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Cureus Apr 2024This article discusses a rare case of isolated xylazine overdose in a human, treated successfully with naloxone. Xylazine, typically used as a veterinary tranquilizer,...
This article discusses a rare case of isolated xylazine overdose in a human, treated successfully with naloxone. Xylazine, typically used as a veterinary tranquilizer, acts as a potent α2 adrenergic agonist, leading to sedation, muscle relaxation, and potential respiratory depression. In this case, a female mistakenly injected herself with xylazine mistaking it for a different medication. The report discusses naloxone's role beyond opioid overdose, especially regarding substances causing central nervous system (CNS) depression via mechanisms similar to those of opioids. While naloxone is traditionally associated with opioid receptor antagonism, its successful application here suggests potential benefits against non-opioid substances such as xylazine. The report emphasizes the need for higher naloxone dosages than those used for opioid toxicity and suggests more research into its use for treating xylazine intoxication, reflecting on the growing trend of xylazine as a recreational drug adulterant and the resulting health risks.
PubMed: 38707050
DOI: 10.7759/cureus.57638 -
Biomedicine & Pharmacotherapy =... Jun 2024Opioid receptor agonists are often used when cancer patients undergo surgery or analgesic treatment. As analgesics in clinical care, opioids can provide intraoperative... (Review)
Review
Opioid receptor agonists are often used when cancer patients undergo surgery or analgesic treatment. As analgesics in clinical care, opioids can provide intraoperative or to chronic cancer pain relief. Immune function plays an important role in anti-cancer therapy, with cellular immunity, comprised principally of T-lymphocytes and natural killer cells, representing the primary anti-cancer immune response. However, it remains unclear whether immune function is further affected with the use of opioids in already immunocompromised cancer patients. This article provides a review of the effects of commonly used clinical opioids, including morphine, oxycodone, fentanyl and tramadol, on immune function in cancer patients. It provides a summary of current evidence regarding the immunomodulatory effects of opioids in the cancer setting and mechanisms underlying these interactions.
Topics: Humans; Analgesics, Opioid; Neoplasms; Cancer Pain; Animals; T-Lymphocytes; Immune System
PubMed: 38701564
DOI: 10.1016/j.biopha.2024.116665 -
Anesthesiology May 2024Acetaminophen and 5-hydroxytryptamine-type-3 (5-HT3) receptor antagonists are administered as standard prophylaxes for postoperative pain, nausea, and vomiting....
BACKGROUND
Acetaminophen and 5-hydroxytryptamine-type-3 (5-HT3) receptor antagonists are administered as standard prophylaxes for postoperative pain, nausea, and vomiting. Preclinical studies however suggest that 5-HT3 antagonists may compromise acetaminophen's analgesic effect. This hospital registry study investigates whether 5-HT3 antagonists mitigate the analgesic effect of prophylactic acetaminophen in a perioperative setting.
METHODS
This study included 55,016 adult patients undergoing general anesthesia for ambulatory procedures at a tertiary healthcare center in Massachusetts, United States of America, from 2015 to 2022. Using binary exposure variables and a comprehensive selection of pre-planned patient- and procedure-related covariates for confounder control, we investigated whether intraoperative 5-HT3 antagonists affected the association between pre- or intraoperative acetaminophen and postoperative opioid consumption, gauged by opioid dose in mg oral morphine equivalents (OME) administered in the post-anesthesia care unit (PACU). A multivariable, zero-inflated negative binomial regression model was applied.
