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Purpose The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. Methods The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg). Results Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above-mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. Conclusions Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone.

Abstract Objective Evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of NKTR-181, a novel mu-opioid agonist molecule, relative to oxycodone. Design This randomized, single-center, double-blind, active- and placebo-controlled five-period crossover study enrolled healthy, adult, non–physically dependent recreational opioid users. Setting Inpatient clinical research site. Subjects Forty-two randomized subjects (73.8% male, 81% white, mean age = 25 years). Methods The primary objective was to evaluate single orally administered 100, 200, and 400 mg NKTR-181 doses in solution compared with 40 mg oxycodone and placebo solutions using the Drug Liking visual analog scale. Secondary measures included the Drug Effects Questionnaire, Addiction Research Center Inventory/Morphine Benzedrine Group Subscale, Price Value Assessment Questionnaire, Global Assessment of Overall Drug Liking, and Take Drug Again Assessment. Central nervous system mu-opioid effects were assessed using pupillometry. The study included qualifying and treatment phases. Subjects received each of the five treatments using a crossover design. Results NKTR-181 at all dose levels had significantly lower Drug Liking Emax than oxycodone (P < 0.0001). Drug Liking scores for oxycodone increased rapidly within 15 minutes and peaked at approximately one hour postdose, whereas Drug Liking (and most secondary abuse potential measures) for all doses of NKTR-181 were comparable with placebo for at least the first hour. Only the 400 mg Drug Liking scores were minimally differentiated vs placebo from one and a half to four hours, but remained significantly lower than oxycodone (P < 0.003). NKTR-181 treatment-related adverse effects were mild and occurred at a lower rate compared with oxycodone. Conclusions NKTR-181 demonstrated delayed onset of CNS effects and significantly lower abuse potential scores compared with oxycodone in recreational opioid users.

Background The aim of this study was to investigate the effects of the cytochrome P450 3A4 (CYP34A) inhibitor itraconazole on the pharmacokinetics and pharmacodynamics of orally and intravenously administered oxycodone. Methods Twelve healthy subjects were administered 200 mg itraconazole or placebo orally for 5 days in a four-session paired cross-over study. On day 4, oxycodone was administered intravenously (0.1 mg/kg) in the first part of the study and orally (10 mg) in the second part. Plasma concentrations of oxycodone and its oxidative metabolites were measured for 48 h, and pharmacodynamic effects were evaluated. Results Itraconazole decreased plasma clearance (Cl) and increased the area under the plasma concentration-time curve (AUC0-∞) of intravenous oxycodone by 32 and 51%, respectively (P < 0.001) and increased the AUC(0-∞) of orally administrated oxycodone by 144% (P < 0.001). Most of the pharmacokinetic changes in oral oxycodone were seen in the elimination phase, with modest effects by itraconazole on its peak concentration, which was increased by 45% (P = 0.009). The AUC(0-48) of noroxycodone was decreased by 49% (P < 0.001) and that of oxymorphone was increased by 359% (P < 0.001) after the administration of oral oxycodone. The pharmacologic effects of oxycodone were enhanced by itraconazole only modestly. Conclusions Itraconazole increased the exposure to oxycodone by inhibiting its CYP3A4-mediated N-demethylation. The clinical use of itraconazole in patients receiving multiple doses of oxycodone for pain relief may increase the risk of opioid-associated adverse effects.

Activation of the μ-opioid receptor (μOR) is responsible for the efficacy of the most effective analgesics. To shed light on the structural basis for μOR activation, here we report a 2.1 Å X-ray crystal structure of the murine μOR bound to the morphinan agonist BU72 and a G protein mimetic camelid antibody fragment. The BU72-stabilized changes in the μOR binding pocket are subtle and differ from those observed for agonist-bound structures of the β 2 -adrenergic receptor (β 2 AR) and the M2 muscarinic receptor. Comparison with active β 2 AR reveals a common rearrangement in the packing of three conserved amino acids in the core of the μOR, and molecular dynamics simulations illustrate how the ligand-binding pocket is conformationally linked to this conserved triad. Additionally, an extensive polar network between the ligand-binding pocket and the cytoplasmic domains appears to play a similar role in signal propagation for all three G-protein-coupled receptors. X-ray crystallography and molecular dynamics simulations of the μ-opioid receptor reveal the conformational changes in the extracellular and intracellular domains of this G-protein-coupled receptor that are associated with its activation. Activation of the μ-opioid receptor The μ-opioid receptor is a G-protein-coupled receptor (GPCR) activated by various analgesics, endogenous endorphins and drugs of abuse such as heroin and opium. Our understanding of the mechanism by which agonist binding leads to recognition, coupling, and activation of a particular G protein subtype is incomplete. In two papers in this issue of Nature , the authors used X-ray crystallography, molecular dynamics simulations, and NMR spectroscopy to probe the structural basis for receptor activation. As well as revealing the conformational changes in the extracellular and intracellular domains of this GPCR associated with receptor activation, these studies help explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this receptor is relatively weak.

Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction. The crystal structure of the mouse μ-opioid receptor bound to an antagonist is described, with possible implications for the future development of analgesics. Where opiates hit home Four papers in this issue of Nature present the long-awaited high-resolution crystal structures of the four known opioid receptors in ligand-bound conformations. These G-protein-coupled receptors are the targets of a broad range of drugs, including painkillers, antidepressants, anti-anxiety agents and anti-addiction medications. Brian Kobilka’s group reports the crystal structure of the µ-opioid receptor bound to a morphinan antagonist and the δ-opioid receptor bound to naltrindole. Raymond Stevens’ group reports on the κ-opioid receptor bound to the selective antagonist JDTic, and the nociceptin/orphanin FQ receptor bound to a peptide mimetic. In an associated News and Views, Marta Filizola and Lakshmi Devi discuss the implications of these landmark papers for research on the mechanisms underlying receptor function and drug development.

NMR spectroscopy reveals the conformational changes of the μ-opioid receptor that are associated with receptor activation, helping to explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this receptor is relatively weak. Activation of the μ-opioid receptor The μ-opioid receptor is a G-protein-coupled receptor (GPCR) activated by various analgesics, endogenous endorphins and drugs of abuse such as heroin and opium. Our understanding of the mechanism by which agonist binding leads to recognition, coupling, and activation of a particular G protein subtype is incomplete. In two papers in this issue of Nature , the authors used X-ray crystallography, molecular dynamics simulations, and NMR spectroscopy to probe the structural basis for receptor activation. As well as revealing the conformational changes in the extracellular and intracellular domains of this GPCR associated with receptor activation, these studies help explain why the allosteric coupling between the agonist-binding pocket and the cytoplasmic G-protein-coupling interface of this receptor is relatively weak. µ-Opioid receptors (µORs) are G-protein-coupled receptors that are activated by a structurally diverse spectrum of natural and synthetic agonists including endogenous endorphin peptides, morphine and methadone. The recent structures of the μOR in inactive 1 and agonist-induced active states (Huang et al. , ref. 2 ) provide snapshots of the receptor at the beginning and end of a signalling event, but little is known about the dynamic sequence of events that span these two states. Here we use solution-state NMR to examine the process of μOR activation using a purified receptor (mouse sequence) preparation in an amphiphile membrane-like environment. We obtain spectra of the μOR in the absence of ligand, and in the presence of the high-affinity agonist BU72 alone, or with BU72 and a G protein mimetic nanobody. Our results show that conformational changes in transmembrane segments 5 and 6 (TM5 and TM6), which are required for the full engagement of a G protein, are almost completely dependent on the presence of both the agonist and the G protein mimetic nanobody, revealing a weak allosteric coupling between the agonist-binding pocket and the G-protein-coupling interface (TM5 and TM6), similar to that observed for the β2-adrenergic receptor 3 . Unexpectedly, in the presence of agonist alone, we find larger spectral changes involving intracellular loop 1 and helix 8 compared to changes in TM5 and TM6. These results suggest that one or both of these domains may play a role in the initial interaction with the G protein, and that TM5 and TM6 are only engaged later in the process of complex formation. The initial interactions between the G protein and intracellular loop 1 and/or helix 8 may be involved in G-protein coupling specificity, as has been suggested for other family A G-protein-coupled receptors.

Naloxegol is a polyethylene glycol derivative of naloxone approved in the US as a once‐daily oral treatment for opioid‐induced constipation (OIC) in adults with chronic noncancer pain. Population exposure–response models were constructed based on data from two phase III studies comprising 1,331 adults with noncancer pain and OIC. In order to characterize the protocol‐defined naloxegol responder rate, the number of daily spontaneous bowel movements (SBMs) was characterized by a longitudinal ordinal nonlinear mixed‐effects logistic regression dose–response model, and the incidence of diary entry discontinuation was described by a time‐to‐event model. The mean number of SBMs per week increased with increasing naloxegol dose. The predicted placebo‐adjusted responder rates (90% confidence interval) were 10.4% (4.6–13.4%) and 11.1% (4.8–14.4%) for naloxegol 12.5 and 25 mg/day, respectively. Model‐predicted response to naloxegol was influenced by the baseline SBM frequency and characteristics of the opioid treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory arthropathy associated with articular damage and attendant comorbidities. Even although RA treatment has advanced remarkably over the last decade, a significant proportion of patients still do not achieve sustained remission. The cause of RA is not yet known despite the many potential mechanisms proposed. It has been confirmed that RA is associated with dysregulated immune system and persistent inflammation. Therefore, management of inflammation is always the target of therapy. Sinomenine (SIN) is the prescription drug approved by the Chinese government for RA treatment. A previous study found that SIN was a robust anti-inflammation drug. In this study, we screened the different secretory cytokines using inflammation antibody arrays and qRT-PCR in both LPS-induced and SIN-treated RAW264.7 cells followed by evaluation of the ability of SIN to modulate cytokine secretion in a cell model, collagen-induced arthritis (CIA) mouse model, and RA patients. Several clinical indexes affecting the 28-joint disease activity score (DAS28) were determined before and after SIN treatment. Clinical indexes, inflammatory cytokine secretion, and DAS28 were compared among RA patients treated with either SIN or methotrexate (MTX). To explore the mechanism of SIN anti-inflammatory function, RA-associated monocyte/macrophage subsets were determined using flow cytometry in CIA mouse model and RA patients, both treated with SIN. The results demonstrated that SIN regulated IL-6, GM-CSF, IL-12 p40, IL-1α, TNF-α, IL-1β, KC (CXCL1), Eotaxin-2, IL-10, M-CSF, RANTES, and MCP-1 secretion and and reduced RA activity and DAS28 in a clinical setting. Furthermore, SIN attenuated CD11b F4/80 CD64 resident macrophages in the synovial tissue, CD11b Ly6C CD43 macrophages in the spleen and draining lymph nodes of CIA mice. The percentage of CD14 CD16 peripheral blood mononuclear cells was reduced by SIN in RA patients. These data indicated that SIN regulates the secretion of multiple inflammatory cytokines and monocyte/macrophage subsets, thereby suppressing RA progression. Therefore, along with MTX, SIN could be an alternative cost-effective anti-inflammatory agent for treating RA.

