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Inhibition of an Alzheimer's disease-associated form of necroptosis rescues neuronal death in mouse models.
No full textNecroptosis is a regulated form of cell death that has been observed in Alzheimer's disease (AD) along with the classical pathological hallmark lesions of amyloid plaques and Tau neurofibrillary tangles. To understand the neurodegenerative process in AD, we studied the role of necroptosis in mouse models and primary mouse neurons. Using immunohistochemistry, we demonstrated activated necroptosis-related proteins in transgenic mice developing Tau pathology and in primary neurons from amyloid precursor protein (APP)-Tau double transgenic mice treated with phosphorylated Tau seeds derived from a patient with AD but not in APP transgenic mice that only exhibited β-amyloid deposits. Necroptosis proteins in granulovacuolar degeneration (GVD) bodies were associated with neuronal loss in mouse brain regions also known to be vulnerable to GVD in the human AD brain. Necroptosis inhibitors lowered the percentage of neurons showing GVD and reduced neuronal loss, both in transgenic mice and in primary mouse neurons. This suggests that a GVD-associated form of necroptosis that we refer to as "GVD-necroptosis" may represent a delayed form of necroptosis in AD. We propose that inhibition of necroptosis could rescue this type of neuronal death in AD
Capmatinib in MET exon 14-mutated non-small-cell lung cancer: final results from the open-label, phase 2 GEOMETRY mono-1 trial.
No full textCapmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib.In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed.Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported.These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC.Novartis Pharmaceuticals
Preclinical comparison of (radio)lanthanides using mass spectrometry and nuclear imaging techniques: biodistribution of lanthanide-based tumor-targeting agents and lanthanides in ionic form.
No full textWith the growing interest in exploring radiolanthanides for nuclear medicine applications, the question arises as to whether they are generally interchangeable without affecting a biomolecule's pharmacokinetic properties. The goal of this study was to investigate similarities and differences of four (radio)lanthanides simultaneously applied as complexes of biomolecules or in ionic form.Inductively coupled plasma mass spectrometry (ICP-MS) was employed for the simultaneous detection of four lanthanides (Ln = lutetium, terbium, gadolinium and europium) in biological samples. In vitro tumor cell uptake and in vivo biodistribution studies were performed with Ln-DOTATATE, Ln-DOTA-LM3, Ln-PSMA-617 and Ln-OxFol-1. AR42J cells, PC-3 PIP cells and KB cells expressing the somatostatin receptor, the prostate-specific membrane antigen and the folate receptor, respectively, were used in vitro as well as to obtain the respective tumor mouse models for in vivo studies. The distribution of lanthanides in ionic form was investigated in immunocompetent mice. Dual-isotope SPECT/CT imaging studies were performed with mice administered with the radiolabeled biomolecules or chloride salts of lutetium-177 and terbium-161.Similar in vitro cell uptake was observed for all four lanthanide complexes of each biomolecule into the respective tumor cell lines. AR42J tumor uptake of Ln-DOTATATE and Ln-DOTA-LM3 in mice showed similar values for all lanthanide complexes (3.8‒5.1% ID/g and 4.5‒5.0% ID/g; 1 h p.i., respectively). Accumulation of Ln-PSMA-617 in PC-3 PIP tumors (24-25% ID/g; 1 h p.i.) and of Ln-OxFol-1 in KB tumors (28-31% ID/g; 24 h p.i.) were also equal for the four lanthanide complexes of each biomolecule. After injection of lanthanide chloride salts (LnCl3; Ln = natLu, natTb, natGd, natEu), the liver uptake was different for each metal (~ 12% ID/g, ~ 22% ID/g, ~ 31% ID/g and ~ 37% ID/g; 24 h p.i., respectively) which could be ascribed to the radii of the respective lanthanide ions. In the bones, accumulation was considerably higher for lutetium than for other lanthanides (25 ± 5% ID/g vs. 14‒15% ID/g; 24 h p.i.). These data were confirmed visually by 177Lu/161Tb-based dual-isotope SPECT/CT images.The presented study confirmed similar properties of Ln-complexes, suggesting that lutetium-177 can be replaced by other radiolanthanides, most probably without affecting the tissue distribution profile of the resultant radiopharmaceuticals. On the other hand, the different radii of the lanthanide ions affected their uptake and resorption mechanisms in liver and bones when injected in uncomplexed form
Identifying chemical stabilizers - presenting a case study using a rapid 3-day accelerated excipient screening methodology.
No full textThis study outlines a practical approach for assessing chemical instability by heating the drug-excipient binary mixtures or multi-excipient formulations at 75°C for 3 days before characterization. Differentiating itself from other excipient compatibility methods, our methodology necessitates a saturated aqueous slurry rather than arbitrarily fixed water content. This allows bulk and surface water in the excipient to contribute to drug degradation. The synergistic impact of surface water and elevated temperature expedites degradation kinetics, resulting in accelerated data generation. Among excipient compatibility methods available, our method is quantitative and merges with traditionally used methodologies. The devised nomograph enables extrapolation of shelf life at 20°C from experimental data obtained at 75°C. This methodology also helped identify stabilizers for the drug NVS-1 where traditional excipient compatibility programs had failed. Incorporation of monovalent salts, such as sodium/potassium chloride and sodium bicarbonate at 5% w/w, significantly enhanced the chemical stability of NVS-1, ensuring stable tablet formulations. Our hypothesis posits that stabilization is due to increased ionic strength in the slurry, which stabilizes an induced dipole within the polar NVS-1 drug. Additionally, the presence of ions in the moisture layer is anticipated to stabilize π-π stacking of two planar aromatic NVS-1 molecules. The expedited generation of experimental data allowed the identification of inorganic salts to supplement a standard excipient compatibility screening panel. Considering the economic implications of stability testing methodologies in effort, cost, and duration, a faster turnaround in chemical stability data enhances formulation selection. This ultimately facilitates the development of drug formulations with greater efficiency without delays
NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.