RESULTS
3,166 (5.8%) patients received only acetaminophen, 15,438 (28.1%) only 5-HT3 antagonists, 31,850 (57.9%) both drugs, and 4,562 (8.3%) neither drug. The median PACU opioid dose was 7.5 mg OME (interquartile range 7.5 to 14.3 mg OME) among 16,640/55,016 (30.3%) patients who received opioids and the average opioid dose was 3.2 mg OME across all patients (maximum cumulative dose: 20.4 mg OME). Acetaminophen administration was associated with a 5.5% (95%CI -9.6% to -1.4%;p=0.009; adjusted absolute difference -0.19 mg OME;95%CI -0.33 to -0.05;p=0.009) reduction in opioid consumption among patients who did not receive a 5-HT3 antagonist, while there was no effect in patients who received a 5-HT3 antagonist (adjusted absolute difference 0.00 mg OME; 95%CI -0.06 to 0.05;p=0.93,p-for-interaction=0.012).
CONCLUSION
A dose-dependent association of pre- or intraoperative acetaminophen with decreased postoperative opioid consumption was not observed when 5-HT3 antagonists were co-administered, suggesting that physicians might consider reserving 5-HT3 antagonists as rescue medication for postoperative nausea or vomiting when acetaminophen is administered for pain prophylaxis.
PubMed: 38700445
DOI: 10.1097/ALN.0000000000005033 -
JBMR Plus Jun 2024Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our...
Cherubism (OMIM 118400) is a rare craniofacial disorder in children characterized by destructive jawbone expansion due to the growth of inflammatory fibrous lesions. Our previous studies have shown that gain-of-function mutations in SH3 domain-binding protein 2 (SH3BP2) are responsible for cherubism and that a knock-in mouse model for cherubism recapitulates the features of cherubism, such as increased osteoclast formation and jawbone destruction. To date, is the only gene identified to be responsible for cherubism. Since not all patients clinically diagnosed with cherubism had mutations in SH3BP2, we hypothesized that there may be novel cherubism genes and that these genes may play a role in jawbone homeostasis. Here, using whole exome sequencing, we identified homozygous loss-of-function variants in the opioid growth factor receptor like 1 () gene in 2 independent autosomal recessive cherubism families from Syria and India. The newly identified pathogenic homozygous variants were not reported in any variant databases, suggesting that is a novel gene responsible for cherubism. Single cell analysis of mouse jawbone tissue revealed that is highly expressed in myeloid lineage cells. We generated OGFRL1 knockout mice and mice carrying the Syrian frameshift mutation to understand the role of OGFRL1. However, neither mouse model recapitulated human cherubism or the phenotypes exhibited by SH3BP2 cherubism mice under physiological and periodontitis conditions. Unlike bone marrow-derived M-CSF-dependent macrophages (BMMs) carrying the SH3BP2 cherubism mutation, BMMs lacking OGFRL1 or carrying the Syrian mutation showed no difference in TNF-ɑ mRNA induction by LPS or TNF-ɑ compared to WT BMMs. Osteoclast formation induced by RANKL was also comparable. These results suggest that the loss-of-function effects of OGFRL1 in humans differ from those in mice and highlight the fact that mice are not always an ideal model for studying rare craniofacial bone disorders.
PubMed: 38699440
DOI: 10.1093/jbmrpl/ziae050 -
Frontiers in Pharmacology 2024Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced...
Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75 μg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0 mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5 mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5 mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.
PubMed: 38698814
DOI: 10.3389/fphar.2024.1381073 -
Cell Death & Disease May 2024Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L...