Sinomenine (SIN), as a potential therapeutic agent for rheumatoid arthritis (RA), exhibits advantages such as non-addictiveness. However, its low aqueous solubility and poor membrane permeability result in limited bioavailability, which compromises its therapeutic efficacy in conventional formulations. To address these limitations, this study developed nanostructured lipid carriers (NLCs) with optimized formulations and evaluated their pharmacodynamic performance. Molecular dynamics (MD) simulations were employed to screen excipients and analyze the blending system. SIN-loaded NLCs (SIN-NLCs) were prepared using high-pressure homogenization. Single-factor experiments were performed to optimize the processing conditions of SIN-NLCs. A three-factor, three-level experimental design was established using Design Expert 13 software and further refined through Box–Behnken design (BBD) response surface methodology. This approach enabled cross-validation between molecular dynamics simulations and conventional experiments. Additionally, transmission electron microscopy (TEM) was used to examine morphology, while X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR) were employed to characterize the physicochemical state of SIN in NLCs. Pharmacodynamic evaluation was performed in a RA model, supplemented by single-pass intestinal perfusion study (SPIP). Initially, MD simulations were employed to evaluate drug–excipient compatibility, thereby identifying suitable formulation excipients: stearic acid and oleic acid as lipid components, and Poloxamer 188 as the surfactant. Subsequently, single-factor experiments combined with the BBD response surface methodology were employed to optimize preparation parameters, establishing the ideal process conditions: drug-to-lipid ratio of 1:42, solid-to-liquid lipid ratio of 5.58:4.42, and Poloxamer 188 concentration of 1.20%. The optimized SIN-NLCs exhibited spherical particles with uniform dispersion and no agglomeration. The average particle size was 173.90 ± 1.97 nm, with a polydispersity index (PDI) of 0.18 ± 0.01, a zeta potential of −22.65 ± 0.60 mV, and an encapsulation efficiency (EE%) of 91.27% ± 0.01. Spectroscopic analysis confirmed that SIN existed in an amorphous state and was successfully encapsulated within the lipid matrix. In vivo, SIN-NLCs significantly reduced paw swelling and arthritis scores in model rats, promoted synovial cell proliferation, and suppressed inflammatory cell infiltration. The intestinal perfusion study demonstrated that SIN-NLCs were primarily absorbed in the small intestine and markedly enhanced drug permeability. SIN-NLCs represent an effective delivery system to enhance the solubility and permeability of SIN. This study provides a novel strategy and methodology for the formulation of hydrophobic drugs, offering valuable insights for future pharmaceutical development.

Sinomenine (SIN) is a promising candidate for the treatment of rheumatoid arthritis (RA). Although it possesses the advantage of being non-addictive, its poor aqueous solubility and low oral bioavailability have limited its clinical application. To address these issues, SIN was encapsulated into lipid cubic liquid crystal nanoparticles (LCNPs) and systematically characterized. Molecular dynamics (MD) simulations were first employed to screen suitable excipients for formulation development. Combined with single-factor optimization and Box–Behnken response surface design, the optimal composition and preparation process were determined. The resulting SIN-LCNPs exhibited a particle size of 149.7 ± 0.9 nm, a polydispersity index (PDI) of 0.223 ± 0.01, a zeta potential of −18.9 mV, and an encapsulation efficiency (EE%) of 92.2%. Spectroscopic analyses confirmed successful incorporation of SIN into the lipid matrix. Pharmacodynamic studies revealed that SIN-LCNPs enhanced targeted drug delivery to inflamed joints, significantly alleviating inflammation and suppressing disease progression in rats. In vivo single-pass intestinal perfusion (SPIP) experiments further demonstrated that SIN was primarily absorbed through the small intestine and that the LCNP carrier effectively improved its intestinal permeability. Collectively, this study provides a novel strategy and theoretical foundation for developing efficient formulations of poorly water-soluble drugs, highlighting the potential clinical application of SIN-LCNPs in RA therapy.