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Patient engagement throughout drug development: understanding the role of patients and best practices for engagement
No full textAlthough greater than 70% of the population believes patients should actively be involved in drug development, patient engagement is currently not a standard practice for the pharmaceutical industry.1 Patients are experts in their disease states, and the pharmaceutical industry can utilize their expertise to improve drug development. Patient engagement can be used in the development process to develop patient-focused protocols, improve recruitment, and gain a better understanding of what it is like to live with a disease. This paper aims to explore recommendations for involving patients in the drug development process, and to discuss the benefits and barriers of patient engagement
The dark side of fluorine
No full textDespite the perceived stability of the C-F bond, chemical instability and drug-metabolizing enzymes can lead to its cleavage. The resulting release of fluoride and formation of certain metabolites may cause safety issues and warrant the medicinal chemists' attention
Low-dose subcutaneous anti-CD20 treatment depletes disease relevant B-cell subsets and attenuates neuroinflammation
No full textObjective: To explore the B-cell depleting capacity of a low-dose (20 µg) subcutaneous mouse anti-CD20 antibody treatment on disease-relevant B-cell populations within lymph nodes and the spleen.
Methods: B-cell depleting capacity was explored in healthy female C57BL/6 and BALB/c mice; following immune activation in two different mouse models: trinitrophenylated lipopolysaccharide model (thymus-independent response) and dinitrophenyl-keyhole limpet hemocyanin model (thymus-dependent response); and in a chronic neuroinflammation experimental autoimmune encephalomyelitis model. CD20 protein expression on B-cell subpopulations was also studied.
Results: The subcutaneous anti-CD20 regimen resulted in rapid depletion of B cells in blood, lymph nodes and spleen. Low-dose subcutaneous treatment did not reduce antigen-specific immunoglobulin M and immunoglobulin G titers in all subgroups, and relatively spared splenic marginal zone (MZ) B cells in both T-cell dependent and T-cell independent B-cell immunization models. Analysis of immune compartments during anti-CD20-modulated autoimmune neuroinflammation showed that the maximal B-cell depletion was achieved within 2 days of treatment and was highest in the lymph node. Regardless of the tissues analyzed, low-dose subcutaneous treatment was characterized by rapid B-cell repletion following treatment cessation. CD20 protein expression was consistent on all B-cell subsets in blood, and was more pronounced in germinal center (GC) B cells of lymph nodes and MZ B-cells of the spleen.
Interpretation: Low-dose subcutaneous anti-CD20 therapy effectively depleted B cells within lymphatic tissues and reduced the severity of neuroinflammation. These data suggest that subcutaneous anti-CD20 therapies can effectively target disease-relevant B-cell populations, have shorter repletion kinetics and maintain vaccination responses, thereby achieving autoimmune amelioration without severely impacting immune surveillance functions
Pyridyl-Ala modified cyclic hexapeptides: in-vitro and in-vivo profiling for oral bioavailability
No full textWe and others have been aiming at modifications to maintain or to enhance solubility while enabling permeability for cyclic hexapeptides. Especially, the 2-pyridyl-Ala modification was investigated, since in this case, the pyridyl-nitrogen is able to form an H-bond to the NH of the same residue. The hypothesis of a backbone side-chain interaction was demonstrated by NMR experiments, and further results obtained on a variety of pyridyl-Ala derivatives, studied systematically in the context of permeability, are presented in this contribution. Thus, this study sheds some more light on the pyridyl-Ala modification, which had been reported earlier. In addition to the in-vitro profiling, the extent of oral bioavailability was assessed in rats. In principle, the pyridyl-Ala residue can be considered as an amino acid supporting oral uptake
Effects of Long-Term Sclerostin Deficiency on Trabecular Bone Mass and Adaption to Limb Loading Differ in Male and Female Mice
No full textA new therapeutic option to treat osteoporosis is focused on Wnt signaling and its inhibitor sclerostin, a product of the Sost gene. In this work, we study the effect of sclerostin deficiency on trabecular bone formation and resorption in male and female mice and whether it affects mechano-responsiveness. Male and female 10- and 26-week-old Sost knockout (KO) and littermate controls (LCs) were subjected to in vivo mechanical loading of the left tibia for 2 weeks. The right tibia served as internal control. The mice were imaged using in vivo micro-computed tomography at days 0, 5, 10, and 15 and tibiae were collected for histomorphometric analyses after euthanasia. Histomorphometry and micro-CT-based 3D time-lapse morphometry revealed an anabolic and anti-catabolic effect of Sost deficiency although increased trabecular bone resorption accompanied by diminished trabecular bone formation occurred with age. Loading led to diminished resorption in adult female but not in male mice. A net gain in bone volume could be achieved with mechanical loading in Sost KO adult female mice, which occurred through a further reduction in resorbed bone volume. Our data show that sclerostin deficiency has a particularly positive effect in adult female mice. Sclerostin antibodies are approved to treat postmenopausal women with high risk of osteoporotic fractures. Further studies are required to clarify whether both sexes benefit equally from sclerostin inhibition
