Impact of renal function on eligibility for chemotherapy and survival in patients who have undergone radical nephro‐ureterectomy

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99046/1/bju11649.pd

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Sensibilisation des cellules de lymphome à la doxorubicine par déméthylation du promoteur de gène SMAD1 ( vers une utilisation rationnelle des inhibiteurs des ADN méthyl-transférases)

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells.

Two endothelin receptor antagonists (ERAs), bosentan and ambrisentan, are currently approved for the treatment of pulmonary arterial hypertension (PAH), a devastating disease involving an activated endothelin system and aberrant contraction and proliferation of pulmonary arterial smooth muscle cells (PASMC). The novel ERA macitentan has recently concluded testing in a Phase III morbidity/mortality clinical trial in PAH patients. Since the association and dissociation rates of G protein-coupled receptor antagonists can influence their pharmacological activity in vivo, we used human PASMC to characterize inhibitory potency and receptor inhibition kinetics of macitentan, ambrisentan and bosentan using calcium release and inositol-1-phosphate (IP(1)) assays. In calcium release assays macitentan, ambrisentan and bosentan were highly potent ERAs with K(b) values of 0.14 nM, 0.12 nM and 1.1 nM, respectively. Macitentan, but not ambrisentan and bosentan, displayed slow apparent receptor association kinetics as evidenced by increased antagonistic potency upon prolongation of antagonist pre-incubation times. In compound washout experiments, macitentan displayed a significantly lower receptor dissociation rate and longer receptor occupancy half-life (ROt(1/2)) compared to bosentan and ambrisentan (ROt(1/2):17 minutes versus 70 seconds and 40 seconds, respectively). Because of its lower dissociation rate macitentan behaved as an insurmountable antagonist in calcium release and IP(1) assays, and unlike bosentan and ambrisentan it blocked endothelin receptor activation across a wide range of endothelin-1 (ET-1) concentrations. However, prolongation of the ET-1 stimulation time beyond ROt(1/2) rendered macitentan a surmountable antagonist, revealing its competitive binding mode. Bosentan and ambrisentan behaved as surmountable antagonists irrespective of the assay duration and they lacked inhibitory activity at high ET-1 concentrations. Thus, macitentan is a competitive ERA with significantly slower receptor dissociation kinetics than the currently approved ERAs. Slow dissociation caused insurmountable antagonism in functional PASMC-based assays and this could contribute to an enhanced pharmacological activity of macitentan in ET-1-dependent pathologies

Endothelium-dependent vasoconstriction in isolated vessel grafts: a novel mechanism of vasospasm?

YC-1-induced vasoconstriction demonstrates the existence of an endothelium-dependent vasoconstrictor pathway in the blood vessels of patients with CAD that to date has been described only in animal models of hypertension. Patients with CAD who have elevated plasma levels of endothelin-1 are thus prone to endothelium-dependent vasoconstriction, which may also play a role in vasospasm in vascular grafts

Mean K_b values for reference ERAs determined by calcium release assays in CHO-ET_A, CHO-ET_B and human PASMC.

*<p>geometric means from n = 3–8 determinations calculated from IC₅₀ values via Cheng-Prusoff equation (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047662#s4" target="_blank">Methods</a>).</p

Contribution of endothelin receptor subtypes to calcium signaling in human primary PASMC.

<p>PASMC or CHO-ET_A or CHO-ET_B cells were pre-incubated with reference ERA dilution series for 120 min and then stimulated in the FLIPR with ET-1 (EC₅₀–EC₇₀). IC₅₀ values were calculated from fluorescence peak responses and transformed into K_b values as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047662#s4" target="_blank">Methods</a>. Correlation scatter plot of K_b values obtained in PASMC versus CHO-ET_A cells (A) or versus CHO-ET_B cells (B). The correlation line and R² value was generated by linear regression of the double-logarithmic data. Geometric means of n = 3–8 determinations are shown.</p

Dissociation kinetics of macitentan, ambrisentan and bosentan determined by calcium release assays in PASMC.

<p>Cells were pre-incubated for 120 min with antagonist dilution series and then either directly stimulated with ET-1 (EC₅₀–EC₇₀) or subjected to a compound washout procedure followed by stimulation with ET-1 at the indicated time points after washout. The peak calcium responses were used to calculate IC₅₀ values which were transformed into K_b values as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0047662#s4" target="_blank">Methods</a>. Shown are the time-dependent changes in K_b after washout. Geometric means are displayed +/− SEM. K_b values after washout significantly different (p<0.05) from the K_b at 0 min are indicated with an asterisk. Test: one-way ANOVA, Dunnett’s post test.</p