Mediated Side Effects Research Articles

Effects of Selective and Mixed-Action Kappa and Delta Opioid Receptor Agonists on Pain-Related Behavioral Depression in Mice.

We recently developed a series of nalfurafine analogs (TK10, TK33, and TK35) that may serve as non-addictive candidate analgesics. These compounds are mixed-action agonists at the kappa and delta opioid receptors (KOR and DOR, respectively) and produce antinociception in a mouse warm-water tail-immersion test while failing to produce typical mu opioid receptor (MOR)-mediated side effects. The warm-water tail-immersion test is an assay of pain-stimulated behavior vulnerable to false-positive analgesic-like effects by drugs that produce motor impairment. Accordingly, this study evaluated TK10, TK33, and TK35 in a recently validated assay of pain-related behavioral depression in mice that are less vulnerable to false-positive effects. For comparison, we also evaluated the effects of the MOR agonist/analgesic hydrocodone (positive control), the neurokinin 1 receptor (NK1R) antagonist aprepitant (negative control), nalfurafine as a selective KOR agonist, SNC80 as a selective DOR agonist, and a nalfurafine/SNC80 mixture. Intraperitoneal injection of dilute lactic acid (IP lactic acid) served as a noxious stimulus to depress vertical and horizontal locomotor activity in male and female ICR mice. IP lactic acid-induced locomotor depression was alleviated by hydrocodone but not by aprepitant, nalfurafine, SNC80, the nalfurafine/SNC80 mixture, or the KOR/DOR agonists. These results suggest that caution is warranted in advancing mixed-action KOR/DOR agonists as candidate analgesics.

A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence

Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl4-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB1 activation. Antinociceptive efficacy of LEI-515 was blocked by CB2, but not CB1, antagonists. The CB1 antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.

Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain.

Opioids are considered the most effective analgesics for the treatment of moderate to severe acute and chronic pain. However, the inadequate benefit/risk ratio of currently available opioids, together with the current 'opioid crisis', warrant consideration on new opioid analgesic discovery strategies. Targeting peripheral opioid receptors as effective means of treating pain and avoiding the centrally mediated side effects represents a research area of substantial and continuous attention. Among clinically used analgesics, opioids from the class of morphinans (i.e., morphine and structurally related analogues) are of utmost clinical importance as analgesic drugs activating the mu-opioid receptor. In this review, we focus on peripheralization strategies applied to N-methylmorphinans to limit their ability to cross the blood-brain barrier, thus minimizing central exposure and the associated undesired side effects. Chemical modifications to the morphinan scaffold to increase hydrophilicity of known and new opioids, and nanocarrier-based approaches to selectively deliver opioids, such as morphine, to the peripheral tissue are discussed. The preclinical and clinical research activities have allowed for the characterization of a variety of compounds that show low central nervous system penetration, and therefore an improved side effect profile, yet maintaining the desired opioid-related antinociceptive activity. Such peripheral opioid analgesics may represent alternatives to presently available drugs for an efficient and safer pain therapy.

Immunomodulatory AVM0703 lacks the association between anti-cancer activity and immune-mediated side-effects of the checkpoint Inhibitors.

