7196 research outputs found
Sort by
Pharmacokinetics of serelaxin in patients with hepatic impairment: A single-dose, open-label, parallel-group study
No full textAIMS
Serelaxin is a recombinant form of human relaxin-2 in development for the treatment of acute heart failure. The present study aimed to evaluate the pharmacokinetics (PK) of serelaxin in patients with hepatic impairment. Secondary objectives included the evaluation of immunogenicity, safety and tolerability of serelaxin.
METHODS
This was an open-label, parallel-group study (NCT01433458) comparing the PK of serelaxin following a single 24-hour intravenous (IV) infusion (30 μg/kg/day) between patients with mild, moderate or severe hepatic impairment (Child-Pugh Class A, B and C, respectively), and healthy matched controls. Blood sampling and standard safety assessments were conducted. Primary non-compartmental PK parameters [including area under the serum concentration-time curve (AUC)0-48h and AUCinf, and serum concentration at 24 hours post-dose (C24h)] were compared between each hepatic impairment group and healthy controls.
RESULTS
A total of 49 subjects (including 25 patients with hepatic impairment) were enrolled, of which 48 subjects completed the study. In all groups, serum concentration of serelaxin increased over the first few hours of infusion, reached steady-state at 12-24 hours and then declined following completion of the infusion with a mean terminal half-life of 7-8 hours. All PK parameter estimates were comparable between each group of patients with hepatic impairment and healthy controls. No serious adverse events, discontinuations due to an adverse event or deaths were reported. No serelaxin-treatment-related antibodies developed during this study.
CONCLUSIONS
The PK and safety profile of serelaxin were not affected by hepatic impairment. No dose adjustment is needed for serelaxin treatment of 48-hr IV infusion in patients with hepatic impairment
Hydrogen borrowing and interrupted hydrogen borrowing reactions of ketones and methanol, catalysed by iridium
No full textWe report herein the use of catalytic [Ir(cod)Cl]2 to facilitate hydrogen borrowing reactions of ketone enolates with methanol at 65 oC. The use of an oxygen atmosphere accelerates the process and, when combined with the use of a bulky monodentate phosphine ligand, interrupts the catalytic cycle by preventing enone reduction. Subsequent addition of pro-nucleophiles to the reaction mixture has allowed a one-pot methylenation/conjugate addition protocol to be developed, which greatly expands the range of products that can be made via this type of methodology
Molecular basis of mRNA cap recognition by Influenza B polymerase PB2 subunit
No full textInfluenza virus polymerase catalyzes the transcription of viral mRNAs by a process known as “cap-snatching”, where the 5'-cap of cellular pre-mRNA is recognized by the PB2 subunit and cleaved 10-13 nucleotides downstream of the cap by the endonuclease PA subunit. Although this mechanism is common to both influenza A (FluA) and B (FluB) viruses, FluB PB2 recognizes a wider range of cap structures including m7GpppGm-, m7GpppG-, and GpppG-RNA, while FluA PB2 utilizes methylated G-capped RNA specifically. Biophysical studies with isolated PB2 cap-binding domain (PB2cap) confirm that FluB PB2 has expanded mRNA cap recognition capability although the affinities towards m7GTP are significantly reduced when compared to FluA PB2. The X-ray co-structures of the FluB PB2cap with bound cap analogs m7GTP and GTP reveal an inverted GTP binding mode that is distinct from the cognate m7GTP binding mode shared between FluA and FluB PB2. These results delineate the commonalities and differences in the cap-binding site between FluA and FluB PB2 and will aid structure-guided drug design efforts to identify dual inhibitors of both FluA and FluB PB2
Building compound archives for the future
No full textWill the targets of the future be covered by the compound libraries of today? This communication will cover a critical review of past strategies before turning to a new measure of diversity, protein pockets. A fingerprint descriptor for pockets will be described
Dual therapeutic approaches to rhodopsin retinitis pigmentosa through Hsp90 inhibition
No full textRetinitis pigmentosa (RP) is characterized by the progressive degeneration of retinal photoreceptor neurons. Mutations in rhodopsin are the most common cause of autosomal dominant Retinitis pigmentosa (adRP). Therapies targeting multiple classes of mutations would be of a great value for retinal dystrophies. It has been previously shown that pharmacological interventions can improve the folding and traffic, or reduce protein aggregation of the class II rod opsin misfolding mutant, P23H. We investigated the capacity of these interventions to modulate the class III rod opsin mutant, R135L, which binds arrestin and disrupts vesicular traffic. R135L acted as a dominant negative, and recruited wild-type rod opsin to intracellular vesicles. Treatment with retinoids or kosmotropes did not improve the vesicular disruption caused by R135L. By contrast, Hsp90 inhibition reduced the intracellular accumulation of R135L and abolished arrestin binding. This effect was mediated by a requirement for Hsp90 in kinase (GRK1) function, which is upstream of arrestin binding. Furthermore, prolonged high dose Hsp90 inhibition reduced photoreceptor GRK1 and PDE without affecting photoreceptor viability. Interestingly, a single low dose inhibition of Hsp90 protected against photoreceptor degeneration caused by P23H rod opsin, without affecting these components but correlated with an activation of HSF1 and heat shock protein induction. These data suggest that Hsp90 could be used as a potential therapeutic target for different types of rhodopsin adRP, but that inhibition might also affect the visual function through the requirement for Hsp90 in the biogenesis of phototransduction machinery components
Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study
No full textSerelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients
Dark chemical matter as a promising starting point for drug lead discovery
No full textHigh-throughput screening (HTS) is an integral part of early drug discovery. Herein, we focused on those small molecules in a screening collection that have never shown biological activity despite having been exhaustively tested in HTS assays. These compounds are referred to as 'dark chemical matter' (DCM). We quantified DCM, validated it in quality control experiments, described its physicochemical properties and mapped it into chemical space. Through analysis of prospective reporter-gene assay, gene expression and yeast chemogenomics experiments, we evaluated the potential of DCM to show biological activity in future screens. We demonstrated that, despite the apparent lack of activity, occasionally these compounds can result in potent hits with unique activity and clean safety profiles, which makes them valuable starting points for lead optimization efforts. Among the identified DCM hits was a new antifungal chemotype with strong activity against the pathogen Cryptococcus neoformans but little activity at targets relevant to human safety
Microarray analyses demonstrate the involvement of Type I Interferons in psoriasiform pathology development in D6 deficient mice
No full textThe inflammatory response is normally limited by mechanisms regulating its resolution. In the absence or resolution inflammatory pathologies can emerge resulting in substantial morbidity and mortality. We had been studying the D6 chemokine scavenging receptor which played an indispensable role in the resolution phase of inflammatory responses and does so by facilitating removal of inflammatory CC chemokines. In D6 deficient mice, otherwise innocuous cutaneous inflammatory stimuli induce a grossly exaggerated inflammatory response that bears many similarities to human psoriasis. In the present study we have used transcriptomic approaches to define the molecular make up of this response. The data presented highlights a number of cytokines as playing potential role is in development of this psoriasis like pathology. Most compellingly, we provide data indicating a key role for the type I interferon pathway in the emergence of this pathology. Neutralising antibodies to type I interferons are able to ameliorate the psoriasis like pathology confirming a role in its development. Comparison of the data generated from this mouse model worth data from transcriptional analysis of human psoriasis further demonstrate their strong similarities. Finally, these transcriptional data provide insights into the cytokine network active in exaggerated inflammatory responses
Pharmacokinetics of Serelaxin in Patients with Severe Renal Impairment or End-Stage Renal Disease Requiring Hemodialysis: A Single-dose, Open-label, Parallel-group Study
No full textSerelaxin, a recombinant human relaxin-2, is currently in clinical development for treating acute heart failure. This open-label parallel-group study investigated serelaxin pharmacokinetics (PK) after a single 4-h intravenous infusion (10μg/kg) in patients with severe renal impairment (n=6) or end-stage renal disease (ESRD) requiring hemodialysis (with PK on the day of dialysis [n=6] or during dialysis-free interval [n=6]) compared with healthy subjects (n=18). In all participants, serum serelaxin concentration peaked at the end of infusion and subsequently declined with a mean terminal elimination half-life of 6.5–8.8h. Compared to healthy subjects, a moderate decrease in serelaxin systemic clearance (37%–52%) and increase in its exposure (30%–115%) were observed in all patients. During the 4-h hemodialysis in ESRD patients, serelaxin was partially removed (30%) from blood with dialysis clearance constituting approximately 52% of total systemic clearance. Anti-serelaxin antibodies were not detected in any participant, and serelaxin was well tolerated with no deaths, serious adverse events (AE), or AE-related discontinuations. The observed serelaxin PK differences in patients with severe renal impairment compared with matched healthy subjects are unlikely to pose a safety risk and do not warrant a predefined dosage adjustment in such patients
Ligand-free regioselective hydrogenation of naphthyl-P(V) scaf-folds to access phosphine oxide ligands.
No full textHerein, we described the first semi- and regioselective hydrogenation of P(V)-substituted naphthalenes. This iridium-catalyzed reaction delivers phosphine oxides or phosphonates in almost quantitative yields and with total regioselectivi-ty. This report also exposed a novel pathway toward the preparation of H8-BINAP ligands derivatives. The importance of HFIP solvent is evidenced. Catalyst analysis also demonstrated the involvement of ultrasmall iridium(0) nanoparticles, with potential recycling of the catalyst