Differential Effects of Alprazolam and Clonazepam on The Immune System and Blood Vessels of Non-Stressed and Stressed Adult Male Albino Rats

Elmesallamy, Ghada; Abass, Marwa; Atta, Amal Hassan; Refat, Nahla

doi:10.21608/mjfmct.2011.55864

Cited by 4 publications

(3 citation statements)

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“…Previous studies in rats injected intravenously with W-256 carcinosarcoma cells indicate that ALP inhibits lung metastases in a central BZD receptor-dependent manner (43). Additionally, ALP, LOR, and CLZ enhance or suppress immune function in cancer and non-cancer settings (44)(45)(46)(47)(48). We are the first to comprehensively assess the impact of commonly prescribed BZDs on interleukin-6 (IL-6) signaling by CAFs (Fig.…”

Section: Discussionmentioning

confidence: 99%

Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer

Cornwell¹,

Tisdale²,

Venkat³

et al. 2023

Preprint

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PurposeThis research investigates the association between benzodiazepines (BZDs) and cancer patient survival outcomes. Due to the high prevalence of BZD use in pancreatic cancer patients, we evaluated the effect of commonly prescribed BZDs on the pancreatic cancer tumor microenvironment and cancer-associated fibroblast (CAF) signaling.Experimental DesignMultivariate Cox regression modeling was used to retrospectively measure associations between Roswell Park cancer patient survival outcomes and BZD prescription records. Immunohistochemistry, H&E, Masson’s trichrome,in situhybridization, and RNA sequencing were used to evaluate the impact of lorazepam (LOR) on the PDAC tumor microenvironment, using murine pancreatic cancer models. ELISA and qPCR were used to determine the impact of BZDs on IL-6 expression/secretion by human immortalized pancreatic CAFs. PRESTO-Tango assays, reanalysis of PDAC single cell sequencing/TCGA datasets, and GPR68 CRISPRi knockdown CAF cells were used to mechanistically determine the impact of BZDs on CAF-specific GPR68 signaling.ResultsLOR is associated with worse progression-free survival (PFS) while alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, IL-6 expression/secretion in CAFs, and ischemic necrosis. LOR promotes inflammatory signaling and IL-6 secretion by CAFs through activation of GPR68. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs significantly increase GPR68 activation under acidic conditions. LOR increases IL-6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP, and other GPR68 non-activator BZDs decrease IL-6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs.ConclusionWe demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

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Section: Discussionmentioning

confidence: 99%

Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer

Cornwell¹,

Tisdale²,

Venkat³

et al. 2023

Preprint

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“…A previous study has reported that long-term benzodiazepine use causes immunologic disorders. 17 Moreover, Elmesallamy et al 18 demonstrated that the administration of clonazepam or alprazolam adversely affects the immune system of rats, which is exacerbated by stress. It has been proposed that diazepam may cause long-lasting changes to gamma-aminobutyric acid (GABA) receptors, resulting in long-lasting disturbances to immune function.…”

Section: Discussionmentioning

confidence: 99%

Prior benzodiazepine use and mortality among adult patients with sepsis: A retrospective population‐based cohort study in South Korea

Park

Han

et al. 2021

Int J Clin Pract

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Sepsis is a life-threatening condition characterised by a dysregulated host immune response to infection. 1 The incidence of sepsis among all hospitalised adults in the United States was reported at 6%, 2 and this rate continuously increases. 3 In 2017, an estimated 48.9 million incident cases of sepsis and 11.0 million sepsis-related deaths were reported worldwide, with the latter representing 19.7% of all global deaths. 4 Thus, sepsis imposes serious health-related burdens and remains a major cause of morbidity and mortality worldwide.

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“…Another experimental report of adult male rats which received alprazolam and clonazepam for 4 weeks showed that the inflammatory toxic effects of benzodiazepine could emerge through decline of anti-SRBC (Sheep RBC) antibody titers and interleukin-2 (IL-2) levels. 43 Anti-SRBC antibodies are used for a sensitive tool to evaluate the degree of inflammatory changes. Natural killer (NK) cells and T-lymphocyte cells produce IL-2, and decreased levels of IL-2 indicate that suppression of the immune system could be progressing.…”

Section: Discussionmentioning

confidence: 99%

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies

et al. 2016

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Several observational epidemiological studies have reported inconsistent results on the association between the use of benzodiazepine and the risk of cancer. We investigated the association by using a meta‐analysis. We searched PubMed, EMBASE, and the bibliographies of relevant articles to locate additional publications in January 2016. Three evaluators independently reviewed and selected eligible studies based on predetermined selection criteria. Of 796 articles meeting our initial criteria, a total of 22 observational epidemiological studies with 18 case‐control studies and 4 cohort studies were included in the final analysis. Benzodiazepine use was significantly associated with an increased risk of cancer (odds ratio [OR] or relative risk [RR] 1.19; 95% confidence interval 1.16–1.21) in a random‐effects meta‐analysis of all studies. Subgroup meta‐analyses by various factors such as study design, type of case‐control study, study region, and methodological quality of study showed consistent findings. Also, a significant dose‐response relationship was observed between the use of benzodiazepine and the risk of cancer (p for trend <0.01). The current meta‐analysis of observational epidemiological studies suggests that benzodiazepine use is associated with an increased risk of cancer.

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Differential Effects of Alprazolam and Clonazepam on The Immune System and Blood Vessels of Non-Stressed and Stressed Adult Male Albino Rats

Cited by 4 publications

References 0 publications

Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer

Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer

Prior benzodiazepine use and mortality among adult patients with sepsis: A retrospective population‐based cohort study in South Korea

Use of benzodiazepine and risk of cancer: A meta-analysis of observational studies

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