-
Scientific African Sep 2021The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent...
The current crisis of the COVID-19 pandemic around the world has been devastating as many lives have been lost to the novel SARS CoV-2 virus. Thus, there is an urgent need for the right therapeutic drug to curb the disease. However, there is time constraint in drug development, hence the need for drug repurposing approach, a relatively fast and less expensive alternative. In this study, 1,100 Food and Drug Administration (FDA) approved drugs were obtained from DrugBank and trimmed to 791 ligands based on illicitness, withdrawal from the market, being chemical agents rather than drugs, being investigational drugs and having molecular weight greater than 500 (Kg/mol). The ligands were docked against six drug targets of the novel SARS CoV-2 - 3-chymotrypsin-like protease (3CLpro), Angiotensin-converting enzyme (ACE2), ADP ribose phosphatase of NSP3 (NSP3), NSP9 RNA binding protein (NSP9), RNA dependent RNA polymerase (RdRp) and Replicase Polyprotein 1a (RP1a). UCSF Chimera, PyRx and Discovery Studio, were used to prepare the proteins, dock the ligands and visualize the complexes, respectively. Remdesivir, Lopinavir and Hydroxychloroquine were used as reference drugs. Pharmacokinetic properties of the ligands were obtained using AdmetSAR. The binding energies of the standard drugs ranged from -5.4 to -8.7 kcal/mol while over 400 of the ligands screened showed binding energy lower than -5.4 kcal/mol. Out of the 791 number of compounds docked, 10, 91, 132, 92, 54 and 96 compounds showed lower binding energies than all the controls against 3CLPro, ACE2, NSP3, NSP9, RP1a and RdRp, respectively. Ligands that bound all target proteins, and showed the lowest binding energies with good ADMET properties and particularly showed the lowest binding against ACE2 are ethynodiol diacetate (-15.6 kcal/mol), methylnaltrexone (-15.5 kcal/mol), ketazolam (-14.5 kcal/mol) and naloxone (-13.6 kcal/mol). Further investigations are recommended for ethynodiol diacetate, methylnaltrexone, ketazolam and naloxone through preclinical and clinical studies to ascertain their effectiveness.
PubMed: 34308004
DOI: 10.1016/j.sciaf.2021.e00845 -
The Journal of Emergency Medicine Feb 2022Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Opioid-induced constipation (OIC) is a frequent consequence of opioid analgesia that may increase patient risk for emergency department visits and hospitalization. Methylnaltrexone is a peripherally acting µ-opioid receptor antagonist indicated for the treatment of OIC.
OBJECTIVE
To assess the safety and efficacy of a single methylnaltrexone dose.
METHODS
Results were pooled from three randomized, placebo-controlled methylnaltrexone (MNTX) studies in opioid-treated patients with advanced illness and OIC, despite treatment with conventional laxatives. Baseline assessments included demographics, disease/treatment characteristics, and functional levels. Efficacy endpoints included rescue-free laxation (RFL) rates within 4 and 24 h, time to first RFL, pain score change, and adverse events (AEs) after a single MNTX dose or placebo.
RESULTS
The analysis included 281 patients receiving MNTX and 237 receiving placebo. Mean age was 66.2 years for MNTX and 65.8 for placebo; ∼50% were men. The most frequent primary diagnosis was cancer (MNTX = 70.5%; placebo = 66.2%) and most (∼98%) were receiving at least one laxative at baseline. RFL occurred in 61.4% vs. 16.0%, and 72.1% vs. 40.1% MNTX vs. placebo patients, within 4 and 24 h of the initial dose, respectively. Relative to placebo, MNTX use reduced the time to first RFL, with most MNTX-treated patients achieving RFL within 2 h. Baseline and posttreatment pain scores were similar (p = 0.9556 vs. placebo for current and worst pain change from baseline), demonstrating that MNTX did not negatively affect opioid analgesia. Most AEs were gastrointestinal related and dissipated by the second dose.
CONCLUSIONS
Methylnaltrexone provides early RFL without compromising analgesia in patients receiving chronic opioid therapy.
Topics: Aged; Analgesics, Opioid; Constipation; Humans; Male; Naltrexone; Opioid-Induced Constipation; Quaternary Ammonium Compounds
PubMed: 34893381
DOI: 10.1016/j.jemermed.2021.10.012 -
Journal of Cellular Physiology Nov 2021The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and...