Sigma-2-ligands (S2L) are characterized by high binding affinities to their cognate sigma-2 receptor, overexpressed in rapidly proliferating tumor cells. As such, S2L were developed as imaging probes (ISO1) or as cancer therapeutics, alone (SV119 [C6], SW43 [C10]) and as delivery vehicles for cytotoxic drug cargoes (C6-Erastin, C10-SMAC). However, the exact mechanism of S2L-induced cytotoxicity remains to be fully elucidated. A series of high-affinity S2L were evaluated regarding their cytotoxicity profiles across cancer cell lines. While C6 and C10 displayed distinct cytotoxicities, C0 and ISO1 were essentially non-toxic. Confocal microscopy and lipidomics analysis in cellular and mouse models revealed that C10 induced increases in intralysosomal free cholesterol and in cholesterol esters, suggestive of unaltered intracellular cholesterol trafficking. Cytotoxicity was caused by cholesterol excess, a phenomenon that contrasts the effects of NPC1 inhibition. RNA-sequencing revealed gene clusters involved in cholesterol homeostasis and ER stress response exclusively by cytotoxic S2L. ER stress markers were confirmed by qPCR and their targeted modulation inhibited or enhanced cytotoxicity of C10 in a predicted manner. Moreover, C10 increased sterol regulatory element-binding protein 2 (SREBP2) and low-density lipoprotein receptor (LDLR), both found to be pro-survival factors activated by ER stress. Furthermore, inhibition of downstream processes of the adaptive response to S2L with simvastatin resulted in synergistic treatment outcomes in combination with C10. Of note, the S2L conjugates retained the ER stress response of the parental ligands, indicative of cholesterol homeostasis being involved in the overall cytotoxicity of the drug conjugates. Based on these findings, we conclude that S2L-mediated cell death is due to free cholesterol accumulation that leads to ER stress. Consequently, the cytotoxic profiles of S2L drug conjugates are proposed to be enhanced via concurrent ER stress inducers or simvastatin, strategies that could be instrumental on the path toward tumor eradication.
Topics: Cholesterol; Receptors, sigma; Humans; Animals; Mice; Endoplasmic Reticulum Stress; Ligands; Cell Line, Tumor; Cell Death; Neoplasms
PubMed: 38697978
DOI: 10.1038/s41419-024-06693-8 -
Stroke and Vascular Neurology May 2024Local brain tissue can suffer from ischaemia/reperfusion (I/R) injury, which lead to vascular endothelial damage. The peptide δ opioid receptor (δOR) agonist [D-ala2,...
BACKGROUND
Local brain tissue can suffer from ischaemia/reperfusion (I/R) injury, which lead to vascular endothelial damage. The peptide δ opioid receptor (δOR) agonist [D-ala2, D-leu5]-Enkephalin (DADLE) can reduce apoptosis caused by acute I/R injury in brain microvascular endothelial cells (BMECs).
OBJECTIVE
This study aims to explore the mechanism by which DADLE enhances the level of mitophagy in BMECs by upregulating the expression of transient receptor potential vanilloid subtype 4 (TRPV4).
METHODS
BMECs were extracted and made to undergo oxygen-glucose deprivation/reoxygenation (OGD/R) accompanied by DADLE. RNA-seq analysis revealed that DADLE induced increased TRPV4 expression. The CCK-8 method was used to assess the cellular viability; quantitative PCR (qPCR) was used to determine the mRNA expression of ; western blot was used to determine the expression of TRPV4 and autophagy-related proteins; and calcium imaging was used to detect the calcium influx. Autophagosomes in in the cells' mitochondria were observed by using transmission electron microscopy. ELISA was used to measure ATP content, and a JC-1 fluorescent probe was used to detect mitochondrial membrane potential.
RESULTS
When compared with the OGD/R group, OGD/R+DADLE group showed significantly enhanced cellular viability; increased expression of TRPV4, Beclin-1, LC3-II/I, PINK1 and Parkin; decreased p62 expression; a marked rise in calcium influx; further increases in mitophagy, an increase in ATP synthesis and an elevation of mitochondrial membrane potential. These protective effects of DADLE can be blocked by a TRPV4 inhibitor HC067047 or RNAi of TRPV4.
CONCLUSION
DADLE can promote mitophagy in BMECs through TRPV4, improving mitochondrial function and relieving I/R injury.
PubMed: 38697767
DOI: 10.1136/svn-2023-003080 -
Heliyon May 2024In the current study, seven (7) aurone derivatives (ADs) were synthesized and employed to LOX and COX-2 assays, models of acetic acid-induced mice writhing,...
