Lethality of opioid and antihistaminic combinations in mice

Simonsen

2020

Basic Clin Pharma Tox

Opioid poisoning is a frequent cause of death in drug addicts and occurs with opioid treatment. Quetiapine is often found in forensic autopsies and may increase the risk of fatal opioid poisoning by enhancing sedation, respiratory depression, hypotension and QT prolongation. We systematically searched for studies of acute toxicity of quetiapine or other antipsychotics combined with morphine or methadone. Case reports describing toxicity of quetiapine combined with morphine or methadone were also included. We retrieved one human study that observed pharmacokinetic interaction between quetiapine and methadone, and 16 other human studies. Fourteen investigated the combination of droperidol and morphine in treatment doses, and some indicated an additive sedative effect. Five animal studies with acepromazine in combination with morphine or methadone were located and indicated an additive effect on sedation and hypotension. Six forensic case reports in which death could have been caused solely by quetiapine, the opioid, or other drugs were found. Thus, acute toxicity of quetiapine combined with morphine or methadone has not been studied. Because of quetiapine's effects on alpha-adrenoceptors, muscarinic and histamine receptors, human ether-ago go channels and methadone kinetics, we suggest further research to clarify if the indicated additive effects of opioids and droperidol or acepromazine are also true for quetiapine.

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 91%

Quetiapine and other antipsychotics combined with opioids in legal autopsy cases: A random finding or cause of fatal outcome?

Simonsen

2020

Basic Clin Pharma Tox

“…These studies proved that tripelennamine potentiates the analgesic, behavioural and toxicological effects of pentazocine (Waller et al 1980;Shannon and Su 1982;Bluhm et al 1983;Poling et al 1983;Grosset et al 1983;Tagashira et al 1984) and that similar effects may also be produced by combining tripelennamine or other antihistaminics with morphine (Poling et al 1985;Sun et al 1985). In particular, we have recently observed (Sansone et al 1986) that not only tripelennamine, but also other two histamine HI-receptor antagonists, chlorpheniramine and diphenhydramine, enhance morphine-induced hyperactivity in mice of the C57BL/6 strain.…”

mentioning

confidence: 88%

Antihistaminics enhance morphine-, but not amphetamine-and scopolamine-induced hyperactivity in mice

et al. 1987

Three histamine H1-receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine, were tested alone or in combination with morphine, amphetamine and scopolamine on locomotor activity in mice. All three antihistaminics, at some dosage levels, enhanced morphine-induced hyperactivity, but did not change or even reduce locomotor stimulation induced by amphetamine and scopolamine. The results suggest that H1-blocking agents may specifically interact, though not necessarily directly, with opiate mechanisms in producing behavioural effects.

“…ELL3 stabilizes p53 expression in breast cancer cells and induces chemo-sensitivity via the ERK1/2 pathway[71]. However, it is also known to initiate anti-5-FU resistance by activating the Wnt pathway[72]. HIC1 and PDCD6 induce apoptosis in a p53-dependent manner in response to DNA damage[73-75].…”

Section: Discussionmentioning

confidence: 99%

KMT2D deficiency enhances the anti-cancer activity of L48H37 in pancreatic ductal adenocarcinoma

Jiang

Xiao

et al. 2019

WJGO

BACKGROUND Novel therapeutic strategies are urgently needed for patients with a delayed diagnosis of pancreatic ductal adenocarcinoma (PDAC) in order to improve their chances of survival. Recent studies have shown potent anti-neoplastic effects of curcumin and its analogues. In addition, the role of histone methyltransferases on cancer therapeutics has also been elucidated. However, the relationship between these two factors in the treatment of pancreatic cancer remains unknown. Our working hypothesis was that L48H37, a novel curcumin analog, has better efficacy in pancreatic cancer cell growth inhibition in the absence of histone-lysine N-methyltransferase 2D (KMT2D). AIM To determine the anti-cancer effects of L48H37 in PDAC, and the role of KMT2D on its therapeutic efficacy. METHODS The viability and proliferation of primary (PANC-1 and MIA PaCa-2) and metastatic (SW1990 and ASPC-1) PDAC cell lines treated with L48H37 was determined by CCK8 and colony formation assay. Apoptosis, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) levels, and cell cycle profile were determined by staining the cells with Annexin-V/7-AAD, JC-1, DCFH-DA, and PI respectively, as well as flow cytometric acquisition. In vitro migration was assessed by the wound healing assay. The protein and mRNA levels of relevant factors were analyzed using Western blotting, immunofluorescence and real time-quantitative PCR. The in situ expression of KMT2D in both human PDAC and paired adjacent normal tissues was determined by immunohistochemistry. In vivo tumor xenografts were established by injecting nude mice with PDAC cells. Bioinformatics analyses were also conducted using gene expression databases and TCGA. RESULTS L48H37 inhibited the proliferation and induced apoptosis in SW1990 and ASPC-1 cells in a dose- and time-dependent manner, while also reducing MMP, increasing ROS levels, arresting cell cycle at the G2/M stages and activating the endoplasmic reticulum (ER) stress-associated protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/activating transcription factor 4 (ATF4)/CHOP signaling pathway. Knocking down ATF4 significantly upregulated KMT2D in PDAC cells, and also decreased L48H37-induced apoptosis. Furthermore, silencing KMT2D in L48H37-treated cells significantly augmented apoptosis and the ER stress pathway, indicating that KMT2D depletion is essential for the anti-neoplastic effects of L48H37. Administering L48H37 to mice bearing tumors derived from control or KMT2D-knockdown PDAC cells significantly decreased the tumor burden. We also identified several differentially expressed genes in PDAC cell lines expressing very low levels of KMT2D that were functionally categorized into the extrinsic apoptotic signaling pathway. The KMT2D high- and low-expressing PDAC patients from the TCGA database showed similar survival rates,but ...