The Mu-opioid receptor (MOR) has been implicated in tumorigenesis and metastasis. Methylnaltrexone (MNTX), an antagonist of MOR, has shown to inhibit tumor growth and metastasis in lung cancer cell lines. The effect of MNTX on other cell lines such as head and neck squamous cell carcinoma (HNSCC) has not been investigated. We measured the expression and activity of the receptor in different HNSCC cell lines. Then, we evaluated the impact of modulating the expression MOR and the effect of MNTX on the proliferation, clonogenic activity, invasion, and migration of two HNSCC (FaDu and MDA686Tu) cell lines expressing MOR and one cell line (UMSCC47) not expressing the receptor. We also evaluated the impact of MNTX on tumor growth and metastasis formation in vivo. Activation of the receptor with [d-Ala2,N-Me-Phe4, Gly5-ol] (DAMGO) caused a significant reduction in cyclic adenosine monophosphate levels in FaDu cells. Knockdown of MOR inhibited in vitro aggressive cell behaviors on FaDu and MDA686Tu cells and correlated with a reduction in markers of epithelial-mesenchymal transition. In vitro studies showed that MNTX strongly inhibited the proliferation, clonogenic activity, invasion, and migration of FaDu and MDA686Tu cells but has no effect on UMSCC47 cells. In vivo experiments demonstrated that MNTX suppresses tumor growth in HNSCC cell tumor-bearing mice. Our studies indicate that MOR could be considered as a therapeutic target to treat HNSCC.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Head and Neck Neoplasms; Humans; Male; Mice, Inbred C57BL; Mice, Nude; Naltrexone; Narcotic Antagonists; Neoplasm Invasiveness; Quaternary Ammonium Compounds; Receptors, Opioid, mu; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tumor Burden; Xenograft Model Antitumor Assays; Mice
PubMed: 34038587
DOI: 10.1002/jcp.30421 -
Brain, Behavior, and Immunity Jul 2020We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance...
We hypothesized that elevations of microparticles (MPs) would occur with morphine administration to mice. Repetitive dosing to induce anti-nociceptive tolerance increases blood-borne MPs by 8-fold, and by 10-fold in deep cervical lymph nodes draining brain glymphatics. MPs express proteins specific to cells including neutrophils, microglia, astrocytes, neurons and oligodendrocytes. Interleukin (IL)-1β content of MPs increases 68-fold. IL-1β antagonist administration diminishes blood-borne and cervical lymph node MPs, and abrogates tolerance induction. Intravenous polyethylene glycol Telomer B, a surfactant that lyses MPs, and intraperitoneal methylnaltrexone also inhibit MPs elevations and tolerance. Critically, neutropenic mice do not develop anti-nociceptive tolerance, elevations of blood-borne or cervical node MPs. Immunohistochemical evidence for microglial activation by morphine does not correlated with the MPs response pattern. Neutrophil-derived MPs appear to be required for morphine-induced anti-nociceptive tolerance. Further, patients entering treatment for opioid use disorder exhibit similar MPs elevations as do tolerant mice.
Topics: Animals; Humans; Mice; Analgesics, Opioid; Brain; Cell-Derived Microparticles; Drug Tolerance; Morphine; Nociception; Opioid-Related Disorders
PubMed: 32001343
DOI: 10.1016/j.bbi.2020.01.017 -
Frontiers in Oncology 2021Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour... (Review)
Review
Opioids are administered to cancer patients in the period surrounding tumour excision, and in the management of cancer-associated pain. The effects of opioids on tumour growth and metastasis, and their consequences on disease outcome, continue to be the object of polarised, discrepant literature. It is becoming clear that opioids contribute a range of direct and indirect effects to the biology of solid tumours, to the anticancer immune response, inflammation, angiogenesis and importantly, to the tumour-promoting effects of pain. A common misconception in the literature is that the effect of opioid agonists equates the effect of the mu-opioid receptor, the major target of the analgesic effect of this class of drugs. We review the evidence on opioid receptor expression in cancer, opioid receptor polymorphisms and cancer outcome, the effect of opioid antagonists, especially the peripheral antagonist methylnaltrexone, and lastly, the evidence available of a role for opioids through non-opioid receptor mediated actions.
PubMed: 35004315
DOI: 10.3389/fonc.2021.792290 -
Journal of Oncology Pharmacy Practice :... Jan 2024Peripherally acting -opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics....
INTRODUCTION
Peripherally acting -opioid receptor antagonists (PAMORAs) are used in the treatment of opioid induced constipation without impacting the actions of opioid analgesics. Subcutaneous methylnaltrexone was one of the first PAMORAs approved in April 2008 for the treatment of opioid induced constipation in adult patients. The safety and effectiveness of methylnaltrexone has not been established in pediatric patients. In this study, the use of subcutaneous methylnaltrexone in pediatric patients is analyzed and reviewed. The primary outcome is occurrence of a bowel movement within 24 h after methylnaltrexone (MNTX) administration and the number of bowel movements following treatment with methylnaltrexone. Secondary outcomes include safety in this patient cohort.
