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Background S‐pindolol has metabolic effects of potential benefit in cancer cachexia: reduced catabolism through nonselective β‐blockade; increased anabolism through partial β2 receptor agonism; and increased appetite and reduced fatigue through central 5‐hydroxytryptamine/serotonin receptor activity. A Phase 2a clinical trial demonstrated that S‐pindolol can reverse weight loss and improve fat‐free mass in patients with cancer‐related weight loss. A comparative phase I bioavailability study of S‐pindolol and racemic pindolol was performed to support the development of S‐pindolol in cancer cachexia. Methods This two‐part study assessed the comparative bioavailability and pharmacokinetics of single doses of S‐pindolol benzoate (ACM‐001.1) or pindolol (Part 1) and the steady‐state pharmacokinetics and pharmacodynamics of multiple doses of ACM‐001.1 and pindolol (Part 2) in healthy volunteers (NCT06028321). ACM‐001.1 5, 10 and 15 mg and pindolol 15, 20 and 30 mg were tested. In Part 1, subjects were randomised to ACM‐001.1 15 mg followed after a 48‐h washout period by pindolol 30 mg, or the reverse sequence; another group received pindolol 15 mg. Subjects in Part 2 were randomised to pindolol 20 mg twice‐daily or ACM‐001.1 5, 10 or 15 mg twice‐daily for 4 days. Bioavailability, pharmacokinetics, pharmacodynamics, potential for and extent of stereoconversion, and tolerability were assessed. Results Parts 1 and 2 included 24 and 27 healthy volunteers, respectively. ACM‐001.1 had predictable pharmacokinetics up to a dose of 15 mg twice daily, with low intersubject variability, after single and multiple doses (Tmax 1 vs. 1.5 h; Cmax 74 vs. 73.6 ng/mL; AUC(0−t) 440 vs. 414 ng·h/mL; t1/2 4.042 vs. 3.566 h). The bioavailability of S‐pindolol after equivalent doses of pindolol (20 mg) and ACM‐001.1 (10 mg) was comparable, and formal bioequivalence margins were met (90% CI for Cmax, AUC(0−t) and AUC(0–inf) within 80%–125% bioequivalence acceptance criteria). No evidence of stereoconversion of the S‐enantiomer into the R‐enantiomer, no accumulation, dose linearity and dose proportionality of S‐pindolol over a range of doses were demonstrated; we also show indirectly that there was no food effect. ACM‐001.1 was generally well tolerated, with no apparent relationship of side effects to dose, no serious adverse events, severe treatment‐emergent adverse events (TEAEs) or deaths, and similar incidences of TEAEs (fatigue, dizziness, somnolence, nausea and headache) with ACM‐001.1 10 and 15 mg and pindolol 20 mg. Conclusions Data from this bridging study of enantiomerically pure ACM‐001.1 and its parent racemic drug, pindolol, support clinical trials of ACM‐001.1 for the treatment of cancer cachexia.

The present study aimed at investigating the effect of MDMA on measures of empathy and social interaction, and the roles of oxytocin and the 5-HT1A receptor in these effects. The design was placebo-controlled within-subject with 4 treatment conditions: MDMA (75 mg), with or without pindolol (20 mg), oxytocin nasal spray (40 IU+16 IU) or placebo. Participants were 20 healthy poly-drug MDMA users, aged between 18-26 years. Cognitive and emotional empathy were assessed by means of the Reading the Mind in the Eyes Test and the Multifaceted Empathy Test. Social interaction, defined as trust and reciprocity, was assessed by means of a Trust Game and a Social Ball Tossing Game. Results showed that MDMA selectively affected emotional empathy and left cognitive empathy, trust and reciprocity unaffected. When combined with pindolol, these effects remained unchanged. Oxytocin did not affect measures of empathy and social interaction. Changes in emotional empathy were not related to oxytocin plasma levels. It was concluded that MDMA (75 mg) selectively enhances emotional empathy in humans. While the underlying neurobiological mechanism is still unknown, it is suggested that peripheral oxytocin does not seem to be the main actor in this; potential candidates are the serotonin 2A and the vasopressin 1A receptors. Trial registration: MDMA & PSB NTR 2636.