No full textThe YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates the initiation of liver regeneration following partial hepatectomy in mice. However, adverse effects in gut and kidney prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway
A general perspective for the conduct of radiolabelled distribution, metabolism, and excretion studies for antibody-drug conjugates
No full textAntibody-drug conjugates (ADCs) are a class of biopharmaceuticals that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxicity of small molecule drugs.
13 ADCs have been approved by regulatory authorities up to now, mainly for indications in oncology.
ADME (Absorption, Distribution, Metabolism, and Excretion) studies are essential for the development of small molecule drugs to evaluate their disposition properties. These studies help to determine the optimal dosing regimen and to identify potential safety concerns for the drug of interest in human. Distribution studies are also important as they help to determine the tissue distribution of the respective drug and its metabolites. This information is critical for understanding the efficacy and safety in preclinical and clinical studies.
For biologics, ADME studies are usually omitted. In this paper, we review the existing approval packages and literature for approved ADCs to see how often and to which extent ADME studies have been applied for registration.
We conclude that ADME studies are necessary for the development of ADCs if new linker and payloads are introduced to humans for the first time as these studies provide valuable information on the pharmacokinetic properties, optimal dosing regimen, and potential safety concerns. However, for the development of ADCs with established linker payload combinations, these studies are not deemed necessary if the distribution, metabolism and excretion properties have been described before.
Keywords: Distribution, Metabolism, Excretion; ADC, Payload, ADME, QWBA, SPECT/CT, AMS, CRD
Editorial for "Relative mediastinal displacement index (RMDI): a prenatal MRI indicator of adverse events in fetuses with isolated left congenital diaphragmatic hernia”
No full textNo abstrac
Visualisation and Quantification of Subcutaneous Injections of Different Volumes, Viscosities and Injection Rates: An Ex-Vivo micro-CT Study
No full textThe effects of subcutaneous (SC) injection parameters such as drug formulation volume, viscosity and injection rate on therapeutic performance and tolerability have not been established for any drug product. In this study four groups of SC injections were performed on fresh ex vivo minipig abdominal tissue samples, varying volume (0.5-1 mL), viscosity (1-11 cP) and rate (0.02-0.1 mL/s). Micro-CT provided high resolution (50 micron) imaging of the SC tissues before and after injection, enabling a detailed 3D visualisation and analysis of how both injection parameters and tissue microstructure influence spatial distribution of injectables. We found that volume was the only significant factor for spatial distribution of injectate within our design space, and there were no significant factors for tissue backpressure. Variability between tests groups was typically greater than differences between group means. Accordingly, whilst the higher viscosity formulations consistently exhibited reduced spatial distribution, the sample size was not large enough to establish confidence in this result
C3 Selective Hydroxylation of Pyridines via Photochemical Valence Isomerization of Pyridine N-OxidesArticle link copied!
No full textThe C–H hydroxylation of the pyridine C3 position is a highly desirable transformation but remains a great challenge due to the inherent electronic properties of this heterocycle core which bring difficulties in chemical reactivity and regioselectivity. Herein we present an efficient method for formal C3 selective hydroxylation of pyridines via photochemical valence isomerization of pyridine N-oxides. This metal-free transformation features operational simplicity and compatibility with a diverse array of functional groups, and the resulting hydroxylated products are amenable to further elaboration to synthetically useful building blocks. The synthetic utility of this strategy is further demonstrated in the effective late-stage functionalization of pyridine-containing medicinally relevant molecules and versatile derivatizations of 3-pyridinols
The therapeutic potential of exercise for improving mobility in multiple sclerosis.
No full textMultiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and demyelination in the central nervous system (CNS) with subsequent axonal and neuronal degeneration. These changes are associated with a broad range of symptoms including skeletal muscle dysfunction. Importantly, musculoskeletal impairments manifest in various ways, compromise the quality of life and often precede the later development of mobility disability. As current standard disease modifying therapies for MS predominantly act on neuroinflammation, practitioners and patients face an unmet medical need for adjunct therapies specifically targeting skeletal muscle function. This review is intended to detail the nature of the skeletal muscle dysfunctions common in people with MS (pwMS), describe underlying intramuscular alterations and outline evidence-based therapeutic approaches. Particularly, we discuss the emerging role of aerobic and resistance exercise for reducing the perception of fatigue and increasing muscle strength in pwMS. By integrating the most recent literature, we conclude that both exercise interventions should ideally be implemented as early as possible as they can address MS-specific muscle impairments. Aerobic exercise is particularly beneficial for pwMS suffering from fatigue and metabolic impairments, while resistance training efficiently counters muscle weakness and improves the perception of fatigue. Thus, these lifestyle interventions or possible pharmacological mimetics have the potential for improving the general well-being and delaying the functional declines that are relevant to mobility