Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study.

BACKGROUND: Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. PATIENT AND METHODS: One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS: Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS: This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23.

Alterations of cardiac contractile function are related to changes in membrane calcium transport in spontaneously hypertensive rats.

OBJECTIVE: Transport activities of cardiac sodium-calcium exchange and sarcoplasmic reticulum calcium ATPase were measured biochemically in spontaneously hypertensive rats (SHR) with hypertrophied myocardium and in normotensive Wistar-Kyoto (WKY) rats and it was tested whether possible differences have consequences for the contractile properties of papillary muscle. METHODS: Sarcolemmal sodium-dependent calcium transport via sodium-calcium exchange and oxalate-supported sarcoplasmic reticulum calcium uptake were measured in left ventricular membranes of 22-week-old rats. Postextrastimulatory potentiated contractions, postrest potentiated contractions, the twitch-to-twitch decay of those potentiations and the response to increasing stimulation frequency of left ventricular papillary muscles were analysed. RESULTS: Compared with WKY rats we found in SHR: a significant increase in sodium-calcium exchange (65%) and in sarcoplasmic reticulum calcium uptake (24%); a steeper twitch-to-twitch decay in postextrastimulatory potentiated contractions and postrest potentiated contractions, suggesting a lower calcium fraction recirculating between myofilaments and sarcoplasmic reticulum and, consequently, a relatively higher calcium efflux via sodium-calcium exchange; a stronger rest-dependent decrease in recirculating calcium fraction in postrest potentiated contractions accompanied by accelerated relaxation, suggesting an increasing driving force for calcium extrusion via sodium-calcium exchange, probably caused by decreasing intracellular sodium during rest; a greater transient decrease in peak force of subsequent twitches after postrest potentiated contractions below pre-interventional level, indicating higher cellular calcium loss; and a smaller negative inotropic effect in response to doubling of stimulation rate as a manoeuvre to increase the intracellular sodium level. CONCLUSION: In SHR, the contractile properties suggest an increased contribution of sodium-calcium exchange to cellular calcium removal, which is strongly supported by the enhanced sodium-calcium exchange activity in cardiac membrane vesicles.

Interpretation of the inotropic effect of 2,3-butanedione monoxime on the isometric twitch of guinea-pig papillary muscle.

The negative inotropic effect of 2,3-butanedione monoxime (BDM) on the isometric twitch of guinea-pig papillary muscle was analysed by parameters characterizing the time course of the mechanogram. BDM at concentrations of up to 4 mmol/l produced a clear negative inotropic effect, whereas the Ca transient measured in isolated cardiomyocytes was only slightly affected. Peak force was more reduced than dF/dtmax and dF/dtmin. This led to an earlier, more narrow peak and a shortening of twitch duration. Based on a reaction scheme for the cross-bridge cycle, a mathematical model using a Ca transient and mechanograms as input data has been developed. The kinetic parameters were estimated by fitting the model to various time courses of force obtained at rising concentrations of BDM. BDM decreased the ratio of rate constants for cross-bridge attachment and detachment in a concentration-dependent manner: the formation of cross-bridges became inhibited, whereas dissociation was promoted. Above 4 mmol/l BDM the more marked alterations of the parameters of the mechanogram indicated an additional suppressing effect on intracellular Ca supply. The computer analysis suggests how the cellular mechanism(s) of the BDM-induced negative inotropic effect are reflected in the time course of the mechanogram.

Effects of hypoxia, simulated ischemia and reoxygenation on the contractile function of human atrial trabeculae.