Chalcogen OCF3-isosteres Modulate Drug Properties without Introducing Inherent Liabilities
No full textThe synthesis of SCF3 as well as SeCF3 isosteres of two OCF3–containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physico-chemical and ADME properties without introducing intrinsic liabilities. The S- and SeCF3 groups are more lipophilic as their O-parent; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for in vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF3 groups as potential key players for future fluorinated pharmaceuticals
Selectivity of (±)-citalopram at nicotinic acetylcholine receptors and different inhibitory mechanisms between habenular α3β4* and α9α10 subtypes
No full textThe inhibitory activity of (±)-citalopram on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) was determined by Ca2+ influx assays, whereas its effect on rat α9α10 and mouse habenular α3β4* AChRs by electrophysiological recordings. The Ca2+ influx results clearly establish that (±)-citalopram inhibits hα3β4 AChRs (5.1 ± 1.3) with higher potency (IC50's in µM) than that for hα7 (18.8 ± 1.1) and hα4β2 (19.1 ± 4.2) AChRs. This is in agreement with the [3H]imipramine competition binding results indicating that (±)-citalopram binds to imipramine sites at desensitized hα3β4 with >2-fold higher affinity than that for hα4β2. The electrophysiological results indicate that (±)-citalopram competitively inhibits rα9α10 AChRs (7.5 ± 0.9) in a voltage-independent manner, whereas it inhibits a homogeneous population of α3β4* AChRs at MHb (VI) neurons (7.6 ± 1.0) in a voltage-dependent manner. The results indicating that citalopram overlaps the imipramine luminal site and inhibits α3β4* AChRs in a voltage-dependent manner, suggest an ion channel blocking mechanism. Both results were in agreement with the conclusions of automatic molecular docking and molecular dynamics experiments. In conclusion, (±)-citalopram inhibits α3β4 and α9α10 AChRs with higher potency compared to other AChRs but by different mechanisms. (±)-Citalopram also inhibits α3β4*AChRs expressed in MHb (VI) neurons, supporting the notion that these receptors are important endogenous targets related to their anti-addictive activities
A Continuous Stirred-Tank Reactor (CSTR) Cascade for Handling Solid-Containing Photochemical Reactions
No full textVisible-light photoredox reactions have been demonstrated to be powerful synthetic tools to access pharmaceutically relevant compounds. However, many photoredox reactions involve insoluble starting materials or products that complicate the use of continuous flow methods. By integrating a new solid-feeding strategy and a continuous stirred-tank reactor (CSTR) cascade, we realize a new solid-handling platform for conducting heterogeneous photoredox reactions in flow. Residence time distributions for single phase and solid particles characterize the hydrodynamics of the heterogeneous flow in the CSTR cascade. Silyl radical-mediated metallophotoredox cross-electrophile coupling reactions with an inorganic base as the insoluble starting material demonstrate the use of the platform. Gram-scale synthesis is achieved in 13 hours of stable operation.
Keywords: flow chemistry・continuous stirred tank reactor・photoredox catalysis・multiphase flow system
Expediting access to medicines in Asia: Recommendations for a new paradigm of global drug development
No full textAbstract:
Currently, there is a requirement from several health authorities in Asia for Phase 1 data in Asian subjects to allow Asian patients to join global Phase 2/3 trials. Here we discuss inherent limitations in the design of Phase 1 ethnic sensitivity studies (ESS) that make it difficult to identify inter-ethnic differences in the safety/PK profile of investigational drugs. We reviewed dosing data for Japan and China from recent Novartis-sponsored NDAs to critically assess the value of conducting separate Phase 1 ESSs in Asian populations and we propose recommendations for a new paradigm of global drug development. If relevant safety, PK, and PG data are available from the original Phase 1 study population, it may be possible to extrapolate these data to the Asian populations to allow inclusion of Asian patients in Phase 2/3 clinical trials, without conducting a Phase 1 ESS in the new population. If feasible, PK/PG data from the Asian populations could be collected during Phase 2/3 trials of drug development. This approach may help to streamline the drug development in Asia, whilst still addressing the requirements of regulatory agencies