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Sleep Sep 2023Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found...
Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXB's mechanism of action on narcolepsy.
Topics: Humans; Mice; Animals; Dogs; Orexins; Sodium Oxybate; Cataplexy; Locus Coeruleus; Narcolepsy; Neurons; Opiate Alkaloids
PubMed: 37155728
DOI: 10.1093/sleep/zsad135 -
Molecular Metabolism Sep 2023Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and...
OBJECTIVE
Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties.
METHODS
Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses.
RESULTS
Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability.
CONCLUSIONS
We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.
Topics: Mice; Humans; Animals; Diabetes Mellitus, Type 2; Insulin; Morphinans; Islets of Langerhans; Glucose; Hypoglycemic Agents; Oxidative Stress
PubMed: 37451343
DOI: 10.1016/j.molmet.2023.101775 -
Bioorganic Chemistry Apr 2024The sigma 2 receptor (σR), which was recently identified as the transmembrane protein 97 (TMEM97), is increasingly attracting interest as a possible therapeutic target...
The sigma 2 receptor (σR), which was recently identified as the transmembrane protein 97 (TMEM97), is increasingly attracting interest as a possible therapeutic target for indications in neuroscience. Toward identifying novel modulators of σR/TMEM97, we prepared a collection of benzoxazocine, benzomorphan, and methanobenzazepine ligands related to the known bioactive norbenzomorphans DKR-1677, FEM-1689, and EES-1686 and determined their K values for σR/TMEM97 and the sigma 1 receptor (σR). The σR/TMEM97 binding affinities and selectivities relative to σR of these new benzoxazocine, benzomorphan, and methanobenzazepine analogs are lower, often significantly lower, than their respective norbenzomorphan counterparts, suggesting the spatial orientation of pharmacophoric substituents is critical for binding to the two proteins. The benzoxazocine, benzomorphan, and methanobenzazepine congeners of DKR-1677 and FEM-1689 tend to be weakly selective for σR/TMEM97 versus σR, whereas EES-1686 derivatives exhibit the greatest selectivity, suggesting the size and/or nature of the substituent on the nitrogen atom of the scaffold may be important for selectivity. Computational docking studies were performed for the 1S,5R-and 1R,5S-enantiomers of DKR-1677, FEM-1689, and EES-1686 and their benzoxazocine, benzomorphan, and methanobenzazepine counterparts. These computations predict that the protonated amino group of each ligand forms a highly conserved salt bridge and a H-bonding interaction with Asp29 as well as a cation-π interaction with Tyr150 of σR/TMEM97. These electrostatic interactions are major driving forces for binding to σR/TMEM97 and are similar, though not identical, for each ligand. Other interactions within the well-defined binding pocket also tend to be comparable, but there are some major differences in how the hydrophobic aryl groups of various ligands interact with the protein surface external to the binding pocket. Overall, these studies show that the orientations of aryl and N-substituents on the norbenzomorphan and related scaffolds are important determinants of binding affinity of σR/TMEM97 ligands, and small changes can have significant effects upon binding profiles.
Topics: Ligands; Benzomorphans; Structure-Activity Relationship
PubMed: 38432153
DOI: 10.1016/j.bioorg.2024.107191 -
JAMA Network Open Oct 2023Oral mucositis (OM) is a common and debilitating adverse effect observed in patients with head and neck cancer (HNC) receiving radiation therapy (RT). Previous studies...
IMPORTANCE
Oral mucositis (OM) is a common and debilitating adverse effect observed in patients with head and neck cancer (HNC) receiving radiation therapy (RT). Previous studies examining associations between OM and clinical outcomes were performed in the era of 3-dimensional conformal RT planning with low rates of concurrent chemotherapy, and thus may not reflect current practice.
OBJECTIVE
To prospectively assess patient-reported OM and identify its associations with clinical outcomes and quality of life.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study performed at a single institution included 702 consecutive patients who underwent definitive or adjuvant intensity-modulated RT (IMRT) for primary HNC from February 9, 2015, to May 27, 2022. Data were analyzed from November 28, 2022, to August 18, 2023.
MAIN OUTCOMES AND MEASURES
Severity of OM was assessed based on highest reported mouth and throat soreness (MTS) score during radiotherapy according to the Oral Mucositis Weekly Questionnaire-Head and Neck Cancer survey, which was administered weekly during IMRT. Linear mixed models were used to compare mean MTS scores grouped by disease site and chemotherapy regimen. Fisher exact tests and 1-way analysis of variance tests were performed to identify associations between severity of OM and clinical outcomes.
