Two multicenter, randomized, double-blind, crossover studies with identical designs evaluated the efficacy of oral extended-release hydromorphone (HHER) administered q24h compared with immediate-release hydromorphone (HHIR) dosed four times daily in patients with persistent moderate to severe pain. Patients titrated to a stable HHER dose were randomized to individualized doses of HHER or HHIR for 3 to 7 days before crossover to the second treatment. Primary efficacy end point was the mean of average pain intensity (API) scores, rated on a 0- to 10-point numeric scale, over the last 2 days before the pharmacokinetics/pharmacodynamics day of each double-blind period. Difference between treatments (HHER - HHIR) in study 1 was 0.17 with a 90% confidence interval (CI) (-0.01, 0.34); in study 2, difference was 0.07 with a 90% CI (-0.12, 0.26). There were no significant differences between treatments in API scores or amount of rescue medication used at any time interval within the 24-hour dosing period. No reduction in pain control occurred in patients administered HHER at the end of the 24-hour dosing period. Most treatment-emergent adverse events were opioid-related. In these studies, HHER administered q24h and HHIR dosed four times daily provided comparable analgesia at an equivalent total daily dose.
Twenty-five patients with a diagnosis of myelodysplastic syndromes (MDS) were randomized to either begin therapy with pentoxifylline, ciprofloxacin and dexamethasone (PCD) immediately (10 patients) or after a 12 week observation period (control arm, 15 patients). PCD was administered with the goal of suppressing cytokine-induced excessive intramedullary apoptosis of hematopoietic cells. No marked fluctuations of blood counts were noted during the period of observation. Twenty-two patients completed at least 12 weeks of therapy: 18/22 showed some type of hematologic response, 9/18 showing an improvement in absolute neutrophil count only (p = < 0.001) and 9/18 showing multi-lineage responses. No unique category of MDS responded better, however 19/25 patients had refractory anemia (RA)/RA with ringed sideroblasts. The median time to response was 6 weeks and 3/18 responding patients maintained their responses beyond a year. We conclude that hematologic improvement in response to PCD therapy supports the validity of this unique anti-cytokine approach. Future trials should combine PCD therapy with established approaches (growth factors/chemotherapy) and also should focus on identifying more effective ways of suppressing the pro-apoptotic cytokines in MDS.
The antithrombotic action of argatroban, a synthetic thrombin inhibitor, was studied in a canine model of coronary cyclic flow having some of the characteristics of acute unstable angina. Heparin was studied as a reference anticoagulant. Localized endothelial damage was induced in the circumflex coronary artery of anaesthetized open‐chest foxhounds and a critical stenosis was applied by use of a Lexan constrictor placed around the artery at the site of endothelial damage. An electro‐magnetic flow probe was placed distal to the lesion, and cyclic flow variations (CFVs) were observed, as thrombi formed at the site of the arterial lesion and were dislodged. Test compounds were administered by i.v. infusion commencing 1 h after the appearance of CFVs, and maintained for 1 h. On termination of the treatments, coronary flow was observed for a further 60 min. A series of blood samples were taken at predetermined times throughout each experiment in order to determine the coagulation parameters, thrombin time (TT) activated partial thromboplastin time (aPTT) and for the determination of fibrinopeptide A (FpA) levels before, during and post‐treatment. Argatroban and heparin showed antithrombotic effects in this model. Argatroban dose‐dependently increased the minimum coronary flow at the nadir of the CFVs from 5.4 ± 1.7 to 9.1 ± 2.1 ml min−1 (30 μg kg−1 min−1, P = 0.041) and from 2.9 ± 0.9 to 16.3 ± 4.5 ml min−1 (100 μg kg−1 min−1, P = 0.023, n = 8 dogs at each dose level). Heparin (5 and 15 iu kg−1 min−1) also increased minimum flow, but the increase was not statistically significant at the 5% level, although the P value in animals treated with 15 iu kg−1 min−1 (P = 0.0521, n = 6 dogs) fell just outside this limit. Although neither compound significantly decreased the overall CFV frequency, argatroban (100 μg kg−1 min−1) significantly (P < 0.01) decreased the number of large amplitude CFVs (minimum coronary flow < 10 ml min−1) by 63%, and heparin (15 iu kg−1 min−1) caused a 50% decrease in this parameter (P < 0.05). The thrombin times were increased by a factor greater than 10 during antithrombotic treatment, irrespective of the compound or doses used. Heparin treatment induced 17 and > 30 fold increases in aPTT at 5 and 15 iu kg−1 min−1 respectively. However, argatroban produced only 2 and 3 fold increases in aPTT at 30 and 100 μg kg−1 min−1, despite significant antithrombotic effects. FpA levels were reduced in the presence of both argatroban and heparin. These data show that, when administered as an intravenous infusion, argatroban is a potent antithrombotic agent in a canine model of coronary cyclic flow.
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