e14585 Background: Immune checkpoint inhibitors are approved to treat a variety of solid tumors and Hodgkin’s Lymphoma. However, they have not been shown to be effective against Non-Hodgkin’s Lymphoma (NHL). Unfortunately, their use is associated with induction of autoimmune reactions, termed immune mediated side-effects (irAEs) (1-3). AVM0703 is an immunomodulatory drug which mobilizes bispecific gd and invariant TCR double-positive NKT-like cells (AVM_NKT), currently enrolling a Phase 2 clinical trial to treat R/R NHL of all subtypes based on strong activity against the aggressive, immune-resistant mouse A20 lymphoma. Unlike the checkpoint inhibitors which trigger irAEs, gdTCR expression of the AVM0703 mobilized AVM_NKT, suggests that AVM0703 should not trigger irAEs, and in fact might be a treatment for autoimmune diseases such as type 1 diabetes (T1D). As monotherapy in the A20 lymphoma model, AVM0703 completely eradicates ~20% of flank tumors, and used as a neoadjuvant prior to cyclophosphamide/fludarabine (CyFlu) it provided additive/synergistic A20 killing. As a single dosed monotherapy, AVM0703 prevented T1D onset in the gold standard NOD model. Reversal of already established T1D has proven difficult, and monotherapy approaches abandoned for lack of efficacy. Based on its activity in combination with CyFlu, and since teplizumab anti-CD3 has been approved to prevent progression to grade 3 T1D in at risk people (4), we investigated the combination with AVM0703 to reverse recent onset T1D in the NOD mouse. Methods: One hundred twenty hyperglycemic non-obese diabetic (NOD) mice were randomized to receive an insulin pellet followed by 1) Oral Placebo (18 mg/kg HED) 2) 5 µg anti-CD3 (for 5 days) i.p. 2) Oral AVM0703 (18 mg/kg HED) – weekly/biweekly/tri-weekly 3) AVM0703 (18 mg/kg HED) followed by 5 µg anti-CD3 (for 5 days) and then AVM0703 – weekly/bi-weekly/tri-weekly. Mice were monitored for body weight, body condition and hyperglycemia. Results: Timing between 18 mg/kg AVM0703 and 5 ug anti-CD3 dosing was taken from lymphoma studies that demonstrated that chemotherapy 3 and 24 hours after AVM0703 dosing maximally eradicated lymphoma. The combinations of AVM0703 (day 1) and anti-CD3 (day 2-6) were able to reverse diabetes in 26 mice for 0-9 weeks, with six mice in ongoing normoglycemia at the time of this report. The combination group that received weekly AVM0703 dosing was more effective than the bi-weekly or tri-weekly AVM0703 groups. Monotherapy with AVM0703 did not reverse diabetes, in contrast to its profound ability to prevent or delay diabetes onset in the NOD model. Conclusions: We hypothesize that the combination of AVM0703 and anti-CD3 will be more effective when anti-CD3 is added 5 days after AVM0703. 1) Tocut, Autoimmun Rev 2018. 2) Sakowska, Front Immunol 2022. 3) Sherry, Lancet. 2011. 4) Hagopian, Diabetes 2013.

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism

Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model, but also in healthy human islets and islets from HI patients.

IDF21-0484 Case cohort, Observational Study to assess Safety and effectiveness of rEmogliflozin in T2DM-CASE study

Background: Remogliflozin, is a short-acting, O-glycoside has been suggested to have differentiated selectivity and inhibition towards SGLT2 and SGLT1 receptors (365:1) for comprehensive glucose, sodium homeostasis and PPBG control during chronic dosing with little potential for compensatory glucagon secretion and mediated side effects.

Safety considerations with the current treatments for peripheral T-cell lymphoma

ABSTRACT Introduction Peripheral T-Cell Lymphomas (PTCL) constitute a heterogeneous group of aggressive T – and natural killer (NK)-cell disorders and are associated with a poor prognosis. Frontline treatments often consist of anthracycline-based combination chemotherapy with the exception of NK-T cell lymphomas, where such combinations are ineffective due to the presence of P-glycoprotein which leads to multidrug resistance. Infectious and immune mediated side effects might be more pronounced in or unique to T-cell lymphomas due to the selection of agents which target multiple T-cell subtypes and also an immunocompromised state induced by the lymphomas themselves. Areas covered This review provides a comprehensive overview of safety considerations of treatment regimens used for peripheral T-cell lymphomas. We cover regimens used in both frontline and relapsed settings including combination chemotherapy, single agent chemotherapies and immunotherapies. Expert opinion Treatment of T-cell lymphomas often requires sequencing of several therapies due to lower efficacy of available treatment regimens in curing the disease compared to that seen in B-cell non-Hodgkin lymphomas. In addition, certain complications are more common in T-cell lymphomas due to their unique immunobiology. An understanding of these salient aspects is important for all providers who treat patients with this challenging disease group.

Cannabinoid receptor 1 signaling in hepatocytes and stellate cells does not contribute to NAFLD

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride-induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

This Month in Anesthesiology

This Month in Anesthesiology

Antigen Presentation of mRNA-Based and Virus-Vectored SARS-CoV-2 Vaccines.

Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of viral Spike S1 protein encoding mRNA incorporated in a lipid nanoparticle and stabilized by polyethylene glycol (PEG). The mRNA vaccines are novel in many respects, including cellular uptake and the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences, encoding the SARS-CoV-2 Spike protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to the induction of virus-neutralizing antibodies and cytotoxic T-lymphocytes, will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. The mRNA-based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG and potential presentation in the context of CD1 will be discussed. Adenovirus vector-based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

The Diagnosis and Management of Endocrine Side Effects of Immune Checkpoint Inhibitors.

The immunologically mediated side effects of immune checkpoint inhibitors (CPI) often involve the endocrine system as well, and they can even be fatal, as in the case of unrecognized hypophysitis. Distinguishing such side effects from tumor-related changes is often difficult, because their clinical features can be nonspecific. This review is based on publications retrieved by a selective search in PubMed, with special attention to international recommendations. Depending on their target molecules, the CPI now in use differ from one another in the incidence of side effects such as autoimmune thyroid disease (4-16%), hypophysitis (0.1- 18%), adrenalitis (0.7-8%), and autoimmune diabetes mellitus (0.5-2%). The typical clinical warning signs and laboratory constellations of hypophysitis include exhaustion, hyponatremia, and headache. Hypo- and hyperthyroidism and primary adrenocortical insufficiency likewise have nonspecific manifestations. Autoimmune diabetes mellitus often takes a fulminant course. Patients being treated with CPI should be monitored at close intervals, at least as frequently as the administration of the drug, so that endocrine side effects can be recognized in time. In case of doubt, glucocorticoid supplementation should be given whenever hypocortisolism is suspected, even before endocrine evaluation is completed and the results are available. Interrupting or discontinuing CPI treatment is rarely indicated. With the increasing number of patients being treated with CPI, more and more physicians from a wide variety of specialties, not necessarily working in specialized centers, now have to consider immunologically mediated endocrine side effects in the differential diagnosis, and treat them properly when they arise. These things should be done in collaboration with endocrinologists. The ongoing study of such side effects of the CPI now in use, and of those that will be introduced in the future, is important and will lead to improved understanding.

Recent Advances in Peripheral Opioid Receptor Therapeutics

Although opioids are excellent analgesics, they are associated with severe short- and long-term side effects that are especially concerning for the treatment of chronic pain. Peripherally acting opioid receptor agonists promise to mitigate the more serious centrally mediated side effects of opioids, and the goal of this paper is to identify and elaborate on recent advances in these peripheral opioid receptor therapeutics. Peripheral opioid receptor agonists are effective analgesics that at the same time circumvent the problem of centrally mediated opioid side effects by (1) preferentially targeting peripheral opioid receptors that are often the source of the pain and (2) their markedly diminished permeability or activity across the blood-brain barrier. Recent novel bottom-up approaches have been notable for the design of therapeutics that are either active only at inflamed tissue, as in the case of fentanyl-derived pH-sensitive opioid ligands, or too bulky or hydrophilic to cross the blood-brain barrier, as in the case of morphine covalently bound to hyperbranched polyglycerols. Recent innovations in peripheral opioid receptor therapeutics of pH-sensitive opioid ligands and limiting opioid permeability across the blood-brain barrier have had promising results in animal models. While this is grounds for optimism that some of these therapeutics will be efficacious in human subjects at a future date, each drug must undergo individualized testing for specific chronic pain syndromes to establish not only the nuances of each drug's therapeutic effect but also a comprehensive safety profile.

Peptide Kappa Opioid Receptor Ligands and Their Potential for Drug Development.

Ligands for kappa opioid receptors (KOR) have potential uses as non-addictive analgesics and for the treatment of pruritus, mood disorders, and substance abuse. These areas continue to have major unmet medical needs. Significant advances have been made in recent years in the preclinical development of novel opioid peptides, notably ones with structural features that inherently impart stability to proteases. Following a brief discussion of the potential therapeutic applications of KOR agonists and antagonists, this review focuses on two series of novel opioid peptides, all-D-amino acid tetrapeptides as peripherally selective KOR agonists for the treatment of pain and pruritus without centrally mediated side effects, and macrocyclic tetrapeptides based on CJ-15,208 that can exhibit different opioid profiles with potential applications such as analgesics and treatments for substance abuse.