RESULTS
Among 576 eligible patients, the median age was 62.5 (IQR, 56.3-69.1) years, and 451 patients (78.3%) were men. In terms of race and ethnicity, 6 patients (1.0%) were American Indian or Alaska Native; 2 (0.3%), Asian; 31 (5.4%), Black; 8 (1.4%), Hispanic or Latino; 509 (88.4%), White; and 28 (4.9%), unknown. The most common treatment site was oropharynx (268 [46.5%]), and most patients received concurrent chemotherapy (464 [80.6%]). By the end of treatment, 360 patients (62.5%) developed severe OM and 568 (98.6%) developed some degree of OM. Linear mixed models found no significant differences in OM between HNC disease sites. Groups with greater highest severity of OM reported had higher rates of measured outcomes (listed respectively by MTS score 0, 1, 2, 3, and 4): feeding tube placement (0%, 3.6% [2 of 56], 6.6% [10 of 152], 14.7% [40 of 272], and 21.6% [19 of 88]; P = .001), hospitalization (12.5% [1 of 8], 10.7% [6 of 56], 15.1% [23 of 152], 23.9% [65 of 272], and 28.4% [25 of 88]; P = .02), opiate use (0%, 19.6% [11 of 56], 42.8%[65 of 152], 61.4% [167 of 272], and 64.8% [57 of 88]; P < .001) and experienced greater weight loss (median, -0.7 [IQR, -1.7 to -0.4] kg; median, 3.9 [IQR, 1.1 to 6.1] kg; median, 5.0 [IQR, 2.2 to 7.7] kg; median, 4.7 [IQR, 2.1 to 7.7] kg; and median, 7.7 [IQR, 2.8 to 10.6] kg; P < .001).
CONCLUSIONS AND RELEVANCE
In this cohort study of patients with HNC, 62.5% developed severe OM. Higher severity of OM was associated with feeding tube placement, hospitalization, opiate use, and weight loss. Improvements in OM prevention and management are needed.
Topics: Male; Humans; Middle Aged; Female; Radiotherapy, Intensity-Modulated; Cohort Studies; Quality of Life; Head and Neck Neoplasms; Stomatitis; Opiate Alkaloids; Weight Loss
PubMed: 37819659
DOI: 10.1001/jamanetworkopen.2023.37265 -
Pediatric Pulmonology Sep 2023International consensus statements on depression and anxiety in adolescents and adults with cystic fibrosis (awCF) recommend assessment for comorbid substance misuse....
BACKGROUND
International consensus statements on depression and anxiety in adolescents and adults with cystic fibrosis (awCF) recommend assessment for comorbid substance misuse. However, at CF centers, the frequency and impact of substance misuse have not been well characterized, and best practices for prevention, identification, and evidence-based treatment have not been routinely implemented.
METHODS
Medical records of 148 awCF over 3 years were reviewed to determine the prevalence of substance misuse (alcohol or opiates) and its relationship with clinical variables and healthcare utilization. Independent sample t test for continuous outcomes and χ test for binary outcomes were used to compare groups with and without substance misuse.
RESULTS
Substance misuse was documented in 28 (19%) awCF, equally distributed between alcohol (n = 13) and opiates (n = 15). Adults with substance misuse were more likely to be male. The prevalence of diagnosed anxiety and depression did not differ significantly between groups, but those with substance misuse had more severe anxiety (Generalized Anxiety Disorder-7 Item [GAD-7]: 10.0 ± 6.1 vs. 3.3 ± 4.4; p < 0.001) and depressive symptoms (Patient Health Questionnaire-9: 10.4 ± 6.5 vs. 4.0 ± 4.8; p < 0.001). Adults with substance misuse had higher annual rates of missed outpatient CF visits, more frequent "sick" visits, more frequent and longer hospitalizations, and a higher mortality rate.
CONCLUSIONS
In awCF, substance misuse is common and associated with adverse indicators of emotional and physical health, including via proxy of service utilization, suggesting that systematic approaches to addressing substance misuse in CF clinics should be considered. Prospective, longitudinal study is warranted to elucidate the complex relationships between depression, anxiety, substance misuse, and health outcomes in individuals with CF.
Topics: Adolescent; Humans; Male; Adult; Female; Longitudinal Studies; Cystic Fibrosis; Prospective Studies; Substance-Related Disorders; Opiate Alkaloids
PubMed: 37294071
DOI: 10.1002/ppul.26541 -
Journal of Pharmaceutical and... Jan 2024Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in...