METHODS
This is a retrospective study of 79 pediatric patients with opioid induced constipation. Patients were administered methylnaltrexone during their inpatient stay. Data on bowel activity after methylnaltrexone was obtained from the hospital information system.
RESULTS
Out of the 79 patients who received methylnaltrexone, there were seven patients from whom data could not be analyzed. Of the 72 patients whose data was available, 38% ( = 27) were documented as having a bowel movement, 62% ( = 45) did not have a bowel movement. Reported adverse events were minimal with nausea ( = 3), vomiting (= 1), and flatulence ( = 6).
CONCLUSION
Methylnaltrexone appears safe in the pediatric population and produces bowel movements in more than a third of pediatric patients. It is a feasible and safe option for opioid induced constipation in pediatric patients.
Topics: Adult; Humans; Child; Analgesics, Opioid; Opioid-Induced Constipation; Retrospective Studies; Constipation; Narcotic Antagonists; Neoplasms; Quaternary Ammonium Compounds; Naltrexone
PubMed: 36946143
DOI: 10.1177/10781552231163540 -
The American Journal of Hospice &... Oct 2023Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist studied in both cancer and non-cancer patients with opioid-induced constipation (OIC), but...
Methylnaltrexone is a peripherally-acting mu-opioid receptor antagonist studied in both cancer and non-cancer patients with opioid-induced constipation (OIC), but mostly in the outpatient setting. For adult hospitalized cancer patients with OIC, its effectiveness is unknown. Objectives: Describe the efficacy of methylnaltrexone for OIC in the inpatient setting, defined as bowel movement (BM) within 24 hours of methylnaltrexone administration. We performed a single-center, retrospective chart review of all hospitalized, adult patients with a cancer diagnosis who received methylnaltrexone from the palliative care team between January 1st, 2012 and July 1st, 2019. We identified 194 patients. The mean age was 59, 50.5% were male and 88% were white. 192 patients (98%) received the 8 mg dose subcutaneously. The median oral morphine equivalent (OME) was 135 mg (IQR 70-354 mg). 45% (95% confidence interval, 38-53%) had a BM within 24 hours. Higher OME was correlated with successful BM, with a response in 93% (86/92) of patients receiving ≥150 OME and 2% (2/102) of patients receiving <150 OME ( < .0001). Prior laxative use did not predict response at 24 hours whether these were osmotic laxatives (40.7% vs 47.1%, = .52), stimulant laxatives (45.7% vs 45.2%, > .99), or stool softeners (44.7% vs 46.1%, = .89). Methylnaltrexone has a high response rate when used as treatment for OIC in hospitalized adult cancer patients, especially for patients taking ≥150 OME.
Topics: Adult; Humans; Male; Female; Analgesics, Opioid; Laxatives; Retrospective Studies; Constipation; Naltrexone; Narcotic Antagonists; Quaternary Ammonium Compounds; Neoplasms; Morphine
PubMed: 36565253
DOI: 10.1177/10499091221147903 -
Paediatrics & Child Health 2021Opioid-induced constipation (OIC) is a common and important problem in paediatric palliative care, critical care, and postoperative settings. Treatment for OIC is often...
BACKGROUND AND OBJECTIVE
Opioid-induced constipation (OIC) is a common and important problem in paediatric palliative care, critical care, and postoperative settings. Treatment for OIC is often ineffective and limited by enteral intake. A new class of drugs called peripherally acting mu-opioid receptor antagonists (PAMORAs) have been shown to be effective treatments of OIC in adults, including the agents methylnaltrexone and naloxegol. Data in children are limited to several small case reports, mostly in the palliative care setting. The goal of this study was to evaluate the effectiveness and safety of methylnaltrexone and naloxegol in hospitalized children, including those with critical illness.
METHODS
We conducted a retrospective study of all children admitted to the Stollery Children's Hospital in Edmonton (Canada) who received either methylnaltrexone or naloxegol for OIC. The primary outcome was median time to first bowel movement (BM) after the first dose of PAMORA.
RESULTS
A total of 27 patients were included in the study. Kaplan-Meier survival analysis showed the median time to the first BM after the first dose of PAMORA was 15.5 hours. Seventeen (63%) patients had laxation within 24 hours of first dose. No significant adverse events were observed.