Lasmiditan for acute treatment of migraine.

Lasmiditan, a selective 5-HT1F receptor agonist, is a harbinger for the novel ditan class of medications for acute migraine treatment. Lasmiditan activates 5-HT1F receptors on presynaptic trigeminal nerve terminals, which impedes the release of calcitonin gene-related peptide (CGRP) from trigeminal nerve endings and thereby suppresses activation of the trigeminovascular system. Notably, lasmiditan does not result in vasoconstriction, making lasmiditan a migraine-specific acute treatment option for those with cardiovascular risk factors. However, lasmiditan does have centrally mediated side effects. This review will discuss the background of lasmiditan development, its preclinical pharmacology, safety, drug interactions and indications for use.

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease.

Pain in the neurodegenerating brain: insights into pharmacotherapy for Alzheimer disease and Parkinson disease.

S1992 Immune Checkpoint Inhibitor-Mediated Eosinophilic Esophagitis and Gastroenteritis

INTRODUCTION: Immune checkpoint inhibitors (ICPI) are immunomodulatory antibodies that enhance the immune system in the management of malignancies resulting in significantly improved prognosis especially in melanoma treatment. They are often associated with immune mediated side effects affecting multiple organ systems. The most common gastrointestinal side effect is colitis resulting in diarrhea, however eosinophilic esophagitis (EoE) and gastroenteritis is rarely reported. CASE DESCRIPTION/METHODS: A 50 year old female with history of stage IIIB melanoma managed with resection and 12 months of adjuvant nivolumab presented after immunotherapy completion with severe pruritis, dysphagia, and epigastric pain. Laboratory workup was notable for 19.9% eosinophilia with an absolute count of 1,700 cells/µL. Esophagogastroduodenoscopy (EGD) revealed ringed esophagus, white plaques and edema in the entire esophagus as well as edema and friability in the stomach and duodenal bulb. Biopsies showed increased intraepithelial eosinophils (eos), greater than 50 per high power field (hpf) in the proximal and distal esophagus. Gastric and duodenal biopsies revealed increased eos in the lamina propria with villous blunting. Her abdominal pain improved with a prednisone taper but she then developed severe heartburn and worsening dysphagia. Repeat EGD showed longitudinal furrows, edema, rings, and exudates consistent with EoE and normal stomach and duodenum. Pathology showed up to 80 eos/hpf in the esophagus, with resolution of the gastric and duodenal eosinophilia. Her symptoms resolved with a course of omeprazole and viscous budesonide slurry. DISCUSSION: Nivolumab is associated with several immune mediated toxicities including pneumonitis, colitis, endocrine and dermatological side effects. Eosinophilia may be seen following treatment with ICPIs and is potentially associated with improved prognosis. Eosinophilic tissue inflammation, particularly involving the GI tract is uncommon. A prior case report described eosinophilic enteritis following combination ICPIs ipilumab and nivolumab. A French case series reported 37 patients with hypereosinophilia following ICPI therapy; 57% had organ involvement, none with esophagitis or gastroenteritis. Most patients responded well to ICPI discontinuation and/or corticosteroids. This is the first report of eosinophilic esophagitis and gastroduodenitis following completion of 1 year of nivolumab therapy. There appears to be resolution with systemic and topical corticosteroid therapy.

Immunohistochemical Analysis of Opioid Receptors in Peripheral Tissues.

Immunohistochemical staining is widely used to identify opioid receptors in specific cell types throughout the nervous system. Opioid receptors are not restricted to the central nervous system, but are also present in peripheral sensory neurons, where their activation exerts analgesic effects without inducing centrally mediated side effects. Here, we describe immunohistochemical analysis of μ-opioid receptors in the peripheral sensory neuron cell bodies, along the axons and their peripheral endings in the hind paw skin, as well as in the spinal cord, under naïve and sciatic nerve damage conditions in mice. Importantly, we consider the ongoing debate on the specificity of antibodies.