Fingerprints left at a crime scene are used to connect the crime to a person who may have been present there. Fingerprints can also be used as alternative material in forensic toxicology. The detection of drugs in fingerprint samples can be used to show that an individual touching an item has consumed specific drugs. The aim of this study was to check the usefulness of fingerprints in drug analyses and detection of some analytes in this material. Fingerprint samples were collected on glass slides from a volunteer who consumed separately tablets containing pseudoephedrine, codeine, dextromethorphan, and used lidocaine spray. Moreover, fingerprints of individuals receiving sertraline, hydroxyzine and trazodone as part of their long-term treatment were analysed. The detection of drugs was conducted using the liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. After administration of single doses of drugs, they were detected up to 36 h (pseudoephedrine), 24 h (codeine), and less than 6 h (dextromethorphan and lidocaine) with maximum concentrations observed at 1-4 h. In fingerprints of a person who has finished treatment with hydroxyzine and sertraline it was possible to detect these drugs even 20 days after last drug administration. Cetirizine (hydroxyzine metabolite) and mCPP (trazodone metabolite) were determined in fingerprints of individuals under long-term treatment. This work has demonstrated that forensic toxicology can use fingerprints as alternative material. Drugs can be detected in fingerprints even after their single doses. Parent compounds predominate over metabolites in the fingerprints. The detection window depends on the type of drug and duration of the treatment.
Topics: Humans; Chromatography, Liquid; Trazodone; Tandem Mass Spectrometry; Dextromethorphan; Pseudoephedrine; Sertraline; Substance Abuse Detection; Pharmaceutical Preparations; Hydroxyzine; Codeine; Lidocaine
PubMed: 37926037
DOI: 10.1016/j.jpba.2023.115835 -
BMJ Supportive & Palliative Care Jan 2024The initiation of peripherally acting μ-opioid receptor antagonists (PAMORAs) should be considered 2 weeks after conventional laxatives have failed to achieve an...
OBJECTIVES
The initiation of peripherally acting μ-opioid receptor antagonists (PAMORAs) should be considered 2 weeks after conventional laxatives have failed to achieve an adequate response, and affected patients should be evaluated every 2 weeks thereafter. However, this guidance is difficult to implement in acute care hospitals. This study aimed to examine how naldemedine (PAMORA) should be introduced in combination with other laxatives in the acute care setting.
METHODS
This retrospective study evaluated 93 inpatients who received at least four doses of naldemedine. We investigated changes in the average daily defecation counts during the first 7 days after compared with before naldemedine administration and the incidence of diarrhoea.
RESULTS
Daily defecation counts during the first 7 days after compared with before naldemedine administration were greater in both the naldemedine, magnesium oxide (MgO) and another laxative group, and in the naldemedine and another laxative other than MgO group than in the naldemedine only group. The incidence rates of diarrhoea were significantly higher in the naldemedine, MgO, and another laxative group, and in the naldemedine and another laxative other than MgO group than in the naldemedine only group.
CONCLUSIONS
The introduction of naldemedine alone or in combination with MgO should be considered.
Topics: Humans; Laxatives; Retrospective Studies; Magnesium Oxide; Inpatients; Analgesics, Opioid; Constipation; Naltrexone; Narcotic Antagonists; Diarrhea
PubMed: 35750467
DOI: 10.1136/spcare-2022-003685 -
Canadian Family Physician Medecin de... Sep 2023
Topics: Humans; Bupropion; Naltrexone; Weight Loss
PubMed: 37704234
DOI: 10.46747/cfp.6909627 -
CNS Drugs Aug 2023Naltrexone is a mu-opioid receptor antagonist with a long half-life compared with naloxone. Both of these drugs, along with others, were developed with the intention of...
Naltrexone is a mu-opioid receptor antagonist with a long half-life compared with naloxone. Both of these drugs, along with others, were developed with the intention of reversing the effects of opioid abuse or toxicity. Evidence has also shown that naltrexone has a benefit in preventing relapse by reducing opioid cravings and reducing symptoms of opioid withdrawal. The benefits of this drug were not only shown with opioid abuse. In 1984 this drug was also approved for alcohol abuse. Naltrexone has been proven to decrease alcohol relapse by decreasing the craving. Apart from these approved indications for the use of naltrexone, with time, it has been seen that this drug has a benefit in treating chronic pain. A number of studies have shown the benefits of this drug with inflammatory bowel disease, fibromyalgia, multiple sclerosis, diabetic neuropathy, and complex regional pain syndrome, among others. More studies are needed to approve this medication for specific chronic pain conditions.
Topics: Humans; Naltrexone; Chronic Pain; Analgesics, Opioid; Narcotic Antagonists; Opioid-Related Disorders; Chronic Disease; Recurrence
PubMed: 37505425
DOI: 10.1007/s40263-023-01018-3 -
CJEM Jul 2023
Topics: Humans; Buprenorphine, Naloxone Drug Combination; Buprenorphine; Emergency Service, Hospital
PubMed: 37389768
DOI: 10.1007/s43678-023-00543-w