Serotonin or 5-hydroxytryptamine (5-HT) regulates a wide spectrum of human physiology through the 5-HT receptor family. We report the crystal structures of the human 5-HT 1B G protein–coupled receptor bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the family-wide agonist activity of 5-HT. Compared with the structure of the 5-HT 2B receptor, the 5-HT 1B receptor displays a 3 angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.

The β1-adrenoceptor (β1AR) is a G protein-coupled receptor (GPCR) that is activated by the endogenous agonists adrenaline and noradrenaline. We have determined the structure of an ultra-thermostable β1AR mutant bound to the weak partial agonist cyanopindolol to 2.1 Å resolution. High-quality crystals (100 μm plates) were grown in lipidic cubic phase without the assistance of a T4 lysozyme or BRIL fusion in cytoplasmic loop 3, which is commonly employed for GPCR crystallisation. An intramembrane Na+ ion was identified co-ordinated to Asp872.50, Ser1283.39 and 3 water molecules, which is part of a more extensive network of water molecules in a cavity formed between transmembrane helices 1, 2, 3, 6 and 7. Remarkably, this water network and Na+ ion is highly conserved between β1AR and the adenosine A2A receptor (rmsd of 0.3 Å), despite an overall rmsd of 2.4 Å for all Cα atoms and only 23% amino acid identity in the transmembrane regions. The affinity of agonist binding and nanobody Nb80 binding to β1AR is unaffected by Na+ ions, but the stability of the receptor is decreased by 7.5°C in the absence of Na+. Mutation of amino acid side chains that are involved in the co-ordination of either Na+ or water molecules in the network decreases the stability of β1AR by 5-10°C. The data suggest that the intramembrane Na+ and associated water network stabilise the ligand-free state of β1AR, but still permits the receptor to form the activated state which involves the collapse of the Na+ binding pocket on agonist binding.

Background It is known that S‐pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. Methods Here, we tested 3 mg/kg/day of S‐pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). Results Treatment of mice with 3 mg/kg/day of S‐pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo‐treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (−0.9 ± 1.0 vs. −2.2 ± 1.4 g for S‐pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour‐bearing controls (−0.4 ± 1.0 vs. −1.5 ± 1.5 g for S‐pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S‐pindolol tumour‐bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S‐pindolol‐treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S‐pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S‐pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S‐pindolol‐treated mice improved by 32.7 ± 18.5 g, tumour‐bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). Conclusions S‐pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

The fascinating framework structures and unique properties of chiral covalent organic frameworks (COFs) make them promising candidates as novel separation medium for high-performance liquid chromatography (HPLC). However, the irregular morphology, inhomogeneous particle size, and low density of conventional COF particles will lead to a low column efficiency, undesirable chromatographic peak shape, and high column backpressure of such COF-packed columns. In this work, a chiral COF CTpBD was synthesized by the Schiff base reaction between benzidine (BD) and chiral organic monomer CTp obtained through the reaction of 1,3,5-triformylphoroglucinol (Tp) and (+)-diacetyl-L-tartaric anhydride ((+)-Ac-L-Ta). The chiral COF CTpBD was immobilized on the surface of amino functionalized silica (SiO.sub.2-NH.sub.2) by an in situ growth approach to prepare the chiral COF core-shell microsphere composite CTpBD@SiO.sub.2, which was used as a novel chiral stationary phase (CSP) for HPLC enantioseparation. Various kinds of racemates were separated on the CTpBD@SiO.sub.2-packed column with a low column backpressure (8-11 bar). Some effects such as the analyte mass and column temperature on the HPLC enantioseparation have been studied in detail. The fabricated CTpBD@SiO.sub.2-packed column exhibited high column efficiency (e.g., 16,800 plates m.sup.-1 for atenolol), high enantioselectivity, and good reproducibility toward various racemates. The highest resolution value, retention factor, and separation factor reach to 2.11, 2.85, and 3.73, respectively. The relative standard deviations (RSD) of peak area, peak height, half-peak width, and retention time of atenolol were all below 3.0%. Graphical abstract