Strategies for Developing κ Opioid Receptor Agonists for the Treatment of Pain with Fewer Side Effects.

There is significant need to find effective, nonaddictive pain medications. κ Opioid receptor (KOPr) agonists have been studied for decades but have recently received increased attention because of their analgesic effects and lack of abuse potential. However, a range of side effects have limited the clinical development of these drugs. There are several strategies currently used to develop safer and more effective KOPr agonists. These strategies include identifying G-protein-biased agonists, developing peripherally restricted KOPr agonists without centrally mediated side effects, and developing mixed opioid agonists, which target multiple receptors at specific ratios to balance side-effect profiles and reduce tolerance. Here, we review the latest developments in research related to KOPr agonists for the treatment of pain. SIGNIFICANCE STATEMENT: This review discusses strategies for developing safer κ opioid receptor (KOPr) agonists with therapeutic potential for the treatment of pain. Although one strategy is to modify selective KOPr agonists to create peripherally restricted or G-protein-biased structures, another approach is to combine KOPr agonists with μ, δ, or nociceptin opioid receptor activation to obtain mixed opioid receptor agonists, therefore negating the adverse effects and retaining the therapeutic effect.

The bivalent ligand, MMG22, reduces neuropathic pain after nerve injury without the side effects of traditional opioids.

Functional interactions between the mu opioid receptor (MOR) and the metabotropic glutamate receptor 5 (mGluR5) in pain and analgesia have been well established. MMG22 is a bivalent ligand containing MOR agonist (oxymorphamine) and mGluR5 antagonist (MPEP) pharmacophores tethered by a 22-atom linker. MMG22 has been shown to produce potent analgesia in several models of chronic inflammatory and neuropathic pain (NP). This study assessed the efficacy of systemic administration of MMG22 at reducing pain behavior in the spared nerve injury (SNI) model of NP in mice, as well as its side-effect profile and abuse potential. MMG22 reduced mechanical hyperalgesia and spontaneous ongoing pain after SNI, with greater potency early (10 days) as compared to late (30 days) after injury. Systemic administration of MMG22 did not induce place preference in naive animals, suggesting absence of abuse liability when compared to traditional opioids. MMG22 also lacked the central locomotor, respiratory, and anxiolytic side effects of its monomeric pharmacophores. Evaluation of mRNA expression showed the transcripts for both receptors were colocalized in cells in the dorsal horn of the lumbar spinal cord and dorsal root ganglia. Thus, MMG22 reduces hyperalgesia after injury in the SNI model of NP without the typical centrally mediated side effects associated with traditional opioids.

Diuretic Activity of a Novel Peripherally-Restricted Orally-Active Kappa Opioid Receptor Agonist.

Kappa-opioid agonists (KOAs) enhance cardiac performance, as well as reduce infarct size and prevent deleterious cardiac remodeling following myocardial infarction. Additionally, KOAs promote diuresis; however, there has been limited development of KOAs as a class due to the promotion of untoward central nervous system (CNS)-mediated side effects. Our laboratory has developed a peripherally-restricted, orally-active, KOA (JT09) for the treatment of pain and cardiovascular disease. Peripherally-restricted KOAs possess a limited side-effect profile and demonstrate potential in preventing heart failure. The aim of this study was to assess the diuretic activity of lead compound JT09 relative to vehicle control and Tolvaptan through single oral administration to adult male Sprague–Dawley rats. JT09-administered rats demonstrated significantly increased urine output relative to vehicle control. However, the effect persisted for 8 h, whereas Tolvaptan-administered rats demonstrated diuretic activity for 24 h. Relative to Tolvaptan, urine output was significantly reduced in JT09 administered animals at all-time points, suggesting that the overall diuretic effect of JT09 is less profound than Tolvaptan. Additionally, JT09-administered rats demonstrated alterations in clinical chemistry; reduced urine specific gravity; and increased urine pH relative to vehicle control. The following study establishes a preliminary diuretic profile for JT09.