CONCLUSION
This study is the largest to date to evaluate efficacy and safety of PAMORAs in children. Future studies should be prospective and include larger numbers of patients with critical illness and postoperative OIC as indications for treatment.
PubMed: 33747318
DOI: 10.1093/pch/pxz165 -
Scientific Reports Jul 2019Opioid-induced constipation (OIC) has become increasingly prevalent with the rise of prescription opioid use and can significantly impact quality of life, especially in...
Opioid-induced constipation (OIC) has become increasingly prevalent with the rise of prescription opioid use and can significantly impact quality of life, especially in patients with advanced illness. Methylnaltrexone has proven effective in treating cancer patients with OIC who have not responded adequately to conventional laxative therapy, though use is relatively contraindicated in those with peritoneal carcinomatosis due to theoretical risk and reported cases of perforation. The aim of this study was to evaluate the safety of methylnaltrexone in patients with carcinomatosis. We performed a retrospective review of 3058 pediatric and adult patients who received methylnaltrexone at Memorial Sloan Kettering Cancer Center from 2009-2016. Data collected included age, cancer diagnosis, history of abdominal surgery, prior radiation therapy, evidence of peritoneal carcinomatosis, and complications. Charts were reviewed for any complications at 24 hours, 72 hours, and one week following drug administration, as well as at present. We identified 3058 patients (median age 56, range 1-95) who received a total of 3995 doses of methylnaltrexone. Three hundred thirty three (median age 55, range 4-88) had peritoneal carcinomatosis. The most common primary malignancies included pancreatic (17.7%), ovarian (13.5%), colon (7.2%), and lung (6.6%). 228/333 (68.4%) had a history of abdominal surgery and 85/333 (25.5%) underwent prior radiation therapy. Three patients had adverse outcomes or complications, with only one (0.3%) thought to be related to methylnaltrexone use. To our knowledge, this is the largest study to evaluate the outcomes of patients with carcinomatosis receiving methylnaltrexone and the first to include pediatric patients. We found one perforation attributed to methylnaltrexone. Methylnaltrexone should be considered for treatment of refractory OIC in cancer patients with peritoneal carcinomatosis due to low risk of complications.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Child; Child, Preschool; Constipation; Female; Humans; Infant; Male; Middle Aged; Naltrexone; Peritoneal Neoplasms; Quaternary Ammonium Compounds; Retrospective Studies; Treatment Outcome; Young Adult
PubMed: 31270339
DOI: 10.1038/s41598-019-44864-2 -
Experimental Cell Research Sep 2022Acute respiratory distress syndrome (ARDS), a severe medical condition, is among the major causes of death in critically ill patients. Morphine is used as a therapeutic...
PURPOSE
Acute respiratory distress syndrome (ARDS), a severe medical condition, is among the major causes of death in critically ill patients. Morphine is used as a therapeutic agent against severe pain. The mechanisms of its reactions over ARDS are not fully understood. The aim of this study was to assess the mechanism of morphine in rats with ARDS.
METHODS
Rats were injected with lipopolysaccharide to induce ARDS, and some rats were pre-treated with graded doses of morphine in the lateral ventricles to assess survival and non-infected mortality. Immunohistochemical and HE staining were performed to measure MPO and CD68 activity in the lungs and lung injury. ELISA was conducted to detect the inflammatory factor levels in the plasma and BALF. Co-labeling of μ-opioid receptor (MOR) and c-Fos was observed in the brain tissues. MOR-positive cells in brain tissues were evaluated using immunohistochemistry. The effect of MOR antagonists on ARDS was examined in rats by pre-injection of naloxone or methylnaltrexone. The expression of MyD88, TLR4, and NF-κB was lastly assessed.
RESULTS
Dose-independent improvement was observed in respiratory capacity and lung injury in ARDS rats after morphine pre-injection, along with reduced inflammatory factors in the plasma and BALF. MOR-positive cells were elevated after morphine, which occurred within the ventral part of the gigantocellular reticular nucleus (GiV). Naloxone and methylnaltrexone blocked the effects of morphine via central and peripheral MOR. Morphine activated TLR pathway in a MyD88-dependent manner.
CONCLUSION
Morphine activates MOR within the GiV and the TLR pathway to attenuate ARDS in rats.
Topics: Animals; Lipopolysaccharides; Lung Injury; Morphine; Myeloid Differentiation Factor 88; Naloxone; Rats; Receptors, Opioid; Respiratory Distress Syndrome
PubMed: 35643178
DOI: 10.1016/j.yexcr.2022.113224