In the current study, seven (7) aurone derivatives (ADs) were synthesized and employed to LOX and COX-2 assays, models of acetic acid-induced mice writhing, formalin-induced mice paw licking and tail immersion test to evaluate their analgesic potential at the doses of 10 mg and 20 mg/kg body weight. Molecular docking was performed to know the active binding site at both LOX and COX-2 as compared to standard drugs. Among the ADs, 2-(3,4-dimethoxybenzylidene)benzofuran-3(2)-one ()possessed optimal LOX and COX-2 inhibitory strength (= and ) as compared to standard (Zileuton = 0.08 μM, Celecoxib = 0.05 μM). Similarly in various pain models compound showed significantly (p < 0.05) highest percent analgesic potency as compared to control at a dose of 20 mg/kg i.e analgesic effect in acetic acid model, (in Phase-1) and (inPhase-2) analgesic effect in formalin pain model and analgesic response in tail immersion model. By the administration of Naloxone, the tail flicking latencies were reversed (antagonized) in all treatments. The (at 10 mg/kg and 20 mg/kg was antagonized after 90 min from ± and ± to ± and ± respectively as compared to standard Tramadol (from 17.74 ± 1.33 to 3.70 ± 0.48), showing the opiodergic receptor involvement. The molecular docking study of ADs revealed that had a higher affinity for LOX and COX-2 with docking scores of and respectively. As a whole, among the tested ADs, compound demonstrated excellent analgesic effects that may have been caused by inhibiting the LOX and COX-2 pathways.
PubMed: 38694111
DOI: 10.1016/j.heliyon.2024.e29658 -
Alzheimer's Research & Therapy May 2024Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's...
N, N-Dimethyltryptamine, a natural hallucinogen, ameliorates Alzheimer's disease by restoring neuronal Sigma-1 receptor-mediated endoplasmic reticulum-mitochondria crosstalk.
BACKGROUND
Aberrant neuronal Sigma-1 receptor (Sig-1r)-mediated endoplasmic reticulum (ER)- mitochondria signaling plays a key role in the neuronal cytopathology of Alzheimer's disease (AD). The natural psychedelic N, N-dimethyltryptamine (DMT) is a Sig-1r agonist that may have the anti-AD potential through protecting neuronal ER-mitochondrial interplay.
METHODS
3×TG-AD transgenic mice were administered with chronic DMT (2 mg/kg) for 3 weeks and then performed water maze test. The Aβ accumulation in the mice brain were determined. The Sig-1r level upon DMT treatment was tested. The effect of DMT on the ER-mitochondrial contacts site and multiple mitochondria-associated membrane (MAM)-associated proteins were examined. The effect of DMT on calcium transport between ER and mitochondria and the mitochondrial function were also evaluated.
RESULTS
chronic DMT (2 mg/kg) markedly alleviated cognitive impairment of 3×TG-AD mice. In parallel, it largely diminished Aβ accumulation in the hippocampus and prefrontal cortex. DMT restored the decreased Sig-1r levels of 3×TG-AD transgenic mice. The hallucinogen reinstated the expression of multiple MAM-associated proteins in the brain of 3×TG-AD mice. DMT also prevented physical contact and calcium dynamic between the two organelles in in vitro and in vivo pathological circumstances. DMT modulated oxidative phosphorylation (OXPHOS) and ATP synthase in the in vitro model of AD.
CONCLUSION
The anti-AD effects of DMT are associated with its protection of neuronal ER-mitochondria crosstalk via the activation of Sig-1r. DMT has the potential to serve as a novel preventive and therapeutic agent against AD.
Topics: Animals; Receptors, sigma; Sigma-1 Receptor; Alzheimer Disease; Endoplasmic Reticulum; Mice, Transgenic; Mitochondria; Mice; Hallucinogens; N,N-Dimethyltryptamine; Neurons; Male
PubMed: 38693554
DOI: 10.1186/s13195-024-01462-3