This review aims to gather the current state of the art on the encapsulation methods using alginate as the main polymeric material in order to produce hydrogels ranging from the microscopic to macroscopic sizes. The use of alginates as an encapsulation material is of growing interest, as it is fully bio-based, bio-compatible and bio-degradable. The field of application of alginate encapsulation is also extremely broad, and there is no doubt it will become even broader in the near future considering the societal demand for sustainable materials in technological applications. In this review, alginate’s main properties and gelification mechanisms, as well as some factors influencing this mechanism, such as the nature of the reticulation cations, are first investigated. Then, the capacity of alginate gels to release matter in a controlled way, from small molecules to micrometric compounds, is reported and discussed. The existing techniques used to produce alginates beads, from the laboratory scale to the industrial one, are further described, with a consideration of the pros and cons with each techniques. Finally, two examples of applications of alginate materials are highlighted as representative case studies.

Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.

The effects of serotonin (5-HT) on anxiety and depression are mediated by a number of 5-HT receptors, including autoreceptors that act to inhibit 5-HT release. While the majority of anxiety and depression-related research has focused on the 5-HT receptor, the 5-HT receptor has a lesser known role in modulating emotional behavior. 5-HT receptors are inhibitory GPCRs located on the presynaptic terminal of both serotonin and non-serotonin neurons, where they act to inhibit neurotransmitter release. The autoreceptor population located on the axon terminals of 5-HT neurons is a difficult population to study due to their diffuse localization throughout the brain that overlaps with 5-HT heteroreceptors (receptors located on non-serotonergic neurons). In order to study the contribution of 5-HT autoreceptors to anxiety and depression-related behaviors, we developed a genetic mouse model that allows for selective ablation of 5-HT autoreceptors. Mice lacking 5-HT autoreceptors displayed the expected increases in extracellular serotonin levels in the ventral hippocampus following administration of a selective serotonin reuptake inhibitor. In behavioral studies, they displayed decreased anxiety-like behavior in the open field and antidepressant-like effects in the forced swim and sucrose preference tests. These results suggest that strategies aimed at blocking 5-HT autoreceptors may be useful for the treatment of anxiety and depression.

Developing positron emission tomography (PET) radioligands for the detection of endogenous serotonin release will enable the investigation of serotonergic deficits in many neuropsychiatric disorders. The present study investigates how acute challenges that aim to increase or decrease cerebral serotonin levels affect binding of the serotonin 2A receptor (5-HT2AR) agonist radioligand [11C]Cimbi-36. In a randomized, double-blind, placebo-controlled, three-arm design, 23 healthy volunteers were PET scanned twice with [11C]Cimbi-36: at baseline and following double-blind assignment to one of three interventions (1) infusion of the selective serotonin reuptake inhibitor (SSRI) citalopram preceded by oral dosing of the 5-HT1AR antagonist pindolol, (n = 8) (2) acute tryptophan depletion (ATD) (n = 7) and (3) placebo (n = 8). Two-sample t-tests revealed no significant group differences in percent change of neocortical [11C]Cimbi-36 binding from baseline to intervention between placebo and citalopram/pindolol (p = 0.4) or between placebo and ATD (p = 0.5). Notably, there was a significantly larger within-group variation in 5-HT2AR binding after intervention with citalopram/pindolol, as compared with placebo (p = 0.007). These findings suggest that neither ATD nor a combination of citalopram and pindolol elicit acute unidirectional changes in serotonin levels sufficient to be detected with [11C]Cimbi-36 PET in neocortex. We suggest that the large interindividual variation in 5-HT2AR binding after citalopram/pindolol reflects that after an acute SSRI intervention, individuals respond substantially different in terms of their brain serotonin levels. Our observation has a potential impact for the understanding of patient responses to SSRI.