Hypoxia, ischemia and reoxygenation cause contractile dysfunction which will be characterized by the time course of isometric contraction of human atrial trabeculae. Post-rest potentiation (PRP) and postextrastimulatory potentiation (PEP) were elicited to obtain indirect information about the the role of the sarcoplasmic reticulum (SR) in excitation-contraction coupling. As lipid peroxidation could cause SR dysfunction, thiobarbituric acid reactive substances (TBARS) were measured. After 30 min of hypoxia (H) or simulated ischemia (H combined with acidosis-SI), contractile force decreased to 15% and 6%, respectively, of control (p < or = 0.05), whereas the normalized rate of both contraction and relaxation increased. In group H, rapid reoxygenation produced a recovery of contractile force to about 60%. After post-hypoxic reoxygenation the TBARS concentration was increased. In group SI, rapid reoxygenation and a rather gradual correction of acidosis produced complete recovery of contractile force. PRP and PEP were maintained during H and SI. Particularly post-ischemic reoxygenation caused a marked depression of PRP and partly of PEP. Thus, alteration of SR Ca2+ handling occurs predominantly during reoxygenation rather than during H or SI, probably associated with the damaging effect of increased oxygen radicals. The depression of potentiation occurred along with delayed relaxation, temporary increased resting force, mechanical alternans, and spontaneous activity which are further characteristics for SR dysfunction. Thus, for a possibly beneficial effect of low pH during SI combined with its gradual correction during reoxygenation on the recovery of contractile function, developed force should not be the only index.

Mechanically induced potentials in fibroblasts from human right atrium.

It has been shown that cardiac fibroblasts of the human heart are electrically non-excitable and mechanosensitive. The resting membrane potential of these cells is -15.9+/-2.1 mV and the membrane resistance is 4.1+/-0.1 G[Omega]. Rhythmic contractions of the myocardium associated with stretch of the surrounding tissue produce reversible changes in the membrane potential of cardiac fibroblasts. These mechanically induced potentials (MIPs) follow the rhythm of myocardial contractions. Simultaneous recording of the action potential of cardiomyocytes and MIPs of cardiac fibroblasts demonstrates a delay of 40.0+/-0.4 ms after the action potential before the appearance of the MIP. Contraction produces a MIP which is more positive or more negative than the reversal potential - the membrane potential due to current injection at which the MIP reverses its direction. Regardless of the initial orientation of the MIP, intracellular polarization increases the amplitude towards the reversal potential if the background MIP had depolarized the membrane or away from the reversal potential if the initial background MIP had hyperpolarized the membrane. Artificial intracellular polarization changed the amplitude but not the frequency of the MIP. The pool of electrically non-excitable mechanosensitive cells, which change their electrical activity during contraction and relaxation of the heart, may play a role in the mechano-electrical feedback mechanism which has to be taken into account in the normal function of the heart as well as in pathological processes.

Decreased susceptibility of contractile function to hypoxia/reoxygenation in chronic infarcted rat hearts.

Cardiac hypertrophy is associated with modifications in Ca2+ transport processes, enzymes of energy metabolism and antioxidant capacity. It is unknown whether these changes occur in infarct-induced hypertrophy with regard to an altered susceptibility to ischemia/reperfusion injury. We examined changes in sarcoplasmic reticulum (SR) Ca2+ transport, creatine kinase (CK) system, and the antioxidant enzymes glutathionperoxidase (GSH-Px) and superoxide dismutase (SOD) in rats 6 weeks after infarction due to coronary ligation (MI). Phenotypic modifications v sham operation (SHAM) were related to the contractile response of hypertrophied papillary muscle to hypoxia/reoxygenation for 30 min each. Under aerobic conditions we observed in MI v SHAM: decreases in isometric contraction and relaxation rate, a reduced Vmax-equivalent of sarcomeric shortening, a faster twitch-to-twitch decay of post-rest potentiation (PRC) which correlated closely to the decrease in SR Ca2+ uptake (-25%), a decrease in CK activity (-20%), reduced CK-MI and CK-MM, increased CK-MB and CK-BB, and enhanced activities of SOD (40%) and GSH-Px (50%). During hypoxia, an initial increase in peak force (PF) was followed by a slower PF decline in MI v SHAM. Reoxygenation caused a recovery of PF to approximately 30% in both groups; rates of contraction and relaxation recovered better in MI. In SHAM but not MI, twitch-to-twitch decay of PRC was accelerated after reoxygenation v aerobic control. The results suggest that adaptive changes in SR Ca2+ handling, CK isoenzymes and antioxidant enzymes may contribute to higher resistance against reduced oxygen supply and reoxygenation in hypertrophy due to MI.