in dysplastic bone marrow disorders (MDS and CMML I) with concomitant fibrosis

In a retrospective study, 43 patients with dysplastic neoplasms of the bone marrow (myelodysplastic syndromes and myelodysplastic/myeloproliferative-overlap neoplasms) associated with marked (grades 2–3) fibrosis were examined. Histopathologic and morphologic findings as well as cytogenetic and molecular results were correlated with clinical endpoints. Multilineage dysplasia (34 of 43 patients, 79 %) and hypercellular bone marrow (64 %) were found in most patients. In ten of 35 patients, poor risk karyotypes according to the International Prognostic Scoring System (IPSS) were recorded. The JAK2 V617F mutation was detected in four of 30 patients (13 %), and the KIT D816V mutation was found in two of 30 patients (6 %). Patients were mainly treated with palliative drugs and best supportive care. After an observation time of 1–41 (median 21) months, ten of 43 patients (23 %) had developed a secondary acute leukemia. The median survival of all 43 patients was 21.4 months (range 1.8–88.2 months). Of all prognostic parameters examined, the blast cell count at diagnosis was found to be a most reliable and most predictive marker concerning survival and leukemia progression. This confirms previous studies in dysplastic bone marrow neoplasms without fibrosis.     

Pharmacological characterization of a novel antiglaucoma agent,Bimatoprost (AGN 192024)

Replacement of the carboxylic acid group of prostaglandin (PG) F(2alpha) with a nonacidic moiety, such as hydroxyl, methoxy, or amido, results in compounds with unique pharmacology. Bimatoprost (AGN 192024) is also a pharmacologically novel PGF(2alpha) analog, where the carboxylic acid is replaced by a neutral ethylamide substituent. Bimatoprost potently contracted the feline lung parenchymal preparation (EC(50) value of 35-55 nM) but exhibited no meaningful activity in a variety of PG-sensitive tissue and cell preparations. Its activity seemed unrelated to FP receptor stimulation according to the following evidence. 1) Bimatoprost exhibited no meaningful activity in tissues and cells containing functional FP receptors. 2) Bimatoprost activity in the cat lung parenchyma is not species-specific because its potent activity in this preparation could not be reproduced in cells stably expressing the feline FP receptor. 3) Radioligand binding studies using feline and human recombinant FP receptors exhibited minimal competition versus [(3)H]17-phenyl PGF(2a) for Bimatoprost. 4) Bimatoprost pretreatment did not attenuate PGF(2alpha)-induced Ca(2+) signals in Swiss 3T3 cells. 5) Regional differences were apparent for Bimatoprost but not FP agonist effects in the cat lung. Bimatoprost reduced intraocular pressure in ocular normotensive and hypertensive monkeys over a 0.001 to 0.1% dose range. A single-dose and multiple-dose ocular distribution/metabolism studies using [(3)H]Bimatoprost (0.1%) were performed. Within the globe, bimatoprost concentrations were 10- to 100-fold higher in anterior segment tissues compared with the aqueous humor. Bimatoprost was overwhelmingly the predominant molecular species identified at all time points in ocular tissues, indicating that the intact molecule reduces intraocular pressure.     

Multislice computed tomography coronary angiography for triaging patients with positive radionuclide myocardial perfusion imaging

Sir, Myocardial perfusion imaging using single-photon emission computedtomography (SPECT) is the most commonly applied diagnostic imagingmodality in patients with suspected coronary artery diseasein the US, with more than 9 million procedures performed annually.¹The positive predictive value of SPECT is limited, and in aconsiderable number of patients with suspected perfusion deficitsconventional coronary angiography shows no significant coronarystenoses. Multislice computed tomography (MSCT) coronary angiographyallows the non-invasive assessment of coronary artery stenoses,and has a high negative predictive value.^2–4 Thus, MSCTmight be applied as a secondary gate-keeper in patients withpositive SPECT, prior to deciding whether to perform conventionalcoronary     

Pharmacodynamic and clinical trials of glycoprotein IIb/IIIa inhibitors and potential relationship of results to dosing

Glycoprotein IIb/IIIa inhibitors have become the standard of care for patients undergoing percutaneous coronary intervention (PCI) and for those presenting with non-ST-segment elevation myocardial infarction (NSTE-ACS). Clinical effects of GP IIb/IIIa inhibitors in PCI and NSTE-ACS strongly correlate with potency, consistency, and durability of platelet aggregation inhibition. Under standardized conditions [light transmission aggregometry (LTA), 20 micromol adenosine diphosphate (ADP) as an agonist, and D-phenylalanyl-L-propyl-L-arginine chloromethyl ketone (PPACK) as an anticoagulant], we demand consistent platelet aggregation inhibition >80% during the time of PCI (initial balloon inflation), and during the entire duration of therapy in NSTE-ACS. The benefit of abciximab (bolus 0.25 mg/kg plus infusion 10 microg/kg/min) correlates with >80% inhibition of platelet aggregation during the intervention (PCI) and immediately thereafter (<6 hours). The absence of a benefit with abciximab in NSTE-ACS is most likely due to <80% inhibition during the major part of the infusion period (>6 hours). Tirofiban does not achieve >80% inhibition at the time of PCI at a dose of 10 microg/kg bolus plus 0.15 microg/kg/min infusion, and at a dose of 0.4 lg/kg/min loading infusion for 30 minutes plus 0.1 microg/kg/min maintenance infusion, the target value is only reached after 18 h. Eptifibatide (double-bolus 180 microg/kg 10 min apart, followed immediately by a 2.0 microg/kg/min infusion) provided an instant, consistent, and durable antiplatelet effect for the entire duration of infusion, and a significant clinical benefit in both PCI (non-ACS patients) and medically managed NSTE-ACS patients.     

Non-invasive assessment of coronary flow reserve--valuable functional information in cardiac workflow

Coronary flow reserve (CFR) can be determined echocardiographically in the LAD in about 90% and in the RCA in more than 70% of patients, respectively, by the use of modern high-resolution ultrasound equipment. For this purpose either high frequency fundamental imaging or echo-contrast enhanced harmonic Doppler technology is used. The main advantage of the method lies in its noninvasiveness and the lack of radiation exposure. In combination with coronary morphologic findings obtained from heart catheterization, CFR is helpful in the planning of further invasive procedures for coronary artery disease and in the estimation of the prognosis of such procedures. The functional status after PTCA of LAD/RCA or mammary bypass surgery can be evaluated during follow-up monitoring. Alteration in the coronary microcirculation can also be discovered in a non-invasive manner; improvement of microcirculatory disorders by adequate therapy can be assessed by serial measurements of CFR